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GLOBAL HEART

JOIN THE FIGHT

Volume 8 Issue 3 September 2013

Ocial Journal of the World Heart Federation

Cardiovascular disease causes 1 in 3 deaths globally. Our aim is to


reduce premature deaths caused by cardiovascular disease (CVD)
by 25% by 2025.

Volume 8 Issue 3 September 2013

Continued Challenge of Rheumatic Heart Disease

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We are looking for cardiologists and other healthcare professionals to become advocates of best
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Working together, we can prolong the lives of people around the globe, help reduce the nancial
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ISSN 2211-8160

9/19/2013 1:05:11 PM

EDITOR-IN-CHIEF

Ofcial Journal of the World Heart Federation

JAGAT NARULA USA

Volume 8  Issue 3  September 2013

DEPUTY EDITORS
Andrew Moran USA
Y. Chandrashekar USA
Nathan D. Wong USA
Ragaven Baliga USA

SPECIAL ISSUE
CONTINUED CHALLENGE OF RHEUMATIC HEART DISEASE
Jonathan R. Carapetis, Liesl Zhlke, and Kathryn Taubert, Guest Editors

ASSOCIATE EDITORS
Eloisa Arbustini Italy
Mark Huffman USA
Prashant P. Joshi India
R. Krishna Kumar India
Rajesh Vedanthan USA

185 EDITOR'S PAGE Continued Challenge of Rheumatic Heart Disease:


The Gap of Understanding or the Gap of Implementation?

SENIOR ADVISORY COUNCIL

187 PREFACE Public Sector Prevention of RF and RHD in South Africa

Valentin Fuster USA, Chair


K. Srinath Reddy India,
Co-Chair
George Alleyne USA
Robert D. Bonow USA
Arun Chockalingam USA
Prakash Deedwania USA
Michael Engelgau USA
Edward L. Kaplan USA
Patrick Kelley USA
Bridget Kelly USA
Vanessa Kerry USA
Darwin Labarthe USA
Philip Landrigan USA
Steve Leeder Australia
Daniel Levy USA
Yan Lijing China
Donald Lloyd-Jones USA
Bongani Mayosi South Africa
Shanthi Mendis Switzerland
George Mensah USA
Rachel A. Nugent USA
Neil Poulter UK
Dorairaj Prabhakaran India
Pekka Puska Finland
Robert Roberts Canada
Samin K. Sharma USA
Richard Smith UK
Sidney Smith USA
Anne E. Sumner USA
Kathryn Taubert Switzerland
Mark Woodward Australia
Yang Feng Wu China
Magdi Yacoub UK
Salim Yusuf Canada
SECTION EDITORS
GLOBAL HERITAGE
Majid Ezzati UK
Gregory Roth USA
GLOBAL INTELLIGENCE
J.C. Mohan India
GLOBAL LEARNING
Rizwan Afzal Canada
Paolo Boffetta USA
GLOBAL ORPHANS
Javier Guzman Colombia
Nitish Naik India
GLOBAL SOLUTIONS
Kanav Kahol USA
Scott Lear Canada
GLOBAL TRACKING
Vamadevan S. Ajay India
Ambuj Roy India
GLOBAL VIGILANCE
Stuart J. Pocock UK
Nupoor Narula USA
GLOBAL VOICES
Mohammad Ali USA
Chowdhury Ahsan USA
GLOBAL WATCH
Rupa Iyengar Grenada
Sumeet Mitter USA

Jonathan R. Carapetis, Liesl Zhlke, Kathryn Taubert, and Jagat Narula


Gwen Ramokgopa

189 REVIEW Estimates of the Global Burden of Rheumatic Heart Disease


Liesl J. Zhlke and Andrew C. Steer

197 REVIEW Echocardiographic Screening for Rheumatic Heart


Disease: Issues for the Cardiology Community
Anita Saxena, Liesl Zhlke, and Nigel Wilson
EDITORIAL BOARD
Deewan Alam Bangladesh
Samir Alam Lebanon
Eric Alexanderson Mexico
Wael Almaheed UAE
Alvaro Avezum Brazil
Andres Budaj Poland
Jonathan Carapetis Australia
Beatriz Champagne USA
Cheng-Wen Chiang Taiwan
Solveig A. Cunningham USA
Anna Dominiczak UK
Shah Ebrahim UK
Maria Grazia Franzosi Italy
Gordon Galea Denmark
Thomas Gaziano USA
Abdul Ghaffar Switzerland
Stephen Harrap Australia
Rodney Jackson New Zealand
Kay Tee Khaw UK
Jaspal Kooner UK
Shyam S. Kothari India
Henry Krum Australia &
New Zealand
Fernando Lanas Chile
Prasart Laothavorn Thailand
Ramanan Laxminarayan India
Basil Lewis Israel
Jean Claude Mbanya Cameroon
Vishwanathan Mohan India
Dary Mozaffarian USA
K.M. Venkat Narayan USA
Jane W. Newburger USA
Sania Nishtar Pakistan
Churchill Onen Botswana
Kaushik Ramaiya Tanzania
Anthony Rodgers Australia
Matthew Roe USA
Adolfo Rubenstein Argentina
Kui-Hian Sim Malaysia
Bambang Siswanto Indonesia
K. K. Talwar India
Nikhil Tandon India
Raj Tandon India
Simon Thom UK
Abani Updhaya Nepal
PUBLISHER
Tamara Lucas UK
JOURNAL MANAGERS
Ryan Hastings USA
Joanne Creek UK
PUBLISHING SUPPORT MANAGER
Dinah Baxter The Netherlands

203 REVIEW Echocardiographic Diagnosis of Chronic Rheumatic


Valvular Lesions
Anita Saxena

213 REVIEW Priorities in Cardiac Surgery for Rheumatic Heart Disease


Kirsten Finucane and Nigel Wilson

221 REVIEW Primary Prevention for Rheumatic Fever: Progress,


Obstacles, and Opportunities
Liesl J. Zhlke and Ganesan Karthikeyan

227 REVIEW Benzathine Penicillin G for the Management of RHD:


Concerns About Quality and Access, and Opportunities for
Intervention and Improvement
Rosemary Wyber, Kathryn Taubert, Stephen Marko, and Edward L. Kaplan

235 REVIEW The Importance of Awareness and Education in


Prevention and Control of RHD
Liesl J. Zhlke and Mark E. Engel

241 REVIEW A Conceptual Framework for Comprehensive Rheumatic


Heart Disease Control Programs
Rosemary Wyber

247 REVIEW Prevention of Rheumatic Fever and Heart Disease:


Nepalese Experience
Prakash Raj Regmi and Rosemary Wyber

253 EXPERT CONSENSUS DOCUMENT The Second Rheumatic Heart


Disease Forum Report
Liesl J. Zhlke, Mark E. Engel, Bo Remenyi, Rosemary Wyber, and
Jonathan Carapetis, for the RHD Forum Meeting Report Writing Committee

263 REVIEW Aiming at Strategies for a Complex Problem of Medical


Nonadherence
Jose M. Castellano, Robert Copeland-Halperin, and Valentin Fuster

Continued on next page

Table of Contentscontinued
273 ORIGINAL RESEARCH Associations of Obesity With Lipoprotein
Subfractions in Japanese American, African American,
and Korean Men
Nobutaka Hirooka, Chol Shin, Kamal H. Masaki, Daniel Edmundowicz, Jina Choo,
Emma J. M. Barinas-Mitchell, Bradley J. Willcox, Kim Sutton-Tyrrell, Aiman El-Saed,
Iva Miljkovic-Gacic, Takayoshi Ohkubo, Katsuyuki Miura, Hirotsugu Ueshima,
Lewis H. Kuller, and Akira Sekikawa, for the ERA JUMP Study Group

281 EDITORIAL VIEWPOINT Visceral Adipose Tissue: At the Intersection of


Lipoprotein Associated CV Risk
Robert S. Rosenson

283 PERSPECTIVES FROM NHLBI A New Global Heart Series


George A. Mensah

285 LETTER TO THE EDITOR Rebuilding the Rheumatic Heart Disease


Program in Sudan
Sulafa K. M. Ali

Ofcial Journal of the World Heart Federation


Volume 8  Issue 3  September 2013
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EDITORS PAGE

gOVERVIEW

Continued Challenge of Rheumatic Heart Disease


The Gap of Understanding or the Gap of Implementation?
Jonathan R. Carapetis*, Liesl Zhlkey, Kathryn Taubertz, Jagat Narulax
Perth, Western Australia, Australia; Cape Town, South Africa; Geneva, Switzerland; and New York, NY, USA
Two decades ago, the American streptococcal researcher
Floyd Denny reected on the history of research, management, and prevention of rheumatic fever (RF) and rheumatic
heart disease (RHD) since T. Duckett Joness pivotal paper
outlining the diagnostic criteria for RF [1,2]. He paraphrased
Milton Markowitzs description of the years between 1950
and 1980, respectively, as the decade of discovery (when the
most important ndings about methods to prevent RF were
made), the decade of dissemination (during which the
message about these approaches, particularly primary prophylaxis, was widely practiced in the Unites States), and the
decade of dissonance (during which limitations of these
approaches were noted, but also when RF began to disappear
from the United States) [3]. Denny went on to label the
1980s as the decade of dismay, because of the return of RF
and of severe group A streptococcal infections in some regions of the Unites States.
Those labels aptly summarized 40 critical years for RF
and RHD, particularly in the United States. But with the
passing of a further 2 decades plus, it may be appropriate
to take a more global view of RF and RHD. As interest in
RHD waned in wealthy countries between the 1970s and
the 1990s, in parallel with reducing rates of disease in
those same countries, attention of the cardiology community turned to the escalating epidemic of ischemic heart
disease, while infectious diseases specialists focused on the
human immunodeciency virus, malaria, tuberculosis, and
the emergence of antibiotic-resistant bacteria.
But it was during this period that the problem of RF
and RHD in developing countries became increasingly
recognized. In 1985, Dr. Alan Bisno stated: While rheumatic fever has become a rare disease in many parts of the
United States. the disease continues to devastate many of
the poorer and most densely populated areas of the globe
[4]. Although it was not clear if RF had always been a
problem in these countries, just under-recognized, or if in
fact there had been a real increase in the disease in recent
years [5], interest began to shift to RF and RHD in low- and
middle-income countries.
Led by the World Health Organization [WHO], a global
program of RHD control was established in 16 countries and
later expanded to 22 in the mid-1980s [6]. Although underfunded, this global program had some remarkable achievements: the concept of register-based control programs was
borne, as was the idea of screening school-aged children for
RHD; the WHO published the rst global guideline on RHD;
and some pilot programs managed to persist and even later
report dramatic reductions in disease burden [7,8]. But by

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 185-186

2000, the WHO global program was abandoned. This


development, combined with the lack of new researchers
emerging from the United States and other afuent countries,
signaled the nadir of global interest in RF/RHD.
But since then, a new era has begun, notable for the
emergence of voices from regions where RF/RHD remains a
major problem. Research, policy, and advocacy are now
dominated by individuals, and some organizations, working
in low- and middle-income countries (particularly in subSaharan Africa, South Asia, the Pacic, and Latin America),
or in wealthy countries where RHD remains prevalent in
subgroups (often indigenous or other populations living in
poverty, such as in Australia and New Zealand). This
remarkable transformation has resulted in increased advocacy
for so-called comprehensive approaches to RF/RHD control,
encompassing primary and secondary prevention, treatment
of established RHD, and broad education and health promotion strategies [9]. It has led to some traditional views being
challenged, including the classic teaching that streptococcal
skin infection has no role in RF pathogenesis [10], molecular
mimicry may not be the basis of disease [11], and even the
Jones criteria have been found to be wanting in places where
RF remains a scourge [12,13]. This southern shift has also
seen a new generation of RF/RHD researchers coming from
these countries, many conducting high-end genetic, epidemiological, clinical, and pathogenesis research.
The new era has also resulted in wonderful collaborations on a global scale. Efforts to develop RF vaccines have
researchers from countries such as the United States,
Australia, and New Zealand collaborating with researchers in
Mali, Nicaragua, Fiji, India, and South Africa [14]. A truly
global effort resulted in a pivotal publication of agreed
criteria for the echocardiographic diagnosis of asymptomatic
RHD [15], and an ongoing collaboration to increase uptake
of these guidelines and ensure that protocols for RHD
screening are evidence-based, practical, affordable, and
supported by essential secondary prophylaxis programs.
New organizational leadership had emerged during
this era as well. The gap left by a waning of activity and
interest from WHO has been partly lled by the World
Heart Federation, which has recently published 5 targets to
achieving control of RF/RHD by 2025 [16]. Organizations
such as NCD Child have also included RHD in their
agendas. As more players come into the eld, and hopefully organizations that have RHD as their major focus, and
if the current sense of collaboration and collegiality continues to be fostered, then the prospects of real progress in
RF/RHD control are excellent over the coming 2 decades.

From the *Telethon Institute for Child Health


Research, University of
Western Australia, Perth,
Western Australia,
Australia; yDepartment of
Paediatrics, Red Cross War
Memorial Childrens Hospital and University of Cape
Town, Cape Town, South
Africa; zWorld Heart
Federation, Geneva,
Switzerland; xIcahn School
of Medicine at Mount
Sinai, New York, NY, USA.
Correspondence: J. Narula
(Narula@mountsinai.org).
GLOBAL HEART
2013 World Heart
Federation (Geneva).
Published by Elsevier Ltd.
All rights reserved.
VOL. 8, NO. 3, 2013
ISSN 2211-8160/$36.00.
http://dx.doi.org/10.1016/
j.gheart.2013.08.003

185

gOVERVIEW

The new era of RF/RHD was encapsulated at the recent


World Congress on Paediatric Cardiology and Cardiac
Surgery, held in Cape Town in February 2013. This conference had a major focus on RHD, and that agenda was
dominated by participants from low- and middle-income
countries. This issue of Global Heart is dedicated to
RF/RHD and largely arises from presentations made at the
2013 World Congress on Paediatric Cardiology and Cardiac Surgery.
We still have a long way to go to control RF and RHD. All
indications are that the disease burden gures commonly
cited (more than 15 million cases and more than 200,000
deaths annually) will be shown to be dramatic underestimates
when the 2010 Global Burden of Disease, Injuries, and Risk
Factors reports its updated data on RHD over the next 12
months. There continue to be no low- or middle-income
countries with coordinated, national control programs. We
still do not have a RF vaccine, although the recent
announcement that the Australian and New Zealand governments are jointly sponsoring a program to fast track
development of a RF vaccine gives hope that this may be
achievable.
But we must keep in mind that, although there are still
gaps in our knowledge about understanding the pathogenesis of RF, the role of skin infections, the relevance of
so-called borderline RHD detected on echocardiography,
and others, the major gap is one of implementation [17].
There is no doubt that, if we put into practice the
knowledge we already have, the majority of deaths from
RHD around the world, as well as the new cases that
continue to occur, could be prevented right now. This
requires implementation science, but it also requires
advocacy, awareness, commitment, coordination, and
resources. At least the new era means that the future of
RF/RHD science and control is in good hands.
REFERENCES
1. Denny FW Jr. A 45-year perspective on the streptococcus and rheumatic fever: the Edward H. Kass Lecture in infectious disease history.
Clin Infect Dis 1994;19:111022.
2. Jones TD. The diagnosis of acute rheumatic fever. JAMA 1944;126:
4814.

186

3. Anonymous. Management of pharyngitis in an era of declining


rheumatic fever. Report of the Eighty-Sixth Ross Conference on
Pediatric Research. Columbus, Ohio: Ross Laboratories; 1984.
4. Bisno AL. Landmark perspective: the rise and fall of rheumatic fever.
JAMA 1985;254:53841.
5. Markowitz M. Observations on the epidemiology and preventability of rheumatic fever in developing countries. Clin Ther 1981;
4:24051.
6. World Health Organization. The WHO Global Programme for the
Prevention of Rheumatic Fever and Rheumatic Heart Disease: Report
of a Consultation to Review Progress and Develop Future Activities.
Geneva, Switzerland: World Health Organization; 2000.
7. WHO Study Group. Rheumatic fever and rheumatic heart disease
report of a WHO study group. Geneva, Switzerland: World Health
Organization; 1988.
8. Nordet P, Lopez R, Dueas A, Sarmiento L. Prevention and control of
rheumatic fever and rheumatic heart disease: the Cuban experience
(1986e1996e2002). Cardiovasc J Afr 2008;19:13540.
9. Karthikeyan G, Mayosi BM. Is primary prevention of rheumatic fever
the missing link in the control of rheumatic heart disease in Africa?
Circulation 2009;120:70913.
10. McDonald M, Currie BJ, Carapetis JR. Acute rheumatic fever: a chink
in the chain that links the heart to the throat? Lancet Infect Dis 2004;
4:2405.
11. Tandon R, Sharma M, Chandrashekhar Y, Kotb M, Yacoub H, Narula J.
Revisiting the pathogenesis of rheumatic fever and carditis. Nat Rev
Cardiol 2013;10:1717.
12. Heart Foundation of New Zealand and Cardiac Society of Australia
and New Zealand. New Zealand Guidelines for Rheumatic Fever. Vol.
1. Diagnosis, Management and Secondary Prevention. Auckland, New
Zealand: Heart Foundation of New Zealand; 2006.
13. National Heart Foundation of Australia and the Cardiac Society of
Australia and New Zealand. Diagnosis and Management of Acute
Rheumatic Fever and Rheumatic Heart Disease in Australia: An
Evidence-Based Review. Melbourne, Australia: National Heart Foundation of Australia; 2006.
14. Dale JB, Fischetti VA, Carapetis JR, et al. Group A streptococcal
vaccines: paving a path for accelerated development. Vaccine 2013;
31(Suppl 2):B21622.
15. Remenyi B, Wilson N, Steer A, et al. World Heart Federation
criteria for echocardiographic diagnosis of rheumatic heart
diseasean evidence-based guideline. Nat Rev Cardiol 2012;9:
297309.
16. Remenyi B, Carapetis J, Wyber R, Taubert K, Mayosi BM. Position
statement of the World Heart Federation on the prevention and
control of rheumatic heart disease. Nat Rev Cardiol 2013;10:
28492.
17. Carapetis JR, Zuhlke LJ. Global research priorities in rheumatic
fever and rheumatic heart disease. Ann Pediatr Cardiol 2011;4:
412.

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 185-186

PREFACE

gOPINION

Public Sector Prevention of RF and RHD in South Africa


Gwen Ramokgopa
Tshwane, South Africa
This gOPINION is adapted from a speech by Gwen
Ramokgopa, MBChB, MPH, the Deputy Minister of
Health South Africa, delivered at a rheumatic heart
disease (RHD) event held during the 2013 World
Health Assembly in Geneva.
This is the rst time that a clear statement has been
made by the government highlighting the importance of
this disease in Africa. It is heartening to note that there
are countries in high RHD-prevalence regions that are
recognizing the public health importance of the disease,
and implementing strategies for control. We are publishing this statement in the interest of raising awareness
among policy makers pertaining to the importance of
RHD and its control.
Editors
Acute rheumatic fever (ARF) and rheumatic heart
disease (RHD) are estimated to affect 15.6 million people
globally and cause 350,000 deaths every year; and even
this is thought to be an underestimate [1]. It is clear,
however, that low- and middle-income countries bear the
highest burden of this condition.
South Africa is in the process of introducing national
health insurance (NHI). At this juncture, the Ministry of
Health recognizes that a key factor for the success of NHI will
be the reduction of disease burden through concerted programs around preventable diseases. RHD is a key preventable
condition that has national priority. South Africas data on
RHD are poor, but in 2010, the incidence of RHD in persons
older than 14 years in Soweto was 23.5 per 100,000 [2].
In the absence of a vaccine, prevention of ARF/RHD
depends on preventing the initial attacks of ARF through
short-term prophylactic penicillin treatment of patients
presenting with acute sore throat based on clinical signs
and symptoms.
Primary prevention of RHD therefore requires wellfunctioning primary health care services, including school
health services where children with streptococcal throat
infections can be adequately identied and managed.
Communicable and noncommunicable diseases do not t
neatly into distinct categories and hence primary prevention of a number of diseases requires a combination of
interventions. Although RHD cannot be transmitted,
group A streptococcus (GAS), which is the underlying
cause, can. This problem is compounded in conditions of
poverty, making primary prevention central to our
strategy [3].
It is clear that there are signicant barriers to primary
prevention of ARF/RHD that depend on access to quality
primary health care services. Barriers to access include lack
of sufciently skilled personnel at the primary level; the

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 187-188

high cost of microbiological diagnosis; poor awareness of


the condition among the public and community; and even
insufcient knowledge of the condition among medical
staff. There is also the concern that a high percentage of
ARF patients present without a sore throat.
Future actions relating to ARF/RHD that will be taken by
the Department of Health include nalization of guidelines for
prevention and management of ARF and RHD. These are
currently being updated in line with the latest research ndings, and will be adopted for focused implementation at the
primary health care (PHC) level. In expanding our program,
we will build on the lessons and successes from the recent HIV
and AIDS campaign and treatment roll-out and the platform
being developed through our primary health care reengineering process. This has 3 pillars: establishment of district clinical specialist teams; strengthening of the School
Health Programme; and establishment of municipalewardbased outreach health teams.
PHC doctors, nurses, and community health workers
will be trained on the guidelines. The School Health Programme is currently being substantially strengthened and
includes a focus on identication of all children with
chronic diseases. The school health system will also review
the current patient management plans of children identied with chronic diseases. In the case of RHD, this will
include ensuring that children with ARF are referred for
treatment while those with previously diagnosed RHD are
adherent to secondary prophylaxis. The School Health
Programme is a unique program in sub-Saharan Africa and
will focus on RHD as one of the important chronic diseases
of childhood and adolescence.
Imitating the Nurse Initiated Management of ART
administration (NIMART) model, PHC nurses are to be
trained in the diagnosis and treatment of ARF to affect early
and effective interventions. Public awareness campaigns,
especially among children, through the School Health
Programme, as well as for parents and guardians, will be
conducted in order to ensure that sore throats are taken
seriously and people with sore throats seek and receive
help. The perspective of live with the sore throat and it
will go away needs to change given that in some cases the
consequences of nontreatment can be very serious.
The government and Department of Health are
committed to the intensication of efforts to address ARF/
RHD on all fronts. Primary prevention of ARF is now rmly
embedded in national health policy, and chronic disease
management will also be integrated within the School Health
Programme. Together with our scientic colleagues and academics, we need to continue efforts to develop an effective
vaccine through international collaboration so that in the
longer term we can eliminate RHD.

Deputy Minister of Health


South Africa, Tshwane,
South Africa.
Correspondence: S. Singh
(SinghS@health.gov.za).
GLOBAL HEART
2013 Published by
Elsevier Ltd. on behalf of
World Heart Federation
(Geneva).
VOL. 8, NO. 3, 2013
ISSN 2211-8160/$36.00.
http://dx.doi.org/10.1016/
j.gheart.2013.08.012

187

gOPINION

REFERENCES
1. Seckeler MD, Hoke TR. The worldwide epidemiology of acute rheumatic fever and rheumatic heart disease. Clin Epidemiol 2011;3:6784.
2. Sliwa K, Carrington M, Mayosi BM, Zigiriadis E, Mvungi R, Stewart S.
Incidence and characteristics of newly diagnosed rheumatic heart

188

disease in urban African adults: insights from the heart of Soweto


study. Eur Heart J 2010;31:71927.
3. Karthikeyan G, Mayosi BM. Is primary prevention of rheumatic fever
the missing link in the control of rheumatic heart disease in Africa?
Circulation 2009;120:70913.

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September 2013: 187-188

REVIEW

gREVIEW

Estimates of the Global Burden of


Rheumatic Heart Disease
Liesl J. Zhlke*,y, Andrew C. Steerz,x,jj
Cape Town, South Africa; and Melbourne, Victoria, Australia
ABSTRACT
In this review, we make the case that currently available gures used to dene the global burden of acute
rheumatic fever and rheumatic heart disease, although crucial to control efforts, are imperfect. Data have been
hindered by methodological differences between studies, by patchy coverage within countries and across
regions, and by an incomplete understanding of the relationship between echocardiographic detection of
asymptomatic mild disease and progression to symptomatic disease. We argue that in order to advocate
effectively for patients with rheumatic heart disease now and into the future, true burden of disease estimates
on local, national, and international levels are urgently required. We critically review previous burden of
disease estimates and outline the issues in dening the true burden of rheumatic heart disease, and we
propose a new model for rheumatic heart disease epidemiologic studies. This is of particular relevance in
2012 with an ever-increasing burden of cardiovascular disease globally.

Acute rheumatic fever (ARF) and its sequel rheumatic heart disease (RHD) continue to cause signicant
morbidity and mortality in developing countries and
have been under-recognized as a global health problem
for decades. There are a number of reasons for this
under-recognition: the competing heavy burden of infectious disease mortality in young children due to the
human immunodeciency virus, malaria, tuberculosis,
diarrheal disease and pneumonia; the impressive decline
in the incidence of ARF in industrialized countries over
the second half of the last century such that ARF/RHD
are uncommon in these countries today and no longer
priority diseases; and the paucity of good quality, widely
collected epidemiologic data from developing countries
[1]. However, more recently, there is increasing awareness of RHD because of prioritization of control of the
disease by a number of individual countries with high
disease burdens, reinvigorated regional initiatives directed
at control of RHD, particularly in the Pacic and Africa,
and advocacy efforts led by international bodies such as
the World Heart Federation. Central to this increased
awareness have been updated and persuasive global
morbidity and mortality gures [2e4]. Recent directives
from the World Health Organization and the World
Heart Federation have pledged to decrease the number
of deaths due to noncommunicable diseases by 25% by
2025 [5]. RHD is a disease where this may be achievable
because there are relatively inexpensive, proven, and
effective control strategies that can lead to reductions in
deaths, especially in young people [6].

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 189-195

BURDEN OF DISEASE ESTIMATES:


POPULATION-BASED STUDIES
World Health Organizations global burden of
group A streptococcal disease study
In 2005, a summary report on the global burden of group
A streptococcal disease, commissioned by the World
Health Organization, was released that encapsulated
population-based data relating to ARF and RHD published
between 1985 and 2005 [4]. This study calculated prevalence of RHD, incidence of ARF, and incidence of new
cases of RHD cases across multiple geopolitical regions. In
determining prevalence, the investigators used populationbased data only, extrapolating from cross-sectional studies
conducted in school-aged children and compiling nal
regional prevalence estimates from studies where prevalence was conrmed using echocardiography as opposed to
auscultation. This study found an overall global burden of
471,000 annual cases of ARF, with the incidence of ARF in
children ages 5 to 15 years ranging from 10 cases per
100,000 in industrialized countries to 374 cases per
100,000 in the Pacic region. The overall burden of RHD
was estimated to be 15.6 million prevalent cases with
282,000 new cases and over 233,000 deaths per year. As
the investigators noted in their publication [4], there are
some important caveats in these estimates relating to the
number of available studies, extrapolations made to reach
all-ages estimates and global mortality estimates, and the
signicance of echocardiographic detection of RHD in
screening studies. All of these issues are discussed here.

L. J. Zhlke is funded by the


Thrasher Foundation, Clinical Infectious Disease
Research Initiative, and the
Hamilton Naki Clinical
Scholarship Programme,
which is funded by Netcare
Limited.
This paper was presented
at the Postgraduate Course
in Rheumatic Heart Disease
at the 7th Global Forum on
Humanitarian Medicine in
Cardiology and Cardiac
Surgery, Geneva,
Switzerland, June 20-22,
2011.
From the *Department of
Paediatrics, Red Cross War
Memorial Childrens Hospital and University of Cape
Town, Cape Town, South
Africa; yDepartment of
Medicine, Groote Schuur
Hospital Cape Town, South
Africa; zCentre for International Child Health, University of Melbourne,
Melbourne, Victoria,
Australia; xDepartment of
General Medicine, Royal
Childrens Hospital, Melbourne, Victoria, Australia;
jjMurdoch Childrens
Research Institute, Melbourne, Victoria, Australia.
Correspondence: A. Steer
(andrew.steer@rch.org.au).
GLOBAL HEART
2013 Published by
Elsevier Ltd. on behalf of
World Heart Federation
(Geneva).
VOL. 8, NO. 3, 2013
ISSN 2211-8160/$36.00.
http://dx.doi.org/10.1016/
j.gheart.2013.08.008

189

gREVIEW

Subsequent reviews of global burden of disease


Three groups subsequently reviewed the global burden of
ARF and RHD; 2 reports were published in 2011 [2,3], and
a third, as part of the Global Burden of Disease 2010 Study,
was published in 2013 [7].
The rst study added several new datasets, used a
clearly dened systematic review design, included only
studies in which RHD was diagnosed by echocardiogram
[8], and incorporated vital registration data from the World
Health Organization. Mortality rates were calculated using
the most recent population data in the World Health
Organization database, but countries were included only if
completeness of death reporting was more than 90% of the
total deaths occurring in the country. The study concluded
that there is considerable global variation in ARF incidence
and RHD prevalence with the sub-Saharan African and
Asian-Pacic regions identied as high disease burden
areas. The study noted several limitations including that
data were unavailable from several parts of the world and
that there were very few data regarding RHD mortality. Key
estimates that were not addressed included the burden
caused by the distal sequelae of RHD (congestive cardiac
failure, infective endocarditis, atrial brillation, and stroke),
average duration of disability for incident cases, average
duration to death, and relative risk of patients with RHD
dying from all causes relative to those without RHD.
The second study [3] observed that the overall global
prevalence of RHD appears to be increasing while the incidence of ARF is decreasing in many parts of the world,
including in Africa. The investigators explained this apparent
discrepancy by reporting bias; that is, that systematic
reporting of ARF in many countries has decreased at the
same time that RHD case ascertainment has increased
because of RHD screening studies. The investigators also
suggested that longer survival of patients with RHD may
have contributed to this discrepancy, but there are few data
to support this assertion [9].
The recently published Global Burden of Disease Study
reports that the number of years lived with disability due to
RHD was estimated in 2010 at 1,430 (944 to 2,067)
worldwide, a gure that represents up to one-fourth of all
neoplasms [10]. Lozano et al. [11] reported 345,100 deaths
due to RHD in 2010, which represents a 25.4% reduction
from 1990, with ages-standardized death rate of 5.2 per
100,000, which was a 53.1% reduction from 1990. These
gures should be viewed with caution, however, particularly
because the modeling method adopted in the analysis of the
data uses a different age-related prole of RHD than that used
in the previous reviews of the global burden of the disease.
Further analysis of these data is currently underway
(J. Carapetis, personal communication, June, 2013).

Uncertainty around estimates of rheumatic heart


disease: inadequate data
The 2005 study included 57 studies of RHD from multiple
geographic regions of the world [4]. Even though the

190

publication of these data lled an important gap in the


literature, there were some signicant limitations. The
major limitation was the poor-quality data from some of
the most affected regions, especially relating to mortality,
with only a single publication available from some regions
of importance, including Eastern Europe and China.
Because of the paucity of data, prevalence gures from a
small number of studies in a limited number of countries
were extrapolated to whole regions, thereby ignoring the
considerable differences in disease burden that are likely to
exist between countries and, indeed, between states and
districts within many of the larger countries. For example,
many prevalence studies of RHD cited in this study were
conducted in urban and peri-urban populations, although
it is known that the prevalence of RHD is often higher in
rural areas [12,13].

Uncertainty around estimate of rheumatic heart


disease: extrapolation of data
Screening for RHD at a population level has been most
consistently carried out in children ages 5 to 15 years. RHD
is a cumulative disease such that there are more people
over 15 years old with the disease than under 15 years. To
extrapolate to all-ages estimates of RHD, the investigators
of both the 2005 and the rst of the 2011 studies used a
multiplication factor of between 5.5 and 7.2 on the basis of
published data from 2 studies [14,15]. Although care was
taken to err on the side of underestimation rather than
overestimation, these extrapolated gures are clearly subject to error. The burden of RHD mortality was derived
from the overall prevalence of RHD by applying an annual
case-fatality rate per year of 1.5%; this extrapolation was
based upon limited data, including data from industrialized
countries where quality of care is higher. Therefore, the
annual number of global deaths due to RHD estimated in
these studies is likely to be an underestimate of the true
situation in endemic regions; for example, in Pakistan and
Ethiopia, the mortality rate has been reported as high as
6.8% and 12.1%, respectively [2,16]. Ideally local mortality
rates should be applied to local RHD prevalence gures to
compile overall mortality.

Uncertainty around estimates: progression of


echocardiographic changes detected as part of
screening
The methodology used for detecting RHD in screening
studies of asymptomatic children has progressively changed
over the past 2 decades from auscultation for a murmur, to
auscultation with second-line echocardiographic conrmation of suspected cases, to rst-line echocardiography
without auscultation. The rst study that used echocardiographic diagnosis as rst-line screening for RHD in asymptomatic school children was published in 1996 [17]. This
study went largely unrecognized until just over 10 years
later, when a new era of prevalence studies in asymptomatic
school children in affected countries commenced [18e24].

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gREVIEW

These studies focused the worlds attention on the seemingly


submerged iceberg of asymptomatic RHD because the
number of cases detected by echocardiography compared
with those detected by auscultation differed by a factor of up
to 10 [18]. The specter of subclinical carditis in the context of
ARF is well recognized [25,26], and the concept of instituting early prophylaxis in asymptomatic RHD in high
prevalence areas to retard progress to RHD is very attractive.
However, application of prevalence gures determined by
studies that used rst-line echocardiography diagnosis to
regional estimates of RHD leads to a considerably higher
burden of disease than has previously been estimated [23].
There are several critical issues regarding echocardiographic
diagnosis of RHD in asymptomatic patients, and these are
discussed in detail herein.

WHAT IS SUBCLINICAL RHEUMATIC HEART


DISEASE?
Subclinical RHD has not been formally dened in the
literature, although subclinical carditis has been dened as
part of the presentation of ARF. A patient with subclinical
RHD is asymptomatic, has no clinically detectable pathologic murmur, but has ndings of RHD on echocardiogram
(Table 1). There is a spectrum of ndings of RHD on
echocardiogram suggestive of subclinical RHD. The establishment of World Heart Federation standardized criteria
for the diagnosis of RHD on echocardiogram has been an
extremely important advance and has helped to rene these
ndings into denite RHD and borderline RHD on the
basis of available evidence and expert consensus opinion
(Table 2) [27].
However, there remain a number of troubling aspects
to subclinical ndings suggestive of RHD on echocardiogram, with few data available to guide both the clinician
deciding upon a course of action for an individual patient
and the epidemiologist trying to determine whether patients with these subclinical ndings should be added to
the total number of RHD cases. This is especially true of
borderline RHD; it has been unclear whether borderline
RHD is at the very mild end of the spectrum of RHD, or
whether it is simply a normal physiologic variant.

Does subclinical carditis occur in rheumatic fever?


The Jones criteria for the diagnosis of ARF were last
updated in 1992, and at that time, echocardiographic

diagnosis was not included in the denition of the major


manifestation of carditis [28]. However, many clinicians
use echocardiography in both the assessment and diagnosis
of carditis in patients with ARF. In Australia and New
Zealand, echocardiographic ndings without clinical signs
(that is, subclinical carditis) is accepted as fullling the
criteria for carditis [29].
Figueroa et al. [30] were the rst to examine the natural
history of subclinical carditis in the context of ARF. Of 25
patients with carditis at presentation of ARF, 15 had clinical
and echocardiographic evidence of carditis and 10 had
echocardiographic evidence only; in both groups, valvular
changes persisted in over 40% of cases at 1- and 5-year
follow-up. Three further studies focused specically on the
long-term follow-up and evaluation of subclinical carditis
[26,31,32]. Taken together, the available data suggest that
subclinical carditis occurs in 15% to 20% of cases of ARF and
that 30% to 50% of patients with subclinical carditis develop
RHD [33]. Karaaslan et al. [32] concluded that subclinical
lesions represent true, albeit mild, carditis and that patients
require secondary prophylaxis and follow-up. They also
concluded that the use of strict criteria for the echocardiographic diagnosis of carditis could increase the sensitivity for
the diagnosis of ARF, especially in patients with atypical
disease such as monoarthritis without leading to overdiagnosis. Stricter criteria have subsequently been developed
[25,34,35].

What is known about the progression of subclinical


rheumatic heart disease over time?
There have been 3 studies in the modern era that have
reported on short-term progress of subclinical RHD in
asymptomatic populations [22,23,36,37]. The rst study
assessed the outcome of mitral regurgitation found at
screening after 2 years of follow-up. The investigators reported that signicant mitral regurgitation coexisting with
morphological abnormalities was more likely to persist on
follow-up examination. Of 15 children with both regurgitation and morphologic changes, 1 child had worsening of
echocardiographic ndings, 10 had persisting changes, and
4 children had regression of regurgitation, although they
still had residual morphological changes. In contrast, 39%
of screened children with isolated regurgitation without
morphologic changes were shown on follow-up to have
completely regressed with no residual pathological

TABLE 1. Spectrum of rheumatic heart disease and correlation to echocardiographic ndings


Clinical
Symptoms

Clinical
Signs

Symptomatic rheumatic heart disease

Yes

Yes

Asymptomatic clinical rheumatic heart


disease
Asymptomatic subclinical rheumatic heart
disease

No

Yes (murmur)

No

No

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 189-195

Echocardiographic Findings
Moderate to severe denite rheumatic heart
disease
Mild (to moderate) denite rheumatic heart
disease
Mild denite rheumatic heart disease or
borderline rheumatic heart disease

191

gREVIEW

TABLE 2. Summarized 2012 World Heart Federation criteria for the echocardiographic diagnosis of rheumatic heart disease [27]
Echocardiographic Criteria for Individuals Aged 20 Years
Denite RHD (A, B, C, or D)
A. Pathological MR and at least 2 morphological features of RHD of the MV
B. MS mean gradient 4 mm Hg
C. Pathological AR and at least 2 morphological features of RHD of the AV
D. Borderline disease of both the AV and the MV
Borderline RHD (A, B, or C)
A. At least 2 morphological features of RHD of the MV without pathological MR or MS
B. Pathological MR
C. Pathological AR
Criteria for Pathological Regurgitation
Pathological mitral regurgitation
Pathological aortic regurgitation
(All 4 Doppler echocardiographic criteria must be met)
Seen in 2 views
Seen in 2 views
In at least 1 view, jet length 2 cm
In at least 1 view, jet length 1 cm
Velocity 3 m/s for 1 complete envelope
Velocity 3 m/s in early diastole
Pan-systolic jet in at least 1 envelope
Pan-diastolic jet in at least 1 envelope
Morphological Features of RHD
Features in MV
Features in AV
AMVL thickening 3 mm (age-specic)
Irregular or focal thickening
Chordal thickening
Coaptation defect
Restricted leaet motion
Restricted leaet motion
Excessive leaet tip motion during systole
Prolapse
These have been summarized for the purposes of this review. Please see the full referenced article for important explanatory notes and caveats.
AMVL, anterior mitral valve leaet; AR, aortic regurgitation; AV, aortic valve; MR, mitral regurgitation; MS, mitral stenosis; MV, mitral valve; RHD,
rheumatic heart disease. Adapted, with permission, from Remenyi et al. [27].

regurgitation on echocardiography, and none of these


children were found to have worsening of echocardiographic ndings. On short- to medium-term follow-up
(range 3 to 27 months) in the RHEUMATIC (Rheumatic
Heart Echo Utilisation and Monitoring Actuarial Trends in
Indian Children) study [22], the severity of subclinical
RHD was nonprogressive in 68% of children, whereas it
worsened in 4% and regressed in 28%. In a follow-up
study of patients detected with RHD by echocardiographic screening in Nicaragua, 9% of the cohort developed progression of anatomic changes or worsening mitral
regurgitation over the 4-to-12-month follow-up period
[23]. These studies represent the rst indication that the
natural history of subclinical lesions in asymptomatic
populations follows that seen in ARF and that denite
disease does have the potential to worsen.
Supporting the echocardiographic follow-up studies,
clinical studies prior to the echocardiographic era also
showed similar results. In a 4- year follow-up study of
patients with abnormalities detected on auscultation,
patients with short systolic murmurs and nonejection clicks
(most likely corresponding to borderline disease using
todays denitions) were most likely to regress or persist with
very few progressing to overt RHD [38]. In comparison,
patients with bona de murmurs were found to have
persistent clinical ndings with a small percentage requiring
tertiary follow-up or intervention [39].

192

Does the prevalence of subclinical rheumatic heart


disease differ between endemic and nonendemic
populations?
An alternate epidemiologic method to determine the true
meaning of subclinical ndings of RHD on echocardiogram
is to assess the prevalence of these ndings in endemic and
nonendemic populations. Two studies have made these
direct comparisons; however, data are not yet available
from either study.

How can the meaning of subclinical rheumatic


heart disease best be determined?
Well-designed, longitudinal, observational studies of patients identied with subclinical disease will be important in
expanding our understanding of subclinical RHD. A potential confounder in these studies that will need to be
accounted for in the analysis will be secondary prophylaxis;
that is, if patients are started on secondary prophylaxis, this
could modify their disease progression and eventual
outcome. Comparison of the progression of echocardiographic changes and incidence of ARF in patients with
subclinical RHD to people with normal echocardiogram
ndings will complement these follow-up studies. Finally, a
randomized controlled study of a known effective intervention for RHD (i.e., antibiotic prophylaxis) in patients with
subclinical RHD may provide the ultimate evidence for

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gREVIEW

dening the meaning of subclinical RHD; however, this


study would require clinical equipoise, which may not exist
if the results from the simpler observational studies are
unequivocal.

How should rheumatic heart disease prevalence


determined by echocardiographic screening be
incorporated into global burden of disease
estimates? Toward a new model of rheumatic
heart disease
The use of echocardiography as a screening tool no doubt has
a major role to play in disease control as well as for advocacy
and awareness of RHD [40]. However, using these numbers
in computing overall disease gures carries the potential for
an inaccurate description of the burden of disease.
It is perhaps time to change the way that we think
about RHD and attempt to describe the disease burden
with greater subtlety that takes into account our increasing
understanding of the disease. Such a revised model might
include an assessment of RHD burden in 2 categories: 1)
symptomatic disease, which could also be called active
disease; and 2) asymptomatic disease, which could also be
called latent disease (Fig. 1). This approach has some
similarities (but also obvious differences) to the model of
disease applied to other latent diseases including infection
with Mycobacterium tuberculosis.

BURDEN OF DISEASE ESTIMATES: THE VALUE OF


ESTIMATING THE BURDEN OF RHEUMATIC HEART
DISEASE CAUSING SYMPTOMATIC DISEASE

print & web 4C=FPO

As noted, the prevalence of RHD detected in screening


studies largely indicates the burden of asymptomatic RHD,
as well as some cases of symptomatic disease that have
previously been undetected. There are a number of other

key data sources that provide important information


regarding symptomatic patients; these include RHD registry data, hospital admission data including RHD in pregnant women, and RHD surgical data. We believe that these
data have been underestimated and an assessment of the
link between asymptomatic and symptomatic disease has
been neglected.
The clinical characterization of cases on RHD registers
and the incidence of cases presenting to the hospital have
been described in very few centers. A study arising from a
clinical registry in Soweto, South Africa, estimated the
annual incidence of new cases of RHD in the region to be
23.5 cases per 100,000 people over 14 years of age [41]. This
study highlighted the severity of disease in patients presenting for the rst time with symptomatic RHD; the majority of patients presented with impaired systolic function,
elevated right ventricular systolic pressure >35 mm Hg and
atrial brillation, and surgery was necessary in 22%. The
study also highlighted the relevance of the complications of
RHD; 26% were admitted within 30 months of initial diagnosis for suspected infective endocarditis.
RHD as a cause of fetal and maternal morbidity and
mortality has been underestimated. In a study of pregnant
women with RHD in Senegal, the maternal mortality rate was
34%, peaking at 54% for women with mitral stenosis [42]. In
South Africa, 0.6% of pregnant women have pre-existing
cardiac abnormalities, with RHD being the commonest
cardiac problem [43]. In the Pacic, RHD is a leading cause
of maternal mortality, and in a study from Fiji, the prevalence
of RHD in pregnant women was 0.2% [44].
Signicant challenges exist in the provision of cardiac
surgery regions where RHD is endemic [45e47]. Cardiac
surgery is expensive and a lack of infrastructure, human
resources, and equipment makes it almost impossible to
provide timely and appropriate surgery. The collaboration
between nongovernmental agencies as well as humanitarian
missions has been essential in providing a cardiac service in
many parts of the developing world [48]. Surgery for RHD is
challenging, with the complication of prosthetic valves,
anticoagulation, and failed repairs, being an ever-present
issue. Results differ among units and relate largely to experience, the time of presentation, timing of surgery, and
presence of comorbidities [49,50]. Comprehensive data
regarding all aspects of cardiac surgery for RHD, including
needs, costs, outcomes, and complications are urgently
needed, especially for countries with a high burden of RHD
attempting to establish cardiac surgical programs [51].

Rheumatic fever incidence, subclinical rheumatic


heart disease, and symptomatic rheumatic heart
disease: Do the numbers add up?
FIGURE 1. A new model for assessing and reporting the
burden of rheumatic heart disease that incorporates
asymptomatic and symptomatic disease. *Sequelae
include atrial brillation, infective endocarditis, and
stroke. RHD, rheumatic heart disease.

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 189-195

There are very few populations worldwide that have been


sufciently studied to allow modeling and linking of RHD
prevalence (denite and borderline), ARF incidence,
RHD incidence (symptomatic cases), RHD surgery, and
RHD mortality. A modeling exercise such as this could

193

gREVIEW

allow for a better understanding of progression rates of


borderline RHD, as well as the ability to use a single marker
of disease burden (such as the number of denite cases
detected through screening programs) to extrapolate to
multiple downstream measures of disease. It is important
to note that the number of denite cases of RHD has been
shown to remain relatively consistent in recent studies in
multiple diverse populations at a prevalence of 3 to 8 per
1,000. Populations in the Pacic (Australia, New Zealand,
and Fiji) as well as in South Africa are currently in the best
position with high-quality data to allow this type of
modeling to be performed, although many other countries
are developing improved disease surveillance systems.

FUTURE EFFORTS TO BETTER DEFINE THE TRUE


BURDEN OF DISEASE DUE TO RHEUMATIC FEVER
AND RHEUMATIC HEART DISEASE
Moving forward, it will be critical to generate high-quality
and comprehensive data regarding all aspects of the
burden of ARF and RHD to better inform national, regional,
and global control strategies [52]. Although there are
increasing data on RHD prevalence from screening studies in
school-aged children, there is considerable value in nonprevalence data. New studies are underway in several highprevalence sentinel areas in diverse geographic locations to
address the need for contemporary data [53]. Particular
emphasis must be given to comprehensive, prospective
cohort studies of long-term outcome particularly related to
progression of disease to the distal sequelae of RHD, such as
stroke, atrial brillation, and infective endocarditis, as well as
duration of disability, mortality rates, and economic impact.
Medium- and long-term data that chart the course of patients
with subclinical disease detected by echocardiography is
necessary to delineate the natural history of subclinical carditis and to inform future control strategies. These data will
provide vital information in order to advocate even more
strongly for directed funding and public health interventions
to control ARF and RHD.
REFERENCES
1. Tibazarwa KB, Volmink JA, Mayosi BM. Incidence of acute rheumatic
fever in the world: a systematic review of population-based studies.
Heart 2008;94:153440.
2. Jackson SJ, Steer AC, Campbell H. Systematic review: estimation of
global burden of non-suppurative sequelae of upper respiratory tract
infection: rheumatic fever and post-streptococcal glomerulonephritis.
Trop Med Int Health 2011;16:211.
3. Seckeler MD, Hoke TR. The worldwide epidemiology of acute rheumatic fever and rheumatic heart disease. Clin Epidemiol 2011;3:
6784.
4. Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden
of group A streptococcal diseases. Lancet Infect Dis 2005;5:68594.
5. Smith SC Jr, Collins A, Ferrari R, et al. Our time: a call to save preventable death from cardiovascular disease (heart disease and
stroke). Circulation 2012;126:276975.
6. Ralston J. New global target on non-communicable diseases: a call to
action for the global cardiovascular disease community. Cardiovasc J
Afr 2012;23:2412.

194

7. Murray CJ, Ezzati M, Flaxman AD, et al. GBD 2010: design, denitions,
and metrics. Lancet 2012;380:20636.
8. Jaffe WM, Roche AH, Coverdale HA, McAlister HF, Ormiston JA,
Greene ER. Clinical evaluation versus Doppler echocardiography in
the quantitative assessment of valvular heart disease. Circulation
1988;78:26775.
9. Nkgudi B, Robertson KA, Volmink J, Mayosi BM. Notication of
rheumatic fever in South Africaevidence for underreporting by
health care professionals and administrators. S Afr Med J 2006;96:
2068.
10. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs)
for 1160 sequelae of 289 diseases and injuries 1990e2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet
2012;380:216396.
11. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality
from 235 causes of death for 20 age groups in 1990 and 2010: a
systematic analysis for the Global Burden of Disease Study 2010.
Lancet 2012;380:2095128.
12. Tantchou Tchoumi JC, Butera G. Rheumatic valvulopathies occurence,
pattern and follow-up in rural area: the experience of the Shisong
Hospital, Cameroon. Bull Soc Pathol Exot 2009;102:1558.
13. Longo-Mbenza B, Bayekula M, Ngiyulu R, et al. Survey of rheumatic
heart disease in school children of Kinshasa town. Int J Cardiol 1998;
63:28794.
14. Agarwal AK, Yunus M, Ahmad J, Khan A. Rheumatic heart disease in
India. J R Soc Health 1995;115:3034, 309.
15. Carapetis JR, Currie BJ, Mathews JD. Cumulative incidence of rheumatic fever in an endemic region: a guide to the susceptibility of the
population? Epidemiol Infect 2000;124:23944.
16. Gnther G, Asmera J, Parry E. Death from rheumatic heart disease in
rural Ethiopia. Lancet 2006;367:391.
17. Anabwani GM, Bonhoeffer P. Prevalence of heart disease in school
children in rural Kenya using colour-ow echocardiography. East Afr
Med J 1996;73:2157.
18. Marijon E, Ou P, Celermajer DS, et al. Prevalence of rheumatic heart
disease detected by echocardiographic screening. N Engl J Med 2007;
357:4706.
19. Steer AC, Jenney AW, Kado J, et al. High burden of impetigo and
scabies in a tropical country. PLoS Negl Trop Dis 2009;3:e467.
20. Beaton A, Okello E, Lwabi P, Mondo C, McCarter R, Sable C. Echocardiography screening for rheumatic heart disease in Ugandan
schoolchildren. Circulation 2012;125:312732.
21. Webb RH, Wilson NJ, Lennon DR, et al. Optimising echocardiographic
screening for rheumatic heart disease in New Zealand: not all valve
disease is rheumatic. Cardiol Young 2011;21:43643.
22. Saxena A, Ramakrishnan S, Roy A, et al. Prevalence and outcome of
subclinical rheumatic heart disease in India: the RHEUMATIC
(Rheumatic Heart Echo Utilisation and Monitoring Actuarial Trends in
Indian Children) study. Heart 2011;97:201822.
23. Paar JA, Berrios NM, Rose JD, et al. Prevalence of rheumatic heart
disease in children and young adults in Nicaragua. Am J Cardiol 2010;
105:180914.
24. Carapetis JR, Hardy M, Fakakovikaetau T, et al. Evaluation of a
screening protocol using auscultation and portable echocardiography
to detect asymptomatic rheumatic heart disease in Tongan schoolchildren. Nat Clin Pract Cardiovasc Med 2008;5:4117.
25. Wilson N. Echocardiography and subclinical carditis: guidelines that
increase sensitivity for acute rheumatic fever. Cardiol Young 2008;18:
5658.
26. Ozkutlu S, Hallioglu O, Ayabakan C. Evaluation of subclinical valvar
disease in patients with rheumatic fever. Cardiol Young 2003;13:4959.
27. Remenyi B, Wilson N, Steer A, et al. World Heart Federation criteria
for echocardiographic diagnosis of rheumatic heart disease-an
evidence-based guideline. Nat Rev Cardiol 2012;9:297309.
28. Special Writing Group of the Committee on Rheumatic Fever,
Endocarditis, and Kawasaki Disease of the Council on Cardiovascular
Disease in the Young of the American Heart Association. Guidelines
for the diagnosis of rheumatic fever. Jones Criteria, 1992 update.
JAMA 1992;268:206973.

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 189-195

gREVIEW

29. RHDAustralia (ARF/RHD writing group). The Australian Guideline for


Prevention, Diagnosis and Management of Acute Rheumatic Fever
and Rheumatic Heart Disease. 2nd edition. Auckland, Australia:
National Heart Foundation of Australia and New Zealand; 2012.
30. Figueroa FE, Fernandez MS, Valdes P, et al. Prospective comparison of
clinical and echocardiographic diagnosis of rheumatic carditis: long term
follow up of patients with subclinical disease. Heart 2001;85:40710.
31. Lanna CC, Tonelli E, Barros MV, Goulart EM, Mota CC. Subclinical
rheumatic valvitis: a long-term follow-up. Cardiol Young 2003;13:
4318.
32. Karaaslan S, Demiroren S, Oran B, Baysal T, Baspinar O, Ucar C.
Criteria for judging the improvement in subclinical rheumatic valvitis.
Cardiol Young 2003;13:5005.
33. Tubridy-Clark M, Carapetis JR. Subclinical carditis in rheumatic fever:
a systematic review. Int J Cardiol 2007;119:548.
34. Caldas AM, Terreri MT, Moises VA, Silva CM, Carvalho AC, Hilario MO.
The case for utilizing more strict quantitative Doppler echocardiographic criterions for diagnosis of subclinical rheumatic carditis.
Cardiol Young 2007;17:427.
35. Vijayalakshmi IB, Vishnuprabhu RO, Chitra N, Rajasri R, Anuradha TV.
The efcacy of echocardiographic criterions for the diagnosis of
carditis in acute rheumatic fever. Cardiol Young 2008;18:58692.
36. Bhaya M, Panwar S, Beniwal R, Panwar RB. High prevalence of
rheumatic heart disease detected by echocardiography in school
children. Echocardiography 2010;27:44853.
37. Bhaya M, Beniwal R, Panwar S, Panwar RB. Two years of follow-up
validates the echocardiographic criteria for the diagnosis and
screening of rheumatic heart disease in asymptomatic populations.
Echocardiography 2011;28:92933.
38. Cohen M, Pocock WA, Lakier JB, McLaren MJ, Lachman AS, Barlow JB.
Four year follow-up of black schoolchildren with non-ejection systolic
clicks and mitral systolic murmurs. Am Heart J 1978;95:697701.
39. McLaren MJ, Hawkins DM, Koornhof HJ, et al. Epidemiology of
rheumatic heart disease in black schoolchildren of Soweto, Johannesburg. Br Med J 1975;3:4748.
40. Zhlke L, Mayosi BM. Echocardiographic screening for subclinical
rheumatic heart disease remains a research tool pending studies of
impact on prognosis. Curr Cardiol Rep 2013;15:343.

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 189-195

41. Sliwa K, Carrington M, Mayosi BM, Zigiriadis E, Mvungi R, Stewart S.


Incidence and characteristics of newly diagnosed rheumatic heart
disease in Urban African adults: insights from the Heart of Soweto
Study. Eur Heart J 2010;31:71927.
42. Diao M, Kane A, Ndiaye MB, et al. Pregnancy in women with
heart disease in sub-Saharan Africa. Arch Cardiovasc Dis 2011;104:
3704.
43. Watkins DA, Sebitloane M, Engel ME, Mayosi BM. The burden of
antenatal heart disease in South Africa: a systematic review. BMC
Cardiovasc Disord 2012;12:23.
44. Steer AC, Kado J, Jenney AW, et al. Acute rheumatic fever and
rheumatic heart disease in Fiji: prospective surveillance, 2005e2007.
Med J Aust 2009;190:1335.
45. Mocumbi AO. The challenges of cardiac surgery for African children.
Cardiovasc J Afr 2012;23:1657.
46. Hoosen EG, Cilliers AM, Hugo-Hamman CT, et al. Paediatric cardiac
services in South Africa. S Afr Med J 2011;101:1067.
47. Hewitson J, Brink J, Zilla P. The challenge of pediatric cardiac services
in the developing world. Semin Thorac Cardiovasc Surg 2002;14:
3405.
48. Dearani JA, Neirotti R, Kohnke EJ, et al. Improving pediatric cardiac
surgical care in developing countries: matching resources to needs.
Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2010;13:
3543.
49. Yankah CA, Siniawski H, Detschades C, Stein J, Hetzer R. Rheumatic
mitral valve repair: 22-year clinical results. J Heart Valve Dis 2011;20:
25764.
50. Agneta Geldenhuys JJK, Human PA, Mtwale JF, Brink JG, Zilla P.
A retrospective review of rheumatic mitral valve repair in a threshold
country. S A Heart 2011;8:235.
51. Severino ES, Petrucci O, Vilarinho KA, et al. Late outcomes of mitral
repair in rheumatic patients. Rev Bras Cir Cardiovasc 2011;26:
55964.
52. Carapetis JR, Zhlke LJ. Global research priorities in rheumatic fever
and rheumatic heart disease. Ann Pediatr Cardiol 2011;4:412.
53. Karthikeyan G, Zhlke L, Engel M, et al. Rationale and design of a
Global Rheumatic Heart Disease Registry: the REMEDY study. Am
Heart J 2012;163:535540.e1.

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Echocardiographic Screening for Rheumatic Heart Disease


Issues for the Cardiology Community
Anita Saxena*, Liesl Zhlkey,z, Nigel Wilsonx
New Delhi, India; Cape Town, South Africa; and Auckland, New Zealand
ABSTRACT
The advent of portable echocardiography has led to screening for rheumatic heart disease (RHD) with high
disease prevalence found in many countries. Data are presented from studies from India, Africa, and New
Zealand. The natural history of subclinical echocardiographically detected RHD is the most important
research question to be answered before more widespread screening is endorsed. The 2012 World Heart
Federation (WHF) criteria for the echocardiographic diagnosis of RHD provide standardization of RHD
diagnosis, increasing the specicity for denite RHD and raising the threshold for borderline RHD. Use of
the criteria should reduce the false positive rate for minor echocardiographic changes due to physiological
valvular regurgitation. This review highlights issues of screening for RHD that are of relevance to the
cardiology community.
In developing countries, rheumatic heart disease
(RHD) remains a signicant cause of cardiovascular
morbidity and mortality [1,2]. Epidemiological studies
from India in the last decade, using clinical screening followed by echocardiography have shown a consistent
decrease in the prevalence of RHD [3e5]. However, several
studies in other parts of the world have shown a very high
prevalence of RHD when asymptomatic children are
screened by echocardiography [6e9]. It is suggested that
echocardiographic screening with institution of secondary
prophylaxis for positive cases may lessen the burden of
RHD, and in 2004, the WHO recommended echocardiographic screening for RHD in high-prevalence regions [1].
However, the natural history of subclinical RHD, identied
using an echocardiographic screening protocol is not
known. Some of the data on echocardiographic screening
from India, Africa, and New Zealand are described herein.
The purpose of this review is to highlight issues of
screening for RHD that are of relevance to cardiologists and
cardiac surgeons.

ECHOCARDIOGRAPHIC SCREENING DATA FROM


INDIA
This cross-sectional epidemiological survey, the RHEUMATIC (Rheumatic Heart Echo Utilization and Monitoring
Actuarial Trends in Indian Children) study [10], was
conducted in the rural primary and secondary schools, in
the Ballabgarh Block of Haryana, North India. After
obtaining institutional ethical approval, consent was taken
from principals of schools and parents of children studying
in these schools. The aim of the study was to diagnose
RHD in asymptomatic children ages 5 to 15 years, living in
rural areas, using portable echocardiography. After cluster
sampling, 6,270 children, ages 5 to 15 years were recruited

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 197-202

from various government and private schools. After a


focused history and examination, echo-Doppler was performed using a bedside portable echocardiography
machine.
The modied World Health Organization (WHO)
criteria [11] dene RHD using echocardiography including
fullling Doppler criteria (a regurgitant jet of >1 cm in
length, regurgitant jet in at least 2 planes, a mosaic color jet
with a peak velocity of >2.5 m/s, and jet persisting
throughout systole or diastole) associated with at least 2
morphologic signs including leaet restriction, subvalvular
thickening, and valve leaet thickening. Other criteria for
diagnosing denite RHD by echocardiography included
mitral stenosis, mitral valve involvement with aortic
regurgitation (AR) in the absence of alternative cause for
AR, and isolated mitral regurgitation with documented
history of rheumatic fever (RF). Two investigators with
experience in interpreting echocardiography separately
analyzed the images. In case of disparity, an opinion of a
third cardiologist was taken. The parents were counseled if
any abnormality was detected either during clinical examination or by echocardiography. Patients with clinical
RHD and those with moderate regurgitation on echocardiogram were advised to commence secondary prophylaxis. Patients with subclinical RHD were advised to report
sore throat, fever, or joint pain to the local health center.

Results
Of the 6,270 children included, 52.65% were male with a
mean age of 10.78  2.63 years (range 5 to 15 years).
Nearly one-third (1,908) of these children were studying in
government-funded schools. Clinical examination detected
mitral regurgitation that was conrmed on echocardiography in 5 patients and the estimated prevalence of clinical

Dr. Zhlke has reported


that she has received funds
from the Thrasher Foundation, Clinical Infectious
Disease Research Initiative,
and the Hamilton Naki
Clinical Scholarship Programme funded by Netcare
Limited. Dr. Wilson has reported that he has received
salary support from Cure
Kids New Zealand. Cure
Kids New Zealand had no
role in the study design or
any other aspect of this
review.
This paper was presented
in part at the Seventh
Global Forum on Humanitarian Medicine in Cardiology and Cardiac Surgery,
June 20e22, 2011, Geneva,
Switzerland.
From the *Cardiology
Department, All India
Institute of Medical Sciences, New Delhi, India;
yDepartment of Paediatric
Cardiology, Red Cross War
Memorial Childrens Hospital and University of Cape
Town, Cape Town, South
Africa; zDepartment of
Medicine, Groote Schuur
Hospital, Cape Town, South
Africa; and the xGreen
Lane Paediatric and
Congenital Cardiology Services, Starship Hospital,
Auckland, New Zealand.
Correspondence: N. Wilson
(NigelW@adhb.govt.nz).
GLOBAL HEART
2013 World Heart
Federation (Geneva).
Published by Elsevier Ltd.
All rights reserved.
VOL. 8, NO. 3, 2013
ISSN 2211-8160/$36.00.
http://dx.doi.org/10.1016/
j.gheart.2013.08.004

197

gREVIEW

RHD was 0.8 per 1,000 schoolchildren. Echocardiography


diagnosed RHD in 128 cases, a prevalence of 20.4
per 1,000 schoolchildren (95% condence interval
[CI]: 16.9 to 23.9 per 1,000 children). On multivariate
analysis, older age (odds ratio [OR]: 1.93, 95% CI: 1.29
to 2.88; p 0.001), female sex (OR: 1.84, 95% CI: 1.25
to 2.72; p 0.002), and studying in a government-funded
school (OR: 1.55, 95% CI: 1.02 to 2.34; p 0.039) were
found to be independent predictors of subclinical RHD.
Thus, the prevalence of RHD is several fold higher using
echocardiographic screening. Prevalence is higher in children who are economically less privileged.

ECHOCARDIOGRAPHIC SCREENING DATA FROM


DIFFERENT REGIONS OF AFRICA
The rst echocardiographic screening study was performed
in Kenya in 1999, demonstrating the feasibility of echobased screening in asymptomatic populations [12]. Since
this rst report, several studies have been conducted in
various parts of Africa [13].

Data from Mozambique


Data from Mozambique has been published [7] and has
proven to be a sentinel study in raising awareness of the
prevalence of previously undetected RHD. In brief, 2,170
children mean age 10.6 years (range 6 to 17) were
recruited randomly from 6 primary schools in the capital,
Maputo. Two-thirds of those children were from suburban
schools and one-third from urban schools. Criteria for
echocardiographic diagnosis of RHD were dened as
presence of any denite evidence of mitral or aortic valve
regurgitation seen in 2 planes by Doppler echocardiography, accompanied by at least 2 of the 3 morphologic abnormalities of the regurgitant valve (restricted leaet
mobility, focal or generalized valvular thickening, and
abnormal subvalvular thickening).

Results The prevalence of echocardiographic RHD was


30.4 per 1,000 children compared with 2.3 per 1,000
diagnosed clinically. The prevalence was higher in girls than
in boys and in suburban than in urban children. Retrospective reanalyses of the same cohort using different criteria
highlighted the need for standardized denitions for diagnosis of subclinical disease [14] as the initial high prevalence
rates were not conrmed by subsequent criteria. Their
recently proposed simplied criteria [15] may have merit
but should be tested prospectively against the World Heart
Federation (WHF) criteria before recommending that
other groups adopt their use.

children for whom the screening echocardiogram was


considered abnormal had a complete study performed and
reviewed by 2 cardiologists. Diagnostic criteria were as per
WHO guidelines [11]. Follow-up echocardiograms were
performed every 6 to 12 months.

Results Twenty-one children had denite RHD, 46


probable RHD, and 233 possible RHD. Overall, approximately 20 per 1,000 children have probable or denite
evidence of RHD by screening echocardiography [16].
Data from Uganda
A recent study conducted in Uganda reported a 2-min
screening echocardiogram of the left-sided valves by a
single operator [17]. This was followed by detailed echocardiograms at a tertiary center by experienced operators.
This screening method was able to screen >200 participants per day.

Results A total of 4,869 children were screened with 25


cases detected. The overall prevalence was 5.1 per 1,000 (95%
CI: 3.49 to 7.6), signicantly lower prevalence rate compared
with the Mozambique study. The concept of abbreviated
echocardiograms has potential, especially in rural areas where
follow-up is problematic. An immediate assessment would aid
immediate counseling of participants and family.
Data from Senegal
A school-based screening program [18] conducted in 2010
in Dakar, Senegal, included 2 groups of schoolchildren:
group 1 (n 1,116) were 5 to 15 years old; group 2 (n
888) were 16 to 18 years old.

Results The prevalence rates in group 1 were almost onehalf those for group 2: 5.4 per 1,000 (95% CI: 2.0 to 11.7)
and 10.1 per 1,000 (95% CI: 4.6 to 19.2) concordant with
previous clinical screening programs showing higher case
detection rates in older children [19]. This study indicates
that screening age is an important consideration in planning
a screening program.
Data from Eritrea
The majority of screening programs in Africa have focused
on schoolchildren [20]. The concern regarding the high
risk of morbidity and mortality due to RHD in pregnant
women led to a screening study of pregnant women in
Keren, Eritrea, using echocardiography [21]. The study
was conducted by 2 specially trained medical students
under the supervision of an experienced cardiologist.

Data from Mali


A total of 3,092 children were selected randomly living in
an urban quarter in Bamako [16]. The age range was 5 to
16 years. After physical examination, screening echocardiograms were performed using parasternal long- and
short-axis views and apical 4-chamber view. Those

198

Results Eight of the 348 screened women had denite


RHD. This corresponds to a prevalence of 23 per 1,000
(95% CI: 7 to 39). Further studies designed to evaluate the
clinical signicance of screening for RHD in early pregnancy are needed.
GLOBAL HEART, VOL. 8, NO. 3, 2013
September 2013: 197-202

gREVIEW

ECHOCARDIOGRAPHIC SCREENING IN NEW


ZEALAND
The results of the initial screening study of 1,274 children
ages 10 to 13 years in urban schools in a high RF prevalence region are reported [9]. The study used modied
WHO criteria [11] but a mitral regurgitant jet of length >2
cm was considered pathological. There was a 26 per 1,000
prevalence of denite or probable RHD and 30 per 1,000
prevalence of possible RHD using those denitions. Since
then, another 2,494 children have been screened in 3
separate rural populations and 1 urban region. Implementation of the 2012 WHF criteria [22] in the 2 most
recent regions found a 10 per 1,000 denite RHD prevalence and a 24 per 1,000 borderline RHD prevalence,
signicantly lower rates than those using the modied
WHO criteria. Following the initial program [9], only those
with a positive test proceed to a specialist clinical consultation with auscultation [23]. The study found that a
considerable health personnel and logistical load was
required for the screening program, the clinical evaluation,
and counseling those with a positive test [23].
Another study of a control population of 400 children
in a high socioeconomic region in New Zealand did not
nd any cases of denite RHD, but 2 children with mild
mitral regurgitation met borderline RHD criteria [24]. This
study provided data about the very low, but not zero
prevalence of subclinical mild mitral regurgitation in low
RF prevalence regions.

ISSUES FOR THE GLOBAL DEVELOPMENT OF RHD


SCREENING
The need to standardize RHD echocardiographic
criteria
As illustrated in this paper, the different criteria used to
dene echocardiographic RHD accounts for some of the
differences of RHD prevalence [3,6e9,23] and essentially
make epidemiological comparisons invalid. In 2009, an
international RHD echocardiographic standardization
study was started with 21 investigators from 11 countries
who had by this time practical experience of screening
many thousands of cases. All available echocardiographic,
pathological, and surgical descriptions of RHD were
analyzed. The aim was to dene the minimal diagnostic
criteria for a diagnosis of RHD that could be used in clinical
cardiology practice as well as for screening programs. The
results were published as the 2012 WHF criteria for
echocardiographic diagnosis of RHD [22]. The 2012 WHF
criteria for denite RHD are more specic than previous
denitions were and the threshold has been raised for
possible RHD (renamed borderline RHD). It was judged
that increasing the threshold for borderline RHD will
reduce the false positive rate of RHD by excluding those
with physiological mitral and aortic regurgitation. The
WHF criteria have quickly been adopted as the current
gold standard for echocardiographic screening [25,26].

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 197-202

The investigators are also undertaking a detailed interobserver and intraobserver study of the criteria. The WHF
criteria should facilitate further echocardiographic RHD
research, such as epidemiological studies, long-term evaluation of the natural history of subclinical RHD, the evaluation of secondary prophylaxis for echocardiographically
detected RHD, and cardiology evaluation of group A
streptococcal vaccine trials.

Does echocardiography meet the requirements for


a population-screening test?
At rst sight, echocardiographic screening for RHD meets
the 3 main requirements for disease screening. First, there
is a suitable condition (RHD); second, the condition is
detectable (by echocardiography); and third, it is treatable
by long-acting benzathine penicillin [25]. A more detailed
list of requirements for screening suggested by the New
Zealand National Health Committee [27] and the Council
of Europe [28] are found on their respective websites.
The rst requirement is met as most subjects positive
for RHD by echocardiography have subclinical disease,
which is latent and pre-clinical. They have the most to gain
from such a program by prevention of progressive RHD.
However, currently, we do not know the natural history of
subclinical RHD. It is known that those with an episode of
acute RF are at high risk of RHD recurrences and progression of RHD severity [1,2], but it is not known whether
an individual with RHD identied by echocardiography is
at the same risk of RHD progression and or clinical acute
RF recurrences. Roberts et al. [25] discussed this and other
aspects of echocardiography screening and concluded that
this is the most important question hindering the recommendation of wider use of echocardiography screening for
RHD. It is important to be aware that in the short term,
RHD screening will increase the prevalence of RHD within
the region and additional resources will need to be allocated to effectively deliver secondary prophylaxis. It follows that it is unethical to begin a screening program if
secondary penicillin delivery is not available in the region
being screened [29].
Each region should decide before screening who
should receive secondary prophylaxis. As already outlined,
in the northern region of India and in New Zealand, those
with borderline RHD by the WHF criteria [22] or possible
RHD by the WHO criteria [11], have not commenced on
penicillin. The lack of disease progression of these categories over 2 to 4 years as reported recently in 3 reports
[8,10,30] gives support to continue the policy of not recommending penicillin for borderline RHD until the natural
history of this category is known. It is still appropriate to
provide active surveillance, which is used for cancers that
may not progress [31,32]. Active surveillance involves
prospectively following the case through time and rescreening at intervals to monitor that the disease has not
progressed. No other active intervention is offered, unless
disease progression is found. When considered as an

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alternative to antibiotic prophylaxis, an active surveillance


approach is appealing as patients are saved the 4-weekly
intramuscular penicillin injections and the RF secondary
prophylaxis register is not inundated with cases that may
never need penicillin.
No single country to date has had the statistical power
by numbers screened and length of follow-up to answer
the question of efcacy of treatment for denite RHD even
though it seems logical to treat this category. It has been
judged that a treatment RCT for denite RHD is not
feasible currently for 3 broad reasons. First, few regions
have sufciently reliable secondary prophylaxis programs
that randomization to penicillin or not would be problematic. Second, intramuscular penicillin is not universally
administered due to the issues of needles/acquired immunodeciency syndrome/safe penicillin availability; and
third, many judge it unethical not to treat denite RHD. In
addition, many programs would not receive funding unless
those detected with RHD were treated. A case-control
study of denite RHD faces the same logistical problems
as outlined herein, especially as many groups will not
enroll if they cannot intend to treat by penicillin. A logical
next level of evidence is the use of registry data as used by
many international groups such as, International Society of
Heart and Lung Transplantation, and interventional cardiology registries.
A prospective, international, multicenter registry of
denite and borderline RHD (known as the DeneRHD
registry) is being implemented. Follow-up of secondary
penicillin status with frequent reporting (3-monthly) and
echocardiography changes (2-yearly) should answer the
question whether those with denite RHD receiving good
secondary prophylaxis will show less disease progression
and more disease regression than will those with no or
poor secondary prophylaxis. Powering allows for a 25%
difference in proportions deteriorating between the treatment arms over 4 years. The signicance of the study is
that it provides a realistic chance of dening the natural
history of subclinical echocardiographically detected denite RHD in the shortest possible time. If the study does
not prove that those with denite RHD are at increased risk
of progression of RHD, then borderline RHD will also not
be a risk factor for RHD progression.
Observational data about RHD disease control may
also come from small well-dened geographical regions
such as the Pacic Islands of Tonga, Samoa, and Fiji.
Screening has continued on a regular basis in Tonga,
population 90,000, following the original study [6].
Another 11,000 children have been screened, which represents a large proportion of the countrys youth at risk of
RF (T. Fakakovikaetau, personal communication, June
2010). Due to considerations, such as the high prevalence
of RHD, the restricted access to surgery, and geographic
isolation, a decision was made to provide secondary prophylaxis for those with denite and borderline changes as
well as denite RHD changes. This policy may well result
in reduced RHD disease burden in dened small regions.

200

TABLE 1. Differential diagnosis of mitral regurgitation in schoolaged children in regions with high prevalence of rheumatic fever
1. RHD
2. Upper limit of physiological mitral valve regurgitation
3. Congenital mitral valve prolapse or oppy mitral valve
syndrome*
4. Infective endocarditis
5. Congenital malformation of the mitral valve, for example,
double orice MV, parachute MV, hammock MV, funnelshaped MV, or cleft MV
6. Congenital heart disease with mitral regurgitation, for
example, primum or secundum atrial septal defect
MV, mitral valve; RHD, rheumatic heart disease.
*May be associated with abnormal body habitus, Marfan syndrome
or other connective tissue disorders; endomyocardial brosis is
common in some countries.

On the other hand, in light of recent follow-up studies


[8,10,30], it is likely that minor echocardiographic changes
may have been overtreated.
Those planning RHD screening should be aware of a
wider discussion of optimal active and passive surveillance
for RHD [11] and the current controversies of screening
[25,26]. Echocardiography screening has increased the
advocacy for RF and RHD, but it has not yet proven to be
cost-effective for disease control. It may be logical for
resource-limited countries to pre-select patients with
pathological murmurs for echocardiography, allowing a
much larger population to be screened for the same dollar
value [33,34]. Sadiq et al. [33] were able to screen an
impressive 24,980 Pakistani children using this model.

Issues for cardiologists


Cardiologists may be asked to review echocardiograms
from screening programs. The cardiologist should be
familiar with the differential diagnoses of rheumatic mitral
regurgitation as listed in Table 1. A mid-systolic click
associated with mitral regurgitation strongly suggests
congenital mitral valve prolapse not RHD, and congenital
mitral variants appear in about 1% of the population [9].
Physiological mitral regurgitation needs to be excluded
[8,9] to prevent overdiagnosis. Aortic regurgitation is less
of a diagnostic problem as the same echocardiogram excludes bicuspid aortic valve and a dilated aortic root as
TABLE 2. Differential diagnosis of aortic regurgitation in schoolaged children in regions with high prevalence of rheumatic fever
1.
2.
3.
4.

RHD
Bicuspid aortic valve with aortic regurgitation
Dilated aortic sinus or root
Infective endocarditis

RHD, rheumatic heart disease.

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TABLE 3. Logistical considerations for RHD echocardiographic


screening
1. RF register with secondary prophylaxis delivery structure
2. Public health, pediatric, cardiology, and community
nursing partnership
3. Cardiologists to read the abnormal echocardiograms
(ideally with second opinion capability)
4. Clinicians to counsel those with abnormalities
5. Financial cost of staff, echocardiography, secondary
prophylaxis, clinical follow-up
RF, rheumatic fever; RHD, rheumatic heart disease.

causes of aortic regurgitation (Table 2). The WHF criteria


[22] are also available on the WHF website.
The acceptability of long-term secondary prophylaxis
for those with echocardiographically detected RHD has not
been established or researched. In most regions, children
with an episode of acute RF are admitted to the hospital
with the acute illness, often with painful arthritis. This allows families to understand well and accept, usually, the
importance of secondary prophylaxis. In contrast, the logic
for secondary prophylaxis may not be understood by the
family of an otherwise healthy child who is found to have
echocardiographic RHD.
Logistical issues for echocardiographic screening are
summarized in Table 3. The program will also detect cases
of congenital heart disease, which require clinical management [9].

Issues for cardiac surgeons


The majority of children with RHD detected by screening
have mild disease. However, some individuals will have
severe disease and cardiac surgery may be indicated. This
must be taken into account from the outset before
screening is planned. Many regions with high prevalence of
RHD do not have access to cardiac surgery. The cardiology
community must continue to advocate for improving secondary prophylaxis, ideally through registry-based programs [11], as they remain the proven method to prevent
RHD progression [35,36].

SUMMARY
Portable echocardiography is a relatively new screening
tool for RHD, which has raised awareness of the high
prevalence of RHD in many countries. Many requirements
of a screening test are met, but the natural history of
subclinical RHD needs further clarication. Use of the
2012 WHF criteria for the echocardiographic diagnosis of
RHD is strongly recommended. Cardiologists and cardiac
surgeons should help provide advocacy for improving
secondary prophylaxis programs, as this remains pivotal
for RHD control.

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ACKNOWLEDGMENTS
The authors would like to thank Charlene Nell, desktop
support administrator, for preparing the manuscript and
for excellent secretarial assistance.

REFERENCES
1. Rheumatic fever and rheumatic heart disease. World Health Organ
Tech Rep Ser 2004;923:1122.
2. Carapetis JR. Rheumatic heart disease in developing countries. N Engl
J Med 2007;357:43941.
3. Jose VJ, Gomathi M. Declining prevalence of rheumatic heart disease
in rural schoolchildren in India: 2001e2002. Indian Heart J 2003;55:
15860.
4. Misra M, Mittal M, Singh R, et al. Prevalence of rheumatic heart
disease in school-going children of Eastern Uttar Pradesh. Indian
Heart J 2007;59:423.
5. Ramakrishnan S, Kothari SS, Juneja R, Bhargava B, Saxena A, Bahl VK.
Prevalence of rheumatic heart disease: has it declined in India? Natl
Med J India 2009;22:724.
6. Carapetis JR, Hardy M, Fakakovikaetau T, et al. Evaluation of a
screening protocol using auscultation and portable echocardiography
to detect asymptomatic rheumatic heart disease in Tongan schoolchildren. Nat Clin Pract Cardiovasc Med 2008;5:4117.
7. Marijon E, Ou P, Celermajer DS, et al. Prevalence of rheumatic heart
disease detected by echocardiographic screening. N Engl J Med 2007;
357:4706.
8. Paar JA, Berrios NM, Rose JD, et al. Prevalence of rheumatic heart
disease in children and young adults in Nicaragua. Am J Cardiol 2010;
105:180914.
9. Webb RH, Wilson NJ, Lennon DR, et al. Optimising echocardiographic
screening for rheumatic heart disease in New Zealand: not all valve
disease is rheumatic. Cardiol Young 2011;21:43643.
10. Saxena A, Ramakrishnan S, Roy A, et al. Prevalence and outcome of
subclinical rheumatic heart disease in India: the RHEUMATIC
(Rheumatic Heart Echo Utilisation and Monitoring Actuarial Trends in
Indian Children) study. Heart 2011;97:201822.
11. Carapetis JR, Parr J, Cherian T. Standardization of epidemiologic
protocols for surveillance of post-streptococcal sequelae: acute
rheumatic fever, rheumatic heart disease and acute poststreptococcal glomerulonephritis [pdf]. January 2006. Available
from:
http://www.niaid.nih.gov/topics/strepThroat/Documents/
groupasequelae.pdf. Accessed July 30, 2013.
12. Anabwani GM, Bonhoeffer P. Prevalence of heart disease in schoolchildren in rural Kenya using colour-ow echocardiography. East Afr
Med J 1996;73:2157.
13. Zuhlke L, Mirabel M, Marijon E. Congenital heart disease and rheumatic heart disease in Africa: recent advances and current priorities.
Heart 2013 May 16 [E-pub ahead of print].
14. Marijon E, Celermajer DS, Tafet M, et al. Rheumatic heart disease
screening by echocardiography: the inadequacy of World Health
Organization criteria for optimizing the diagnosis of subclinical disease. Circulation 2009;120:6638.
15. Mirabel M, Celermajer DS, Ferreira B, et al. Screening for rheumatic
heart disease: evaluation of a simplied echocardiography-based
approach. Eur Heart J Cardiovasc Imaging 2012;13:10249.
16. Scheel JN. Data from Mali presentation. Data presented at: RHD Echo
Standardization Workshop; March 25e7, 2011; Bangkok, Thailand.
17. Beaton A, Okello E, Lwabi P, Mondo C, McCarter R, Sable C. Echocardiography screening for rheumatic heart disease in Ugandan
schoolchildren. Circulation 2012;125:312732.
18. Kane A, Mirabel M, Toure K, et al. Echocardiographic screening for
rheumatic heart disease: age matters. Int J Cardiol 2012 Dec 13
[E-pub ahead of print].
19. McLaren MJ, Hawkins DM, Koornhof HJ, et al. Epidemiology of
rheumatic heart disease in black shcoolchildren of Soweto, Johannesburg. Br Med J 1975;3:4748.

201

gREVIEW

20. Engel ME, Zhlke LJ, Robertson KA. ASAP programme: rheumatic
fever and rheumatic heart disease: where are we now in South
Africa? S Afr Heart J 2009;6:203.
21. Otto H, Saether SG, Banteyrga L, Haugen BO, Skjaerpe T. High prevalence of subclinical rheumatic heart disease in pregnant women in a
developing country: an echocardiographic study. Echocardiography
2011;28:104953.
22. Remenyi B, Wilson N, Steer A, et al. World Heart Federation criteria
for echocardiographic diagnosis of rheumatic heart diseasean
evidence-based guideline. Nat Rev Cardiol 2012;9:297309.
23. Cramp G, Stonehouse M, Webb R, Chaffey-Aupouri G, Wilson N.
Undetected rheumatic heart disease revealed using portable echocardiography in a population of school students in Tairawhiti, New
Zealand. N Z Med J 2012;125:5364.
24. Webb R, Gentles TL, Stirling J. Echocardiographic ndings in a low risk
population for rheumatic heart disease (RHD): implications for
screening. Abstract presented at: XVIII Lanceeld International
Symposium; September 4-8, 2011; Palermo, Italy.
25. Roberts K, Colquhoun S, Steer A, Remenyi B, Carapetis J. Screening
for rheumatic heart disease: current approaches and controversies.
Nat Rev Cardiol 2013;10:4958.
26. Zhlke L, Mayosi BM. Echocardiographic screening for subclinical
rheumatic heart disease remains a research tool pending studies of
impact on prognosis. Curr Cardiol Rep 2013;15:343.
27. National Advisory Committee on Health and Disability. Screening to
Improve Health in New Zealand: Criteria to Assess Screening

202

28.

29.

30.

31.
32.

33.
34.

35.
36.

Programmes. Wellington, New Zealand: National Health Committee.


p. 149. Pdf available from: http://nhc.health.govt.nz/; 2003.
Council of Europe. Committee of Ministers, Recommendation. No. R
(94) 11 on screening as a tool of preventive medicine, Oct. 10,
(1994). July 5, 2013.
Mayosi BM. Letter regarding article, Echocardiography screening for
rheumatic heart disease in Ugandan schoolchildren. Circulation 2012;
126:e476. author reply e478e9.
Bhaya M, Beniwal R, Panwar S, Panwar RB. Two years of follow-up
validates the echocardiographic criteria for the diagnosis and
screening of rheumatic heart disease in asymptomatic populations.
Echocardiography 2011;28:92933.
Bangma CH, Bul M, van der Kwast TH, et al. Active surveillance for
low-risk prostate cancer. Crit Rev Oncol Hematol 2013;85:295302.
DallEra MA, Albertsen PC, Bangma C, et al. Active surveillance for
prostate cancer: a systematic review of the literature. Eur Urol 2012;
62:97683.
Sadiq M, Islam K, Abid R, et al. Prevalence of rheumatic heart disease
in schoolchildren of urban Lahore. Heart 2009;95:3537.
Steer AC, Kado J, Wilson N, et al. High prevalence of rheumatic heart
disease by clinical and echocardiographic screening among children
in Fiji. J Heart Valve Dis 2009;18:32735. discussion 336.
Manyemba J, Mayosi BM. Penicillin for secondary prevention of
rheumatic fever. Cochrane Database Syst Rev 2002;(3):CD002227.
Wilson N. Secondary prophylaxis for rheumatic fever: simple concepts,
difcult delivery. World J Pediatr Congenit Heart Surg 2013. In press.

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Echocardiographic Diagnosis of Chronic


Rheumatic Valvular Lesions
Anita Saxena
New Delhi, India
ABSTRACT
Rheumatic heart disease continues to be a signicant public health problem in many developing countries and
in some of the aboriginal populations in developed countries. Echocardiography has become indispensable in
the assessment of valve lesions secondary to rheumatic heart disease. It conrms the rheumatic etiology of
valvular abnormality as the features are quite typical in most cases. It also helps to exclude nonrheumatic
causes of valve lesions. M-mode and cross-sectional echo helps to assess the severity of valve abnormality
and its hemodynamic effects on the heart. Further, color ow imaging evaluates the ow across a valve,
both qualitatively and quantitatively. Serial echocardiography plays a crucial role in the follow-up of
patients with rheumatic heart disease and is very helpful for determining the timing of intervention.
Recently, addition of real-time 3-dimensional echocardiography has further improved imaging of cardiac
valves, especially the mitral valve.
Rheumatic heart disease (RHD) continues to be a signicant cause of cardiovascular morbidity and mortality in
developing countries [1,2]. Echocardiography has become
indispensable in the assessment of valve lesions secondary
to RHD. Although echo is the key noninvasive test for valve
assessment, it is essential to combine clinical data with 2dimensional (2D) echo and Doppler ndings in order to
make a decision regarding the management of the patient.
Real-time 3-dimensional echo (RT3DE) may have an
advantage over 2D echo because it provides multiple imaging planes. It must, however, be kept in mind that factors
such as loading conditions of the heart, irregular rhythm,
and low cardiac output inuence ows and gradients
across the valves, thereby interfering with the assessment of
the valve abnormality. In this review, the echocardiographic features of RHD will be discussed, primarily
focusing on the qualitative and quantitative value of
echocardiography in diagnosis, management, and followup. Each valvular abnormality will be subdivided into
regurgitant and stenotic lesions. Pulmonary valve abnormality is not being discussed as it is hardly ever affected by
the rheumatic process.

MITRAL REGURGITATION
Mitral regurgitation (MR) is the most common abnormality
seen in RHD patients [3,4]. Although MR can occur due to
several other etiologies, the echocardiographic picture of
rheumatic mitral valve is very characteristic. This helps
with diagnosing MR secondary to RHD, even in patients
with no previous history of rheumatic fever, especially in
populations living in endemic regions. Typically, the valve
leaets are thick and may show some doming and
restricted mobility, but the valve area is generally normal
except in cases with associated mitral stenosis (MS).

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M-mode echo
The left atrium and left ventricle are enlarged in patients
with signicant MR. The degree of dilation of the left
ventricle determines the timing of surgery in these patients.
In children, the measurement should be indexed. The left
ventricular function is preserved until late in the natural
history of the disease. In isolated chronic MR, the pulmonary pressures are not much elevated unless the left
ventricular dysfunction has set in. Hence, the right atrium
and right ventricle are not enlarged and the interventricular
septal motion remains normal.

2D echo
Mitral valve leaets are thickened and elongation of chordae may result in prolapse of the anterior mitral leaet
(Fig. 1). Chordal rupture leading to ail anterior mitral
leaet may occur in severe cases secondary to infective
endocarditis or acute rheumatic carditis [5]. In some cases
of pure MR and in those associated with MS, the restricted
movement of mitral leaets results in doming, producing
an elbow or dog leg deformity of the anterior mitral leaet.
Mitral valve leaet calcication is unusual in children and
young adults, but it is seen in older patients with longstanding MR. Echocardiography is very useful to assess
mitral valve suitability for repair. In those with suboptimal
transthoracic images, transesophageal echocardiography,
performed pre-operatively or in the operating room, is
done to gather this information.
The left atrium and left ventricle are enlarged in those with
signicant MR. The assessment of left ventricle size by 2D
echo is likely to be more accurate than it would be by M-mode
echo. End-systolic and end-diastolic volumes and ejection
fraction can be calculated using Simpson or area-length

From the Department of


Cardiology, All India Institute of Medical Sciences,
Ansari Nagar, New Delhi,
India. Correspondence:
A. Saxena (anitasaxena@
hotmail.com).
GLOBAL HEART
2013 World Heart
Federation (Geneva).
Published by Elsevier Ltd.
All rights reserved.
VOL. 8, NO. 3, 2013
ISSN 2211-8160/$36.00.
http://dx.doi.org/10.1016/
j.gheart.2013.08.007

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FIGURE 1. Two-dimensional echo from a patient with severe mitral regurgitation showing dilated left atrium (A), left
ventricle, thickened mitral leaets (B), and prolapse of the anterior leaet (arrow). Ao, aorta; LA, left atrium; LV, left
ventricle.
methods. The interatrial septum may be bowed toward the
right atrium. A left atrial clot is unusual in isolated MR.

Doppler echo

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FIGURE 2. Color ow mapping showing severe mitral


regurgitation. RA, right atrium; RV, right ventricle; other
abbreviations as in Figure 1.

204

RT3DE is increasingly employed in evaluation of mitral


valve pathology and is considered as the modality of choice
for surgical planning in many centers. The mitral valve has
a saddle-shaped, nonplanar annulus and displays variation
in size and shape during a cardiac cycle. RT3DE can
distinguish the differences in annular shape and function in
various types of MR. Most of the published data is on MR
secondary to myxomatous mitral valve and ischemia, but
RT3DE is likely to be very useful for patients with RHD as
it clearly shows the pathomechanism of MR [8]. RT3DE
not only guides the surgical repair but also assesses the
success of repair in the post-operative period. The quantication of MR is evaluated better by 3D echo. Because
RT3DE provides multiple imaging planes, the narrowest
portion of the regurgitant color ow jet can be easily
assessed [9]. One can accurately measure cross-sectional
area of the vena contracta, anatomic regurgitant orice

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The degree of MR is best judged by color ow mapping.


Often the MR jet is directed posteriorly (Fig. 2). The
severity of regurgitation is assessed by grading the regurgitant jet area in comparison to the total left atrial area. It is
important to distinguish mild pathologic MR from physiologic MR, sometimes seen in normal individuals. A
pathological MR is seen in at least 2 views, with the
regurgitant jet length of >2 cm in at least 1 view, peak
velocity of the jet 3 m/s, and pansystolic Doppler signal
in at least 1 beat. The other methods to quantify MR
include measuring vena contracta, ow convergence
(proximal isovelocity surface area, or PISA), and systolic
pulmonary ow reversal in pulmonary veins. All these
techniques are more accurate but time-consuming [6].
MR can be classied into mild, moderate, or severe
based on various parameters by 2D echo and Doppler
echocardiography [7].

3D echo

FIGURE 3. M-mode echo of mitral valve in a patient


with mitral stenosis and atrial brillation, showing
thickened mitral valve, reduced EF slope of anterior
mitral leaet and paradoxical motion of posterior mitral
leaet.

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FIGURE 4. M Mode echo of a patient with mitral stenosis showing enlarged left atrium. Abbreviations as in
Figure 1.
area, and PISA for the calculation of the effective regurgitant orice area [10]. Poor echo windows produce poor
images similar to the case of 2D echo. In such patients,
electrocardiogram-gated reconstructed images develop
stitch artefacts, interfering with the interpretation.

MITRAL STENOSIS
MS is secondary to RHD in a vast majority of cases.
Chronic rheumatic process results in brosis and thickening of the valve and commissural fusion. In some of the
developing countries, severe MS develops at a young
age [11]. The mitral valve leaets are thick with restricted
openings, and subvalvular apparatuses with chordal
shortening and fusion may be involved. Balloon valvuloplasty is the treatment of choice for patients with MS, and
echocardiography plays a crucial role in the assessment of
severity of MS and suitability for balloon valvuloplasty.

fusion, the hallmark of rheumatic etiology is best seen in


the parasternal short-axis view (Fig. 6). The mitral valve
area can be calculated by planimetry performed in the
parasternal short-axis view at the tips of the leaet. Twodimensional echo also allows detailed evaluation of the
subvalvular deformity. The subvalvular apparatus is often
abnormal with thickening and shortening of chordae
(Fig. 7). The valve may be calcied in some cases, especially in those over 30 to 40 years of age. Several scoring
systems have been described for the morphology of the
mitral valve leaets and subvalvular apparatus, the most
commonly used is the Wilkins score. In this scoring system, leaet mobility, leaet thickening, subvalvular thickening, and calcication are scored on a scale of 1 to 4, and
a total score is estimated. A score of >8 may be associated
with a lower rate of success of balloon valvuloplasty [12].
The left atrium is enlarged as a consequence of chronic
pressure overload. Left atrial thrombus is not uncommon
in MS, especially in those with atrial brillation and/or very
large left atrium (>50 mm). The clot is commonly located
in the left atrial appendage and may escape detection unless the appendage is visualized specically in short-axis
view (Fig. 8). This is of utmost importance in patients
undergoing balloon dilation of mitral valve. In patients
with a suboptimal transthoracic window, a transesophageal
echocardiography is mandatory to rule out a left atrial clot.
Presence of left atrial spontaneous contrast is a predictor of
thromboembolic risk.
Increased left atrial pressure leads to pulmonary
venous and thereby pulmonary arterial hypertension. The
right-sided chambers may be enlarged in those with signicant pulmonary hypertension, leading to functional
tricuspid regurgitation (TR). In these cases, the interventricular septum may exhibit at or paradoxical movement.
Echocardiography is commonly performed in the
catheterization lab to assess a valve immediately after

M-mode echo

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The ndings on M-mode echo are very typical, showing


thickened mitral valve leaets, reduced E-F slope of the
anterior mitral leaet, paradoxical or anterior motion of the
posterior mitral valve leaet reduced valve leaet excursion
(D-E excursion), and absent or reduced A-wave of the mitral
leaet (Fig. 3). The left atrium is enlarged (Fig. 4). The left
ventricular size and systolic function are generally preserved;
in some cases, the function may be reduced secondary to
acute rheumatic carditis or chronic atrial brillation. The
right atrium and right ventricle may also be enlarged in those
with signicant pulmonary hypertension. The interventricular septal motion is paradoxical in these cases.

2D echo
The mitral valve is thickened, and often the anterior mitral
leaet measures >5 mm in thickness. The motion of the
mitral valve is restricted, producing doming and the
characteristic dog leg deformity (Fig. 5). Commissural

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FIGURE 5. Parasternal long-axis view in a patient with


mitral stenosis showing thickened mitral valve with dog
leg deformity of the anterior mitral leaet (arrow). Abbreviations as in Figure 1.

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balloon dilation. The split of commissures can be seen in


cases with successful dilation.

Doppler echo
The ow across the mitral orice is turbulent with decreased
E-F slope of the mitral inow Doppler trace. Mitral valve area
can be estimated by pressure half-time method (PHT) or
continuity method and will be described in detail later.
Echocardiography has replaced cardiac catheterization as the
gold standard for determining the severity of MS, and the
main reason now for catheterization of these patients is for
performing balloon mitral valvotomy. The Doppler trace
across the mitral valve is used to derive mean and enddiastolic gradients (Fig. 9). Color ow imaging in apical 4chamber view is very useful to identify the diastolic jet
because it may be eccentric due to subvalvular involvement
(Fig. 10). The gradients derived using color jets are more
reliable. The gradients can vary depending on the heart rate.
In atrial brillation, an average of 5 or more cardiac cycles
should be used to calculate the mean gradient. The mean
gradient may not correlate with severity of MS as it is affected
by heart rate, cardiac output, and concomitant MR.
The severity of pulmonary hypertension is estimated
by measuring the TR jet velocity using Bernoulli equation
(gradient 4  velocity2). Concomitant presence of MR
should be looked for. In all patients with MS, other valves
must be carefully examined for any involvement by RHD.
Following balloon dilation, the transmitral gradients
decrease and the severity of pulmonary hypertension reduces, indicating the procedure was successful. In case the
patient develops MR, its mechanism can be easily identied, and the patient can be managed accordingly. In those
with MR due to valve tear or chordal avulsion, urgent
surgery for repair or replacement of the mitral valve is often
required, whereas commissural MR, which is not severe,
can be closely followed conservatively.

3D echo
RT3DE provides an en face view of the complete mitral
apparatus, dening the valve morphology much better.

206

FIGURE 7. Apical 4-chamber view showing thickened


mitral leaets with restricted opening and severe subvalvular deformity (arrow). Abbreviations as in Figure 1.
Three-dimensional echo is better than 2D echo because it
identies the ideal plane where the planimetry should be
done for mitral valve area calculation. The likelihood of
obtaining good images is greater with 3D than with 2D
echo. It has been seen that the mitral valve area by 3D echo
is less than that by 2D echo, but 3D is more likely to be
correct for estimating mitral orice area for the reasons
previously mentioned [13]. RT3DE also allows excellent
assessment of commissures, both before and after balloon
valvuloplasty [14]. It also identies any complication that
may occur following balloon dilation more accurately.

Evaluation of severity of mitral stenosis


Accurate assessment of MS severity is important for decisions regarding patient management. Echo-derived mitral
valve area is used as the main criteria for dening severity.
MS is considered severe, moderate, or mild depending on
whether the mitral valve area is <1.0 cm2, 1.0 to 1.5 cm2,
or >1.5 cm2, respectively [15]. Severity based on

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FIGURE 6. Parasternal short-axis view showing severe


mitral stenosis with commissural fusion (arrows).

FIGURE 8. Parasternal short-axis view showing thrombus


in left atrial appendage (arrow) in a patient with mitral
stenosis. Abbreviations as in Figures 1 and 2.

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done properly or when the acoustic window is poor.


This method may not be feasible when the valve
anatomy is severely distorted. Addition of RT3DE has
greatly helped in determining the exact place where
planimetry should be done, and the accuracy is likely to
be maintained even when performed by less-experienced
personnel.

FIGURE 9. Maximum and mean gradients across mitral


valve as seen on Doppler signal across mitral valve in a
patient with mitral stenosis.
transmitral gradients is less useful as it depends upon heart
rate, rhythm, and cardiac output. The severity assessment
of MS should rely more on mitral valve area, as mean
gradient and pulmonary artery pressure are inuenced by
several factors. Normal resting values of pulmonary artery
pressure may be seen in some cases of severe MS. Four
methods are described for dening the mitral valve area by
echocardiography.

Planimetry Planimetry measures the anatomic orice of


the mitral valve. Planimetry should be performed in parasternal short-axis at the tips of the mitral valve leaets
(Fig. 11). The scan should slowly start from the apex
moving toward the base of the heart, and the mitral
valve area should be calculated at the narrowest orice.
The correct timing for measuring planimetry is middiastole and several measurements should be made to
minimize error. It is a very accurate method in
experienced hands, but it can be very fallacious if not

Pressure half-time method Originally described by


Hatle et al. [16], PHT is the interval in milliseconds
between the maximum early diastolic gradient and the
time point at which this gradient is halved.
Normal PHT is 30 to 60 ms; in severe MS, it is >220
ms. A good quality contour of the Doppler ow must be
obtained for accurate PHT.
The main advantage of the PHT method is the ease of
calculating mitral valve area through the simple calculation
of mitral valve area equaling 220 divided by PHT (Fig. 12).
However, this method is likely to be inaccurate in determining mitral valve area in presence of tachycardia, atrial
brillation, severe aortic regurgitation (AR), and immediate
post-balloon dilation.
Continuity equation In this method, mitral valve area is
calculated by dividing aortic stroke volume by mitral time
velocity integral. Aortic stroke volume is derived by
multiplying diameter of left ventricular outow with aortic
time velocity integral. Again, this method cannot be used in
the presence of MR or AR. In patients with atrial brillation, an average of >5 beats should be taken. Because this
method involves a number of measurements, its accuracy
and reproducibility is questionable.

Proximal isovelocity surface area method This


method is often used for assessing the severity of regurgitant lesions, but it is sometimes used for MS cases also. It
is based on the hemispherical shape of the convergence of
color mitral ow in diastole, which is seen on the atrial
aspect of the mitral valve. This method can be used in the
presence of MR also. It is time-consuming and requires
good images of the hemisphere crossing the mitral
orice. The ow convergence region must be magnied
to minimize error. Because it is technically demanding,
its use in routine practice is limited.
AORTIC REGURGITATION

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The involvement of aortic valve in RHD is less common


and is often associated with mitral valve abnormalities. AR
is far more common than aortic stenosis (AS) is, especially
in a younger population. Some degree of AS may be
associated with AR. Generally, these patients have long
asymptomatic periods, and cardiac symptoms suggest severe disease.

M-mode echo
FIGURE 10. Color Doppler across mitral valve in a patient with mitral stenosis. Abbreviations as in Figure 1.

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The aortic valve is usually thick and a trileaet. The left


ventricle is dilated; degree of dilation depends on severity

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FIGURE 11. Planimetry for calculating mitral valve area


in parasternal short-axis view in a case with severe
mitral stenosis, area being 0.55 cm2.

FIGURE 13. Parasternal short-axis view showing thick


aortic valve with 3 cusps (*) in a patient with rheumatic
aortic stenosis. Abbreviations as in Figures 1 and 2.

of AR. Echocardiography is very important in follow-up of


patients with chronic AR, as the timing of surgery is
conventionally based on these M-mode parameters. In
general, the degree of left ventricular dilation is more than
it is in MR cases. A mitral valve may show diastolic utter
of anterior mitral leaet. The left atrium tends to remain
normal sized unless there is associated mitral valve disease.
The aortic root and ascending aorta dilate in severe cases of
AR. The mitral valve may show premature closure in severe
or acute AR.

2D echo. Left ventricular volumes and ejection fraction are


calculated using Simpson or area-length methods.

2D echo
The valve leaets have variable degrees of thickening,
especially at the level of their edges (Fig. 13). Commissural
fusion is the hallmark of rheumatic etiology of AR.
Sometimes it may be difcult to discern 3 different cusps of
the aortic valve due to fusion and/or calcication. Incomplete coaptation of the aortic valve is often seen in the
short-axis view. Dilated aortic root is better appreciated by

Doppler echo
The jet of rheumatic AR is mostly central (Fig. 14). Doppler
with color ow imaging is very useful for quantifying the
severity of AR [17]. The width of the color ow jet in relation
to left ventricular outow width as measured in the parasternal long-axis view is a good indicator of AR severity
(Fig. 15). Severe AR results in two-thirds or more of color jet
width when compared with the left ventricular outow
width. Similarly, if the area of the color jet of AR is 66% or
more of the left ventricular outow tract area, the AR is severe
[17]. Measuring PHT of the aortic regurgitant jet is also useful
(Fig. 16); a value of <200 ms indicates severe AR, and a value
of >500 ms suggests mild AR. Heart rate and left ventricular
end-diastolic pressure can inuence PHT of the AR Doppler
jet. A very strong parameter for severity of AR assessment is
the degree of diastolic reversal in descending thoracic aorta,
as imaged from the suprasternal notch. Pan-diastolic reversal
of ow in descending thoracic aorta indicates moderate or
severe AR (Fig. 17). In more severe cases, the reversed diastolic ow is seen in the abdominal aorta also. Use of vena
contracta and PISA are good methods, but they are timeconsuming and, hence, are not performed routinely.

Assessing the severity of AR

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Table 1 shows the Doppler-derived parameters that can be


used to describe the severity of AR.
Transesophageal echo and RT3DE may provide better
quality images for assessing valve morphology and aortic
root dimensions. They should be considered in adult patients being planned for aortic valve surgery.

AORTIC STENOSIS
FIGURE 12. Mitral valve area calculated by pressure-half
time method in a case with mild mitral stenosis.

208

Isolated AS secondary to RHD is unusual. It is generally


associated with AR, and the mitral valve is often involved.
RHD patients with signicant AS tend to have MS also.

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FIGURE 14. Parasternal long-axis (A) and apical 3-chamber (B) views showing color jet of aortic regurgitation.
Abbreviations as in Figure 1.

Echocardiographic ndings
The aortic valve is thickened, especially at the cusp edges
and has a restricted opening. Typically there is commissural fusion resulting in a triangular systolic orice. In
older patients, the edges of the cusp may be calcied. Left
ventricle size may be normal, but it is hypertrophied, the
degree of hypertrophy depends upon the severity of AS.
Left ventricular function remains normal until the very late
stage of the disease. The left atrium tends to be normal or
minimally enlarged unless there is concomitant mitral valve
disease.
Doppler echo is very useful for obtaining peak and
mean gradients across the aortic valve. It is important to
interrogate the aortic valve from multiple echo windows,
including apical, suprasternal, high right parasternal, and
subcostal. This will ensure that the Doppler line is well

aligned to the jet giving the appropriate gradient across the


aortic valve. The peak instantaneous and mean gradients
across the aortic valve are best estimated using a dedicated
small dual crystal continuous wave transducer. This small
transducer allows optimal position and angulation especially in suprasternal and right parasternal regions. Peak
instantaneous gradient across aortic valve tends to be
higher than the peak-to-peak gradient obtained at cardiac
catheterization, and the correlation of the catheter gradient
with the echo-derived mean gradient is better. Patients who
have isolated severe AR may show ow gradients across the
aortic valve by Doppler; care must be taken in interpreting
these as being due to AS (Fig. 18). One can also derive the
aortic valve area by Doppler echocardiography using the
continuity equation; this is especially useful in patients
with left ventricular dysfunction wherein the gradients may
be reduced, even though the stenosis is severe. A valve area
of <1.0 cm2 indicates severe AS. The grading of severity of
AS derived by AS jet velocity is given in Table 2.

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TABLE 1. Doppler-derived parameters used to describe the


severity of AR

FIGURE 15. Color M-mode echo for measuring the width


of aortic regurgitant jet in relation to left ventricular
outow width.

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September 2013: 203-212

Parameter

Mild

Moderate Severe

Jet width, % of LVOT


Vena contracta, cm
Regurgitation volume, ml/beat
Regurgitation fraction, %
Effective regurgitant orice
area, cm2
AR pressure half-time
Diastolic ow reversal in DTA

<25
<0.3
<30
<30
<0.1

25e64
0.3e0.6
30e59
30e49
01e0.29

>65
>0.6
>60
>50
>0.3

>400 250e400

<250
Holo

AR, aortic regurgitation; DTA, descending thoracic aorta; Holo,


holodiastolic; LVOT, left ventricular outow tract.

209

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FIGURE 16. Pressure half-time of aortic regurgitant


Doppler jet suggestive of moderate aortic regurgitation.
TABLE 2. Grading the severity of AS derived by AS jet velocity
Echo Parameter

Mild

Moderate

Severe

Jet velocity, m/s


Mean gradient, mm Hg
Valve area, cm2

<3
<25
>1.5

3e4
25e40
1.0e1.5

>4
40
<1.0

AS, aortic stenosis.

TRICUSPID VALVE DISEASE


Tricuspid regurgitation (TR) is almost always functional,
secondary to pulmonary hypertension, and most commonly
seen in severe MS. The pulmonary artery pressure can be
estimated using TR jet velocity (Fig. 19). Organic tricuspid
valve disease secondary to RHD is always associated with
mitral valve disease and often with aortic valve abnormalities. Most of these patients are in atrial brillation.

Tricuspid stenosis

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FIGURE 17. Color M-mode echo showing pan-diastolic


reversal of ow in descending thoracic aorta suggestive of severe aortic regurgitation.

210

doming of its leaets due to restricted motion (Fig. 20).


Three-dimensional echo may have an advantage over 2D
echo as it shows the en face view of the tricuspid valve,
allowing the visualization of commissural fusion. The right
atrium is enlarged and the inferior vena cava is dilated.
Doppler echo shows turbulent ow across the tricuspid
valve. Although the valve area can be calculated using the
PHT method for mitral valve area, it has not been validated
for tricuspid stenosis (TS). It is preferable to measure mean
gradient across the valve to grade the severity of the stenosis (Fig. 21). As a general rule, the pressure gradients are
lower in TS than in MS. A mean pressure gradient of 5 mm
Hg or more suggests signicant TS. A variable degree of TR
is almost always associated with TS and may increase the
mean gradient (Fig. 22).

Tricuspid regurgitation
Organic TR secondary to RHD is rare. In these cases, some
degree of TS may be present. The echo shows a thick

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The valve is thickened with reduced E-F slope, the posterior leaet shows anterior motion. Tricuspid valve shows

FIGURE 18. Doppler signal across aortic valve showing


maximum and mean gradients of aortic stenosis in a
patient with both aortic stenosis and aortic
regurgitation.

FIGURE 19. Doppler signal of hypertensive tricuspid


regurgitation in a patient with severe mitral stenosis.
The estimated pulmonary artery systolic pressure is 105
mm Hg.

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FIGURE 20. Apical 4-chamber view from a patient with


tricuspid stenosis showing doming of the tricuspid valve
and turbulent color ow across it. Note that this patient
also has mitral stenosis. Abbreviations as in Figures 1
and 2.
tricuspid valve with restricted motion of leaets. It is
important to note that some degree of tricuspid valve
thickening is seen in functional TR also. The tricuspid
annulus, right ventricle, and right atrium are dilated, and,
in severe cases, inferior vena cava and hepatic veins are also
enlarged. Color ow mapping is used to assess the severity
of TR. Systolic ow reversal in hepatic veins is also suggestive of severe TR. In cases with elevated right atrial
pressure secondary to severe TR, normal inspiratory
collapse of inferior vena cava may be absent. The TR jet
velocity is indicative of right ventricular systolic pressure.
In organic tricuspid valve disease, the calculated right
ventricular pressure is unlikely to be high.

MULTIVALVULAR INVOLVEMENT IN RHD

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In regions with a high prevalence of RHD, it is common to


see patients in whom more than 1 valve is affected. The

FIGURE 22. Apical 4-chamber view showing tricuspid


regurgitation in a patient with rheumatic tricuspid stenosis. Abbreviations as in Figures 1 and 2.
common combinations are MR with AR and MS with AR.
Tricuspid involvement is often secondary to pulmonary
hypertension. Echocardiography is very useful for assessment of severity of individual lesions. However, it is
important to remember that proximal lesions may mask
the severity of distal lesions. For example, a patient with
severe AR may not show a dilated left ventricle if severe MS
is associated. Similarly, a patient with signicant TS may
not show features of severe MS or AR. The severity of AS
may be underestimated in the presence of severe MS. This
is especially applicable where load-dependent methods are
used to assess severity by echo Doppler.

SUMMARY
Echocardiography is a very important tool in the diagnosis
of valve lesions in chronic RHD. It not only provides the
anatomic information, but it also accurately quanties the
severity of the valve stenosis or regurgitation. Echocardiography with Doppler and color ow imaging may be able
to give more information as compared to that obtained at
cardiac catheterization. Further, the assessment of valvular
regurgitation by angiography may be affected by ectopic
beats, a common occurrence during cardiac catheterization. In patients with chronic RHD, the timing of intervention and the type of intervention is generally decided by
echocardiographic ndings in conjunction with clinical
picture. RT3DE is increasingly being used for evaluating
valves for suitability for balloon valvuloplasty as well as for
surgical valve repair.

REFERENCES
FIGURE 21. Doppler ow across tricuspid valve showing
elevated mean gradient across tricuspid valve due to
tricuspid stenosis.

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 203-212

1. Rheumatic fever and rheumatic heart disease. World Health Organ


Tech Rep Ser 2004;923:1122.
2. Carapetis JR. Rheumatic heart disease in developing countries. N Engl
J Med 2007;357:43941.

211

gREVIEW

3. Chockalingam A, Gnanavelu G, Elangovan S, Chockalingam V. Clinical


spectrum of chronic rheumatic heart disease in India. J Heart Valve
Dis 2003;12:57781.
4. Enriquez-Sarano M, Akins CW, Vahanian A. Mitral regurgitation.
Lancet 2009;373:138294.
5. Marcus RH, Sareli P, Pocock WA, et al. Functional anatomy of severe
mitral regurgitation in active rheumatic carditis. Am J Cardiol 1989;
63:57784.
6. Enriquez-Sarano M, Avierinos JF, Messika-Zeitoun D, et al. Quantitative determinants of the outcome of asymptomatic mitral regurgitation. N Engl J Med 2005;352:87583.
7. Lancellotti P, Moura L, Pierard LA, et al. European Association of
Echocardiography recommendations for the assessment of valvular
regurgitation. Part 2: mitral and tricuspid regurgitation (native valve
disease). Eur J Echocardiogr 2010;11:30732.
8. Apor A, Nagy A, Nagi A, Merkely B. The role and potential of 3D
echocardiography in the assessment of mitral regurgitation. Eur
Cardiol 2012;8:16570.
9. Yosefy C, Hung J, Chua S, et al. Direct measurement of the vena
contracta area by real-time 3-dimensional echocardiography for
assessing severity of mitral regurgitation. Am J Cardiol 2009;104:
97883.
10. Marasan NA, Westenberg JJ, Ypenburg C, et al. Quantication of
functional mitral regurgitation by real-time 3D echocardiography:

212

11.
12.

13.

14.

15.

16.

17.

comparison with 3D velocity-encoded cardiac magnetic resonance.


JACC Cardiovasc Imaging 2009;2:124552.
Roy SB, Bhatia ML, Lazaro EJ, Ramalingaswami V. Juvenile mitral
stenosis in India. Lancet 1963;2:11935.
Wilkins GT, Weyman AE, Abascal VM, Block PC, Palacios IF. Percutaneous balloon dilatation of the mitral valve: an analysis of echocardiographic variables related to outcome and the mechanism of
dilatation. Br Heart J 1988;60:299308.
Min SY, Song JM, Kim YJ, et al. Discrepancy between mitral valve
areas measured by two-dimensional planimetry and threedimensional transoesophageal echocardiography in patients with
mitral stenosis. Heart 2013;99:2538.
Schlosshan D, Aggarwal G, Mathur G, Allan R, Cranney G. Real-time
3D transoesophageal echocardiography for the evaluation of rheumatic mitral stenosis. JACC Imaging 2011;4:5808.
Baumgartner H, Hung J, Bermejo J, et al. Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. Eur J Echocardiogr 2009;10:125.
Hatle L, Angelsen B, Tromsdal A. Noninvasive assessment of atrioventricular pressure half-time by Doppler ultrasound. Circulation
1979;60:1096104.
Perry G, Helmcke F, Nanda NC, Byard C, Soto B. Evaluation of aortic
insufciency by Doppler color ow mapping. J Am Coll Cardiol 1987;
9:9529.

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gREVIEW

Priorities in Cardiac Surgery for Rheumatic Heart Disease


Kirsten Finucane, Nigel Wilson
Auckland, New Zealand
ABSTRACT
This review outlines a philosophy of surgical cardiac care for rheumatic heart disease, which has evolved over
the past 2 decades, in the young in the Oceania region. Topics covered include the optimal timing of surgery,
recommended strategies for mitral and aortic valve disease, and the importance of the team approach to these
patients. There is a global priority for more cardiac surgeons to become skilled in repair of the rheumatic
mitral valve. Surgeons operating on patients from remote regions with RHD are encouraged to audit
outcomes and help these communities develop their health services to optimize continued RHD care.

As has been highlighted in other reports in this issue of


Global Heart, 80% of the worlds countries still have rheumatic fever and its important long-term sequel, rheumatic
heart disease (RHD). Those with severe RHD that do not have
access to cardiac surgery will die. The mean age of death in
some regions of Africa is as young as 25 years [1] and for the
indigenous Aborigine population of Australia, 22 years [2].
The particular challenge for a cardiac surgeon dealing
with severe RHD is to repair as many valves as possible
rather than replace them. The populations that suffer from
rheumatic fever, and the affected families within those
ethnic populations, have the least resources, lowest levels
of education, and worst access to health care. There is good
evidence to demonstrate how poorly people in these circumstances do with mechanical valve insertion and anticoagulation [3]. Unfortunately, rheumatic disease damages
the valve leaets and subchordal apparatus, making repair
difcult in comparison to other mitral and aortic lesions.
The surgeon and the cardiology unit need a team approach
to achieve good outcomes. It is not just about what happens in the operating theater, but it also involves good
triage, timely intervention, echocardiographic detailed
assessment, outreach clinics, nursing input for family education, post-operative case audit, and more.
This review outlines some of the approaches we have
used in Starship Hospital Auckland for the New Zealand
and Pacic Island pediatric rheumatic population over the
past 2 decades to improve the outcomes of these children
and teenagers.

EVIDENCE FOR THE SURVIVAL VALUE OF MITRAL


VALVE REPAIR
Antunes [4] in 1990 in South Africa was among the rst to
publish the dangers of using mechanical or bioprosthetic
valves in the mitral position in the rheumatic population, both
adult and pediatric. This included both mortality rate per
patient-year and the mortality rate of reoperation (Table 1) [4].
In 1999, a similar message was reported from New
Zealand in a study of women of child-bearing age requiring

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 213-220

valve surgery, the commonest indication being rheumatic.


The outcome for those who had mechanical valve replacements was signicantly worse than those with repairs
or bioprostheses, many of which were aortic homografts
(Fig. 1) [5]. Pacic Islanders and the indigenous Maori
women with mechanical valves had over 6 to 8 times
higher mortality than other ethnic groups did (Table 2).
Our unit has recently reported a survival advantage
following mitral valve (MV) repair compared with mitral
valve replacement (MVR) for the young with RHD [6]. This
retrospective study of 81 patients showed that from the time
of patient discharge, the long-term durability of mitral repair
was equal to that of MVR. Despite the need for early reoperation in 11% who underwent repair, freedom from reoperation was equal in the 2 groups for the duration of the
follow-up. Analysis of those with MVR reveals that 50% of
the patients with MVR had a signicant hemorrhagic,
thrombotic, or embolic event within 11 years, and rates of
endocarditis were also high. There was 100% freedom from
embolic, thrombotic, or hemorrhagic events in those with
MV repairs in this and other studies in the young [7e10].
For adults, despite the absence of a randomized
comparison between the results of valve replacement and
repair, it is widely accepted that valve repair is the optimal
surgical treatment in patients with severe mitral regurgitation (MR) [11e13]. Compared with valve replacement,
MV repair has a lower perioperative mortality, better
preservation of post-operative left ventricular function,
improved survival, and lower long-term morbidity [13]. In
adults who are in sinus rhythm, repair avoids the need for
anticoagulation and risks of thromboembolism with prosthetic valves, makes pregnancy safe, allows for continued
participation in contact sports such as rugby, and avoids
the sudden deterioration that can occur with bioprosthetic
valves in the mitral position.
These data challenge the assumption that if there is
funding for 1 operation only, it is best to replace a valve
rather than repair it. This needs to be conrmed with more
studies specically in these populations that are vulnerable
to medication shortages, lack of monitoring, endocarditis,

N. Wilson receives salary


support from CureKidz,
New Zealand.
From Green Lane Paediatric and Congenital
Cardiology Services,
Starship Hospital, Auckland, New Zealand. Correspondence: K. Finucane
(KirstenF@adhb.govt.nz).
GLOBAL HEART
2013 Published by
Elsevier Ltd. on behalf of
World Heart Federation
(Geneva).
VOL. 8, NO. 3, 2013
ISSN 2211-8160/$36.00.
http://dx.doi.org/10.1016/
j.gheart.2013.08.010

213

gREVIEW

TABLE 1. Incidence of late mortality


Valve-Related %/
Total %/
Patient-Year
Ratio* %
Patient-Year
Bioprosthetic
MVR
Mechanical
MVR
Mitral valve
repair

7.4

4.2

56.8

5.7

2.5

43.1

2.6

1.0

38.5

MVR, mitral valve replacement.


*Valve-related/total.
Adapted, with permission, Antunes [4].

and medically unsupervised pregnancies, usually in early


adulthood. Following cardiac surgery, the challenge is to
achieve good follow-up by optimizing outreach clinics,
rheumatic fever registries, and nursing networks and
linking with the local staff who deliver secondary
prophylaxis.

MITRAL VALVE REGURGITATION


Indications for cardiac surgery
There are many published guidelines addressing indications for cardiac surgery for adult patients [11,13,14]
that are largely based on symptoms and echocardiographic assessment of left ventricular size and function
(Table 3). Cardiologists, physicians, and pediatricians
should use these guidelines to refer RHD cases in a timely

TABLE 2. Relative risk of death in women with bioprosthetic or


mechanical valves
RR (95% CI)
Mechanical valve
Age at valve replacement, yrs
Number of concurrent valves
Years of operation
Maori
Pacic Islander
Pregnancy
Valve site*

2.17
1.00
0.86
1.04
8.45
6.54
0.38
0.50

(0.78e5.88)
(1.00e1.01)
(0.39e1.92)
(0.93e1.16)
(1.82e39.3)
(1.16e36.7)
(0.17e0.84)
(0.11e2.39)

*Aortic or tricuspid versus mitral.


Adapted, with permission, from North et al. [5].

fashion for surgery whether or not the patient is in a highincome or low-income country setting. Patients with
chronic RHD who develop cardiac failure and impaired
ventricular function may be too late for effective cardiac
surgery due to failure of the myocardium to recover normal
function. Physicians working in remote settings historically
refer the sickest patients, but it may be appropriate for the
cardiac unit to decline such patients when ventricular
function is irrevocably impaired. A decision to not offer
surgery may be more humane after assessment in the local
setting rather than after the patient has traveled to an
overseas cardiac unit.

MITRAL VALVE REPAIR


This complex topic is beyond the scope of this review, but
we have included several tables and gures outlining the
TABLE 3. Class I indications for mitral valve surgery in adults
1

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FIGURE 1. Long-term survival of women according to


type of valve replacement. Among 232 women, 35 had
>1 valve state included. Test of difference in survival
between 3 valve types: p 0.002. Test of difference
between mechanical and bioprosthetic valve types: p
0.04. B, bioprosthetic; H, homograft; and M, mechanical.
Adapted, with permission, from North et al. [5].

214

MV surgery is recommended for the symptomatic


patient with acute severe MR. (Level of Evidence: B)
MV surgery is benecial for patients with chronic
severe MR and NYHA functional class II, III, or IV
symptoms in the absence of severe LV dysfunction
(severe LV dysfunction is dened as ejection
fraction <0.30) and/or end-systolic dimension >55
mm. (Level of Evidence: B)
MV surgery is benecial for asymptomatic patients with
chronic severe MR and mild to moderate LV
dysfunction, ejection fraction 0.30 to 0.60, and/or
end-systolic dimension 40 mm. (Level of
Evidence: B)
MV repair is recommended over MV replacement in the
majority of patients with severe chronic MR who
require surgery, and patients should be referred to
surgical centers experienced in MV repair. (Level of
Evidence: C)

LV, left ventricular; MR, mitral regurgitation; MV, mitral valve; NYHA,
New York Heart Association.

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TABLE 5. Mitral repair: surgical tactics


Shorten primary chordae of anterior leaet (different
degrees according to echocardiogram)
Peel thickened layers off posterior leaet
Resect small triangle from posterior leaet (tends to be
redundant when annuloplasty is done)
Divide or extend posterior chordae that are retracting
leaetusually intermediate, not primary
Insert complete annuloplasty ring to restore oval shape
Close scallops in anterior or posterior leaets to correct
localized areas of prolapse
Add Gore-Tex chords, translocate chords, use partial rings in
young children (not so durable)

and decisions are based on many factors beyond the degree


of residual regurgitation and stenosis: the age of the patient; the expected lifestyle of the patient, including plan
for pregnancy; the realistic chance of good anticoagulation
control; and the surgeons knowledge as to whether there is
any further improvement that can be made. Mild-moderate
valve regurgitation is often moderate by the time the patient is discharged. We use the left atrial pressure, measure
the valve gradient and detail the anatomy of the residual
valve regurgitation by transesophageal echocardiography.
Technical considerations include: Are the chords overcorrected? Does the annuloplasty ring need downsizing? Is
there still localized leaet prolapse? The nal decision
whether to revise the repair, accept it, or replace the valve
is made jointly by the surgeons and cardiologists.
Analysis of our own data has demonstrated some patient features that are risk factors for failure of mitral repair.
Valves with mixed mitral stenosis and regurgitation (Fig. 3)
or calcied valves in the older adult may also be difcult to

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important pathologic features and the repair techniques in


current use (Tables 4 and 5, Fig. 2). Cardiac surgeons in
different countries describe variable patterns of rheumatic
involvement in their patients, and each surgeon needs to
adapt techniques for these regional variations of RHD. The
more cases seen, the more obvious these patterns become
and the more practiced the surgeon can become. It is
sensible, at least at rst, for a surgeon at each unit to
achieve expertise before training another, given the technical difculty of achieving good durable repairs.
A successful repair strategy starts with an understanding of the patients status: acute or chronic; degree of
dilation of the left ventricle; body-mass index; and
involvement of valves other than mitral. Following that, the
echocardiograph needs to be reviewed with the cardiologist
and it would be even better if this were repeated by a
transesophageal study as the operation starts. The hallmark
of the competent heart surgeon is the aim to repair rheumatic MV and to create repairs with good durability.
The echocardiographic detail of the site and severity of
excessive leaet motion (prolapse), valve deciency,
chordal thickening, and retraction is better than the information gained by direct inspection. Detailed echocardiography demonstrated by the cardiologist enables the
strategy of repair to be planned in detail before the operation starts and saves cross-clamp time.
Each segment of anterior and posterior leaet should
be analyzed for prolapse and retraction, with an estimate of
the misalignment of the leaets (slight, moderate, severe).
This allows the surgeon to plan how much to shorten cords
by allowing for the fact that the annuloplasty will tend to
aggravate the prolapse of the anterior leaet particularly, so
mild prolapse cannot be ignored. The pre-operative echo
gives a better assessment of the valve mechanics than direct
inspection does, so little time needs to be wasted on
examining the valve once the cross clamp is on.
Replacement is a faster, easier job than repair, and
there can be pressure placed on the surgeon to give up if
the rest of the operative team has not been prepared for the
longer cross-clamp time that repair entails. Surgeons
should make sure these cases are scheduled with time
available, including the potential for a second bypass run if
the rst echo off bypass shows that the valve needs more
work. In our series, a long cross-clamp time is not a risk
factor for mortality or prolonged intensive care stay.
Transesophageal echocardiography at the end of the
procedure is used to decide whether the repair is adequate,

TABLE 4. Rheumatic mitral valve pathology


Softening of chordae, elongation, rupture
Prolapse of part or all of 1 or both leaets (often opposite)
Dilation of annulus, loses oval shape
Leaet thickening and brosis causing restriction of motion
Long-term evolution toward stenosis in adulthood,
independent of penicillin

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September 2013: 213-220

FIGURE 2. Chordal shortening technique using pledgeted 4-0 ti-cron mattress suture. The degree of shortening is honed by adjusting the distance from start of
suture to the base of the chord.

215

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repair. Repair can look acceptable on the operating table,


but patients may return early with severe mitral stenosis.
Kaplan-Meier survival curves and reoperation curves are
shown for a personal series of 135 mitral rheumatic operations from 1996 to 2010, and they show that repair can
be achieved in 90% of rst-comers (Figs. 4 and 5).
Multivariate analysis from our units published retrospective series showed that a left ventricular end-systolic
dimension of Z-score greater than 5 was the most important determinant for mortality [6]. The hazard for the
myocardium not to recover appears especially high for
those with combined mitral and aortic disease [15]. The
clinical implication of this data is that referring physicians
in remote regions need to refer early, rather than when the
children are severely symptomatic, often with very dilated
left ventricles. We have experience of children referred
with massively enlarged left ventricles, and surgery will not
improve their life expectancy.
The probability of a durable valve repair is of crucial
importance. Until recently, durability of adult rheumatic
mitral repairs were not as good as nonrheumatic mitral
repairs [16], but there are several contemporary series from
experienced repair centers with high mitral repair rates and
low operative mortality [8,17e22].

ALTERNATIVES TO MITRAL REPAIR MITRAL


VALVE REPLACEMENT
As a junior surgeon, I once replaced a mitral bioprosthesis
in a 12-year-old in whom it had been inserted only 2 years
before. Figure 6 demonstrates how quickly it had calcied
in this Polynesian boy. This case illustrates how mitral
bioprostheses in the young are hazardous with frequent
life-threatening early failures [4,6]. Their only place is in
carefully supervised women intending to have pregnancies
within the next few years to avoid a mechanical valve with
warfarin.

216

FIGURE 4. MV repair versus MV replacement survival.


For MV repair:

For MV replacement:

By 4 years, survival is 95%.

By 4 years, survival is 100%.

By 8 years, survival is 90%.

By 8 years, survival is 76%.

By 12 years, survival is 90%.

By 12 years, survival is 38%.

MV, mitral valve.

A better alternative for the unrepairable mitral is the


On-X mechanical valve (On-X Life Technologies, Austin,

print & web 4C=FPO

FIGURE 3. Three-dimensional transesophageal echocardiographic appearance of a severely thickened, immobile rheumatic mitral valve (sh-mouth appearance)
with mixed stenosis and regurgitation.

print & web 4C=FPO

print & web 4C=FPO

FIGURE 5. MV repair versus MV replacement freedom


from reoperation.
For MV repair:

For MV replacement:

By 4 years, probability is
84%.

By 4 years, probability is 91%.

By 8 years, probability is
80%.

By 8 years, probability is 57%.

By 12 years, probability is
61%.

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September 2013: 213-220

gREVIEW

valve and is more efcacious than balloon mitral valvuloplasty when there is signicant calcication of the valve or
there is mixed mitral stenosis and regurgitation.

print & web 4C=FPO

AORTIC VALVE SURGERY

FIGURE 6. Calcied mitral bioprosthesis (porcine stented


valve) inserted 24 months prior to removal.
Texas), a new-generation bileaet prosthetic valve with
design features that, compared with other mechanical
valves, help reduce the risk of thrombosis. After an initial
promising study from South Africa in patients who failed
to take adequate warfarin [3], there is now increasing evidence of freedom from embolic or thrombotic events,
including a U.S. Food and Drug Administrationeapproved
study of large numbers of patients in the United States
(PROACT [Prospective Randomized On-X Anticoagulation
Clinical Trial]; U.S. registration NCT00291525) [23].
Although these are mostly nonrheumatic patients, the
study conrms that in carefully audited populations,
bleeding is closely linked to warfarin target levels of international normalized ratio. We need to study dose
warfarin regimens in mitral patients to reduce the bleeding
complication rates without increasing thrombotic valve
complications.
We have a dedicated international normalized ratio
program in our unit using nurse practitioners to manage
warfarin in the community [24]. Surgeons inserting these
valves have a responsibility to advocate for optimized
systems for management of anticoagulation that will ensure
patient safety. Otherwise, it is conceivable that a mechanical valve operation will shorten, not lengthen the life of
some of these children and teenagers.

MITRAL STENOSIS
The treatment of choice of pure mitral stenosis is balloon
mitral valvuloplasty [11,13,14], which usually is as effective as surgery and the hospital stay is short. However, in
some regions of the world, closed surgical mitral valvotomy may be less expensive than transferring to a country
with a cardiac catheterization laboratory. Open surgical
mitral valvuloplasty allows surgical debridement of the

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September 2013: 213-220

Pathologic features and repair tactics for aortic rheumatic


disease are shown in Tables 6 and 7.
Rheumatic aortic regurgitation is common in our
mitral cohort, but it is often only mild and therefore left
alone. When there is moderate aortic regurgitation in
conjunction with severe MR, echocardiographic analyses
may show single leaet prolapse, which is amenable to
repair. Single leaet prolapse produces an eccentrically
directed jet on echo and can be corrected by shortening the
free edge of the affected leaet and slightly reducing the
annulus using subcommisural annuloplasty sutures.
However, if the aortic jet is directly back through the left
ventricular outow tract and all leaets are at equal level,
then the mechanism is pure leaet retraction and repair is
more difcult unless leaet tissue is added. Our unit has
not had a policy of adding tissue, as we have excellent
results from homograft aortic valve insertion [25] and
prefer to use that if the valve regurgitation is signicant
enough to warrant it (moderate to severe or severe aortic
regurgitation). The homografts provide 8 to 12 years of
anticoagulant-free childhood and seem to allow some
annular growth so that a reasonable-sized mechanical valve
can then be inserted in adulthood.
Alternatively, the On-X aortic valve is proving a durable alternative, with the promise of potentially avoiding
warfarin in patients with good left ventricular function and
normal rhythm. A current On-X trial. PROACT, aims to
show that aspirin and clopidogrel are as safe as warfarin.
We have been wary of using the Ross procedure in rheumatic patients given the degree of aortic annular dilation
present and the difculty of detecting whether the pulmonary has been damaged by the disease process [26].

OPTIMIZING PRE-OPERATIVE CARDIAC CARE


In our unit, we spend a lot of time discussing individual
cases to optimize the timing of their operations. Acute
patients are admitted and settled with diuretics and urgent
operations are rare: only indicated if the patient is in
TABLE 6. Pathologyaortic
Dilation of annulus
Softening of leaets, lose elasticity
Cup shape becomes like a saucer
Free edge becomes longer than attached edge, so prolapse
occurs
Free edge retracts/rolls back leaving a triangle-shaped
decit centrally
Leaets thicken, develop parallel ridges or folds
Dilation of annulus

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TABLE 7. Aortic repair tactics


Subcommisural annuloplasty sutures
Shortening of free edge of prolapsing leaetresect or
plicate
Reduce size of noncoronary sinus
Peel brous layers or ridges off very thick areas of leaet
allows leaet to extend
Extend 1 or more leaets with autologous or animal tissue
Check opening is adequate with calibrator
Subcommisural annuloplasty sutures

pulmonary edema; does not settle with intravenous diuretics; and requires mechanical ventilation. Occasionally
they present as acute pneumonia and on a ventilator, when
the ail leaet and severe MR is diagnosed on echo [27]. If
this is the childs rst episode of acute rheumatic fever, the
noncompliant left atrium cannot dilate and pulmonary
venous hypertension causes pulmonary edema, which
sometimes has a remarkably unilateral appearance on the
chest radiograph and is often misdiagnosed as pneumonia.
Mitral repair is achievable in most of these acute cases.
Left ventricular dimensions are followed closely as well
as the erythrocyte sedimentation rate, because some patients have such torrential MR, or mitral and aortic
regurgitation, that the dimensions steadily increase to a
level that requires early intervention. Data following up
some of our combined valve disease patients suggest that
the left ventricular dimensions do not return to the normal
range at 6 to 12 months after surgery in those with severe
pre-operative dilation [15].
Early surgery raises concerns: 1) that overall complication rates will be higher due to the presence of systemic
inammation; and 2) that the durability of repair will be
affected due to the softness of the tissues that are being
sutured. The technique of repair needs to be adjusted to
allow for this softening and to allow for the remodeling
process as the disease settles, which may shrink leaets and
shorten chordae. There is a balance between the need to
protect the ventricle and the need for stronger tissues on
which to operate. We often compromise and operate at 2
or 3 months into the course of the illness when the Creactive protein has normalized and the ESR is settling.

DELIVERY OF CARE
There is a single pediatric cardiothoracic unit in New
Zealand, with its population of 4.5 million, delivering pediatric and congenital cardiac care throughout the country.
We perform around 350 bypasses per year with a mortality
rate of 1.5% to 2.5% for the last decade. The service is
publicly funded and free to New Zealand citizens. We
accept children from Pacic Island countries of our region
for assessment and operation who are able to get funding
from a variety of charitable sources, but we are careful to
triage these children so that costs of care do not exhaust the

218

funds. Up to 50% of our rheumatic patients operated on


each year are from overseas.
All members of our cardiology team are involved in
outreach clinics, both around New Zealand and in many of
the Pacic nations. The number of clinics has increased
steadily, and these visits have also allowed links to develop
between local doctors and our service. In the 2 decades since
these links began, the triage of patients and their management in the community has improved markedly. In recent
years, a 3-year follow-up project in New Zealand and the
Pacic Island countries has allowed us to track patients after
surgery and collect data on their survival and outcomes [6].
This valuable feedback then assists us in future decision
making so that operations can be tailored to the population
we are serving.
One of our concerns is the increasing number of teams
visiting third-world countries to perform operations for a
short period and then leaving. In many countries, these
visits provide the only chance of surgery for children. They
also provide valuable experience for those performing the
operations and are a great team-building exercise. Some
simpler congenital repairs are suitable for that situation,
and we know the patients are likely to do well even if there
is no further medical follow-up. However, the difculty of
achieving a rheumatic valve repair in the type of theater set
up for such a visit leads many surgeons to perform mechanical valve replacements. Unless there is an adequate
health structure developed and supported for those patients, they may not do well. It is the responsibility of the
operating surgeon and team to audit the outcomes of this
type of surgery rather than assuming the outcomes will be
similar to those in a rst-world situation. In our opinion,
most rheumatic valve repair surgery is complex and requires machinery and skills not easily set up for a week in a
third-world country.
The most worthwhile effort, particularly in the poorest
countries, is probably not in replacing valves in sick children but in the less glamorous development of rheumatic
disease registries, penicillin delivery, and cardiac care
clinics with links to more-developed services. This is
harder to sell to charities raising money, but surgeons
involved in overseas visits or operating on these patients
also advocate for continued development of medical cardiac programs for RHD and prevention in those countries
they support. Some small countries may never have their
own surgical pediatric cardiac service, but the local doctors
and nurses can be educated and supported over a number
of years to a level that will vastly improve the long-term
outcomes for those with RHD.

SUMMARY
The main global priority for rheumatic heart surgery is to
increase the number of surgeons able to perform durable
repairs on mitral and aortic valves and to resort less often to
the easier option of replacement. This can only be achieved
by a multifactorial approach that includes careful workup of

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TABLE 8. Gems or golden rules: Rheumatic heart surgery


1.

2.
3.

4.

5.

6.

7.

8.

Rheumatic patients are at high risk for complications


of anticoagulation. Mitral repair, even with some
residual MS or MR, has a signicant survival
advantage over replacement.
Mitral bioprostheses may calcify very rapidly
(and silently) in children and young adults.
Mitral repair is difcult and demands time and
dedication, so concentrate the experience into the
hands of 1 surgeon if possible.
Exact echocardiogram details of each segment of a
valve allows accurate planning for the operation
and saves surgical time.
Using a complete mitral annuloplasty ring restores the
oval shape and makes the most of the leaet area
available.
Achieving a durable repair in a valve during an acute
episode of rheumatic fever is difcult. If possible,
an operation is best avoided until the ESR settles.
Encourage local pediatricians and hospital
cardiologists to communicate closely to optimize
timing of operation. Survival and repair durability
are best if surgery is not left until the left ventricle
is grossly dilated.
Get involved in obtaining follow-up data, especially on
patients from other countries, to learn what works
and what is needed for the setting to which the
patient will return.

3.
4.

5.

6.

7.

8.

9.
10.

11.

12.

ESR, erythrocyte sedimentation rate; MR, mitral regurgitation; MS,


mitral stenosis.

13.

patients, high-quality echocardiography, referral to a unit


with a dedicated surgeon experienced in rheumatic repair,
time allowed by the operative team, and development of the
service in the local community to continue optimal medical
care. Above all, RHD is an area that requires very good
communication between the surgeon and the cardiologist,
sometimes under stressful circumstances (leaky repair!), but
with a great sense of achievement for the patient when a
damaged valve is salvaged.
Our Units golden rules for rheumatic heart surgery are
listed in Tables 8.

14.

ACKNOWLEDGMENT
The authors would like to thank Charlene Nell, desktop
support administrator, for preparing the manuscript and
for excellent secretarial assistance.
REFERENCES
1. Remenyi B, Carapetis J, Wyber R, Tauber K, Mayosi BM. Position
statement of the World Heart Federation on the prevention and
control of rheumatic heart disease. Nat Rev Cardiol 2013;10:28492.
2. Lawrence JG, Carapetis JR, Grifths K, Edwards K, Condon JR. Acute
rheumatic fever and rheumatic heart disease: incidence and

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 213-220

15.

16.

17.

18.

19.

20.

21.

progression in the northern territory of Australia, 1997 to 2010.


Circulation 2013;128:492501.
Williams MA, van Riet S. The On-X heart valve: mid-term results in a
poorly anticoagulated population. J Heart Valve Dis 2006;15:806.
Antunes MJ. Mitral valvuloplasty, a better alternative: comparative
study between valve reconstruction and replacement for rheumatic
mitral valve disease. Eur J Cardiothorac Surg 1990;4:25762. discussion 63e4.
North RA, Sadler L, Stewart AW, McCowan LM, Kerr AR, White HD.
Long-term survival and valve-related complications in young women
with cardiac valve replacements. Circulation 1999;99:266976.
Remenyi B, Webb R, Gentles T, et al. Improved long-term survival for
rheumatic mitral valve repair compared to replacement in the young.
World J Pediatr Congenit Heart Surg 2013;4:15564.
Gometza B, al-Halees Z, Shahid M, Hatle LK, Duran CM. Surgery for
rheumatic mitral regurgitation in patients below twenty years of age:
an analysis of failures. J Heart Valve Dis 1996;5:294301.
Kalangos A, Christenson JT, Beghetti M, Cikirikcioglu M, Kamentsidis D,
Aggoun Y. Mitral valve repair for rheumatic valve disease in children:
midterm results and impact of the use of a biodegradable mitral ring.
Ann Thorac Surg 2008;86:1618. discussion 8e9.
Pomerantzeff PM, Brando CM, Faber CM, et al. Mitral valve repair in
rheumatic patients. Heart Surg Forum 2000;3:2736.
Rocha e Silva A, Herdy GV, Vieira AA, Simes LC. Surgical mitral valve
repair in children with rheumatic fever. Arq Bras Cardiol 2009;92:
4004. 417e21, 433e8.
Bonow RO, Carabello BA, Chatterjee K, et al. 2008 focused update
incorporated into the ACC/AHA 2006 guidelines for the management
of patients with valvular heart disease: a report of the American
College of Cardiology/American Heart Association Task Force on
Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease).
Circulation 2008;118:e523661.
Manji RA, Menkis AH, Ekser B, Cooper DK. Porcine bioprosthetic
heart valves: the next generation. Am Heart J 2012;164:17785.
Vahanian A, Aleri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012): the Joint Task Force on
the Management of Valvular Heart Disease of the European Society
of Cardiology (ESC) and the European Association for Cardio-Thoracic
Surgery (EACTS). Eur J Cardiothorac Surg 2012;42:S144.
Walsh W, Brown A, Carapetis J, RF/RHD Guideline Development
Working Group, National Heart Foundation of Australia, Cardiac Society of Australia and New Zealand. The diagnosis and management
of chronic rheumatic heart diseasean Australian guideline. Heart
Lung Circ 2008;17:27189.
Gentles TL, Colan SD, Wilson NJ, Biosa R, Neutze JM. Left ventricular
mechanics during and after acute rheumatic fever: contractile
dysfunction is closely related to valve regurgitation. J Am Coll Cardiol
2001;37:2017.
David TE, Ivanov J, Armstrong S, Christie D, Rakowski H. A comparison
of outcomes of mitral valve repair for degenerative disease with
posterior, anterior, and bileaet prolapse. J Thorac Cardiovasc Surg
2005;130:12429.
The Society of Thoracic Surgeons. Adult Cardiac Surgery Database:
Executive Summary 10 Years STS Report. Durham, NC: Duke Clinical
Institute, Duke Medical Center; 2010.
The European Association for Cardio-Thoracic Surgery. Fourth EACTS
Adult Cardiac Surgical Database Report 2010. Henley-on-Thames, UK:
European Association for Cardio-Thoracic Surgery; 2010.
Gummert JF, Funkat A, Beckmann A, et al. Cardiac surgery in Germany during 2009: a report on behalf of the German Society for
Thoracic and Cardiovascular Surgery. Thorac Cardiovasc Surg 2010;58:
37986.
Gammie JS, Sheng S, Grifth BP, et al. Trends in mitral valve surgery in
the United States: results from the Society of Thoracic Surgeons
Adult Cardiac Surgery Database. Ann Thorac Surg 2009;87:14317.
discussion 7e9.
Gammie JS, OBrien SM, Grifth BP, Ferguson TB, Peterson ED. Inuence of hospital procedural volume on care process and mortality

219

gREVIEW

for patients undergoing elective surgery for mitral regurgitation.


Circulation 2007;115:8817.
22. Bridgewater B, Keogh B, Kinsman R, et al. The Society for Cardiothoracic Surgery in Great Britain and& Ireland: 6th National Adult
Cardiac Surgical Database Report; Demonstrating Quality, 2008.
Henley-on-Thames, UK: Dendrite Clinical Systems Ltd.; 2009.
23. Chambers JB, Pomar JL, Mestres CA, Palatianos GM. Clinical event rates
with the On-X bileaet mechanical heart valve: a multicenter experience
with follow-up to 12 years. J Thorac Cardiovasc Surg 2013;145:4204.
24. Soper J, Chan GT, Skinner JR, Spinetto HD, Gentles TL. Management
of oral anticoagulation in a population of children with cardiac

220

disease using a computerised system to support decision-making.


Cardiol Young 2006;16:25660.
25. Barratt-Boyes BG. Aortic allograft valve implantation: freehand or root replacement? J Card Surg 1994;9(Suppl 2):
1967.
26. Kumar N, Gallo R, Gometza B, al-Halees Z, Duran CM. Pulmonary
autograft for aortic valve replacement in rheumatic diseasean ideal
solution? J Heart Valve Dis 1994;3:3847.
27. Anderson Y, Wilson N, Nicholson R, Finucane K. Fulminant mitral
regurgitation due to ruptured chordae tendinae in acute rheumatic
fever. J Paediatr Child Health 2008;44:1347.

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gREVIEW

Primary Prevention for Rheumatic Fever


Progress, Obstacles, and Opportunities
Liesl J. Zhlke*, Ganesan Karthikeyany
Cape Town, South Africa; and New Delhi, India
ABSTRACT
Acute rheumatic fever and rheumatic heart disease are noninfectious sequelae of group A streptococcal pharyngeal
infection. These diseases represent a huge public health burden in developing countries with signicant mortality
and morbidity. Early diagnosis and appropriate antibiotic treatment with group A streptococcal pharyngitis
provides an opportunity for prevention of acute rheumatic fever and rheumatic heart disease. The use of locally
adapted clinical algorithms for diagnosing group A streptococcal pharyngitis has great potential in resource-poor
settings for earlier diagnosis and early treatment. Intramuscular penicillin is the drug of choice in developing
country settings. Recent work has demonstrated the cost-effectiveness of a treat-all strategy with intramuscular
penicillin, whereas incorporating a clinical decision rule remains the preferred strategy. We strongly support the
adoption of a comprehensive prevention and control program for acute rheumatic fever and rheumatic heart
disease, incorporating primary prevention, as critical to underpinning the efforts in many parts of the world to
stem the tide of this devastating disease.
Acute rheumatic fever (ARF) and rheumatic heart disease
(RHD) continue to kill children, adolescents, and young
adults living in poverty. Yet, a cheap and effective preventative
agent to these sequelae of group A streptococcal (GAS)
infection has existed for decades in the form of penicillin.
Despite strong evidence of penicillins efcacy in primary
prevention of ARF, debate still rages on regarding the appropriate role for primary prevention within RHD prevention and
control strategies. Some of the arguments against the incorporation of primary prevention into RF/RHD control strategies are based on the expense and logistics of delivery, but as
has been discussed elsewhere [1], these need not be limiting
factors. Conversely, a recent publication has demonstrated the
cost-effectiveness of such a strategy [2]. More importantly,
these arguments serve, unwittingly, to undermine the role of
primary prevention in the control of RHD.

BURDEN OF DISEASE
Group A streptococcal disease
GAS has been studied for decades and is a well-known
pathogen. It is responsible for over 600 million infections
annually, ranging from self-limiting pharyngitis to invasive
and life-threatening toxic shock syndrome and necrotizing
fasciitis [3]. The global burden of severe GAS infections has
been estimated to be as high as 18.1 million cases with
1.78 million new cases a year and over 500,000 deaths
each year [4]. This predominantly occurs in developing
countries and poor subpopulations within middle- and
high-income countries (such as the indigenous populations
of Australia and New Zealand). Although long ignored as a
disease of the developing world, the recent resurgence of
invasive disease in developed countries [5], coupled with

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 221-226

evidence of hypervirulent strains has resulted in increased


academic interest and activities relating to vaccine development. This has also highlighted the many unknowns
relating to this organism, especially in terms of pathogenicity, distribution of isolates, and virulence factors.

Acute rheumatic fever and rheumatic heart


disease
ARF is the systemic noninfectious sequel to the often selflimiting pharyngitis caused by rheumatogenic strains of
GAS. The only permanent and devastating sequel to ARF is
RHD, for which no proven treatment exists to alter the
natural history of the disease. ARF has shown a dramatic
decrease in incidence in developed countries, with
increasing standards of living and access to health care being
the major determinants of this change [6]. In developing
countries, this pattern is following a similar though markedly
attenuated trend. A systematic review [7] of studies reporting
incidence of ARF conducted in 2008 still demonstrated a
high incidence (>10 per 100,000) in poorer regions of
Eastern Europe, Middle East (highest), Asia, and Australasia,
while no data could be included for Africa. A more recent
review was able to include data from Sub-Saharan Africa and
recorded the highest incidence in the Western Pacic and
Asia [8]. Mortality due to ARF relates strongly to differences
in health care with higher case fatality rates in developing as
opposed to developed countries.
In contrast, the prevalence of RHD appears to be
increasing. Seckeler et al. [8] were able to show this trend
through almost all the World Health Organization regions
of the world except for Europe. Given the decreasing
incidence of ARF, this is most likely due to advances in

L. Zhlke is funded by the


Thrasher Foundation, Clinical Infectious Disease
Research Initiative, and the
Hamilton Naki Clinical
Scholarship Programme,
which is funded by Netcare
Limited.
This manuscript is based in
part upon a presentation
given at the Postgraduate
Course on Rheumatic Heart
Disease Challenges and
Opportunities at the Seventh Global Forum on Humanitarian Medicine in
Cardiology and Cardiac
Surgery, June 20e22, 2011,
Geneva, Switzerland.
From the *University of
Cape Town and Red Cross
War Memorial Childrens
Hospital, Cape Town, South
Africa; yDepartment of
Cardiology, All India Institute of Medical sciences,
New Delhi, India. Correspondence: L. Zhlke. (liesl.
zuhlke@uct.ac.za).
GLOBAL HEART
2013 Published by
Elsevier Ltd. on behalf of
World Heart Federation
(Geneva).
VOL. 8, NO. 3, 2013
ISSN 2211-8160/$36.00.
http://dx.doi.org/10.1016/
j.gheart.2013.08.005

221

gREVIEW

medical and surgical treatments for RHD and the resultant


increased survival. Most importantly, the diagnosis of RHD
has also become more rigorous with the use of echocardiography. The increased sensitivity of echocardiography
has resulted in rates that are 10-fold that of RHD diagnosed
by auscultation alone [9]. Vital registration data have
determined that mortality rates from RHD follow the same
pattern as that for ARF: highest in developing countries,
although high-quality mortality data are lacking from SubSaharan Africa [10]. The highest case fatality rate for RHD
was recorded in Pakistan at 3.7 per 100,000 [10]. Clearly,
it is irrefutable that the highest burden of disease for both
ARF and RHD lies in developing countries with concomitant high mortality rates. What is also clear is that in the
absence of a cure for RHD, and being cognizant of the
limited health resources of developing countries, our focus
should turn toward effective prevention.

RATIONALE FOR PRIMARY PREVENTION


Pharyngitis is a common childhood illness with up to 26%
of these infections being caused by GAS [11]. ARF is
thought to occur in 0.3% to 3% of individuals infected
with GAS as an autoimmune response to the initial infection. Controversy remains regarding the role of GAS infections other than pharyngitis [12]. There is anecdotal
evidence for the potential role of skin infections, particularly in the Australian Aboriginal population, yet this remains circumstantial and as yet unproven in other
populations [13e15]. What is clear is that GAS infection is
causally related to the development of ARF, as is evidenced
by outbreaks of GAS pharyngitis followed by outbreaks of
ARF and the increased antistreptococcal antibodies found
in patients with ARF [16]. Primary prevention strategies
focus on the early diagnosis and timely treatment of GAS
pharyngitis with antibiotics to prevent the autoimmune
consequences resulting from the infection in susceptible
individuals. It is thought that antibiotic therapy initiated
within 9 days of onset of pharyngitis is effective in preventing ARF [17].

EVIDENCE FOR PRIMARY PREVENTION


The value of primary prevention has been known as early
as the 1950s when randomized control trials demonstrated
that ARF could be prevented by treating GAS pharyngitis
with penicillin. Research conducted among army personnel
demonstrated proof of effectiveness of primary antibiotic
prophylaxis as a strategy for high-risk populations [18].
This was followed by successful programs such as the
Baltimore-based program that demonstrated a 50-fold drop
in ARF incidence 15 years after instituting a comprehensive
prevention program focusing on the diagnosis and treatment of streptococcal sore throats in inner-city children
[19]. A report from the House of the Good Samaritan,
Boston, noted that although mortality due to rheumatic
carditis had been steadily declining in the United States
since about 1921, a 4-fold acceleration of the decline

222

occurred after 1945, the approximate time when penicillin


began to be widely used for streptococcal pharyngitis [20].
A systematic review of hospital-based primary intervention strategies evaluated the effectiveness of antibiotics
in preventing ARF and was able to determine a substantial
protective effect using pooled meta-analysis of randomized
and quasi-randomized trials. In patients with a sore throat
and symptoms suggestive of GAS infection, antibiotic
treatment reduced the risk of ARF by 70% and by 80%
when intramuscular penicillin was used [21]. The subgroup analysis, focusing on the group treated with intramuscular penicillin, yielded a number needed to treat
of 60.

IMPORTANT CASE STUDIES


Like the hospital-based programs, community efforts such
as those in Cuba, Costa Rica, and Martinique have also
shown remarkable success and have resulted in the virtual
elimination of ARF using comprehensive, integrated programs targeting primary and secondary prevention [22,23].
These 10-year programs were able to demonstrate a
reduction in ARF in Martinique and Guadeloupe of 78%
and 72%, respectively and from 18.6 per 100,000 to 2.5 per
100,000 in Cuba. These were both comprehensive community interventions, consisting of awareness campaigns,
establishment of registries and medical training with
particular emphasis on primary and secondary prevention.
Both these programs resulted in dramatic declines in direct
costs (86% in both Cuba and Martinique). Although it is
difcult to tease out which specic component was primarily responsible for the rapid decrease in incidence of
ARF, it does provide convincing evidence that a strategy
that includes primary prevention can be markedly effective.

COST OF PRIMARY PREVENTION


In the resource-limited areas where ARF and RHD are most
rife, the importance of cost analyses cannot be overestimated. The cost of chronic RHD treatment has been
estimated at US$319 per patient per year, whereas an open
heart operation would cost anywhere from US$35,000 to
US$50,000 [24]. In Brazil, it was estimated in 2001 that
the chronic care costs for a patient with ARF could
constitute as much as 1.3% of annual family income. As
ARF and RHD are intimately related to poverty, this economic burden is unsustainable for the countries and people involved. Yet the cost of the prevention program in
Martinique was a fraction of the cost of cardiac surgery:
US$44,500 per year for the program compared with
US$654,000 for open-heart surgery [23]. This is also the
case in more recent comprehensive RHD control programs,
which have been run for only a fraction of the cost of
performing heart valve surgery on severe RHD patients
[25]. Until recently, the costs of a focused primary prevention strategy were thought to be prohibitive [26].
However, Irlam et al. [2] described a cost-effective analysis
of various strategies for the primary prevention of ARF in

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September 2013: 221-226

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an urban primary healthcare clinic. Using a Markov model,


they were able to determine that a treat-all strategy using
intramuscular penicillin was the least costly, whereas the
strategy of incorporating a clinical decision rule is overall the
preferred strategy. This landmark study reinforced the belief
that culturing all children with pharyngitis was prohibitively
expensive in developing country settings [2].

OBSTACLES TO EFFECTIVE PRIMARY PREVENTION


Taranta and Gordis [27] described prevention for RHD, in
the face of no cure, as not only desirable but essential. They
did acknowledge, though, the inherent difculties associated
with the accurate diagnosis and treatment of streptococcal
pharyngitis in the general population. Signicant barriers to
the adequate diagnosis and treatment of streptococcal
pharyngitis and thus primary prevention remain namely: 1)
the diagnosis of GAS pharyngitis; 2) treatment options and
concerns; 3) patient and physician awareness; and 4) the
positioning of primary prevention within a control program.

Diagnosis of GAS pharyngitis


The gold standard conrmatory test for streptococcal
pharyngitis is largely accepted to be a pharyngeal swab culture that is positive for GAS [28]. Ofce pediatricians in
developed countries make use of rapid strep tests to make
this diagnosis. However, there are very few countries in
highly affected regions of the world utilizing routine rapid
antigen or microbiological testing due to the cost involved.
Furthermore, the delay involved in awaiting results of culture before a diagnosis can be made will result in missed
diagnoses and tragic consequences. Finally, rapid antigen
detection tests, although demonstrating positive results [29],
should be tested within the local setting prior to advocating
their use. The use of a locally adapted, risk stratied, clinical
prediction rules such as those used in New Zealand and
Cuba [22,30,31] offers a different approach to detect GAS
pharyngitis. A recent pragmatic scoring system tested in
Brazil was able to demonstrate a receiver-operator characteristic curve of 0.66 (95% condence interval: 0.62 to 0.71)
and allowed for signicant (35% to 55%) sparing of antibiotic prescriptions while still maintaining an 88% specicity
[32]. This is in stark contrast with the World Health Organization prediction rule, which missed up to 96% of children
with positive cultures when applied to children in poorer
settings [33]. Clinical prediction rules thus do run the risk of
over- or underdiagnosis. However, this risk is substantially
decreased when algorithms incorporating local ARF pre-test
risk factors are applied. This will improve correct diagnosis
of GAS sore throat while keeping unnecessary antibiotic
usage to a minimum.

Treatment options and concerns


The current treatment guidelines for GAS pharyngitis were
revised in 2009 and are detailed in Table 1 [17]. The
American Heart Association has recommended penicillin
V or amoxicillin as rst-choice antibiotics, followed by

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September 2013: 221-226

benzathine penicillin. Evidence for recommending oral


penicillin as rst-line treatment is scant. Given that the few
trials testing the efcacy of penicillin for preventing ARF
were limited to intramuscular (as opposed to oral) penicillin
[34,35], our recommendation is that intramuscular penicillin should be the rst choice in keeping with the evidence.
This will also result in better compliance [21]. However,
there are problems with both the consistency of supply and
quality of benzathine penicillin G around the world. There
are a number of studies documenting that different batches
from suppliers may have variable pharmacokinetic properties, and the batches may vary physically, resulting in unreliable serum penicillin levels [36e40]. Benzathine
penicillin G is on the Core List of Essential Medicines for
developing countries, so it is critical that we nd a solution to
this problem. Patients treated with oral penicillin are advised
to complete a 10-day course and pediatric solutions need to
be kept refrigerated. This clearly is highly problematic in the
countries in question and has resulted in lack of concordance
with treatment regimes. In addition, reluctance on behalf of
patients due to the associated pain from an intramuscular
injection and practitioners relating to concerns regarding
anaphylaxis must be taken into consideration. The use of
intramuscular penicillin must be balanced against the risk of
incomplete oral regimes for GAS pharyngitis and local
quality and supply of intramuscular penicillin.

Patient and community awareness


In a study from Dar Es Salaam, Tanzania, the following
barriers to the diagnosis and treatment of GAS pharyngitis
were identied: 1) that patients do not present for treatment of sore throat; and 2) that there is little patient and
community knowledge regarding the importance of treating a sore throat. In addition, the concomitant lack of
awareness of primary prevention had resulted in a lack of
prioritization of GAS screening and treatment [41].
Even RHD patients themselves uniformly stated that
they would not take their children with a sore throat to
professional healthcare providers. Cost and travel to a
district-level clinic was a major factor in their decision
making, a factor that was also in a report from Jimma,
Ethiopia [42]. A concerningly high level of ignorance
around the causality of ARF and RHD was encountered in
this and other papers, with few of the respondents with
RHD questioned in a paper from South Africa knowing the
cause of ARF [43]. Patients had poor knowledge of the
connection between pharyngitis and RHD and preferred
local remedies or simple pain medication. Physicians in
these 3 studies were of the overwhelming opinion that
patients and their families were not aware about the consequences of untreated GAS infection. Patients reported
little prior knowledge of ARF before their diagnosis, an
indication of the lack of community awareness of the disease. Physician awareness of the importance of sore throat
management was generally good, although respondents
indicated that screening patients with GAS might be seen

223

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TABLE 1. Primary prevention of rheumatic fever (treatment of streptococcal tonsillopharyngitis)


Dose

Mode

Duration

Children: 250 mg 3 times daily for <27 kg


Adolescents and adults: 500 mg 2 to
3 times daily
50 mg/kg once daily (maximum 1 g)
600,000 IU for patients 27kg
1,200,000 IU for patients >27 kg

Oral

10 days

Oral
Intramuscular

10 days
Once

Variable

Oral

10 days

20 mg/kg per day divided in 3 doses


(maximum 1.8g/d)
12 mg/kg once daily (maximum 500 mg)
15 mg/kg per day divided into 2 doses
(maximum 250 mg twice daily)

Oral

10 days

Oral
Oral

5 days
10 days

Agent*
Penicillin
 Penicillin V

 Amoxicillin
 Benzathine
penicillin G
Allergic to penicillin
 Narrow-spectrum
cephalosporin
 Clindamycin
 Azithromycin
 Clarithromycin

IU, international units.


*The following antibiotics are not acceptable: sulphonamides; trimethoprim; tetracyclines; and uoroquinolones.
Adapted from Gerber MA et al. [17].

as interfering with other priority diseases such as the human immunodeciency virus and malaria.

Positioning of primary prevention within a control


program
There is international disagreement regarding the way in
which primary prophylaxis should be incorporated into
control strategies [1,44e46]. Everyone seems to be in
agreement that promotion of sore throat diagnosis and
treatment within existing primary healthcare systems is
important, although it is not clear how this should be
done. The particular role of systematic sore throat
screening and treatment programs in schools or communities is also contentious. The debate revolves around the
role of sore throat screening and treatment programs in
schools, with one side claiming that there is sufcient evidence to promote this approach and the other claiming
that the evidence of efcacy, effectiveness, and costeffectiveness is insufcient to recommend it [31,47]. We
believe that the existing evidence is insufcient, that a more
denitive study would be logistically difcult and expensive, and, furthermore, that even if it were proven to be
effective, such a strategy would be difcult to implement
and unaffordable in low-income countries [48]. Unlike the
school-based model, the community models from Cuba,
Costa Rica, and the islands of Martinique and Guadeloupe
represent the best evidence for integration. Here a
comprehensive strategy involving syndromic treatment of
suspected GAS pharyngitis with penicillin was introduced
and maintained for over 10 years. This was within a
concerted educational campaign that attempted to involve
and target the public, social, and educational professionals,
as well as healthcare workers at every level, in particular
those at primary care facilities. A media education

224

campaign involving radio, television, and pamphlets


together with workshops and symposia for healthcare
workers ran throughout the period of the program and
stressed the benign presentation of sore throat and contrasted it with the severity of heart disease [22,23].
It is critical to be reminded that even in the most optimal
circumstances, as many as 60% of patients subsequently
diagnosed with ARF cannot recall a previous episode of sore
throat [49]. Therefore, it is crucial that the patients who do
present with sore throats, provide us with an important
opportunity for intervention that should not be missed.

OPPORTUNITIES FOR PRIMARY PREVENTION


We are currently witnessing a surge in ARF and RHD
control activity largely driven from parts of the world
where ARF/RHD mostly occurs. Research, as well as public
health programs and political advocacy, are now centered
in developing countries and those subpopulations within
middle- and high-income countries where high burdens of
disease still exist. A real opportunity exists for dramatic
progress to occur toward the goal of eradicating ARF and
RHD in our lifetime [50,51].
Following up on the excellent work carried out in Cuba,
Costa Rica, and other countries, similar programs have now
evolved in several other sites, a world-leading program of
RHD control in Pacic Island nations has individuals from
Tonga, Fiji, and Samoa at the helm, whereas the ASAP
(Advocacy, Surveillance, Awareness, and Prevention) program, under the auspices of the Pan-African Society of Cardiology has galvanized efforts in Africa to combat this disease
[52]. These programs all feature a comprehensive approach
combining education, awareness, and primary care management as key components [26,53e55]. Collaborations
between developing countries, such as India, Brazil, and

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September 2013: 221-226

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South Africa, promise to yield important insights into understanding of the GAS antigenic processes and RF pathogenesis and inform vaccine development [56].
These efforts have been met with renewed support from
global organizations such as the World Heart Federation,
which has made a major commitment to leading the charge
on RHD control, supporting programs in the Pacic and
Africa, establishing an international web-based resource in
ARF/RHD, and, in their most recent strategic plan,
committing to eliminating rheumatic fever and minimizing
the burden of rheumatic heart disease. The World Heart
Federation also hosted the Postgraduate Course on Rheumatic Heart Disease: Challenges and Opportunities at the
Seventh Global Forum on Humanitarian Medicine in Cardiology and Cardiac Surgery in Geneva, Switzerland. Not
only will this raise the prole of ARF and RHD within the
medical community, but also the community at large,
through their partners and global alliances [57].
A major limitation of an integrated primary prevention
strategy relates to existing healthcare infrastructure, which is
grossly under-resourced and poorly serviced in the very
populations in which RF/RHD is rampant. The everincreasing need for skilled healthcare workers has led to the
formation of cadres of assistant medical ofcers and task
shifting [58]. Using community health workers in integrated
primary health care, human immunodeciency virus management has achieved much success in resource-limited
countries such as Haiti and Rwanda [59,60]. By integrating
treatment of sore throat into other programs, and the innovative use of community health workers to strengthen the
program, in terms of treatment as well as education, similar
successes could be achieved.

SUMMARY
Rheumatic heart disease is unique among chronic cardiovascular diseases in several ways. It is entirely preventable.
It is among the few chronic cardiovascular diseases of
childhood, adolescence, and young adulthood, and it
straddles the silos of infectious and noncommunicable
diseases and, therefore, represents perfectly the needs of
developing countries in the 21st century, now dealing
increasingly with this double burden [61]. The potential
economic burden of chronic cardiovascular disease in the
developing world is overwhelming, and any opportunity to
prevent chronic disease should be embraced and strongly
advocated at the highest levels. We have presented the
progress made in primary prevention of acute rheumatic
fever, as well as listing some of the obstacles and opportunities in this eld. Primary prevention is the cornerstone
of any RHD program and integration into existing primary
care systems should be a priority.
REFERENCES
1. Karthikeyan G, Mayosi BM. Is primary prevention of rheumatic fever
the missing link in the control of rheumatic heart disease in Africa?
Circulation 2009;120:70913.

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 221-226

2. Irlam J, Mayosi BM, Engel M, Gaziano TA. Primary prevention of


acute rheumatic fever and rheumatic heart disease with penicillin in
South African children with pharyngitis: a cost-effectiveness analysis.
Circ Cardiovasc Qual Outcomes 2013;6:34351.
3. Lynskey NN, Lawrenson RA, Sriskandan S. New understandings in
Streptococcus pyogenes. Curr Opin Infect Dis 2011;24:196202.
4. Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden
of group A streptococcal diseases. Lancet Infect Dis 2005;5:68594.
5. Pastore S, De Cunto A, Benettoni A, Berton E, Taddio A, Lepore L. The
resurgence of rheumatic fever in a developed country area: the role
of echocardiography. Rheumatology (Oxford) 2011;50:396400.
6. Gordis L. The virtual disappearance of rheumatic fever in the United
States: lessons in the rise and fall of disease: T. Duckett Jones memorial lecture. Circulation 1985;72:115562.
7. Tibazarwa KB, Volmink JA, Mayosi BM. Incidence of acute rheumatic
fever in the world: a systematic review of population-based studies.
Heart 2008;94:153440.
8. Seckeler MD, Hoke TR. The worldwide epidemiology of acute rheumatic fever and rheumatic heart disease. Clin Epidemiol 2011;3:6784.
9. Marijon E, Ou P, Celermajer DS, et al. Prevalence of rheumatic heart
disease detected by echocardiographic screening. N Engl J Med 2007;
357:4706.
10. Jackson SJ, Steer AC, Campbell H. Systematic review: estimation of
global burden of non-suppurative sequelae of upper respiratory tract
infection: rheumatic fever and post-streptococcal glomerulonephritis.
Trop Med Int Health 2011;16:211.
11. Vieira FM, Figueiredo CR, Soares MC, et al. Prevalence of Streptococcus pyogenes as an oropharynx colonizer in children attending
daycare: a comparative study of different regions in Brazil. Braz J
Otorhinolaryngol 2006;72:58791.
12. McDonald MI, Towers RJ, Andrews RM, Benger N, Currie BJ,
Carapetis JR. Low rates of streptococcal pharyngitis and high rates of
pyoderma in Australian aboriginal communities where acute rheumatic fever is hyperendemic. Clin Infect Dis 2006;43:6839.
13. Bryant PA, Robins-Browne R, Carapetis JR, Curtis N. Some of the
people, some of the time: susceptibility to acute rheumatic fever.
Circulation 2009;119:74253.
14. Carapetis JR, Currie BJ. Group A streptococcus, pyoderma, and
rheumatic fever. Lancet 1996;347:12712.
15. Carapetis J, Gardiner D, Currie B, Mathews JD. Multiple strains of
Streptococcus pyogenes in skin sores of aboriginal Australians. J Clin
Microbiol 1995;33:14712.
16. Cunningham MW. Pathogenesis of group A streptococcal infections.
Clin Microbiol Rev 2000;13:470511.
17. Gerber MA, Baltimore RS, Eaton CB, et al. Prevention of rheumatic
fever and diagnosis and treatment of acute Streptococcal pharyngitis:
a scientic statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the
Council on Cardiovascular Disease in the Young, the Interdisciplinary
Council on Functional Genomics and Translational Biology, and the
Interdisciplinary Council on Quality of Care and Outcomes Research.
Circulation 2009;119:154151.
18. Monya-Tambi I, Robertson KR, Volmink JA, Mayosi BM. Acute rheumatic fever. Lancet 2005;366:1355, author reply 1355e6.
19. Markowitz M. The decline of rheumatic fever: role of medical intervention: Lewis W. Wannamaker memorial lecture. J Pediatr 1985;106:
54550.
20. Massell BF, Chute CG, Walker AM, Kurland GS. Penicillin and the
marked decrease in morbidity and mortality from rheumatic fever in
the United States. N Engl J Med 1988;318:2806.
21. Robertson KA, Volmink JA, Mayosi BM. Antibiotics for the primary
prevention of acute rheumatic fever: a meta-analysis. BMC Cardiovasc Disord 2005;5:11.
22. Nordet P, Lopez R, Duenas A, Sarmiento L. Prevention and control of
rheumatic fever and rheumatic heart disease: the Cuban experience
(1986e1996e2002). Cardiovasc J Afr 2008;19:13540.
23. Bach JF, Chalons S, Forier E, et al. 10-year educational programme
aimed at rheumatic fever in two French Caribbean islands. Lancet
1996;347:6448.

225

gREVIEW

24. Terreri MT, Ferraz MB, Goldenberg J, Len C, Hilrio MO. Resource
utilization and cost of rheumatic fever. J Rheumatol 2001;28:13947.
25. Colquhoun SM, Carapetis JR, Kado JH, Steer AC. Rheumatic heart
disease and its control in the Pacic. Expert Rev Cardiovasc Ther
2009;7:151724.
26. Steer AC, Carapetis JR. Prevention and treatment of rheumatic heart
disease in the developing world. Nat Rev Cardiol 2009;6:68998.
27. Taranta A, Gordis L. The prevention of rheumatic fever: opportunities,
frustrations, and challenges. Cardiovasc Clin 1972;4:110.
28. Steer AC, Danchin MH, Carapetis JR. Group A streptococcal infections
in children. J Paediatr Child Health 2007;43:20313.
29. Rimoin AW, Walker CL, Hamza HS, et al. The utility of rapid antigen
detection testing for the diagnosis of streptococcal pharyngitis in
low-resource settings. Int J Infect Dis 2010;14:e104853.
30. Carapetis JR, Brown A, Wilson NJ, et al., for the Rheumatic Fever
Guidelines Writing Group. An Australian guideline for rheumatic fever and rheumatic heart disease: an abridged outline. Med J Aust
2007;186:5816.
31. Atatoa-Carr P, Lennon D,Wilson N, for the New Zealand Fever Guidelines
Writing Group. Rheumatic fever diagnosis, management, and secondary prevention: a New Zealand guideline. N Z Med J 2008;121:5969.
32. Joachim L, Campos D Jr., Smeesters PR. Pragmatic scoring system for
pharyngitis in low-resource settings. Pediatrics 2010;126:e60814.
33. Rimoin AW, Hamza HS, Vince A, et al. Evaluation of the WHO clinical
decision rule for streptococcal pharyngitis. Arch Dis Child 2005;90:
106670.
34. Brumtt W, Slater JD. Treatment of acute sore throat with penicillin; a
controlled trial in young soldiers. Lancet 1957;272:811.
35. Zwart S, Rovers MM, de Melker RA, Hoes AW. Penicillin for acute sore
throat in children: randomised, double blind trial. BMJ 2003;327:1324.
36. Zaher S, Kassem A, Abou-Shleib H, El Khouly A, Madkour A, Kaplan E.
Differences in serum penicillin concentrations following intramuscular injection of benzathine penicillin G (BPG) from different manufacturers. J Pharm Med 1992;2:1723.
37. Stollerman GH, Rusoff JH. Prophylaxis against group A streptococcal
infections in rheumatic fever patients; use of new repository penicillin preparation. J Am Med Assoc 1952;150:15715.
38. Kassem AS, Zaher SR, Abou Shleib H, el-Kholy AG, Madkour AA,
Kaplan EL. Rheumatic fever prophylaxis using benzathine penicillin G
(BPG): two-week versus four-week regimens: comparison of two
brands of BPG. Pediatrics 1996;97:9925.
39. Kaplan EL, Berrios X, Speth J, Siefferman T, Guzman B, Quesny F.
Pharmacokinetics of benzathine penicillin G: serum levels during the
28 days after intramuscular injection of 1,200,000 units. J Pediatr
1989;115:14650.
40. Bass JW, Longeld JN, Jones RG, Hartmann RM. Serum levels of
penicillin in basic trainees in the U.S. Army who received intramuscular penicillin G benzathine. Clin Infect Dis 1996;22:7278.
41. Bergmark R, Bergmark B, Blander J, Fataki M, Janabi M. Burden of disease
and barriers to the diagnosis and treatment of group a beta-hemolytic
streptococcal pharyngitis for the prevention of rheumatic heart disease in Dar Es Salaam, Tanzania. Pediatr Infect Dis J 2010;29:11357.
42. Kadia Petricca YM, Haileamlak A, Seid E, Parry E. Barriers to effective
follow-up treatment for rheumatic heart disease in Jimma, Ethiopia: a
grounded theory analysis of the patient experience. Ethiop J Health
Sci 2009;19:414.

226

43. Robertson KA, Volmink JA, Mayosi BM. Lack of adherence to the
national guidelines on the prevention of rheumatic fever. S Afr Med J
2005;95:526.
44. Carapetis J, Steer A. Prevention of rheumatic fever. Pediatr Infect Dis
J 2010;29:912, author reply 92.
45. Carapetis JR. Letter by Carapetis regarding article, Is primary prevention of rheumatic fever the missing link in the control of rheumatic heart disease in Africa?. Circulation 2010;121:e384, author
reply e385.
46. Lennon D, Stewart J, Farrell E, Palmer A, Mason H. School-based
prevention of acute rheumatic fever: a group randomized trial in New
Zealand. Pediatr Infect Dis J 2009;28:78794.
47. Atatoa-Carr P, Bell A, Lennon DR. Acute rheumatic fever in the
Waikato District Health Board region of New Zealand: 1998e2004.
N Z Med J 2008;121:96105.
48. Carapetis JR, Zhlke LJ. Global research priorities in rheumatic fever
and rheumatic heart disease. Ann Paediatr Cardiol 2011;4:412.
49. Carapetis JR, McDonald M, Wilson NJ. Acute rheumatic fever. Lancet
2005;366:15568.
50. Robertson KA, Volmink JA, Mayosi BM. Towards a uniform plan for
the control of rheumatic fever and rheumatic heart disease in
Africathe Awareness Surveillance Advocacy Prevention (A.S.A.P.)
Programme. S Afr Med J 2006;96:241.
51. Mayosi B, Robertson K, Volmink J, et al. The Drakensberg declaration
on the control of rheumatic fever and rheumatic heart disease in
Africa. S Afr Med J 2006;96:246.
52. Mayosi B. The four pillars of rheumatic heart disease control. S Afr
Med J 2010;100:506.
53. Steer AC, Colquhoun S, Kado J, Carapetis JR. Secondary prophylaxis is
important for the prevention of recurrent rheumatic fever in the
Pacic. Pediatr Cardiol 2011;32:8645.
54. Steer AC, Jenney AW, Kado J, et al. Prospective surveillance of
streptococcal sore throat in a tropical country. Pediatr Infect Dis J
2009;28:47782.
55. Engel ME, Zhlke LJ, Robertson KA. ASAP programme: rheumatic
fever and rheumatic heart disease: where are we now in South
Africa? SA Heart 2009;6:2703.
56. Dale JB, Fischetti VA, Carapetis JR, et al. Group A streptococcal
vaccines: paving a path for accelerated development. Vaccine 2013;
31(Suppl 2):B21622.
57. Remenyi B, Carapetis J, Wyber R, Taubert K, Mayosi BM. Position
statement of the World Heart Federation on the prevention and
control of rheumatic heart disease. Nat Rev Cardiol 2013;10:28492.
58. Fulton BD, Schefer RM, Sparkes SP, Auh EY, Vujicic M, Soucat A.
Health workforce skill mix and task shifting in low income countries:
a review of recent evidence. Hum Resour Health 2011;9:1.
59. Koenig SP, Leandre F, Farmer PE. Scaling-up HIV treatment programmes in resource-limited settings: the rural Haiti experience.
AIDS 2004;18(Suppl 3):S215.
60. Walton DA, Farmer PE, Lambert W, Leandre F, Koenig SP,
Mukherjee JS. Integrated HIV prevention and care strengthens primary health care: lessons from rural Haiti. J Public Health Policy
2004;25:13758.
61. Mayosi BM, Flisher AJ, Lalloo UG, Sitas F, Tollman SM, Bradshaw D.
The burden of non-communicable diseases in South Africa. Lancet
2009;374:9347.

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Benzathine Penicillin G for the Management of RHD


Concerns About Quality and Access, and Opportunities
for Intervention and Improvement
Rosemary Wyber*, Kathryn Tauberty, Stephen Markoz, Edward L. Kaplanx
Perth, Western Australia, Australia; Geneva, Switzerland; Farmington, CT, USA; and Minneapolis, MN, USA
ABSTRACT
Benzathine penicillin G is an important antibiotic for the treatment and prevention of group A streptococcal
infections associated with rheumatic fever and rheumatic heart disease. However, as rheumatic heart disease
has receded as a public health priority in most high-income settings, attention to the supply, manufacture, and
accessibility of benzathine penicillin G has declined. Concerns about the quality, efcacy, and innovation of
the drug have emerged following plasma analysis and anecdotal reports from low-resource settings. This
review collates core issues in supply and delivery of benzathine penicillin G as a foundation for concerted
efforts to improve global quality and access. Opportunities for intervention and improvement are explored.

Rheumatic fever (RF) and rheumatic heart disease


(RHD) are an autoimmune sequel of group A streptococcal
(GAS) infections. Recurrences of RF accelerate progression
of cardiac valve damage, culminating in heart failure, arrhythmias, and often fatalities. The global burden of RF/
RHD is signicanteconservatively estimated at 471,000
cases of RF annually and 233,000 deaths per year. At least
15.6 million people suffer from RF/RHD worldwide. RF/
RHD is a neglected disease of poverty endemic in lowresource settings and some subpopulations in highincome countries [1].
Antibiotics are essential for prophylaxis to prevent
recurrences of RF (secondary prophylaxis) and for treatment
of symptomatic GAS infections (primary prevention). Since
the 1950s, prophylaxis has been achieved via intramuscular
(IM) administration of benzathine penicillin G (BPG) [2].
Although other antibiotics have been used, BPG is a particularly effective agent for primary and secondary prevention
because its long half-life provides prolonged bactericidal
protection from GAS infection. With effective secondary
prophylaxis recurrence, the progression of RF to RHD can be
prevented [3,4]. A small number of oral alternatives for RF
secondary prophylaxis have been used; these are all less
effective than IM BPG in preventing recurrences of RF
[3,5,6]. Alternative regimes for individuals with severe
penicillin allergy or intolerance are addressed in most
RF/RHD treatment guidelines but are outside the scope of
this review [5,7e11].
This review presents an overview of the current issues
surrounding BPG for the management of RHD and RF.
A systematic search of peer-reviewed literature identied a
small number of basic science articles and commentaries
on BPG. Expanding bibliographic review identied a range
of other articles documenting concerns about supply,
quality, and access. These issues were explored with

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September 2013: 227-234

targeted searches of public records revealing patent information, commercial details, and correspondence.

PHARMACOLOGY OF BPG
Benzathine penicillin G is a crystalline powder formed
through the fusion of 2 penicillin G molecules and characterized by very low solubility and in vivo hydrolysis
[2,12e14]. These features are associated with slow absorption from IM injection, producing prolonged therapeutic
serum concentrations [12,15]. Prolonged concentration in
serum provides excellent protection from GAS infection. No
GAS resistance to BPG has been documented in vitro [16].
The mechanism for the apparent persistent susceptibility of
GAS to BPG is relatively poorly understood [15,17,18].

DISEASES, DOSES, AND DEMANDS FOR BPG


From the 1950s, BPG was widely used as the rst list drug for
an array of conditions: syphilis, yaws, Lyme disease, and
pneumococcal prophylaxis in sickle cell disease [19e21].
However, development of new antibiotics has narrowed the
clinical indications for BPG. Conditions requiring BPG
treatment have also become less common in high-resource
settings, further shrinking demand. This section proles
the existing indications for BPG, providing a foundation for
much-needed research work on the potential size of commercial markets.

From the *Telethon Institute for Child Health


Research, Perth, Western
Australia, Australia; yWorld
Heart Federation, Geneva,
Switzerland; zUniversity of
Connecticut School of
Medicine, Farmington, CT,
USA; and xUniversity of
Minnesota Medical School,
Minneapolis, MN, USA.
Correspondence: R. Wyber
(rwyber@ichr.uwa.edu.au).

Secondary prophylaxis for RHD

GLOBAL HEART
2013 World Heart
Federation (Geneva).
Published by Elsevier Ltd.
All rights reserved.
VOL. 8, NO. 3, 2013
ISSN 2211-8160/$36.00.
http://dx.doi.org/10.1016/
j.gheart.2013.08.011

The World Health Organization (WHO) denes secondary


prophylaxis as the continuous administration of specic
antibiotics to patients with a previous attack of rheumatic
fever, or well-documented rheumatic heart disease. The
purpose is to prevent colonization or infection of the upper
respiratory tract with group A beta-hemolytic streptococci

227

gREVIEW

and the development of recurrent attacks of rheumatic


fever [9]. The internationally accepted dose for secondary
prophylaxis with BPG in adults is 900 mg (1.2 million IU)
intramuscularly. There is some uncertainly over the optimum frequency of administration; some papers suggest
2-weekly administration [22], others report very good
outcomes on a 3-weekly regime [23,24]. Most guidelines
recommend 4-weekly administration as a pragmatic
choice, with an option to escalate to 3-weekly administration if there are unexplained recurrences or very high
risk [3,5,9,10,25]. The recommended BPG dose for children varies between guidelines: 450 mg (0.6 million IU) up
to 20 kg in Australia; 450 mg up to 27 kg in American
Heart Association guidelines; and 450 mg up to 30 kg in
WHO guidelines [5,9,10].
The optimal duration of secondary prophylaxis is
controversial. In most guidelines, duration depends on the
initial presentation of RF and location within a high-risk
population [5,10]. An array of anecdotal factors have
been distilled into consensus guidelines for local implementation [7,10]. Exploring the indications for prolonged
prophylaxis is outside the scope of this review. However, it
is noteworthy that the minimum duration of secondary
prophylaxis in most guidelines is 10 years [5,7,9e11]. In
severe cases, lifelong regular BPG administration may be
recommended [5,10]. Missing even a single dose of BPG
raises the risk of recurrent RF and can undermine entire
secondary prophylaxis programs. Stability of supply is a
critical issue for programmatic success.

Primary treatment of group A streptococcal


pharyngitis
Antibiotic treatment of symptomatic GAS pharyngitis is
widely recommended [5,7,9,10]. However, access to culture
or rapid antigen tests is limited in low-resource settings, and
may delay treatment. Evidence for empiric treatment of
childhood sore throats according to a clinical decision rule in
high-risk populations has recently been published [26]. A
single dose of BPG (between 225 g and 900 g depending on
weight) is recommended in high-risk settings or where oral
compliance is challenging [7,10]. Treatment of asymptomatic GAS carriers is not routine but may be considered in rare
circumstances, such as disease outbreaks in closed communities [5,27,28].

Syphilis
An estimated 12 million people are infected with the
spirochete Treponema pallidum [29]. T. pallidum is particularly responsive to penicillin in the form of BPG [30]. The
recommended dose is double the RF/RHD prophylaxis
dose at 1.44 g (2.4 million IU) as a single immediate dose
for primary syphilis or 3 doses for late syphilis [31]. There
is some evidence that use of oral azithromycin is comparable to a single dose of BPG for treatment of early syphilis
[32]. However, BPG remains the only agent suitable for

228

treating pregnant women to prevent transmission to the


fetus and avert congenital syphilis in neonates [30,31].

Yaws
Yaws is a skin infection caused by the spirochete bacterium
Treponema pallidum subspecies pertenue, which is related to
the causative organism of syphilis. The disease is estimated
to affect approximately half a million people, predominantly children in low-resource rural areas [33]. The
burden of yaws in Africa, South East Asia, and the Pacic
Islands parallels the particular persistence of RF/RHD in
resource-limited settings. Treatment of yaws has traditionally been with 1.2 MU of IM BPG for adults and 0.6
MU IM BPG for children [34]. Evidence for the role of oral
azithromycin as a treatment of choice for yaws is emerging,
potentially reducing demand in the BPG market [35]

PAST AND PRESENT BPG SUPPLIES


BPG was developed by J. Lester Szabo in 1951, and the rst
BPG patent appears to have been held in the United States
in 1953 by Bruce [2,36,37]. Advances in stabilizing this
original powdered formulation were patented in subsequent
years [37]. Initial clinical application was for the treatment of
syphilitic infections, spurring considerable demand, commercial interest, and a variety of branded products throughout
the 1950s [36,38]. The patents, production, and formulation
of powdered BPG over the last 60 years is difcult to track
amid a crowded manufacturing market, frequent stock outages, and changes in suppliers [39e43].
A pre-mixed liquid formulation of BPG has been
developed, eliminating the need for a dilutant, but requiring
refrigeration. The initial patent on this new product was rst
held by Wyeth under the brand name Bicillin L-A, a 2-ml
formulation distributed in a Bicillin Tubex injector [15].
Wyeths Bicillin L-A, distributed by Aspen Pharmaceuticals,
was introduced into the Australia market in 1995 and
became the sole source of BPG to the country [44]. Industry
statements suggest that global rights to Bicillin L-A were
transferred to U.S.-based King Pharmaceuticals (reportedly
owned by Monarch at this time) in August 2005 [39,45,46].
Some conicting reports suggest that the patent rights had
been transferred years earlier, but that Wyeth had continued
to produce for King under contract [47]. In 2007, the U.S.
Food and Drug Administration approved King Pharmaceutical to produce Bicillin L-A at a new manufacturing and
production facility in Michigan, USA [48]. A company press
release from that time records King Pharmaceuticals as the
only manufacturer of Bicillin L-A in the United States [48].
Pzer acquired King/Monarch Pharmaceuticals in 2010 and
Wyeth in 2009 and now appears to be the sole provider
of the suspension formulation of BPG in high-resource settings [49].
In this complicated patent and manufacturing landscape, shortages of BPG have occurred. Details of stock
outages have been best documented in high-resource settings with pockets of endemic RF/RHD in vulnerable

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September 2013: 227-234

gREVIEW

populations. Supply of BPG for secondary prophylaxis was


limited in countries of the former Yugoslavia in the early
1990s [50]. Shortages have occurred in North America
from 2002 when Wyeth-Ayerst stopped producing BPG
from a Canadian plant [51,52]. Liquid Bicillin-LA stock
outages occurred in Australia and New Zealand between
2001 and 2008 [15,53]. In the United States, shortages
were notied to the Center for Disease Control in 2005; by
2010, 15% of 353 surveyed directors of pharmacy were
still dealing with shortages in America [54,55]. A World
Heart Federation survey of healthcare providers who treat
patients with RF/RHD prophylaxis collected data from 24
countries in Africa, the Asia-Pacic region, and Central and
South America in 2011 [56]. Minimal access to BPG was
reported in almost all settings, with some respondents
indicating no access to BPG at all [56]. Of 39 respondents,
35% indicated that their BPG supply is inadequate to treat
all of their patients using recommended prophylaxis
schedules [56].

COST OF BPG
Reliable data on the purchase price of BPG is difcult to
secure. Powdered BPG is available to some providers through
the support of the United Nations Childrens Fund pooled
procurement [57]. A 2010 report from the United Nations
Childrens Fund records 2.4 million IU vials of powdered
benzathine benzylpenicillin at a median of US$0.31 per dose.
A 2010 human immunodeciency virus guide for Zambia
documents Monarch-branded 1.2 million IU of pre-mixed
BPG priced at $57.60 [58]. South African researchers used a
value of US $1 in 2010 (sensitivity range 0 to 13), for a single
vial of powdered BPG in a recent cost-effectiveness analysis
guided by local pharmacy data [26]. A recent newspaper
report from Kenya suggests the cost of a single dose of
BPG costs Sh250, approximately US$2.90 [59]. In Australia,
a 900-mg dose of Pzer-branded Bicillin L-A is listed in the
Pharmaceutical Benets Scheme at a cost of AU$29.32
(US$29.85) per dose [60]. This is comparable with the same
product in the New Zealand Pharmaceutical Schedule, which
indicates a price of NZ $31.50 (US$25.03) (http://www.
pharmac.health.nz/ckeditor_assets/attachments/15/sched.pdf).
Finally, understanding the uses and supply of BPG has
been confused by a number of similarly named products.
In particular, Bicillin C-R (controlled release) and Bicillin
A-P (all purpose) [15,61,62]. These formulations contain
procaine penicillin G and/or aqueous penicillin, which
achieve higher and shorter serum concentration levels after
IM administration. Combinations of BPG and procaine
penicillin G have been proposed for the treatment of respiratory tract infections, scarlet fever, and skin infections,
but they are not suitable for RF secondary prophylaxis
[63].

BPG QUALITY
The paucity of readily accessible quality control guidelines
in BPG manufacturing has been a source of concern within

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the RHD community for some years [46,64,65]. Attempts


to obtain process information from manufacturers have
been unsuccessful despite a number of concerted efforts
[46,66]. In Canada, 2 notice of compliance documents
have been issued for branded, liquid formulation Bicillin LA (Pzer and King); those documents represent compliance
with local Food and Drug Regulations [67]. The need for
continuous quality improvement activities to address
different preparations of BPG has also been identied by
WHO with little effect [68].

Efcacy
In the absence of readily available manufacturing standards
or chemical composition assays, the efcacy of BPG formulations must be determined from clinical testing. Analysis of BPG is complicated by its prolonged half-life,
necessitating lengthy and potentially expensive follow-up
[69]. This is important for U.S. Food and Drug Administration licensing of generic medications, which evaluates
bioequivalence via a plasma concentration-time curve from
zero to complete drug excretion [69,70].
Secondary prophylaxis for RF/RHD is thought to
require a minimum serum concentration of 0.02 mg/ml
BGP to prevent GAS infection, based on a reported minimum inhibitory concentration 90 of 0.0016 [66,71]. The
oft-recommended 28-day dosing interval of BPG is calculated to keep serum concentrations above this therapeutic
threshold in order to prevent GAS infection. However,
there are well-founded concerns about the variability of
penicillin serum concentration from an array of manufacturers over a period of some years [46,65,66]. In a recent
trial, young American military recruits received a single stat
dose of 1.2 MU of BPG; mean serum concentrations were
less than the minimum serum concentration of 0.02 mg/ml
by day 9 after administration in one-half of the subjects.
Generalizing these results to the RHD secondary prophylaxis population suggests that patients may be unprotected
from GAS infection for up to 19 days prior to the next dose
administration [66]. A meta-analysis of 37 similar studies
evaluated trends in therapeutic penicillin serum concentrations; investigators have reported that the duration of
therapeutic serum concentrations is signicantly shorter in
studies since 1990 than it is in data from earlier decades
[71]. This raises signicant concerns about the effectiveness of contemporary secondary prophylaxis programs.

Safety
Generally accepted international data suggests that the
incidence of allergic reactions to monthly BPG injection is
3.2% and anaphylactic reactions is 0.2% [9,72]. However,
anecdotal reports of adverse reactions appear to have
increased in recent years, in conjunction with concerns
about medication quality. Three deaths documented in
Zimbabwe in 2000 were associated with BPG from 3
different manufacturers [73]. A high frequency of
anaphylaxis events has also been reported in World Heart

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Federations BPG survey; 26% of 39 clinicians reported at


least 1 anaphylactic reaction, and 21% of all providers
reported that they have had a patient die due to anaphylaxis after BPG injection [56]. At present, it is impossible to
determine whether adverse drug reactions are caused by
penicillin, reactions to other components of the medication/dilatant, unrelated to BPG administration, or misclassied reactions. The role of vasovagal reactions to IM
injection, particularly in diverse cultural settings, may also
be an important area for further research. A system for
reporting adverse drug events is important for BPG as a
way of monitoring both penicillin safety and perhaps a
proxy guide to BPG quality [74].

Administration challenges
Powdered BPG forms a suspension when reconstituted prior
to administration. This incomplete dissolution predisposes
to precipitation and needle blockage during administration
[75]. Worldwide anecdotal reports suggest this precipitation
is a common problem. For example, when Australia used
powdered Pan Benz during the 2006 stock outage of Bicillin
L-A, up to 40% of injections of Pan Benz were affected by
needle blockages. Concerns were reportedly raised to the
Therapeutic Goods Administration via the Centers for Disease Control, though no record of subsequent regulatory
intervention can be found [76]. Many countries are dependent on powdered BPG for the near future, and effective
administration remains an unmet challenge.

BPG AS AN ESSENTIAL MEDICINE


WHO has biennially produced a list of essential drugs since
1977, forming the foundation for 156 national Essential
Medicines Lists (EML) [77,78]. The success of EML spurred the development of further specic lists, including the
Interagency List of Essential Medicines for Reproductive
Health in 2006 and the Essential Medicines List for Children (EMLc) in 2007 [79,80]. These lists were supplemented by a WHO publication on model prescribing
information for RF/RHD in 1999 [68].
The adult 1.2 million MU dose of BPG appears in the
(current) 17th edition 2011 EML of WHO [81]. The pediatric EML also includes BPG but only at the standard
adult dose. Theoretically, this could be problematic for
countries with a high burden of RF/RHD in young children
or with widespread growth stunting. The inclusion of pediatric doses for RHD prophylaxis received specic attention during the drafting of the EMLc, including in a
detailed report [80,82]. Similarly, BPG appears on the
Interagency List of Essential Medicines for Reproductive
Health in a 1.44 g (2.4 million IU) form for treatment of
syphilis [79]. It is unclear whether the recommended formulations of BPG, which appear on the WHO EML, are
translated to national level EMLs. This requires a targeted
investigation to evaluate which countries with a high
burden of RHD have adopted the EML recommendations
to national formularies.

230

DELIVERY MECHANISMS
Delivering each injection in secondary prophylaxis regimes
is a global challenge. In many settings, far fewer than 80%
of scheduled injections are delivered, signicantly
increasing the risk of rheumatic fever [83e87]. Although
the link between the pain of BPG administration and
compliance has little published support, it is reasonable to
assume that discomfort is a factor for young people
[10,88,89]. Adherence with secondary prophylaxis is critically low in many settings; any attempt to improve
acceptability of BPG warrants vigorous investigation.
Some centers employ techniques to reduce the pain of
IM injections, such as use of smaller gauge needles, direct
pressure, slow injections, and distractions [10]. In some
programs, local anesthetic is routinely used as a dilutant for
powdered BPG to reduce injection pain [90]. There is good
evidence that the practice is effective at relieving pain,
without reducing absorption or serum concentration of
BPG [10,91,92]. However, pain could be further minimized by alternative delivery mechanisms, potentially an
implantable device.
An implantable or longer acting BPG delivery device
would be a more appropriate and acceptable mechanism
for delivering secondary prophylaxis [64,93,94]. Although
this is a conceptually promising approach, there has been
little reported innovation in this eld.

IMPROVING BPG ACCESS


Control of RF and RHD depends on supply, procurement,
and delivery of BPG. Vaccine prospects remain years from
clinical implementation, forcing primary and secondary prevention activities to the fore [95]. Improved global burden of
disease data and echocardiographic screening programs are
likely to expand demand for BPG, particular if echocardiography moves from a descriptive to an interventional phase
[95,96]. Thus, improving access to BPG and supporting
compliance should be a key priority for the RHD community
[64,95]. Three domains of intervention are required.

Technical and clinical research interventions


Technical manufacturing standards or specications for
BPG have not been located during this review, nor in
earlier attempts by other investigators [64]. Some specications may reside with patent holders for pre-mixed BPG.
Older standards for powdered formulations may be held by
regulatory agencies that are inaccessible to electronic review. Locating and distributing of nonproprietary standards is needed in order to evaluate generic formulations
and ensure standardization. Simple assays for establishing
the quality and purity of BPG may also need to be developed to assist procurement agencies in purchasing
decisions.
Updated data for anaphylaxis and adverse drug reactions
is essential, particular if use of BPG is to be expanded. Adverse
drug reaction data may be accessible by interrogating existing
national level databases or supporting the development of

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gREVIEW

pharmaco-vigilance programs [97]. In settings without any


mechanism for reporting drug events, a BGP-specic register
may be needed as an interim measure.

Market interventions and research partnerships


interventions
Increasing attention to the market dynamics of pharmaceutical products in low- and middle-income countries has
emerged in recent years. Organizations such as the United
Nations Childrens Fund, UNITAID, Drugs for Neglected
Diseases Initiative, and the Medicines Patent Pool illustrate
new ways of tackling access to medicines barriers
[98e101]. The RHD community should seek engagement
with these kinds of organizations to tackle BPG supply and
provide ongoing, disease-specic, technical support. Partnerships with other diseases still using BPGyaws and
congenital syphilisare also likely to be important opportunities for strengthening an economically viable BPG
market. Developing relationships with the pharmaceutical
industry to foster research, development, manufacturing
standards, and quality outcomes is a likely prerequisite for
success.

Systems, policy, and applied research


interventions
BPG is already incorporated in the core and subsidiary
WHO EML. Further research is needed to compare national formularies against the EML; if BPG has been
omitted, advocacy for inclusion and supply will be needed
at a national level. At a local level, documenting costs,
stock outages, and administration challenges will be a
critical metric of success for global level advocacy and
partnerships. Innovative inclusion of people living with RF/
RHD may be possible. For example, Stop Stock-outs! is a
campaign for consumers to report medication shortages by
text message in Kenya and Uganda [102]. Constructive,
sustainable improvements at a local level require a health
systems approach. A systems framework allows consumers,
prescribers, and procurers to address forecasting, purchasing, delivery, cost, and other macrodeterminants of
actual medication uptake [103].

SUMMARY
Securing and delivering high-quality supplies of BPG is a
surmountable challenge; powdered formulations are offpatent, xed-dose, do not require a cold chain, and demand can be forecast in predictable volumes for many years.
In comparison to the complexities of early antiretroviral
regimes and vaccination efforts, universal access to BPG is
eminently achievable. Working with novel partners provides
an opportunity to foster integration, avoiding the development of unsustainable monolithic programs for RHD
control [9]. This review and commentary provides a
compilation on the historic and existing issues for BPG
supply and delivery. Global institutional leadership will be

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required to move forward on priority issues for improving


access [95].

ACKNOWLEDGMENTS
The authors are grateful for the feedback and additional
references provided by Professors Bongani Mayosi, Diana
Lennon, and Stanford T. Shulman. Participants in the World
Heart Federations survey on access to BPG are warmly
acknowledged.

REFERENCES
1. Carapetis JR, Steer AC, Mulholland EK, Weber M. The global
burden of group A streptococcal diseases. Lancet Infect Dis 2005;
5:68594.
2. Stollerman GH, Rusoff JH. Prophylaxis against group A streptococcal
infection in rheumatic fever patients: use of new repository penicillin preparation. JAMA 1952;150:15715.
3. Manyemba J, Mayosi B. Penicillin for secondary prevention of rheumatic fever [pdf]. October 7, 2009. Available at: http://onlinelibrary.
wiley.com/doi/10.1002/14651858.CD002227/pdf. Accessed.
4. Strasser T, Dondog N, El Kholy A, et al. The community control of
rheumatic fever and rheumatic heart disease: report of a WHO
international cooperative project. Bull World Health Organ 1981;59:
28594.
5. Gerber MA, Baltimore RS, Eaton CB, et al. Prevention of rheumatic
fever and diagnosis and treatment of acute streptococcal pharyngitis: a scientic statement from the American Heart Association
Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee on
the Council of Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology,
and the Interdisciplinary Council on Quality of Care and Outcomes
Research. Circulation 2009;119:154151.
6. Wood HF, Feinstein AR, Taranta A, Epstein JA, Simpson R. Rheumatic
fever in children and adolescents: a long-term epidemiologic study
of subsequent prophylaxis, streptococcal infections and clinical
sequelae. III. Comparative effectiveness of three prophylaxis regimes
in preventing streptococcal infections and rheumatic recurrences.
Ann Intern Med 1964;60:3146.
7. Heart Foundation of New Zealand and The Cardiac Society of Australia
and New Zealand. New Zealand Guidelines for Rheumatic Fever [pdf].
June 2006. Available at: http://www.heartfoundation.org.nz/uploads/
Rheumatic%20fever%20guideline%201(2).pdf Accessed.
8. World Heart Federation. Diagnosis and Management of Acute Rheumatic Fever and Rheumatic Heart Disease [pdf]. October 2008. Available
at: http://www.world-heart-federation.org/leadmin/user_upload/
documents/RHD-net/RHD%20Curriculum.Oct.2008.pdf Accessed.
9. World Health Organization. Rheumatic Fever and Rheumatic Heart
Disease. WHO Technical Report Series 923 [pdf]. 2001. Available at:
http://whqlibdoc.who.int/trs/WHO_TRS_923.pdf. Accessed.
10. RHD Australia (ARF/RHD Writing Group), National Heart Foundation
of Australia and the Cardiac Society of Australia and New Zealand
Australian Guideline for Prevention, Diagnosis and Management of
Acute Rheumatic Fever and Rheumatic Heart Disease. 2nd edition
[pdf]. 2012. Available at: http://www.rhdaustralia.org.au/sites/
default/les/guideline_0.pdf. Accessed.
11. Western Cape Government, South Africa. National Guidelines on
Primary Prevention and Prophylaxis of Rheumatic Fever (RF) and
Rheumatic Heat Disease (RHD) for Health Professionals at Primary
Level [pdf]. 2003. Available at: http://www.kznhealth.gov.za/chrp/
documents/Guidelines/Guidelines%20National/Rheumatic%20Heart
%20Disease/Rheumatic%20heart%20disease%20ndoh.pdf. Accessed.
12. King Pharmaceuticals. Bicillin-LA (penicillin g benzathine) Injection,
Suspension. Archived drug label. 2007. Available at: http://dailymed.
nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid5765.
Accessed.

231

gREVIEW

13. Pzer. Bicillin L-A [pdf]. 2009. Available at: http://labeling.pzer.


com/ShowLabeling.aspx?id691. Accessed.
14. Stollerman GH, Rusoff JH, Hirschfeld I. Prophylaxis against group A
strepotocci in rheumatic fever: the use of single monthly injections
of benzathine penicillin G. N Engl J Med 1955;252:78792.
15. Currie B. Benzathine penicillindown but not out. Northern Territory Dis Control Bull 2006;13:13.
16. Gutmann L, Tomasz A. Penicillin-resistant and penicillin-tolerant
mutants of group A streptococci. Antimicrob Agents Chemother
1982;22:12836.
17. Horn D, Zabriskie JB, Austrian R, et al. Why have group A streptococci remained susceptible to penicillin? Report on a symposium.
Clin Infect Dis 1998;26:13415.
18. Macris MH, Hartman N, Murray B, et al. Studies of the continuing
susceptibility of group A streptococcal strains to penicillin during
eight decades. Pediatr Infect Dis J 1998;17:37781.
19. Cameron D, Gaito A, Harris N, et al, ILADS Working Group. Evidencebased guidelines for the management of Lyme disease. Expert Rev
Anti Infect Ther 2004;2(Suppl 1):S113.
20. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment,
treatment, and prevention of Lyme disease, human granulocytic
anaplasmosis, and babeiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006;43:
1089134.
21. Nascimento-Caralho C. Penicillin prophylaxis for sick cell disease.
Arch Dis Child 2002;87:21.
22. Kassem AS, Zaher SR, Abou Shleib H, el-Kholy AG, Madkour AA,
Kaplan EL. Rheumatic fever prophylaxis using benzathine penicillin
G (BPG): Two-week versus four-week regimes: comparisons of two
brands of BPG. Pediatrics 1996;97:9925.
23. Lue H, Wu MH, Hsieh KH, Lin GJ, Hsieh RP, Chiou JF. Rheumatic fever
recurrences: controlled study of 3-week versus 4-week benzathine
penicillin prevention programs. J Pediatr 1986;108:229304.
24. Lue H, Wu MH, Wang JK, Wu FE, Wu YN. Long-term outcome of
patients with rheumatic fever receiving benzathine penicillin G
prophylaxis every three weeks versus every four weeks. J Pediatr
1994;125:8126.
25. Spinetto H, Lennon D, Horsburgh M. Rheumatic fever recurrence
prevention: A nurse-led programme of 28-day penicillin in an area
of high endemnicity. J Paediatr Child Health 2011;47:22834.
26. Irlam J, Mayosi BM, Engel M, Gaziano TA. Primary prevention of
acute rheumatic fever and rheumatic heart disease with penicillin in
South African children with pharyngitis: a cost-effectiveness analysis. Circ Cardiovasc Qual Outcomes 2013;6:34351.
27. Pickering L, editor. Group A streptococcal infections, in Red Book
2006: Report of the Committee on Infectious Diseases. Elk Grove
Village, IL, USA: American Academy of Pediatrics; 2006. p. 61020.
28. Kaplan EL. The group A streptococcal upper respiratory tract carrier
state: an enigma. J Pediatr 1980;97:33745.
29. World Health Organization. Global Prevalence and Incidence of
Selected Curable Sexually Transmitted Infections [pdf]. 2001. Available at: http://whqlibdoc.who.int/hq/2001/WHO_HIV_AIDS_2001.
02.pdf. Accessed.
30. Blencowe H, Cousens S, Kamb M, Berman S, Lawn JE. Lives Saved
Tool supplement detection and treatment of syphilis in pregnancy
to reduce syphilis related stillbirths and neonatal mortality. BMC
Public Health 2011;11(Suppl 3):S9.
31. Workowski KA, Berman S, CDC. Sexually transmitted diseases
treatment guidelines, 2010. MMWR Recomm Rep 2010;59:1110.
32. Bai Z, Wang B, Yang K, et al., Azithromycin vs penicillin G benzathine
for early syphilis, in Cochrane Review. 2012. Available at:. Accessed.
33. World Health Organization, Division of Emerging, Viral, and Bacterial
Diseases Surveillance and Control. Informal Consultation on
Endemic Treponematoses: Report of an Informal Consultation,
Geneva, Switzerland, 6e7 July 1995. Technical Report WHO/EMC/
95.3. Geneva, Switzerland: World Health Organization; 1995.
34. World Health Organization. Yaws. Fact sheet no. 316. October 2012.
Available at: http://www.who.int/mediacentre/factsheets/fs316/
en/. Accessed May 15, 2013.

232

35. Mitj O, Hays R, Rinaldi AC, McDermott R, Bassat Q. New treatment


schemes for yaws: the path toward eradication. Clin Infect Dis 2012;
55:40612.
36. Guthe T. Benzathine penicillin in the management of treponematoses. Br J Vener Dis 1955;31:16074.
37. Apat JK, Brady JE, Elias WF. Stabilized Benzathine Penicillin Compositions. U.S. Patent 3351527. Washington, DC, USA: U.S. Patents
Ofce; 1967.
38. Wright W. Benzathine penicillin G. JAMA 1954;156:1527.
39. Lan G. Availability of benzathine penicillin (reply). inTouch 2006;23:6.
40. Loudon J. Pan benzathine penicillin protocol. Department of Health and
Community Services; 2006. Available at: http://www.carpa.org.au/Pan
%20Benz%20advocacy%20memo%20nal.pdf. Accessed September 4,
2013.
41. Hebi Huari Pharmaceuticals. Introduction [web page]. 2010. Available
at: http://www.huari-pharm.com/en/view.aspx?cid46. Accessed
January 27, 2013.
42. UNICEF, WHO. Sources and prices of selected medicines for children.
2nd edition. April 2010. Available at: http://www.who.int/medicines/
publications/essentialmedicines/Sources_Prices2010.pdf. Accessed
September 4, 2013.
43. Australian Government, Department of Health and Aging. Schedule
of Pharmaceutical Benets: Summary of Changes [pdf]. August 1,
2008. Available at: http://www.pbs.gov.au/publication/schedule/2
008/2008-08-01-general-schedule-soc.pdf. Accessed.
44. Schultz R. Benzathine penicillin. inTouch 2006;23:4.
45. Anonymous. Statement regarding Bicillin L-A (Reply). inTouch 2006;
23:6. Available at: http://www.phaa.net.au/documents/intouch_
sep06.pdf. Accessed September 4, 2013.
46. Kaplan EL, Zaher SR. Benzathine penicillin formulations. Pediatr
Infect Dis J 2004;23:5923.
47. HIV, STD and Hepatitis Prevention Branch, Public Health Services,
Health and Human Services Agency, County of San Diego. Information
regarding availability of benzathine penicillin [memo]. June 22, 2005.
Available
at:
http://www.sdcounty.ca.gov/hhsa/programs/phs/
documents/STDHEP17.pdf. Accessed.
48. Anonymous. King Pharmaceuticals Announces FDA Approval of
New Bicillin Manufacturing Facility [press release]. February 21,
2007. Available at: http://nance.boston.com/boston/news/
read/1410647/king_pharmaceuticals_announces_fda_approval_of_
new_bicillin. Accessed January 26, 2013.
49. Sorkin AR. Pzer to buy King Pharmaceuticals for $3.6 Billion. New
York Times. Available at: http://dealbook.nytimes.com/2010/10/12/
pzer-to-buy-king-pharmaceuticals-for-3-6-billion/?_r0; October
12, 2010. Accessed August 26, 2013.
50. Schaller J. The Impact of War on Child Health in the Countries of the
Former Yugoslavia. Institute of Medicine (U.S) Committee on the
Impact of War in the Countries of the Former Yugoslavia. Washington, DC, USA: National Research Council (U.S), Ofce of International Affairs; 1994.
51. Benzathine penicillin for syphilis. Coll Pharm B C 2003;27:6.
52. Scolnick D, Aronson L, Lovinsky R, et al. Efcacy of a targeted, oral penicillin-based yaws control program among
children living in rural South America. Clin Infect Dis 2003;36:
12328.
53. Blue J. Kids Still Missing Out on Effective Penicillin for Rheumatic
Fever. 2008. Available at: http://www.scoop.co.nz/stories/PA0704/
S00363.htm. Accessed January 27, 2013.
54. Kaakeh R, Sweet BV, Reilly C, et al. Impact of drug shortages
on the U.S. health systems. Am J Health Syst Pharm 2011;68:
e1321.
55. Douglas J, National Center for HIV, STD and TB Prevention, Centers
for Disease Control and Prevention. Availability of Bicillin-LA for
Treatment of Syphilis [memo]. August 22, 2005. Available at: http://
www.cdc.gov/std/Syphilis/BicillinLA8-22-05.pdf. Accessed.
56. Taubert K, Marko S. Access to essential medicines: illuminating
disparities in the global supply of benzathine penicillin G in the
context of rheumatic fever/rheumatic heart disease. J Am Coll
Cardiol 2013;61(Suppl 10):e-2004.

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 227-234

gREVIEW

57. United Nations Childrens Fund. Who is eligible for UNICEF procurement services? [web page]. May 26, 2012. Available at: http://
www.unicef.org/supply/index_10363.html. Accessed May 5, 2013.
58. Pham PA, Bartlett JG. HIV GuideZambia [web page]. October 20, 2010.
Available from: http://www.zambiahivguide.org/drugs/antimicrobial_
agents/benzyl_penicillin.html?contentInstanceId441458#. Accessed
May 13, 2013.
59. Kibira H. Kenya: Heart Foundation Battles Childrens Illness [news
article]. Star, July 12, 2013 Available at: http://allafrica.com/
stories/201307121316.html. Accessed.
60. Australian Government, Department of Health and Aging. Benzathine Benzylpenicillin Powder for Injection. 2012. Available at:
http://www.pbs.gov.au/publication/schedule/2013/08/2013-08-01general-schedule.pdf. Accessed July 9, 2012.
61. Anonymous. Bicillin C-R and Bicillin L-A labels changed to avoid
confusion. ObGynNews; January 1, 2005. p. 5.
62. Centers for Disease Control and Prevention. Inadvertent use of
Bicillin C-R to treat syphilis infectionLos Angeles, California,
1999e2004. MMWR Morb Mortal Wkly Rep 2005;54:2189.
63. Anonymous. Bicillin CR 900/300. Available at: http://labeling.pzer.
com/showlabeling.aspx?id=692 2013. Accessed August 30, 2013.
64. Carapetis JR, Zuhlke L. Global research priorities in rheumatic fever
and rheumatic heart disease. Ann Paediatr Cardiol 2011;4:412.
65. Kaplan EL. Benzathine penicillin G: a documentably important
antibiotic in need of a tune up? Pediatr Infect Dis J 2012;317:7268.
66. Broderick MP, Hansen CJ, Russell KL, Kaplan EL, Blumer JL, Faix DJ.
Serum penicillin G levels are lower than expect in adults within two
weeks of administration of 1.2 million units. PLoS One 2011;6:
e25308.
67. Health Canada. Notice of Compliance Search Results. 2012. Available at: http://webprod5.hc-sc.gc.ca/noc-ac/search-recherche.do?
langeng. Accessed July 12, 2013.
68. World Health Organization. WHO Model Prescribing Information:
Drugs Used in the Treatment of Streptococcal Pharyngitis and
Prevention of Rheumatic Fever [pdf]. 1999. Available at: http://
apps.who.int/medicinedocs/pdf/s2252e/s2252e.pdf. Accessed.
69. Shahbazi M, Azimi K, Hamidi M. Benzathine penicillin G: a model for
long-term pharmacokinetic comparison of parenteral long-acting
formulations. J Clin Pharm Ther 2013;38:1315.
70. Hottinger M, Liang B. Deciencies of the FDA in evaluating generic
formulations: addressing narrow therapeutic index drugs. Am J Law
Med 2012;38:66789.
71. Broderick MP, Hansen CJ, Faix DJ. Factors associated with loss of
penicillin G concentrations in serum after intramuscular benzathine
penicillin G injection: a meta-analysis. Pediatr Infect Dis J 2012;31:
7225.
72. Allergic reactions to long-term benzathine penicillin prophylaxis for
rheumatic fever. International Rheumatic Fever Study Group. Lancet
1991;337:130810.
73. World Health Organization. Benzathine penicillin: three fatal reports
following mega unit injections. Drug Inform Bull 2000;4:2000.
74. Amin RM, Basher A, Zaman F, Faiz MA. Global eradication of yaws:
neglected disease with research priority. J Med 2009;10:10914.
75. Public Health Agency of Canada. Protocol for the Preparation of
Benzathine Penicillin [web page]. August 10, 2006. Available at:
http://www.phac-aspc.gc.ca/std-mts/protocol-eng.php. Accessed
May 13, 2013.
76. Gov N. Pan benzathine administration. In: Best Practice Communique. Northern Territory Government, Remote Health Branch; 2007.
Available at:. Accessed.
77. Laing R, Waning B, Gray A, Ford N, t Hoen E. 25 years of the WHO
essential medicines list: progress and challenges. Lancet 2003;361:
17239.
78. van dem Ham R, Bero L, Laing R. The World Medicines Situation 2011:
Selection of Essential Medicines [pdf]. 2011. Available at: http://apps.
who.int/medicinedocs/documents/s18770en/s18770en.pdf. Accessed.
79. World Health Organization, International Planned Parenthood
Federation, John Snow Inc., PATH, Population Services International,
United Nations Population Fund, World Bank. The Interagency List of

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 227-234

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

Essential Medicines for Reproductive Health [pdf]. 2006. Available at:


http://whqlibdoc.who.int/hq/2006/WHO_PSM_PAR_2006.1_eng.pdf.
Accessed.
World Health Organization. The Selection and Use of Essential
Medicines: Report of the WHO Expert Committee. October 2007
(including the Model List of Essential Medicines for Children) [pdf].
WHO Technical Report Series 950. 2008. Available at: http://
whqlibdoc.who.int/trs/WHO_TRS_950_eng.pdf. Accessed.
World Health Organization. WHO Model List of Essential Medicines.
18th List, April 2013. Available at: http://www.who.int/medicines/
publications/essentialmedicines/18th_EML_Final_web_8Jul13.pdf.
Accessed August 20, 2013.
Beggs S, Peterson G, Tompson A. Antibiotic Use for the Prevention
and Treatment of Rheumatic Fever and Rheumatic Heart Disease in
Children: Report for the 2nd Meeting of World Health Organizations
Subcommittee of the Selection and Use of Essential Medicines [pdf].
September 29 to October 3, 2008. Available at: http://www.who.int/
selection_medicines/committees/subcommittee/2/RheumaticFever_
review.pdf. Accessed.
Gasse B, Baroux N, Rouchon B, Meunier JM, Frmicourt ID,
DOrtenzio E. Determinants of poor adherence to secondary antibiotic
prophylaxis for rheumatic fever recurrence on Lifou, New Caledonia: a
retrospective cohort study. BMC Public Health 2013;13:131.
Pelajo CF, Lopez-Benitez JM, Torres JM, de Oliveira SK. Adherence to
secondary prophylaxis and disease recurrence in 536 Brazilian children
with rheumatic fever. Pediatr Rheumatol Online J 2010;8:22.
Eissa S, Lee R, Binns P, Garstone G, McDonald M. Assessment of a
register-based rheumatic heart disease secondary prevention program in an Australian Aboriginal community. Aust N Z J Public
Health 2005;29:5215.
Kimbally-Kaky G, Gombet T, Voumbo Y, et al. [Rheumatic heart
disease in children in Brazzaville]. Med Trop (Mars) 2008;68:6035
[French].
Musoke C, Mondo CK, Zhang W, et al. Benzathine penicillin adherence for secondary prophylaxis among heart patients affected with
rheumatic heart disease attending Mulago Hospital. Cardiovasc J
Africa 2013;24:1249.
Tullu M, Ghandi A, Ghildiyal R. Benzathine penicillin prophylaxis in
children with rheumatic fever/rheumatic heart disease: a study of
compliance. Al Ameen J Med Sci 2010;3:1405.
Petricca K, Mamo Y, Haileamlak A, Seid E, Parry E. Barriers to effective
follow-up treatment for rheumatic heart disease in Jimma, Ethiopia: a
grounded theory analysis of the patient experience. Ethiopian J Health
Sci 2009;19:3944.
Counties Manakau District Health Board. Procedure: Administration of
Bicillin Injections in the Community [pdf]. 2011. Available at: http://
www.heartfoundation.org.nz/uploads/Administration%20of%20Bicillin
%20Injections%20in%20the%20Community%20-%20Procedure.pdf.
Accessed.
Amir J, Ginat S, Cohen YH, Marcus TE, Keller N, Varsano I. Lidocaine
as a diluent for administration of benzathine penicillin G. Pediatr
Infect Dis J 1998;17:8903.
Morsy M, Mohamed MA, Abosedira MM. Lidocaine as a dilutant for
benzathine penicillin G reduces injection pain in patients with
rheumatic fever: a prospective, randomized, double-blinded crossover study. Australian J Basic Appl Sci 2012;6:23640.
Maguire GP, Carapetis JR, Walsh WF, Brown AD. The future of
rheumatic fever and rheumatic heart disease in Australia. Med J
Aust 2012;197:1334.
Holnda e Silva KG, Xavier-Junior FH, Farias IEG, et al. A new insight
about pharmaceutical dosage forms for benzathine penicillin G. J Basic
Appl Pharm Sci 2006;27:216.
Remenyi B, Carapetis J, Wyber R, Taubert K, Mayosi BM. Position
statement of the World Heart Federation on the prevention and
control of rheumatic heart disease. Nat Rev Cardiol 2013;10:
28492.
Roberts K, Colquhoun S, Steer A, Remnyi B, Carapetis J. Screening
for rheumatic heart disease: current approaches and controversies.
Nat Rev Cardiol 2013;10:4958.

233

gREVIEW

97. Ossen S, Pal SN, Stergachis A, Couper M. Pharmacovigilance activities in 55 low- and-middle income countries: a questionnaire-based
analysis. Drug Saf 2010;33:689703.
98. UNITAID. Annual Report 2011: Five Years of Innovation for Better
Health [pdf]. 2011. Available at: http://www.unitaid.eu/images/
Annual_Report_2011/UNITAID_AR2011_EN.pdf. Accessed.
99. United Nations Childrens Fund. Supply Annual Report 2011 [pdf].
2011. Available at: http://www.unicef.org/supply/les/UNICEF_
Supply_Annual_Report_2011_web.pdf. Accessed.
100. Medicines Patent Pool. Annual Report 2010e2011 [pdf]. 2011.
Available at: http://www.medicinespatentpool.org/wp-content/

234

uploads/Medicines-Patent-Pool-Annual-Report-2010-2011-RevFinal.
pdf. Accessed.
101. Drugs for Neglected Diseases Initiative. 2011 Annual Report:
Towards Sustainable Change for Neglected Patients [pdf]. 2011.
Available at: http://www.dndi.org/images/stories/annual_report/
2011/DNDi_Annual%20report%202011_low-res.pdf. Accessed.
102. Stop Stock-Outs! Ensure Access to Essential Medicines for All [pdf].
2013. Available at: http://stopstockouts.org/. Accessed May 25, 2013.
103. Bigdeli M, Jacobs B, Tomson G, et al. Access to medicines from a
health system perspective. Health Policy Plan 2012 Nov 22 [E-pub
ahead of print].

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The Importance of Awareness and Education in


Prevention and Control of RHD
Liesl J. Zhlke*,y,z, Mark E. Engel*
Cape Town, South Africa
ABSTRACT
Acute rheumatic fever and rheumatic heart disease are diseases of poverty, low socioeconomic status, and
inadequate access to health care. These preventable diseases remain largely ignored by the developed world
while they continue to cause signicant mortality and morbidity in the developing world. In the face of no
existing cure, we need to focus on prevention and control methods. To this end, creating awareness of the
disease and its effects on millions of people in the world is critically important. In this review, we will
outline the importance of these efforts, discuss the barriers to awareness and education, and highlight
some important models in this arena. We strongly support awareness-raising and health promotion
strategies as an integral part of a rheumatic heart disease prevention and control program.

Acute rheumatic fever (ARF) and rheumatic heart


disease (RHD) are diseases of poverty, low socioeconomic
status, and poor access to health care that remain endemic
in developing and emerging economies while being largely
ignored by the developed world [1]. It is conservatively
estimated that there are over 15 million cases of RHD
worldwide, with 282,000 new cases and 233,000 deaths
annually. Until such time that far-reaching socioeconomic
changes take place throughout the world, and in the face of
no existing cure, we need to focus on prevention and
control methods that can help to stem the tide of ARF/
RHD. Thus, the importance of creating awareness of the
disease and its sequelae cannot be underestimated,
particularly in resource-limited conditions. The importance
of these efforts needs to be recognized and barriers to
awareness and education understood and overcome while
health promotion research for ARF and RHD is prioritized.

IMPORTANCE OF AWARENESS AND EDUCATION


Over the last 2 decades, increasing emphasis has been
placed on health communication strategies that are
collaboratively designed, implemented, and evaluated [2].
Consequently, various successful strategic health communications campaigns have been developed, notably in
the human immunodeciency virus/acquired immune
deciency syndrome arena. However, as regards ARF/
RHD, it is well known that as the incidence of ARF
waned in the developed world, so did the awareness of
and attention to this global public health problem. This
has resulted in limited funding for RHD activities,
decrease in research and publications, and reduced
mention of RHD in textbooks published in more afuent
parts of the world [3]. This is despite the reality that
although ARF and RHD are almost exclusively restricted
to developing countries, they have mortality rates

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September 2013: 235-239

comparable to that of rotavirus, and about 50% of that of


malaria, and they are still the most common cause of
acquired heart disease in the world [4,5].
Establishing the true burden of disease of RHD and ARF
is particularly important when considering methods to
control RHD, assigning priority to specic efforts, and
informing policy. A key element of establishing the true
burden of disease lies in case detection of both ARF and
RHD. Maximized case detection within a community implies
that all members of that community are aware of the presentation and diagnosis of the disease, with the highest
awareness needed among healthcare workers at the primary
healthcare level. In South Africa, where disease notication is
mandatory, a review of notications has demonstrated that
the legal requirement to notify has not been sufciently
stressed nor has notication been correctly implemented,
resulting in poor capture of the burden of ARF [6]. Studies
have shown that ARF is underdiagnosed in primary healthcare clinics in developing countries and that there is an
increasing burden of RHD on autopsy in the same population [7]. It is feasible that these studies demonstrate the real
possibility of multiple missed diagnoses and their tragic
consequences.
Improving community awareness has been demonstrated by programs incorporating public education campaigns into their RHD control strategies as a vital element.
It is critical that public awareness of the role of group A
streptococcal (GAS) pharyngitis and its potential consequences are addressed, as this will result in increased
health-seeking behavior regarding sore throat as well as
earlier presentation with signs and symptoms consistent
with ARF. School and educational institutions should be
targeted, as the most vulnerable population for GAS
infections are school-aged children. These institutions have
tremendous potential to improve the reach of primary and
secondary prevention and case detection.

L. Zhlke is funded by the


Thrasher Foundation,
Clinical Infectious Disease
Research Initiative, and the
Hamilton Naki Clinical
Scholarship Programme,
which is funded by Netcare
Limited.
This paper is partially
based on an address given
at the Postgraduate Course
on Rheumatic Heart
Disease Challenges and
Opportunities at the
Seventh Global Forum on
Humanitarian Medicine in
Cardiology and Cardiac
Surgery, June 20 to 22,
2011, Geneva, Switzerland.
From the *Red Cross War
Memorial Childrens Hospital, Cape Town, South
Africa; yDepartment of
Medicine, Groote Schuur
Hospital, Cape Town, South
Africa; zUniversity of Cape
Town, Cape Town, South
Africa. Correspondence:
L. J. Zhlke (liesl.zuhlke@
uct.ac.za).
GLOBAL HEART
2013 Published by
Elsevier Ltd. on behalf of
World Heart Federation
(Geneva).
VOL. 8, NO. 3, 2013
ISSN 2211-8160/$36.00.
http://dx.doi.org/10.1016/
j.gheart.2013.08.009

235

gREVIEW

Despite the fact that RHD is the leading cause of acquired


heart disease in the world and a key contributor to the
burden of chronic cardiovascular diseases in the world today
[8], there remains insufcient political incentive to control
global cardiovascular disease, let alone address cardiovascular diseases limited to the poor. Yet, the burden of disease
has major health, economic, and even sociodevelopmental
consequences [9]. A key priority is creating political awareness around this disease and building organizational structures to promote control activities that will be supported by
national funding and concerted political will.

BARRIERS TO AWARENESS AND EDUCATION


It has been concerning to note from several reports that the
level of awareness of ARF/RHD is low in the communities
most affected by it. The vast majority of clinicians (87%) in
a study from Tanzania felt that their patients and families
were unaware of the consequences of untreated GAS
infection [10]. Even patients with RHD had poor knowledge of the connection between GAS and RHD, a nding
also prevalent in South Africa, and where most patients and
their guardians had not yet heard of RHD until they were
diagnosed with the condition, demonstrating a low level of
awareness in the general community [11].
There are some possible explanations for this phenomenon. The countries dealing with RHD are, understandably, dealing with other serious health priorities. Only
38% of the respondents in the Tanzania study felt that their
clinic prioritized the diagnosis and treatment of GAS
infection; in fact, clinicians were in conict over the
possible inference with other priority health concerns such
as malaria and tuberculosis [10]. Furthermore, the human
immunodeciency virus pandemic has inicted untold
mortality in sub-Saharan Africa. In addition, access to
health care and healthcare resources are, almost by denition, restricted and under-resourced in these areas with
endemic RHD. Faced with human resource and organizational crises in health in many parts of the world, it is clear
that more resources in terms of staff and structure are
needed to care for the millions of people living with RHD.
In sub-Saharan Africa, it is claimed that the inadequacies in
the health workforces are the greatest impediment to
health, with a decit of 2.4 million doctors and nurses [12].
Only 1.3% of the worlds health workers care for people
who experience 25% of the global disease burden. The
consequences for some countries are dire, with completely
inadequate services to rural and primary care settings,
which are the very focus of an effective prevention and
treatment program for ARF/RHD [13].
Another dichotomy is the high levels of ARF/RHD in the
pockets of indigenous people living beside their more
afuent neighbors. This stark disparity is evident in New
Zealand and Australia [14,15], as well as in South Africa and
Brazil, with high-income inequality rates among their populations [16]. Together with these disparities are gaps
perpetuated in the training of medical personnel. Teaching

236

in the countries most affected by ARF/RHD tends to mimic


that in developed countries and is unlikely to take into
account differences in public, private, and primary healthcare strategies. It is crucial that medical education in developing countries be dened by the needs and services
required by the majority of the people [17]. We have recently
seen, though, that the importance of integrated primary
healthcare services and management of chronic diseases is
gaining momentum and the articial dichotomy between
diseases is slowly receding in favor of a combined approach
that will benet all conditions. This is of particular importance in 2013, following the U.N. Global Summit on NonCommunicable Diseases and as developing countries
struggle with the impending (and rapidly approaching)
burden of noncommunicable diseases [5,18]. This integration of comprehensive services, especially within existing
and established primary and secondary healthcare structures, should be strongly supported by clinicians, policy
makers, and the community.
Although physicians report attempts to educate patients
on the causes of their disease, pathogenesis, and the
importance of adhering to secondary prophylaxis, patients
still have very low levels of understanding regarding the
specics of their disease. There are several coinciding factors
involved. Although younger patients may not understand
the complexity of the disease processes, this trend seemed to
be evident in older patients as well. Also, caregivers
accompanying patients are often different individuals on
each visit to the clinic/hospital. Language also plays a very
important role [19]. We need to recognize the importance of
performing these explanations in the local language
observing cultural observances and levels of literacy and
understanding. Even complex concepts can be clearly understood, given appropriate communication strategies.
Awareness of the patients needs and cultural background
should take precedence in the conversation around expectations of adherence and follow-up. It is known that physicians explanations and the level of patients understanding
signicantly affect treatment adherence, treatment outcome,
and patients satisfaction [20]. We need to be critically aware
of these issues when communicating with patients and their
caregivers, select health information that is appropriate to
the clients level of understanding, and employ a systematic
approach utilizing a variety of mechanisms (e.g., printed
material, displays, videos, and discussions) to educate and
improve awareness in and stress motivating principles, cultural relevance, and feasibility.
Finally, RHD has not been called a disease of social
injustice without good reason [21]. It has long fallen
between the cracks, and without commercial interests or
dynamic action groups to drive intervention, it remains a
neglected disease. This has resulted in the lack of political
will to signicantly improve awareness and education of the
disease in communities and schools. The onus thus falls on
the medical community to take up the challenge of advocating for the return of diseases of the poor such as RHD to
the political agenda.

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gREVIEW

BEST PRACTICE MODELS


Several programs have reshaped the landscape in terms of
RHD control and achieved remarkable successes. The
programs of the 1950s based in Baltimore and New York
not only set the scene for RHD control activities, but they
also gathered important epidemiological evidence to
document important trends. A comprehensive community
program was suggested by Grifth in 1949 [22] that
stressed the importance of community organization to
combat the disease, especially in the face of the socioeconomic, psychological, and epidemiological aspects of the
disease. The importance of education in early case detection
is emphasized, as well as utilizing lessons learned from
other infectious diseases programs such as tuberculosis
interventions. Although this community was experiencing a
gradual decline in the incidence of ARF, these and other
similar initiatives resulted in a precipitous fall in the incidence of ARF.
A remarkable model has been implemented by
Martinique Guadeloupe and Cuba [11,23]. Here, a
comprehensive 10-year plan was initiated with education,
with awareness strategies at all levels, and with primary and
secondary prevention delivered through a registry as the
mainstays of the program. Communication efforts were
strengthened by a multichannel approach, targeting several
areas, as well as mass media, to reach as many people as
possible. All health messages were coordinated centrally to
ensure consistency, which also offered synergy to the
campaign. In the French Caribbean Islands, a rapid decline
in ARF incidence was achieved at modest cost and an overall
reduction of ARF by 78% in Martinique and 74% in
Guadeloupe. In Cuba, similar reductions in incidence of
ARF, prevalence of RHD, and cost were followed-up for 5
years subsequent to the study. Years after the project ended,
most of the measures initiated at the start of the program
were still in place and occurrence of ARF/RHD remained
low.
More recently, 2 programs initiated in and by communities affected by RHD have established important programs
in their regions. The Pacic Rheumatic Heart Disease Control Program has focused on health education and promotion while stressing secondary prevention delivered through
an effective register-based system [24]. Importantly, this
program is now self-supporting and run by individuals from
the Pacic Islands. Critical to the success of this program was
identication of key priorities a priori and setting realistic
and focused goals. This is key to eventual evaluation of such
intricate community interventions. Education has been
directed at all levels, and multiple channels have been used to
disseminate information. Clinical care has also been
addressed with the incorporation of clinical care coordination, standardized delivery methods, and case-nding
activities [24,25].
The Pan-African Society of Cardiology convened a
meeting of cardiologists from all over Africa in 2005 that
resulted in a uniform plan for the control of RF and RHD in

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September 2013: 235-239

Africa. That plan, the ASAP (Awareness Surveillance Advocacy Prevention) program, details the 4 pillars imperative in
the goal to eradicate RHD in our lifetime [26,27]. The
primary objective of this program was to create a simple,
modular, but comprehensive model for RF/RHD control in
Africa, building on the best evidence-based interventions, to
be adopted by national departments of health and countries/
organizations with a combined commitment to reducing the
burden of disease attributable to RF/RHD in Africa. This
program has galvanized efforts in Africa and the world [28]
and has lead the way to establishing demonstration sites
across Africa [29]. Currently, a large multicenter study,
coordinated from Cape Town and involving sites all over
Africa and including India, the middle East, and South
America, is seeking to collect prospective data and document
the course of morbidity and mortality of this neglected disease [30]. Like the example of Boston and Baltimore in the
1950s, this study will be a source of valuable information for
governments as they formulate policy and guidelines for the
control and treatment of RHD.

STRATEGIES TO IMPROVE AWARENESS AND


EDUCATION AROUND ARF/RHD
The key element in successful health program is strategic
design. To improve health in a lasting and signicant way, it is
critical to initiate health promotion strategies that are collaboratively designed, locally adapted, implemented on multiple
levels, and comprehensively evaluated [31]. Although it was
initially thought that medical communication related only to
the doctor addressing the patient, the medical monologue, we
now see the limited reach this strategy has had. We have
moved into the era of strategic communication characterized
by multichannel integration, multiplicity of stakeholders,
attention to evaluation, and evidence-based programming,
and the use of mass media, social networks, and a conversation communication process [32].
Some important characteristics to consider follow:
 Integrated services with, for example, RHD and maternal
and child health serviced by noncommunicable disease
staff: Other aligned programs such as integrated management of childhood illnesses lends itself to incorporating important RHD messages such as sore throat
diagnosis and management [33].
 Integrated communication messages: Heart health for
kids includes not only RHD, but also healthy eating
habits, exercise, and nonsmoking.
 Mobile phones and health: Africas mobile usage has
been growing by almost 50% annually, which is faster
than any other region of the world. Cellphone usage in
Africa has jumped from 63 million users 2 years ago to
152 million today. This provides us a unique opportunity to educate people at a fraction of the cost of
individual efforts while being language-, culture-, and
age-sensitive [34,35].

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 Role of electronic media and social networks such as


Twitter and Facebook: Video sites such as YouTube have
also made connections with the younger generation, the
ones most at risk [36,37].
 Involvement of the local community is mandatory with a
strong consultative process: It is particularly important in
indigenous communities such as Aboriginal Australians or
Yoruba tribes in Africa to respect cultural differences and
observe religious and cultural practices [38].
 Increased attention to evaluation and evidenced-based
programming: Finally, increased attention to evaluation
and evidenced-based programming will provide much
needed data to inform and strengthen the process. Evaluations of complex interventions are not without their
problems, especially if the intervention has not been fully
dened and developed. Therefore, it is essential to create a
framework for the design and evaluation of such complex
interventions de novo [39].
The overarching component of an effective health
communication program, however, remains a powerful,
well-articulated, long-term vision. This needs to reect the
core values and beliefs of the team and the shared scenario
for the future. It should stimulate teamwork and inspire a
concerted, committed effort in creating constructive conversations around the core messages.

RESEARCH PRIORITIES
In order to strongly advocate for the widespread adoption of
strategies employed in other countries, it is essential that
evaluation, particularly to determine cost, cost-effectiveness,
practicality, sustainability, and cultural acceptance be performed prior to scaling-up these programs. To date, there
have been only 2 economic analyses of RHD control, based
on data collected in the United States in the mid-20th century and few robust analyses of RHD awareness and education programs [40,41]. There is a strong need for these
analyses to determine disease estimates (using disability- and
quality-adjusted life-years) and for cost-benet and costeffectiveness analyses to model the most appropriate
approach for RHD control in developing countries.
RHD falls squarely within the 2 major disease paradigms
(i.e., infectious and noninfectious), and disease control
activities have suffered from this unusual position. Yet, this is
an articial distinction in many ways, and it is increasingly
clear that there is a need for diagonal models of integrative
health rather than horizontal or vertical silos. RHD control
programs lie mainly within primary health care, both for
effective management of GAS infections and delivery of
secondary prophylaxis. We need to examine the role of
centralized community-based care structures incorporating
community-health workers/noncommunicable disease
nurses/heath ofcers in effecting RHD control. This promises to be the most sustainable model in resource-poor settings where task-shifting and differently trained cadres of
medical personnel carry a large burden of the preventative
activities [42].

238

The importance of increased awareness in patients,


caregivers, and the community is clear and will have farreaching effects. By raising awareness within the community, we in turn will inuence case detection, raise the prole
of the disease, advocate effectively for our patients, and,
hopefully, mobilize political will. Therefore, it is important
that communities efforts be designed effectively to achieve the
desired health outcomes. To date, the best methods to do this
have not been systematically evaluated. For communication
strategies to succeed, they need to be science- and researchbased with a focus on the formative data and to have identied the solutions, audience, and mechanisms necessary to
evaluate the outcomes.
With all communication and promotional strategies,
consideration should always be given to the possibility of
expansion to scale and sustainability. Mass media campaigns
are easier to scale up than community interventions are, and
this should be part of the initial design if it would be
required at a later stage. Health promotion and communication strategies need a long-term goal, and, therefore, they
need a vision for sustainability with commitment from signicant role players to achieve longevity and continuity in
the program.

SUMMARY
ARF/RHD is a disease of poverty, social deprivation, and
inequality. Yet, it is entirely preventable using simple costeffective measures. We have evidence from past and current initiatives, instituted in various parts of the world, that
comprehensive programs incorporating awareness-raising,
surveillance, and prevention can not only control RHD
but also create a global RHD agenda and construct a
platform for collaboration. Communication and health
promotion is an essential part of an effective RHD control
and prevention program. The key construct is a strong,
shared, long-term vision, which is evidence-based, resultsoriented, and that strengthens all elements of the program
to allow for scalability. Translational research, incorporating these constructs, will serve to bring the needed
attention back to this neglected, yet devastating illness
[31,41].

REFERENCES
1. Watkins DA, Zhlke LJ, Engel ME, Mayosi BM. Rheumatic fever:
neglected again. Science 2009;324:37.
2. OSillivan GA, Yonkler JA, Morgan W, Merritt AP. A Field Guide to
Designing a Health Communication Strategy. Baltimore, MD: John
Hopkins Bloomberg School of Public Health/Center for Communication Programs; 2003.
3. Moran M, Guzman J, Ropars AL, et al. Neglected disease research and
development: how much are we really spending? PLoS Med 2009;6:
e30.
4. Zhlke L, Mirabel M, Marijon E. Congenital heart disease and rheumatic heart disease in Africa: recent advances and current priorities.
Heart 2013 May 16 [E-pub ahead of print].
5. Mayosi BM, Flisher AJ, Lalloo UG, Sitas F, Tollman SM, Bradshaw D.
The burden of non-communicable diseases in South Africa. Lancet
2009;374:93447.

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 235-239

gREVIEW

6. Nkgudi B, Robertson KA, Volmink J, Mayosi BM. Notication of


rheumatic fever in South Africaevidence for underreporting by
health care professionals and administrators. S Afr Med J 2006;96:
2068.
7. Singh PI, Carapetis JR, Buadromo EM, Samberkar PN, Steer AC. The
high burden of rheumatic heart disease found on autopsy in Fiji.
Cardiol Young 2008;18:629.
8. Gersh BJ, Sliwa K, Mayosi BM, Yusuf S. Novel therapeutic concepts:
the epidemic of cardiovascular disease in the developing world:
global implications. Eur Heart J 2010;31:6428.
9. Broder S, Hoffman SL, Hotez PJ. Cures for the Third Worlds problems: the
application of genomics to the diseases plaguing the developing world
may have huge medical and economic benets for those countries and
might even prevent armed conict. EMBO Rep 2002;3:80612.
10. Bergmark R, Bergmark B, Blander J, Fataki M, Janabi M. Burden of
disease and barriers to the diagnosis and treatment of group a betahemolytic streptococcal pharyngitis for the prevention of rheumatic
heart disease in Dar Es Salaam, Tanzania. Pediatr Infect Dis J 2010;29:
11357.
11. Nordet P, Lopez R, Dueas A, Sarmiento L. Prevention and control of
rheumatic fever and rheumatic heart disease: the Cuban experience
(1986e1996e2002). Cardiovasc J Afr 2008;19:13540.
12. Anyangwe SC, Mtonga C. Inequities in the global health workforce:
the greatest impediment to health in sub-Saharan Africa. Int J Environ Res Public Health 2007;4:93100.
13. Mayosi B. The four pillars of rheumatic heart disease control. S Afr
Med J 2010;100:506.
14. Steer AC, Carapetis JR. Acute rheumatic fever and rheumatic heart disease in indigenous populations. Pediatr Clin North Am 2009;56:14019.
15. Parnaby MG, Carapetis JR. Rheumatic fever in indigenous Australian
children. J Paediatr Child Health 2010;46:52733.
16. Robertson KA, Mayosi BM. Rheumatic heart disease: social and
economic dimensions. S Afr Med J 2008;98:7801.
17. Ahmed M, Vellani CW, Awiti AO. Medical education: meeting the
challenge of implementing primary health care in sub-Saharan Africa.
Infect Dis Clin North Am 2011;25:41120.
18. Mayosi BM, Lawn JE, van Niekerk A, et al. for the Lancet South Africa
Team. Health in South Africa: changes and challenges since 2009.
Lancet 2012;380:202943.
19. David RA, Rhee M. The impact of language as a barrier to effective
health care in an underserved urban Hispanic community. Mt Sinai J
Med 1998;65:3937.
20. Clayton L. Strategies for selecting effective patient nutrition education materials. Nutr Clin Pract 2010;25:43642.
21. Brown A, McDonald MI, Calma T. Rheumatic fever and social justice.
Med J Aust 2007;186:5578.
22. Grifth GC. A community program for the control of rheumatic fever.
Am J Public Health Nations Health 1949;39:615.
23. Bach JF, Chalons S, Forier E, et al. 10-year educational programme
aimed at rheumatic fever in two French Caribbean islands. Lancet
1996;347:6448.
24. Colquhoun SM, Carapetis JR, Kado JH, Steer AC. Rheumatic heart
disease and its control in the Pacic. Expert Rev Cardiovasc Ther
2009;7:151724.

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 235-239

25. Steer A, Colquhoun S, Noonan S, Kado J, Viale S, Carapetis J. Control


of rheumatic heart disease in the Pacic region. Pac Health Dialog
2006;13:4955.
26. Robertson KA, Volmink JA, Mayosi BM. Towards a uniform plan for
the control of rheumatic fever and rheumatic heart disease in
Africathe Awareness Surveillance Advocacy Prevention (A.S.A.P.).
Programme. S Afr Med J 2006;96:241.
27. Mayosi B, Robertson K, Volmink J, et al. The Drakensberg declaration
on the control of rheumatic fever and rheumatic heart disease in
Africa. S Afr Med J 2006;96:246.
28. Marijon E, Ou P, Celermajer DS, et al. Prevalence of rheumatic heart
disease detected by echocardiographic screening. N Engl J Med 2007;
357:4706.
29. Engel M, Zhlke L, Robertson KA. ASAP programme: rheumatic fever
and rheumatic heart disease: where are we now in South Africa? SA
Heart 2009;6:2703.
30. Karthikeyan G, Zhlke L, Engel M, et al. Rationale and design of a
Global Rheumatic Heart Disease Registry: the REMEDY study. Am
Heart J 2012;163:535540.e1.
31. David R. Changing therapeutic paradigms in glaucoma management.
Expert Opin Investig Drugs 1998;7:106386.
32. Kearney MH, OSullivan J. Identity shifts as turning points in health
behavior change. West J Nurs Res 2003;25:13452.
33. Alleyne G, Binagwaho A, Haines A, et al, for the Lancet NCD Action
Group. Embedding non-communicable diseases in the post-2015
development agenda. Lancet 2013;381:56674.
34. Nsanzimana S, Ruton H, Lowrance DW, et al. Cell phone-based and
internet-based monitoring and evaluation of the National Antiretroviral Treatment Program during rapid scale-up in Rwanda: TRACnet, 2004e2010. J Acquir Immune Dec Syndr 2012;59:e1723.
35. Ngabo F, Nguimfack J, Nwaigwe F, et al. Designing and implementing
an innovative SMS-based alert system (RapidSMS-MCH) to monitor
pregnancy and reduce maternal and child deaths in Rwanda. Pan Afr
Med J 2012;13:31.
36. Rajani R, Berman DS, Rozanski A. Social networksare they good for
your health? The era of Facebook and Twitter. QJM 2011;104:81920.
37. Bottles K. Twitter: an essential tool for every physician leader.
Physician Exec 2011;37:802.
38. Campbell M, Fitzpatrick R, Haines A, et al. Framework for design and
evaluation of complex interventions to improve health. BMJ 2000;
321:6946.
39. Cohen E, Lacombe-Duncan A, Spalding K, et al. Integrated complex
care coordination for children with medical complexity: a mixedmethods evaluation of tertiary care-community collaboration. BMC
Health Serv Res 2012;12:366.
40. Michaud GJ, Cruz C, Pearson T. The World Bank Health Sector Priorities Review: Rheumatic Heart Disease. Washington, DC: World
Bank; 1991. p. 131.
41. Michaud RRC, Narula J. Cost-effectiveness analysis of intervention
strategies for reduction of the burden of rheumatic heart disease. In:
Natula J, Virmani R, Reddy KS, Tandon R, editors. Rheumatic Fever.
Washington, DC: American Registry of Pathology; 1999. p. 48597.
42. Carapetis JR, Zhlke LJ. Global research priorities in rheumatic fever
and rheumatic heart disease. Ann Pediatr Cardiol 2011;4:412.

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A Conceptual Framework for Comprehensive


Rheumatic Heart Disease Control Programs
Rosemary Wyber
Perth, Western Australia, Australia
ABSTRACT
The World Health Organization, World Heart Federation, and other organizations recommend comprehensive
control programs for rheumatic fever (RF) and rheumatic heart disease (RHD). However, advice on
components of control programs are simple lists, with little guidance on program structure or priorities. In
particular, there are limited recommendations on stepwise implementation and few guidelines on which
program components should take temporal priority. An evidence-based framework for describing,
prioritizing, and implementing comprehensive RF/RHD control programs is needed. A literature review of
existing RF/RHD control program recommendations generated a list of program components. Descriptions
and analysis of RF/RHD control programs informed temporal prioritizing of component parts. Relevant
programmatic research from other vertical disease control programs was reviewed for generalizable
implementation experiences. Twenty-ve individual components of comprehensive RF/RHD control
programs were identied. These fell into baseline program requirements (including burden of disease
data, treatment guidelines, and human resources) and requirements for providing primary, secondary, and
tertiary interventions. Primordial prevention and research priorities were overarching themes. These
components were developed into a conceptual framework schema. Existing literature contains valuable
lessons on the design and implementation of comprehensive RF/RHD control programs. Fashioning these
guidelines and programmatic experiences into a conceptual framework schema benets clinicians, policy
makers, and RHD advocates.

By the most conservative estimates, more than 15.6


million people globally suffer from rheumatic heart disease
(RDH) and 233,000 die of the disease each year around the
world [1]. RHD is precipitated by group A streptococcal
infection, progressing to the post-infectious syndrome of
rheumatic fever (RF) in some people. Approximately 60%
of these cases of RF induce the persistent valvular damage
of RHD [2]. RF/RHD are endemic in most low- and
middle-income countries and in some socioeconomically
deprived groups in high-resource settings [1]. RF/RHD
disproportionately affect young people and constitute a
signicant economic burden for low-income families,
contribute to maternal mortality, and further strain already
overstretched health systems [3e5].
RF/RHD have been successfully controlled in a number
of settings through the implementation of register-based
control programs [6e9]. This register-based approach to
RF/RHD control has been recommended by the World
Health Organization (WHO) and World Heart Federation
(WHF) for many years [10e12]. Most control programs
are comprehensive in that they attempt to intervene at
multiple points along the protracted etiological pathway of
RF/RHD [13,14]. (Although poorly dened, the concept of
comprehensive RF/RHD control programs functionally
reects a spectrum of approaches with variable weighting
of primary and secondary approaches. [14e16].)

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Guidelines for the activities and components of


comprehensive RF/RHD control programs have historically
been simple lists [11,12]. These lists have tended to have
few details on program structure or priorities. A stepwise
approach to implementation is recommended, though little
guidance about initial steps or program structure has been
published to date [12,17]. This has spurred concerns that
complex interventionsincluding surgery and active case
nding with echocardiographycould occur in isolation,
without ensuring program capacity to deliver other
essential services, or at the expense of cost effectiveness
[14,18e21]. Need for a preliminary protocol with basic
components for stepwise implementation has already been
identied [9].
A new wave of RF/RHD control programs is likely in
the wake of pending global burden of disease data, renewed
international advocacy, and the expansion of early diagnosis through echocardiographic screening [16,22,23]. Yet,
among the greatest challenges in RF/RHD disease control is
putting proven approaches into practice [16,23]. An
evidence-based framework for describing, designing,
implementing, and evaluating comprehensive RF/RHD
control programs would maximize the benet of new and
reinvigorated efforts in disease control. A conceptual
framework may also provide a common foundation for
international collaboration and implementation research.

From the Telethon Institute


for Child Health Research,
Perth, Western Australia,
Australia. Correspondence:
R. Wyber (rwyber@ichr.
uwa.edu.au).
GLOBAL HEART
2013 World Heart
Federation (Geneva).
Published by Elsevier Ltd.
All rights reserved.
VOL. 8, NO. 3, 2013
ISSN 2211-8160/$36.00.
http://dx.doi.org/10.1016/
j.gheart.2013.07.003

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This paper collates published recommendations about


RF/RHD control programs. Core components are identied
and arranged in an attempt to reect relative complexity
and priority. The conceptual framework is intended as a
starting point for programmatic discussions by clinicians,
managers, policy makers, and government and funding
agencies. This rst iteration will be open to revision as new
evidence and programmatic experience emerges.

METHODS
Benchmark World Health Organization and World Heart
Federation guidelines on RF/RHD control programs were
reviewed to inform search strategy. Current recommendations have largely appeared in institutional documents,
limiting utility of a systematic peer-reviewed approach.
Countries with existing RF/RHD guidelinesdrawn from
World Heart Federations RHDNetwere reviewed to
identify recommendations applicable to other settings.
Bibliographic review and a snowball approach were used to
identify other program reviews and recommendations.
Listed recommendations for RF/RHD control programs
were coded to identify common themes. Program reports that
did not make specic recommendations for other initiatives

were excluded from formal thematic analysis. Content from


these papers was used qualitatively to inform prioritization
and to identify potentially under-represented areas. A number
of contemporary areas were specically reviewed: tertiary
interventions; active case nding via echocardiography; and
primordial prevention.
Themes identied from the literature review were
condensed into a list of components of comprehensive RF/
RHD control programs. The list was arranged into domains
representing the classic primordial, primary, secondary,
and tertiary approach to RF/RHD control (Fig. 1). Within
each domain, components were arranged in order of potential priority or temporal sequence based on narrative
descriptions of program implementation.

RESULTS
Four institutions have published recommendations for
comprehensive control programs [10,12,24e26]. Five
more papers identied specic program recommendations
applicable to other initiatives [17,27e30]. One book
chapter was identied and excluded from formal analysis,
because the depth and specicity of the recommendations
exceeded the requirements for this review [31]. Thus,

Terary

Ancoagulaon

Triage of
intervenon
candidates

Priority based
follow up
(clinical review)

Provision of
intervenonal
services

Secondary

RF/RHD register

BPG supply

Provision of
secondary
prophylaxis

Priority based
follow up
(clinical review)

Acve case
nding
(echo screening)

Community
educaon

GAS diagnosis
and treatment
guidelines

Delivery of
primary
prophylaxis

Acve case
nding
(sore throat clinics)

Vaccine
development

Government
engagement

Disease
nocaon

Human
resources

Health worker
training

Program
evaluaon

Burden of
disease data

RF/RHD advisory
commiee

Funding

Laboratory
services

Integraon with
primary care and
health systems

print & web 4C=FPO

Baseline

Medical
management

Primary

Research

Poverty

Overcrowding

Malnutrion

Health access

FIGURE 1. A conceptual framework for comprehensive, register-based, rheumatic heart disease control programs.
BPG, benzathine penicillin G; GAS, group A streptococcal; RF, rheumatic fever; RHD, rheumatic heart disease.

242

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9 core sources were used to generate a list of comprehensive program components. A much larger number of
papers described or reviewed existing programs, but they
did not make explicit recommendations directly relevant to
other programs [6,9,21,32e45]. These papers were used
to generate original recommendations on program components and to inform priority setting.
Twenty-ve individual components of comprehensive
RF/RHD control programs were identied (Fig. 1). Domains included baseline components and requirements for
providing primary, secondary, and tertiary interventions.
Primordial prevention and research were identied as
overarching themes.

DISCUSSION
Research, advocacy, and funding are generating renewed
momentum for the global control of RF/RHD [16,23].
These developments may encourage countries to develop
new RF/RHD control programs, revive previous efforts, or
evaluate existing programs. A systemic approach to disease
control programs would maximize clinical benet for individuals, reduce inefciency, and provide opportunities
for global knowledge sharing.
The conceptual framework is structured to provide a
visual overview of priorities, moving from left to right
across the page (Fig. 1). For example, a new RF/RHD
program should address burden of disease data, government engagement, community education, register development, and medical management of established cases as
initial goals. Programs will necessarily be adaptable to local
settings and may elect to have slightly different areas of
long-term focus. However, a singular focus on advanced
components (e.g., active case nding of sore throats,
echocardiographic screening, or interventional services)
without attention to interim steps is to be discouraged.

Inclusions in the framework


Many components of RF/RHD control programs are the
subject of widespread agreement, including community
education, development of a register, and training health
workers. However, some areas have been less well
explored, necessitating a brief rationale for inclusion:

Primary prevention and active case nding for


group A streptococcal pharyngitis Treatment of
symptomatic group A streptococcal pharyngitis infections
presenting to clinicians is broadly accepted and encouraged
[41,46,47]. There is less clarity around active case ndings
via sore throat clinics in schools, which are widely adopted
in some settings and eschewed in others [15,42,48].
Detailed exploration of this issue is outside the scope of
this paper. Sore throat clinics are included in the
framework as an advanced component of potential
relevance in some settings.

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Active case nding with echocardiographic


screening The clinical benets of active case ndings
via echocardiographic screening is yet to be fully explored
[21]. However, the theoretical benet is dependent upon a
functional register-based program, complete with access to
benzathine penicillin G and case follow-up [21]. The
conceptual framework helps to illustrate this dependency
to funders and policy makers, ensuring that screening
programs are coupled with prerequisite components of
service delivery.

Tertiary components The framework includes a more


detailed approach to tertiary interventionmedical management, anticoagulation, surgical or endovascular approachesthan existing program recommendations. The
historic disconnect between comprehensive programs and
tertiary interventions may reect lack of access to open and
endovascular procedures. However, access to interventional
surgical services is increasing in many endemic regions and
should align closely with existing RHD programs [49].
Strong links between register-based programs and tertiary
services are likely to potentiate triage of candidates and
help support post-intervention follow-up. Interventional
options should not be delivered in isolation by local
providers, charitable groups, or overseas governments.
Isolated efforts risk diverting funds from more costeffective preventative approaches or without ensuring
adequate mechanisms for follow-up [21,49].

Vaccine development Few RF/RHD control programs


in highly endemic settings will have the capacity for vaccine development activities. However, individual programs
can support vaccine development through advocacy to
governments and identifying endemic populations appropriate for clinical trials. This programmatic support is
critical for eventual vaccination development and delivery.
Driving the momentum for an RF/RHD vaccine is a shared
responsibility of control programs internationally.

Integration with primary care and health


systems Many existing program recommendations
include references to integration, primary care, or existing
health care delivery systems [10,27,29]. However, achieving
meaningful integration remains a challenge in most settings
[16]. Although integration is not a discrete block of
activities, it should be given explicit and conscious attention
during program planning [50]. Awaiting opportunities for
integration to emerge and pervade RF/RHD programs has
been historically insufcient. Allocating time, funding, and
resources to create space for integration activities is critical.
Primordial prevention is an overarching, but often
underarticulated, theme of RF/RHD efforts. Populationlevel prevention activities have fallen largely outside the
scope of traditional comprehensive control programs. An
array of complex socioeconomic factors appear to inuence
manifestation of RF/RHD, including overcrowding, nutrition, and health access [14,42]. Many others, particularly

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socioeconomic status and inequality, may also be


contributory factors. Although these issues may be difcult
for control programs to address directly, program implementers bring a unique perspective to the need for primordial intervention [51]. Policy advocacy is an important
role for RF/RHD control programs, particularly given the
relative contribution of socioeconomic conditions to disease burden [13]. Broadly strengthening the advocacy capacity of the RF/RHD community is critical for addressing
persistent neglect of the disease among decision makers
[52].
Research is a second overarching theme for RF/RHD
programs. A broad array of disease control questions
remain unanswered, including natural history of subclinical carditis, the role of echo screening, program optimization, and the development of novel therapies [16]. Many
of these questions can only be answered in highly endemic
communities. Coupling research activities with a comprehensive service delivery program is more appropriate and
ethically defensible than stand-alone research projects are
[53]. Engagement in the research community also fosters
collaboration for clinicians and academics in remote and
low-resource settings. Maintaining a rigorous evidence base
for disease control efforts is a shared responsibility for all
register-based programs.

Rening the conceptual framework


Identifying best practices for RF/RHD control programs
require comparison and analysis of implementation experiences. A large volume of this information already exists in
peer-reviewed literature. However, only some investigators
make explicit recommendations for improving existing
programs and very few make suggestions applicable to new
programs. These formal publications represent only a
fraction of program reports provided to governments and
external donors. Collating and analyzing this experiential
evidence base will be critical for advancing implementation
science [16,23].
The proposed conceptual framework provides a starting point for knowledge sharing with a common set of
terminology. Calls for standardization of terms have been
longstanding [54]; some progress has been achieved in
simple disease categories and echocardiographic terms but
not in program implementation to date [11,55]. Capitalizing on shared terms and structure, collaborative efforts to
build a more robust framework should be encouraged.
New components may be added; for example, a protocol
for managing anaphylaxis may be prioritized before delivery of secondary prophylaxis is commenced. Pooling
international service delivery experience will continue to
inform ongoing development of the framework. More
substantial program implementation recommendations
should be possible. Although anticoagulation is identied
as a conceptual framework component, there is no detail
on possible approaches, relative costs, compliance, or
clinical protocols. Exploring the substance of components

244

within the framework requires signicant development and


international collaboration.
A number of areas were consciously excluded from
this initial version of the framework. Prescriptive lists of
staff and equipment have been avoided at this stage (e.g.,
echo machines, sonographers, information pamphlets,
disease notication forms), as these will depend on local
conditions. Development of a practical program implementation handbook may be a natural extension of the
framework in the future.

Application of the conceptual framework


The conceptual framework is applicable to a number of
stakeholders in global RF/RHD control. For most, the
framework adds value through visual comprehensibility.
RF/RHD is a complex disease with unwieldy acronyms, a
protracted course, and multiple opportunities for intervention. Few of the constituent groups needed for disease
control will be technical experts. Providing a concise
snapshot of control program activities enhances communication to all. Some stakeholders may identify specic
benets:

Governments and policy makers The framework may


simplify options for decision makers by offering guidance on
stepwise program intervention. In resource-limited settings,
staged rollout may be more politically and economically
feasible than de novo development of a complete program.
Governments should be encouraged to take any action
toward RF/RHD control, ideally rst-tier interventions,
with a plan to provide increasingly advanced services.

Donors and funders One of the challenges in securing


much-needed resources for RF/RHD is the breadth and
complexity of comprehensive programs. Without specialist
knowledge of the disease, donors may struggle to
understand how their contribution adds to program
delivery and prevention efforts. The conceptual framework
provides a common ground for funders and implementers
to take stock of a proposed program and agree on areas to
be strengthened. This approach may help to avoid
sequestration of funding for tertiary services, without
addressing basic needs such as benzathine penicillin G
supply.

Program reporting and evaluation template With


the expansion of comprehensive RF/RHD programs comes
increasing reporting and evaluation requirements. Without a
structured framework, critical program issues may be
overlooked. Encouraging programs to report on activities in
each of the program components would ensure that core
components were addressed and improve comparability
between programs. With improvements in the model, it may
be possible to develop an objective evaluation template
specifying gold-standard practice in each domain and
providing customized feedback to programs.

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Program handbook The framework provides a broad


overview of activities and priorities in comprehensive
control programs. It provides no detail about how these
can best be achieved. Collating detailed implementation
experiencecomponents of register-based programs,
technical specications for echo screening programsare
best addressed in an implementation handbook that
could be structured around the headings of the
conceptual framework.
SUMMARY
Decades of global experience in the design and implementation of comprehensive RF/RHD control programs
already exist. The conceptual framework distills some of this
experience, and existing recommendations, into a concise
visual overview. Design, development, implementation, and
evaluation of programs benet from a strategic approach.
This standardized approach facilitates international collaboration, fostering efforts to achieve excellence in program
delivery. Evolution and development of the model is inevitable and encouraged; this rst iteration is designed to provide a foundation for policy makers, governments, donors,
researchers, and program implementers. Ultimately, a focus
on comprehensive control programs benets the millions of
people living with RHD.
REFERENCES
1. Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden
of group A streptococcal diseases. Lancet Infect Dis 2005;5:68594.
2. Bland EF, Duckett Jones T. Rheumatic fever and rheumatic heart
disease; a twently year report on 1000 patients followed since
childhood. Circulation 1951;4:83643.
3. Robertson KA, Mayosi BM. Rheumatic heart disease: social and
economic dimensions. South African Medical Journal 2008;98:7801.
4. Petricca K, Mamo Y, et al. Barriers to effective follow-up treatment
for rheumatic heart disease in Jimma, Ethiopia: a grounded theory
analysis of the patient experience. Ethiopian Journal of Health Science 2009;19:3944.
5. Watkins D, Sebitloane M, Engel ME, Mayosi BM. The burden of
antenatal heart disease in South Africa: a systematic review. BMC
Cardiovasc Disord 2012;12:23.
6. Argueda A, Mohs E. Prevention of rheumatic fever in Costa Rica.
J Pediatr 1992;121:56972.
7. Bach F, Chalons S, Forier E, et al. 10-year educational programme
aimed at rheumatic fever in two French Caribbean islands. Lancet
1996;347:6448.
8. McDonald M, Brown A, Noonan S, Carapetis JR. Preventing recurrent
rheumatic fever: the role of register based programmes. Heart 2005;
91:11313.
9. Nordet P, Lopez R, Dueas A, Sarmiento L. Prevention and control of
rheumatic fever and rheumatic heart disease: the Cuban experience
(1986e1996e2002). Cardiovasc J Afr 2008;19:13540.
10. WHO. Community Prevention and Control of Cardiovascular Diseases.
Geneva, Switzerland: World Health Organization; 1986.
11. WHO. Rheumatic Fever and Rheumatic Heart Disease. WHO Technical
Report Series. Geneva, Switzerland: World Health Organisation; 2001.
12. WHF. Diagnosis and Managment of Acute Rheumatic Fever and
Rheumatic Heart Disease. Geneva, Switzerland: World Heart Federation; 2008.
13. Carapetis JR. Rheumatic heart disease in developing countries. N Engl
J Med 2007;357:43941.

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 241-246

14. Marijon E, Mirabel M, Celermajer DS, Jouven X. Rheumatic heart


disease. Lancet 2012;379:95364.
15. Karthikeyan G, Mayosi BM. Is primary prevention of rheumatic fever
the missing link in the control of rhuematic heart disease in Africa?
Circulation 2009;120:70913.
16. Carapetis J, Zuhlke L. Global reasearch priorities in rheumatic fever
and rheumatic heart disease. Ann Pediatr Cardiol 2011;4:412.
17. Robertson KA, Volmink JA, Mayosi BM. Towards a uniform plan for
the control of rheumatic fever and rheumatic heart disease in
Africathe Awareness Surveillance Advocacy Prevention (A.S.A.P).
Programme. S Afr Med J 2006;96:2415.
18. Essop MR, Nkomo VT. Rheumatic and nonrheumatic valvular heart
disease: epidemiology, management and prevention in Africa. Circulation 2005;112:358491.
19. Wright IG, Walker IA, Yacoub MH. Specialist surgery in the developing
world: luxury or necessity? Anaesthesia 2007;62(Suppl 1):849.
20. Zuhlke L. Rheumatic heart disease and the ASAP programme: fresh
insights into an old disease: rheumatic heart disease continues to
affect and kill millions of children, adolescents and young adults in the
developing world. Continuing Medical Education 2011;29 [online
journal]. Available at: http://www.cmej.org.za/index.php/cmej/article/
view/2281/2050. Accessed September 3, 2013.
21. Roberts K, Colquhoun S, Steer A, Remnyi B, Carapetis J. Screening
for rheumatic heart disease: current approaches and controversies.
Nat Rev Cardiol 2012;10:4958.
22. Beaton A, Okello E, Lwabi P, Mondo C, McCarter R, Sable C. Echocardiographic screening for rheumatic heart disease in Ugandan
schoolchildren. Circulation 2012;125:312732.
23. Remenyi B, Carapetis J, Wyber R, Taubert K, Mayosi BM. Position
statement of the World Heart Federation on the prevention and
control of rheumatic heart disease. Nat Rev Cardiol 2013;10:28492.
24. WHO. Rheumatic Fever and Rheumatic Heart Disease. Geneva,
Switzerland: World Health Organization; 2004.
25. NZHF. New Zealand Guidelines for Rheumatic Fever. Greenlane,
Auckland, Australia: Heart Foundation of New Zealand and The
Cardiac Society of Australia and New Zealand; 2006.
26. RHD Australia (ARF/RHD writing group). Australian Guideline for
Prevention, Diagnosis and Management of Acute Rheumatic Fever
and Rheumatic Heart Disease. 2nd ed. Wellington, New Zealand,
Australia: National Heart Foundation of Australia and Cardiac Society
of Australia and New Zealand; 2012.
27. Falase A. Epidemiology and Prevention of Rheumatic Fever/Rheumatic
Heart Disease. Geneva, Switzerland: World Health Organization; 1987.
28. Nordet P. Rheumatic fever/rheumatic heart disease prevention: lessons
learned. Paper presented at: First Virtual Congress of Cardiology; 1999;
online. Available at: http://www.fac.org.ar/cvirtual/cvirteng/cienteng/
sweng/swc6002i/inordet/inordet.htm. Accessed December 20, 2012.
29. Steer A, Colquhoun S, Noonan S, Kado J, Viale S, Carapetis J. Control
of rheumatic heart disease in the Pacic region. Pac Health Dialog
2006;13:4955.
30. Mayosi B. The four pillars of rheumatic heart disease control. S Afr
Med J 2010;100:506.
31. Vijayalakshmi I. Rheumatic fever, rheumatic heart disease registry
and control program. In: Vijayalakshmi I, editor. Acute Rheumatic
Fever and Chronic Rheumatic Heart Disease. New Delhi, India: Jaypee
Brothers Medical Publishers; 2011.
32. Strasser T, Dondog N, El Kholy A, et al. The community control of
rheumatic fever and rheumatic heart disease: report of a WHO international cooperative project. Bull World Health Organ 1981;59:
28594.
33. Alto W, Rikin T, et al. Rheumatic fever in Micronesia. Pac Health
Dialog 1992:1.
34. Thornley C, McNicholas A, et al. Rheumatic fever registers in New
Zealand. New Zealand Public Health Report 2001;8:414.
35. Viali S, Saena P, Futi V. Rheumatic Fever Programme in Samoa. N Z
Med J 2011;124:2635.
36. Brown A, Purton L, et al. Central Australian rheumatic heart disease
control program: a report to the Commonwealth, November 2002.
The Northern Territory Disease Control Bulletin 2003;10:19.

245

gREVIEW

37. Eissa S, Lee R, Binns P, Garstone G, McDonald M. Assessment of a


register-based rheumatic heart disease secondary prevention program in an Australian Aboriginal community. Aust N Z J Public Health
2005;29:5215.
38. Grayson S, Horsburgh M, Lennon D. An Auckland regional audit of
the nurse-led rheumatic fever secondary progphylaxis programme.
N Z Med J 2006;119:U2255.
39. Viali S. Rheumatic fever and rheumatic heart disease in Samoa. Pac
Health Dialog 2006;13:318.
40. Engel M, Zuhlke L, et al. Rheumatic fever and rheumatic heart
disease: Where are we now in South Africa? SA Heart 2009;6:
203.
41. Gerber M, Baltimore R, Eaton CB, et al. Prevention of rheumatic fever
and diagnosis and treatment of acute Streptococcal pharyngitis: a
scientic statement from the American Heart Asssociation Rheumatic
Fever, Endocarditis, and Kawaskai Disease Committee on the Council
of Cardiovascular Disease in the Young, the Interdisciplinary Council
on Functional Genomis and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research. Circulation 2009;119:154151.
42. Kerdemelidis M, Lennon DR, Arroll B, Peat B, Jarman J. The primary
prevention of rheumatic fever. J Paediatr Child Health 2010;46:
53448.
43. Petricca K. Successes and challenges of secondary prevention programs for rheumatic fever and rheumatic heart disease. Univ Toronto
Med J 2010;87:1703.
44. Wilson N. Rheumatic heart disease in indigenous populationsNew
Zealand experience. Heart Lung Circ 2010;19:2828.
45. Webb R, Wilson N. Rheumatic fever in New Zealand. J Paediatr Child
Health 2013;49:17984.

246

46. Irlam J, Mayosi BM, Engel M, Gaziano TA. Primary prevention of


acute rheumatic fever and rheumatic heart disease with penicillin in
South African children with pharyngitis: a cost-coffectiveness analysis. Circ Cardiovasc Qual Outcomes 2013;6:34351.
47. Carapetis JR. Letter by Carapetis regarding article, Is primary prevention of rheumatic fever the missing link in the control of rheumatic heart disease in Africa?". Circulation 2010;121:e384.
48. Lennon D, Stewart J, Farrell E, Palmer A, Mason H. School-based
prevention of acute rheumatic fever: a group randomized trial in New
Zealand. Pediatr Infect Dis J 2009;28:78794.
49. Dearani JA, Neirotti R, Kohnke EJ, et al. Improving pediatric cardiac
surgical care in developing countries: matching resources to needs.
Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2010;13:3543.
50. Atun R, de Jongh T, Secci F, Ohiri K, Adeyi O. Integration of targeted
health interventions into health systems: a conceptual framework for
analysis. Health Policy Plan 2010;25:10411.
51. Brown A, McDonald M, Calma T. Rheumatic fever and social justice.
Med J Aust 2007;186:5578.
52. Watkins DA, Zuhlke LJ, Engel ME, Mayosi BM. Rheumatic fever:
neglected again. Science 2009;324:37.
53. Emanuel EJ, Wendler D, Killen J, Grady C. What makes clinical
research in developing countries ethical? The benchmarks of ethical
research. J Infect Dis 2004;189:9307.
54. WHO. The WHO Global Programme for the Prevention of Rheumatic
Fever and Rheumatic Heart Disease: Report of a Consultation To
Review Progress and Develop Future Activities. Geneva, Switzerland:
World Health Organization, 1999.
55. Remanyi B, Wilson N, Steer A, et al. World Heart Federation criteria
for echocardiographic diagnosis fo rheumatic heart diseasean
evidence-based guideline. Nat Rev Cardiol 2012;9:297309.

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Prevention of Rheumatic Fever and Heart Disease:


Nepalese Experience
Prakash Raj Regmi*, Rosemary Wybery
Kathmandu, Nepal; and Perth, Western Australia, Australia
ABSTRACT
Rheumatic heart disease (RHD) is a major public health problem in Nepal that affects young children and
adolescents. Historically, many young people suffered severe valvular disease and died awaiting heart valve
replacement. For some years, the Nepal Heart Foundation (NHF) advocated for a more comprehensive
program to reduce the burden of RHD. In 2007, the government of Nepal announced funding for an RHD
control program to be implemented by the NHF. The core focus of the program was to deliver antibiotics
for the secondary prophylaxis of RHD. The NHF has developed a program of community awareness, free
medication, RHD register development, health worker training, guideline development, and clinical audit.
These services are being implemented with expanding geographic scope. This paper provides a narrative
overview of the Nepalese experience designing, implementing, and beginning to evaluate this program.
Challenges and successes relevant to register-based programs are highlighted.
Acute rheumatic fever (RF) is an immunologically
mediated sequel of group A beta hemolytic streptococcal
(GAS) tonsillopharyngitis [1]. The most common cardiac
manifestations are valvulitis and myocarditis, which can
lead to the chronic valve damage of rheumatic heart disease
(RHD). RHD is estimated to affect more than 15.6 million
people worldwide, cause 233,000 deaths every year, and
contribute to signicant morbidity in young people [2,3].
The vast majority of cases of RF and RHD occur in
developing countries, including Nepal [4].
The burden of RF and RHD can be controlled through
a program of primary, secondary, and tertiary interventions. RF can be prevented by treating GAS tonsillopharyngitis with antibiotics (primary prevention) or valve
damage can be minimized by administration of prophylactic antibiotics (secondary prevention). Treatment of
symptomatic RHDincluding medical therapy and operative interventionis considered tertiary intervention. This
paper provides a narrative overview of the Nepalese
experience designing, implementing, and beginning to
evaluate a register-based RHD control program to deliver
secondary prevention.

NEPAL
Nepal is a developing nation in South Asia with a population of 30.49 million people [5]. Rural inhabitants make
up 80% of the population; life expectancy at birth is 69.1
years; and 34% of the population are aged 0 to 14 years
[5,6]. Government health spending on health is about 7%
of gross domestic product and more than half of the costs
of health care are paid out of pocket by consumers [7].
Human resources for health are limited and concentrated
in urban settings [8]. Although these challenges are

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September 2013: 247-252

considerable, there is growing momentum for enhancing a


robust primary care system throughout Nepal [9].

BURDEN OF RF AND RHD


Data on the burden of RF and RHD in Nepal is limited.
Most of the studies are school-based and are from the
capital city, Kathmandu. The prevalence of RHD among
schoolchildren of the 5 to 16 years age group is reported to
be 1.0 to 1.35 per 1,000 in different studies [10e13].
Extrapolating throughout Nepal, the Nepal Heart Foundation (NHF) has made an expert estimate of prevalence of
RHD at 2 per 1,000 schoolchildren. On this basis, the NHF
estimates approximately 75,000 RHD patients live
throughout the country [14]. The incidence of RF is estimated to be 15,000 per year [15]. RHD is among the
leading causes of admission to cardiology services and
cardiothoracic surgery [16].

THE NEPAL RF/RHD PREVENTION AND CONTROL


PROGRAM
Historically, the government of Nepal funded heart valve
replacements for low-income RHD patients. Over 300
valve replacements were provided each year, at a cost of
approximately US$3,000 per operation. This tertiary
approach generated lengthy waiting lists and many patients
with end-stage disease died awaiting surgery. The government of Nepal became interested in developing a control program, which could decrease the morbidity and
mortality in children and represent a more cost-effective
strategy. Advocacy for a comprehensive approach to disease control was led by the NHF. The NHF was founded in
1988 and now has 37 district ofces throughout the
country [17]. The NHF is a member of the World Heart

From the *National Academy of Medical Sciences


(NAMS), Bir Hospital,
Kathmandu, Nepal;
yTelethon Institute for
Child Health Research,
Perth, Western Australia,
Australia. Correspondence:
P. R. Regmi (prregmi@
wlink.com.np).
GLOBAL HEART
2013 World Heart
Federation (Geneva).
Published by Elsevier Ltd.
All rights reserved.
VOL. 8, NO. 3, 2013
ISSN 2211-8160/$36.00.
http://dx.doi.org/10.1016/
j.gheart.2013.08.001

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gREVIEW

Federation and supports the World Heart Federations


mission to unite members and lead the global ght against
RHD through aligning around the WHO-related target
of 25 percent reduction in RF/RHD mortality by 2025
in under 25 year olds [18]. The Nepal government
announced approximately US$30,000 of funding for an
RHD control program in 2006 [19]. The NHF was contracted to design and implement this program in 2007.

PROGRAM DESIGN
The NHF investigated a number of models for delivering
disease-specic health care while developing the national
program for control of RF and RHD. In particular,
decisions were required about the relative contribution of
independent disease-specic activities (vertical) and integration of RHD care delivery into the broader health system
(horizontal) [20]. The NHF identied that a purely vertical
approach was prohibitively costly and a purely horizontal
approach lacked the urgent focus needed for reducing RF/
RHD morbidity and mortality. A combination (diagonal
approach) was chosen in order to focus on RHD within the
framework of the existing healthcare system. The RHD
control program is a diagonal partnership between the
government of Nepal and the NHF. As part of this partnership, the government of Nepal has included RHD in the
national health program and provides the key antibiotic for
the program free of charge to consumers. The NHF continues to advocate for including RHD in noncommunicable
disease planning, on the recommendation of the World
Heart Federation [21].
The national RF/RHD prevention and control program
in Nepal has 3 objectives and 8 elements, outlined in
Tables 1 and 2. Activities in some of these elements are
addressed to illustrate some of the successes and challenges
of implementing RHD control activities in a very low
resource setting.

1.
2.
3.
4.
5.
6.
7.
8.

Epidemiological studies.
Awareness activities.
Training of health workers.
Case detection (heart screening).
Registry of RF/RHD patients.
Delivery of medicines for secondary prophylaxis.
Surveillance system.
Evaluation and monitoring.

Abbreviations as in Table 1.

chorea (2.8%), subcutaneous nodules (1.8%), and erythema marginatum (1.1%) [22]. This is the only data
available on manifestations of acute RF in Nepalese
patients.

AWARENESS FOR RHD CONTROL


Community awareness activities are essential for a successful RHD program [23]. Health literacy at baseline in
Nepal has been limited; few schoolchildren, parents, or
teachers were aware that untreated streptococcal throat
infection could lead to RHD [24]. The NHF has conducted
a range of activities to improve awareness about RHD:
putting large hoarding boards throughout the cities;
mobilizing the media; including RHD materials in school
curriculums; showing street dramas; distributing pamphlets, posters, and calendars [24]. A telecast of a documentary lm on RHD on the national TV channel was
instrumental in raising public awareness about the disease.
Mobilization of celebrities in awareness campaigns was also
applied with good effect. As a result of these activities, the
awareness on RHD increased by 40% (from 8% to 48%) in
schoolchildren and teachers of Nepal [24].

EPIDEMIOLOGICAL STUDIES

TRAINING FOR RHD CONTROL

The NHF has developed an RF/RHD register and used this


as a resource for improving local descriptive epidemiology.
NHF conducted a retrospective analysis of 4 years of register data, including 6,028 patients (June 2007 to October
2011). Of these, 5,356 (88%) had been diagnosed with
RHD and 672 (12%) with RF. Manifestations of RF were
described as arthritis (82%), carditis (60%), Sydenham

Health care in Nepal is mainly delivered by paramedics,


who are responsible for overseeing small clinics. Paramedics are responsible for delivering benzathine penicillin
G (BPG) injections for secondary prevention of RF. However, many paramedics were unfamiliar with this process
and unwilling to deliver intramuscular injections for prophylaxis. The major goal of paramedic training was to
support paramedics and enable them to provide secondary
prophylaxis at a primary care level. After completing the
training, more than 90% of paramedics who had earlier
refused to inject BPG agreed to do it under the guidance
and supervision of the NHF. Training and support was
critical for achieving the support and engagement of
paramedics. Future NHF training programs are being
considered for community health workers, teachers, adolescents, and mother groups. Education that encourages
people to seek help for a streptococcal throat infection and
treat it with a suitable antibiotic is the next step.

TABLE 1. Core program objectives


1. Early detection and registration of RF/RHD patients.
2. Establishment of centers for safe administration of BPG
injection for secondary prophylaxis.
3. Establishment of a national strategy for RF/RHD prevention and control with development of RHD control
toolkit.
BPG, benzathine penicillin G; RF, rheumatic fever; RHD, rheumatic
heart disease.

248

TABLE 2. Elements of the program

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ECHOCARDIOGRAPHIC SCREENING OF
SCHOOLCHILDREN
World Health Organization (WHO) guidelines recommend
screening for RHD in high prevalence settings [25].
Screening for RHD in schoolchildren has been an important part of the RHD prevention program in Nepal. The
NHF has screened more than 100,000 schoolchildren between 2007 and 2012. A 2-stage method has been used:
brief clinical examination and auscultation, followed by
conrmation of the suspected cases with echocardiography. NHF have just completed screening 30,000 schoolchildren in 38 government schools of the Lalitpur district
in Nepal. In this district, the prevalence of RHD was found
to be 1.8 per 1,000 schoolchildren of ages 5 to 16 years
(NHF, unpublished data, May 2013).

REGISTERS OF RF/RHD PATIENTS


Register-based programs have been shown to improve the
rates of secondary prophylaxis and decrease the prevalence
of RHD [25e28]. The RHD program in Nepal maintains
registers as a core component of the disease control efforts
[29]. The RHD control program has enrolled hospitals and
health centers at different levels, with progressive implementation from central, regional, zonal, and district areas.
Gradual expansion to the periphery has made the program
accessible to more and more rural people. Initially, 22 government hospitals participated in the program, but by the
end of April 2013, 35 hospitals were delivering secondary
prophylaxis. These hospitals maintain registers of the
RF/RHD patients and deliver the BPG injections free of cost.
Patients allergic to penicillin receive oral erythromycin, and
patients unable to receive BPG injections receive oral penicillin V. The WHO recommendations for dose and duration
of secondary prophylaxis are applied [25].
Nepal has adopted a 3-tiered system for maintaining
the RF/RHD registry:
1. Hospital register
This is a paper register with details of the RF/RHD
patients: name; age; sex; contacts; diagnosis; clinical
manifestations; echo ndings; medicines delivered;
dose; batch number; results of allergy test; and dates of
BPG injection delivery. All participating hospitals have a
separate register for RF/RHD patients receiving secondary prophylaxis. These hospitals forward the data to
the national register.
2. National (central) register
All the patients registered in this program and receiving
penicillin nationwide are entered into the National
RF/RHD register, which is maintained at the program
ofce of the NHF. This is paper and database register.
3. Penicillin injection card
A penicillin injection card is issued to all the patients
receiving secondary prophylaxis. This card contains
patient information, diagnosis, batch number, and

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September 2013: 247-252

expiry date of BPG injection that the patient is receiving,


dates of injections given, due date, and signature of
health personnel delivering the injection.

SECONDARY PROPHYLAXIS OF RHD


Secondary prophylaxis requires regular administration of a
long acting antibioticgenerally BPGto prevent recurrent
GAS infections and RF in patients with a history of RF or
RHD. WHO recommends 1,200,000 IU of BPG every 4
weeks to those with weight 30 kg in most circumstances
[25]. Individuals who have an RF recurrence on this
regimeor in settings where the incidence of RF is particularly highshould be considered for 3 weekly BPG injections. Three weekly regimes reect concerns that serum
drug levels may fall below a protective level before the fourth
week after administration in some cases [30,31]. Given the
very high burden of RF in Nepal, secondary prophylaxis with
penicillin once every 3 weeks is recommended by the NHF.
An alternative but less effective method is the use of daily
oral penicillin V. Even with optimal patient adherence, the
risk of recurrence is higher in individuals receiving oral
prophylaxis than in those receiving intramuscular benzathine penicillin G [32].
The NHF recently conducted an audit of patients
receiving secondary prophylaxis from the RF/RHD registers. In a period from June 2007 to February 2010 in 35
hospitals, there were 4,712 patients receiving 3 weekly
injections of BPG: 2,540 (53.9%) female patients and 2,172
(46.1%) male. Diagnosis was RF in 665 (14.1%) and RHD
in 4,047 (85.9%). Of those, 1,728 (36.7%) were younger
than 18 years age and 2,994 (63.3%) were older than 18
years. Out of 4,712 patients, there were 286 (6.0%) defaulters who had missed more than 2 consecutive doses of
BPG injections. Reasons for dropout were reported as injection phobia (4.9%), prohibitive distance (0.8%), prohibitive cost (0.2%), and other (0.3%). Compliance to
secondary prophylaxis was calculated to be 89.3% (NHF,
unpublished data, March 2012).

HURDLES TO SECONDARY PROPHYLAXIS


The NHF has identied a number of specic challenges in the
early days of the secondary prophylaxis program
implementation.

Reluctance to administer BPG


The predominant challenge of the program has been the
reluctance of paramedics to administer BPG for fear of
anaphylaxis. Paramedics were particularly concerned about
community reaction following adverse drug reactions;
anecdotal reports suggested some health workers had
suffered physical assault, claims for nancial compensation, and jail sentences following deaths. Overcoming these
concerns was the most difcult part of the program.
Paramedics involved in the RHD prevention program were
provided with training on penicillin skin testing and safe
penicillin delivery, which increased their knowledge and

249

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condence. The NHF developed recommendations on


penicillin skin testing (Table 3) and safe penicillin injection
delivery (Table 4). This was of great practical use to the
paramedics. It also became apparent that paramedics were
also struggling to differentiate between anaphylactic reactions and vasovagal reactions. Providing training about
the difference of these conditions and management
approach was considered very helpful (Table 5).

Pain of injection
Another major issue that affected the compliance to penicillin injection was the injection pain. Nearly 5% of patients
on secondary prophylaxis stopped taking BPG injections
due to pain (NHF, unpublished data). The NHF developed
recommendations for pain reduction (Table 6).

Concerns about BPG quality


BPG appears on the WHO essential medicines list and on
the Nepal national list [33,34]. Supplies for the national
RHD control program are provided by the government of
Nepal. There are no local manufacturers and all BPG
supplies are imported from India. Three brands of BPG are
available in Nepal: Penidure LA (Wyeth, Madison, New
Jersey); Pencom (Alembic, Gujarat, India); and Longacillin
(Hindusthan Antibiotic, Pimpri, India). Anecdotal concerns
about quality have been reported for all manufacturers. Of
the 3 options, paramedics were most satised with Penidure LA, because they felt it was easy to reconstitute, had
less clogging, and fewer allergic reactions. More quality
concerns were reported during the period when Wyeth
discontinued manufacturing Penidure LA and Pencom was
substituted [35]. This appeared to be associated with more
minor allergic reactions and blocking of the needle during
injection [35]. The association between brand and frequency of adverse drug reaction is concerning for the
TABLE 3. NHF recommendations on penicillin skin testing
1. Perform penicillin allergy skin test in the following
situations:
a. Before rst penicillin injection.
b. With change in batch number.
c. With change in brand name.
2. Steps for penicillin skin test:
a. Use 23-G needle.
b. Clean the middle of forearm with spirit swab.
c. Inject 0.1 ml of diluted BPG intradermal on the
forearm.
d. Wait for 15 to 20 min.
e. Look for local signs and symptoms of allergy (e.g.,
redness, inammation, itching, erythema, swelling,
blistering).
f. If any of the local signs are present and if the swelling
is >10 mm, the test is considered positive.
BPG, benzathine penicillin G.

250

TABLE 4. NHF recommendations on safe benzathine penicillin


injection delivery
1. Take consent from the patient or his/her relative before
the rst penicillin injection, with change in batch number
and brand.
2. Record the brand name and batch number of the BPG.
3. Reconstitute the BPG powder with 3.5 ml of sterile
distilled water.
4. Use 2 separate needles: 1 for pricking the vial and the
other for injecting into the patient.
5. Use 10 ml syringe and 21-G needle for deep intramuscular
injection.
6. Patient should lie down on trolley or bed on abdomen
with head resting on pillow in a comfortable and relaxed
position. In hospital settings, bed should be portable to
rush the patient to the intensive care unit in case of
emergency.
7. Inject BPG deep intramuscularly in the upper outer
quadrant of the buttock.
8. Stay prepared for the treatment of possible anaphylaxis.
The following medicines and instruments should be
ready for emergency use:
a. Adrenaline injection: l ampoule pre-loaded into the
syringe.
b. Atropine injection.
c. Dexamethasone or antihistamine injection.
d. Intubation set.
e. Suction machine.

manufacturing process of BPG. A safe, reliable, and highquality supply of BPG is critical for the continued condence of patients, paramedics, and the community.
Research to support this goal is urgently needed.

STRATEGIES FOR ADDRESSING BARRIERS


Penicillin injection delivery rooms
One of the objectives of the NFH program was to establish
centers for safe delivery of injection BPG. Hospitals with
large numbers of patients receiving secondary prophylaxis
TABLE 5. Signs, symptoms, and treatment of anaphylactic reaction and vasovagal reaction
Anaphylactic
reaction

a. Low blood
pressure
b. Tachycardia
c. Sweating
d. Dizziness
e. Dyspnea
f. Syncope

If not treated
immediately, it may
lead to death.
Treat anaphylaxis with
adrenaline injection.
Repeat injection
after 2 to 3 min if
necessary.

Vasovagal
reaction

a. Low blood
pressure
b. Bradycardia
c. Syncope

Treat vasovagal
reaction with
atropine injection.

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TABLE 6. NHF recommendations for minimizing pain of BPG


injections
1. Shake the powdered BPG vial after adding 3.5 ml of
distilled water until the powder dissolves and an opaque, viscous, suspension is formed with a nal volume
of w5.0 ml. The penicillin crystal can easily pass
through a 21- to 23-G needle. If the crystals are
attached to each other, they form large particles that
get clogged inside the needle. To avoid this situation,
reconstitution of the powder with 3.5 ml of distilled
water rather than 3 ml is advised.
2. Use 21-G taper cut needle for intramuscular injection.
3. Properly select the injection site and apply nger
pressure for 10 s.
4. Stretch the skin at the injection site with the thumb and
index nger.
5. Inject the liquid medicine at 90 angle with taper cut
needle tip facing downward in vertical plane, which will
cause minimum nerve end damage.
6. Never double prick with the same needle.
7. Push the syringe slowly, applying sufcient pressure in
a gradually increasing manner to allow the crystals in
the viscous medicine to ow smoothly. It may take up
to 1 min to push 5.0 ml of solution.
8. Distract the attention of the patient away from the
injection.
9. Maintain the injection delivery room temperature
below 30 C. In hot air and moist skin, the injections are
more painful.
10. Apply ice pack in case of pain immediately after
injection.
11. Mix 0.5 to 1.0 ml of 1% lignocaine with the BPG solution for reducing pain if all other techniques fail.

respectively, and fatal reactions are rare [36,37]. The risk of


a serious reaction is reduced in children under the age of
12 years and the duration of prophylaxis does not appear
to increase the risk of an allergic reaction [36]. The longterm benets of BPG therapy in preventing RF far
outweigh the risk of a serious allergic reaction [25,36].
The NHF audited adverse drug reactions to BPG over
77,300 injections delivered to 4,712 RHD patients for
secondary prophylaxis during the period from June 2007
to February 2010 [35]. Sixty-ve patients (1.4%) had an
adverse drug reaction: 5 were anaphylactic reactions, an
incidence of 0.1% (0.7/10,000 injections); 60 were minor
reactions, an incidence of 1.3%. Ten patients had minor
allergy while receiving new batch of benzathine penicillin
(incidence of 0.2%), and 18 patients had minor allergy
with new brand of injection BPG (change from Penidure
LA to Pencom), an incidence of 0.4%. There were 8
vasovagal reactions (0.16%). No deaths were reported [35].
RHD patients, because of poor cardiac function, may be
more susceptible to vasovagal reactions [36]. All health
workers dispensing secondary prophylaxis need proper
training in performing penicillin skin test and delivery of
intramuscular injection. Training the health workers who
deliver secondary prophylaxis helps improve survival from
anaphylaxis. Mortality from anaphylaxis signicantly
decreased after the launch of RHD control program in Nepal.
There were no standardized guidelines about indications
for skin testing in Nepal prior to the advent of the national RF/
RHD control program. Some centers performed skin test
before each penicillin injection, whereas others limited the test
to the rst penicillin injection only. The NHF has published
recommendations on penicillin skin testing [35] (Table 3). In
Nepal, skin testing for allergy is recommended in all patients
who are to receive penicillin injections.

BPG, benzathine penicillin G.

were advised to have a separate room dedicated only for


penicillin injection delivery. Hospitals with smaller
numbers of RHD patients could use the same room for
injections and dressings. The RHD control program had to
put forth tremendous efforts to establish penicillin injection delivery rooms for safe and smooth injection administration and managing anxiety for paramedics and for
patients. Recommendations were developed to standardize
the process, maximize safety, and minimize pain. Staff were
trained to recognize and treat adverse drug reactions.
Rooms were equipped with an emergency care kit box
containing medication and equipment to manage anaphylaxis. Recommendations for a model penicillin injection
delivery room were developed to include patient trolley,
oxygen cylinder, IV stand, suction machine, intubation set,
and emergency care kit with necessary medicines.

NEXT STEPS FOR RHD CONTROL IN NEPAL


Pilot project on primary prevention of acute RF
The NHF is collaborating with the District Public Health
Ofce, the government of Nepal, and Rotary International
district 3292 to initiate a pilot project on primary prevention
of RF in the Lalitpur district. This region has a population of
400,000 of which 40% are children of 5 to 16 years of age.
The program was launched in July 2013 with 42 primary
health centers participating and paramedic training
completed. Tonsillitis and pharyngitis registers will be
maintained. Developing a protocol for diagnosing GAS has
been challenging; the NHF has decided to treat children with
clinical signs and symptoms, aiming for a nancially viable
treat all approach [38]. One group of patients will receive
amoxicillin 3 daily for 7 days and the other group will
receive azithromycin once for 5 days for sore throat.

CONCLUSIONS
Penicillin allergy and penicillin skin testing
The incidences of allergic and anaphylactic reactions to
BPG injections are reported to be 3.2% and 0.2%,

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September 2013: 247-252

The Nepalese model of a diagonal RF/RHD control program illustrates the feasibility of care delivery in very lowresource settings. The commitment from the government

251

gREVIEW

and the community involvement support program sustainability. Developing an RF/RHD registry, training paramedics, publishing recommendations and guidelines, and
securing a supply of BPG are signicant achievements and
advances in practice. The extensive involvement and
coordination by the NHF has been critical for success.
Improving the quality and safety of BPG supplies and
piloting primary prophylaxis are the next steps for disease
control. Comprehensive program evaluation is an ongoing
requirement but there are early signs of enormously valuable progress.
REFERENCES
1. Dajani A, Taubert K, Ferrieri P, Peter G, Shulman S. Treatment of acute
streptococcal pharyngitis and prevention of rheumatic fever: a
statement for health professionals. Committee on Rheumatic Fever,
Endocarditis, and Kawasaki Disease of the Council on Cardiovascular
Disease in the Young, the American Heart Association. Pediatrics
1995;4:75864.
2. Gerber M. Rheumatic fever. In: Rehrman R, Kliegman R, Jenson H,
editors. Nelson Textbook of Pediatrics. New Delhi, India: Elsevier;
2004. p. 8749.
3. Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden
of group A streptococcal diseases. Lancet Infect Dis 2005;5:68594.
4. Marijon E, Mirabel M, Celermajer DS, Jouven X. Rheumatic heart
disease. Lancet 2012;379:95364.
5. United Nations. World Statistics Pocketbook 2013 Edition. Series V.
No. 37. New York, NY: United Nations, Department of Economic and
Social Affairs, Statistics Division, 2013.
6. United Nations Development Programme. Nepal: Country prole:
human development indicators [online index]. 2013. Available from:
http://hdrstats.undp.org/en/countries/proles/NPL.html. Accessed
July 25, 2013.
7. Health Sectore Reform Support Programme. Health Care Financing in
Nepal. Kathmandu, Nepal: Health Sectore Reform Support Programme, Ministry of Health and Population, Government of Nepal,
2010.
8. Shrestha C, Bhandari R. Insight into human resources for health
status in Nepal. Health Prospect 2012;11:401.
9. Vaidya A. Tackling cardiovascular health and disease in Nepal:
epidemiology, strategies and implementation. Heart Asia 2011.
http://dx.doi.org/10.1136/heartasia-2011.010000.
10. Shrestha BR, Baniya GB, Raut KB, Sharma S. Rheumatic fever in
adults. J Nepal Med Assoc 1996;34:23641.
11. Shrestha UK, Bhattarai TN, Pandey MR. Prevalence of rheumatic fever
and rheumatic heart disease in school children in a rural community
of the hill region of Nepal. Indian Heart J 1991;43:3941.
12. Regmi PR, Pandey MR. Prevalence of rheumatic fever and rheumatic
heart disease in school children of Kathmandu city. Indian Heart J
1997;49:51820.
13. Bahadur KC, Sharma D, Shrestha MP, et al. Prevalence of rheumatic
and congenital heart disease in schoolchildren of Kathmandu valley
in Nepal. Indian Heart J 2003;55:6158.
14. Government of Nepal. Nepal Population Report. Ramshahpath,
Kathmandu, Nepal: Government of Nepal, Ministry of Health and
Population, 2011.
15. National RF/RHD prevention and control program. Annual Report.
Nepal Heart Foundation: 2011.
16. Limbu Y, Maskey A. Current status of rheumatic fever and rheumatic
heart disease in Nepal. J Nepal Med Assoc 2002;41:5147.
17. NHF. Introduction of Nepal Heart Foundation [web page]. 2012.
Available from: http://nehfc.webs.com/. Accessed July 28, 2013.

252

18. Remenyi B, Carapetis J, Wyber R, Taubert K, Mayosi BM. Position


statement of the World Heart Federation on the prevention and
control of rheumatic heart disease. Nat Rev Cardiol 2013;10:28492.
19. NHF. National Rheumatic Fever (RF)/Rheumatic Heart Disease (RHD)
Prevention and Control Program [online report]. 2006. Available
from: http://nehf.webs.com/rheumaticheartdisease.htm. Accessed
July 25, 2013.
20. Frenk J. Bridging the Divide: Comprehensive Reform to Improve Health
in Mexico. Nairobi, Kenya: Commission on Social Determinants of
Health; 2009.
21. World Heart Federation. Call for action, now! RHD newsApril
2013(online press release). 2013. Available from: http://www.worldheart-federation.org/what-we-do/rheumatic-heart-disease-network/
rhd-news/april-2013/. Accessed July 27, 2013.
22. Regmi P, et al. Prevalence of Sydenhams chorea in patients with
acute rheumatic fever in Nepal. Nepalese Heart J 2012;9:302.
23. Bach JF, Chalons S, Forier E, et al. 10-year educational programme
aimed at rheumatic fever in two French Caribbean islands. Lancet
1996;347:6448.
24. Regmi P. Proceedings of "Have a Heart, Save a Heart" Project. South
Asian Youth Summit (SAYS) 2011 with support from the US Embassy
and technical support from the Nepal Heart Foundation: Kathmandu,
Nepal: 2012.
25. WHO. Rheumatic Fever and Rheumatic Heart Disease. Geneva,
Switzerland: World Health Organization; 2004.
26. Thornley C, et al. Rheumatic fever registers in New Zealand. New
Zealand Public Health Rep 2001;8:414.
27. Nordet P, Lopez R, Dueas A, Sarmiento L. Prevention and control of
rheumatic fever and rheumatic heart disease: the Cuban experience
(1986e1996e2002). Cardiovasc J Afr 2008;19:13540.
28. McDonald M, Brown A, Noonas S, Carapetis JR. Preventing recurrent
rheumatic fever: the role of register based programmes. Heart 2005;
91:11313.
29. Regmi P, Upadhyaya A. Rheumatic fever and rheumatic heart disease
RHD prevention and control program in Nepal. Nepalese Heart J
2009;6:8893.
30. Lue HC, Wu MH, Hsieh HK, Lin GJ, Hsieh RP, Chiou JF. Rheumatic fever
recurrences: controlled study of 3-week versus 4-week benzathine
penicillin prevention programs. J Pediatr 1986;108:229304.
31. Lue H, Wu MH, Wang JK, Wu FF, Wu YN. Long-term outcome of
patients with rheumatic fever receiving benzathine penicillin G prophylaxis every three weeks versus every four weeks. J Pediatr 1994;
125:8126.
32. Feinstein AR, Wood HF, Epstein JA, Taranta A, Simpson R, Tursky E.
A controlled study of three methods of prophylaxis against streptococcal infection a population of rheumatic children II: results of the
rst three years of the study including methods for evaluating the
maintenance of oral prophylaxis. N Engl J Med 1959;260:689702.
33. Government of Nepal. National List of Essential Medicines Nepal.
Kathmandu, Nepal: Government of Nepal, Department of Health and
Population; 2009.
34. WHO. WHO Model List of Essential Medicines. 17th list. Geneva,
Switzerland: World Health Organization; 2011.
35. Regmi P, Upadhyaya A. Allergic reaction to long-term benzathine
penicillin injection for secondary prevention of acute rheumatic fever
and recommendations for skin testing. Nepalese Heart J 2011;8:168.
36. Allergic reactions to long-term benzathine penicillin prophylaxis for
rheumatic fever. Lancet 1991;337:130810.
37. Markowitz M, Lue HC. Allergic reactions in rheumatic fever patients
on long-term benzathine penicillin G: the role of skin testing for
penicillin allergy. Pediatrics 1996;97:9813.
38. Irlam J, Mayosi BM, Engel M, Gaziano TA. Primary prevention of
acute rheumatic fever and rheumatic heart disease with penicillin in
South African children with pharyngitis: a cost-effectiveness analysis.
Circ Cardiovasc Qual Outcomes 2013;6:34351.

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EXPERT CONSENSUS DOCUMENT

gRECS

The Second Rheumatic Heart Disease Forum Report


Liesl J. Zhlke*,y, Mark E. Engely, Bo Remenyiz, Rosemary Wyberx, Jonathan Carapetisx, for the RHD Forum
Meeting Report Writing Committee
Cape Town, South Africa; and Darwin, Northern Territory, and Perth, Western Australia, Australia
ABSTRACT
The second rheumatic heart disease (RHD) forum was held on February 18, 2013, at the Sixth World
Congress of Pediatric Cardiology and Cardiac Surgery in Cape Town, South Africa, to focus attention on
key areas in global RHD control, management, and prevention. Building on the foundation of the rst
RHD forum, over 150 interested participants met to discuss critical issues on the RHD landscape. Unique
to this meeting was a mixture of diverse backgrounds and disciplines, all crucially important to the
conversation around RHD control and prevention. Some clear priorities have emerged for RHD activities in
the next era: the necessity for political intervention and policy change; increasing the health workforce by
incorporating teaching, training, and task-shifting; revitalizing the research agenda by merging basic,
clinical, and translational research; and obtaining universal access to high-quality penicillin. There was also
an urgent request for new resources; for existing resources to be further developed, improved, and shared
across platforms; and for resources to be supported in the nonmedical arena. Finally, the necessity of
involving the patient community in the ongoing discussion was highlighted. The participants of both the
rst and second RHD forum represent a new, thriving, and growing community of RHD activists who
should usher in a new era of signicant improvements in RHD control and prevention.
TABLE OF CONTENTS
Participants ................................................... 253
Objectives .................................................... 253
Advocacy, policy, public health, and government
engagement ...................................... 254
National level advocacy ........................... 255
Advocacy into actionknowledge translation,
translational research ........................... 255
RHD control at a global level .................... 255
Science and researchpriorities and translation .. 256
Interdisciplinary interaction to direct research
priorities ......................................... 256
Global collaboration ............................... 257
Development of effective screening and
treatment interventions ........................ 257
Basic sciences research ............................ 257
Training and capacity building ...................... 257
Practical issues in RHD control at a country
level ............................................... 258
Penicillin............................................. 258
Treatment of sore throat .......................... 259
Warfarin ............................................. 259
National policy of notiable diseases ........... 260
Surgical capacity ................................... 260
Conclusions .................................................. 260
Acknowledgments ........................................... 260
References .................................................... 261

of those involved in acute rheumatic fever (ARF)/RHD control, prevention, and management activities across the globe.
This meeting provided 33 participants the opportunity to
meet, share successes, and network mutual challenges. The
World Congress of Pediatric Cardiology and Cardiac Surgery
held in Cape Town from February 17 to 22, 2013, was the
natural venue for the second RHD forum as RHD remains the
most common cause of acquired heart disease in children,
adolescents, and young adults [1]. In addition, this conference had as a central tenet a deliberate focus on issues
affecting the majority of the worlds children with particular
references to diseases of the poor and marginalized people
[2]. For this forum, 4 discussion groups were chaired by
experts in the RHD community: 1) advocacy, policy, public
health, and government engagement; 2) science and
researchpriorities and translation; 3) training and capacitybuilding; and 4) practical issues in RHD at the country level.

PARTICIPANTS
It was expected that 50 to 60 participants would attend; yet
overwhelming interest resulted in over 150 delegates
attending from 38 countries and all major continents, only
20% of whom had been at the previous RHD forum (Fig. 1,
Table 1). Interestingly, the delegates represented a diverse
group with interests and backgrounds outside of medicine
including law, advocacy, fundraising, and lmmaking.

OBJECTIVES
The rst rheumatic heart disease (RHD) forum was held
in April 2012 at the World Congress of Cardiology in Dubai,
United Arab Emirates, and assembled for the rst time many

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 253-261

The major objective of the forum was to discuss critical


needs around RHD and to share common goals, visions, and
strategies. Another objective was to encourage the

Financial support for the


second rheumatic heart
disease forum was provided by the Medtronic
Foundation and Cure Kids.
L. Zhlke is funded by
the Thrasher Foundation,
Clinical Infectious Disease
Research Initiative, and the
Hamilton Naki Clinical
Scholarship Programme,
which is funded by Netcare
Limited.
From the *Department of
Paediatrics, Red Cross War
Memorial Childrens Hospital and University of Cape
Town, Cape Town, South
Africa; yDepartment of
Medicine, Groote Schuur
Hospital, Cape Town, South
Africa; zMenzies School of
Health Research, Darwin,
Northern Territory,
Australia; xTelethon Institute for Child Health
Research, University of
Western Australia, Perth,
Western Australia,
Australia. Correspondence:
L. Zhlke (liesl.zuhlke@uct.
ac.za).
GLOBAL HEART
2013 World Heart
Federation (Geneva).
Published by Elsevier Ltd.
All rights reserved.
VOL. 8, NO. 3, 2013
ISSN 2211-8160/$36.00.
http://dx.doi.org/10.1016/
j.gheart.2013.08.006

253

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print & web 4C=FPO

FIGURE 1. Countries represented at the second RHD forum. RHD, rheumatic heart disease.
development of collaborative platforms and programs, and
stress key areas of research, intervention, and emerging
priorities. As the cardiovascular community tackles the
vision of a 25% reduction in premature deaths from RHD in
the under 25 years olds by the year 2025 [3], it is critical for
all interested groups working in the RHD space to contribute
to this important conversation and build a new, vibrant,
growing RHD community, allowing for new networks and

friendships to develop (and strengthening of more established ones) and to highlight major common areas of need.
The major discussion points follow (Table 2).

Advocacy, policy, public health, and government


engagement
RHD activities have suffered in the recent past by dwindling
public health and government interest, due to decreasing

TABLE 1. Countries represented at the second RHD forum


North America
Canada
United States of America

South America

Africa

Europe

Australasia/Oceania

Asia

Brazil

Angola
Cameroon
Cote DIvore
Egypt
Ghana
Kenya
Mozambique
Namibia
Nigeria
Rwanda
South Africa
Sudan
Uganda
Zambia
Zimbabwe

Austria
Poland
Switzerland
United Kingdom

Australia
Fiji
New Zealand
Republic of Tuvalu

Bangladesh
India
Indonesia
Malaysia
Pakistan
Philippines
Saudi Arabia

RHD, rheumatic heart disease.

254

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TABLE 2. Advocacy, policy, public health, and government


engagement
National level advocacy

 Importance of data
 Mobilizing and engaging
governments
 Community involvement
 RHD champions
 Multimodal media messages

Advocacy to action

 Very specic asks


 Need for equipped medical
workforce
 Health system support

Expansion of RHD control


on a global level

 Mutual support of countries


with variable development
of RHD programs
 Extension of the role of
international organizations

RHD, rheumatic heart disease.

prevalence in high-income countries and competing health


interests in lower-income countries [4]. Yet, engagement
with government is critical to effect policy and public health
interventions, whereas community awareness is vital to
encourage activism around RHD. This group focused on
3 key questions in this area:
1. What helps with national level advocacy?
2. How to translate advocacy to action?
3. How to expand RHD control at a global level?

National level advocacy There is an urgent need for


surveillance to detail the ARF/RHD burden of disease,
particularly in low-income countries and rural settings. This
is fundamental to comprehensively inform governments
concerned about endemic disease conditions and
morbidity and mortality gures. Strategies for translating
burden of disease data to government engagement and
action were explored. Approaches included: politicizing
the issue (with the elevation of RHD in the national policy
agenda of New Zealand as an example); leveraging the
millennium development goals; and aligning RHD with
issues of child health, maternal morbidity/mortality, and
the noncommunicable disease agenda currently of interest
to many governments.
An essential element to activism and advocacy was to put
a face to RHD and escalate active community participation.
Approaches should involve parent, community, and patient
groups such as the patient clubs that have been successful in
Kerala, India [5]. These occasions can provide important
opportunities for education and can draw much-needed
media attention (e.g., the work in Vietnam around
nephrotic syndrome [6]). Educated, adherent patients can be
powerful advocates, and a health minister with a personal
connection to RHD can present a wonderful opportunity.

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The suggestion of teaching children at school and having


them educate families at home was also raised.
Leading clinicians with a national prole are needed to act
as clinical champions for RHD and to encourage nonclinical
champions to develop from other arenas. Advocates and
prominent clinicians from within heart foundations have
already been successful in mobilizing governmental support.
Film stars and sporting heroes can be very powerful role models
and lessons could be learned from other disease intervention
strategies such as the polio eradication campaign in India.
The importance of multimodal media outputs was
stressed. Brochures can help people living with ARF/RHD
understand the condition; however, literacy can be a signicant challenge. Increasing public messages can build
media interest, creating a global chorus for action. Documentaries, short lms, and interviews can be powerful
advocacy tools and can mobilize people otherwise
disconnected from ARF/RHD, particularly from highresource settings. Finally, using social media platforms
such as Facebook and Twitter was proposed, acknowledging that these could be difcult to access in very lowresource settings (Table 3).

Advocacy into actionknowledge translation,


translational research The greatest challenge in RHD is
implementing the knowledge and evidence that already
exists. ARF/RHD can be controlled with sufcient awareness, advocacy, and mobilization of political will.
Some specic asks may be the rst step in this regard.
ARF/RHD is a disease of poverty and poor social infrastructure; advocacy efforts should always emphasize primordial
prevention. The next major ask relates to the health workforce. Translating our current evidence into practicable programs requires a trained medical workforce able to implement
RHD programs. Countries reported variable compliance with
clinical guidelines and inadequate education regarding the
importance of secondary prevention. Even within the medical
profession, inadequate understanding of the disease may exist
and result in suboptimal promotion of secondary prophylaxis.
In addition, the informal medical sector may be difcult to
access or regulate in many areas.

RHD control at a global level One of the main objectives of the rst RHD forum was to support those working in
countries with less-developed RHD programs. This can take
various guises: sharing of protocols and scientic data visits;
joint projects; introductions to funding opportunities and
establishing local and regional priorities; advocating to
government; and forming groups of disease champions.
The World Heart Federation (WHF) position statement
is expected to be helpful for countries to adapt to local settings
or recommendations, although more technical support may
be needed to help with local-level implementation (Table 3).
International organizations and industry have an
important role exerting a top-down inuence on policy
makers at international and government levels. The importance of the World Health Assembly (held in May 2013) was

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TABLE 3. Selected resources for RHD community (cited in this document)


Curricula/resources

 WHO technical report: http://whqlibdoc.who.int/trs/WHO_TRS_923.pdf


 WHF curriculum: http://www.world-heart-federation.org
 Position statement of the WHF on the prevention and control of rheumatic heart disease: http://
www.nature.com/nrcardio/journal/v10/n5/full/nrcardio.2013.34.html
 UNICEFs Facts for Life: http://www.unicef.org/publications/index_53254.html
 WHF criteria for echocardiographic diagnosis of rheumatic heart diseasean evidence-based
guideline: http://www.nature.com/nrcardio/journal/v9/n5/full/nrcardio.2012.7.html
 WHO pocket book: http://www.who.int/maternal_child_adolescent/documents/9241546700/en/

Websites

 www.worldheart.org/rhd
B Includes resources, training manuals, guidelines, and articles
 www.RHDaustralia
B Includes resources, training manuals, guidelines, and monthly newsletter
 http://www.ncdalliance.org/
 http://www.clanchildhealth.org/
 http://www.ncdchild.org/
 http://www.curekids.org.nz/

Training

 http://www.pih.org/library/the-pih-guide-to-chronic-care-integration-for-endemic-noncommunicable-dise
 Global research priorities in rheumatic fever and rheumatic heart disease: http://www.ncbi.nlm.
nih.gov/pmc/articles/PMC3104531/
 Simplied Echocardiographic Strategy for Heart Failure Diagnosis and Management Within an
Integrated Non-Communicable Disease Clinic at District Hospital Level for Sub-Saharan Africa:
http://www.ghdonline.org/ncd/discussion/simplied-echocardiographic-strategy-for-heart-fa/?
id308828&formathtml&typedigest
 African pediatric fellowship program: http://www.scah.uct.ac.za/apfp/APFP

Basic sciences research

 Vaccine development: http://ip.bio-med.ch/cms/cms

Videos, interviews,
YouTube links








Apps for iPhone, iPad, or


Android

 www.rhdaustralia.au

Guidelines

 Australia and New Zealand: http://www.rhdaustralia.org.au/sites/default/les/guideline_0.pdf


 India: http://www.ncbi.nlm.nih.gov/pubmed/1869527

http://www.youtube.com/watch?vtWMGNG61SRA
http://www.youtube.com/watch?vMoWJiupOBo4
http://www.youtube.com/watch?veUFpNK2ljgw
http://www.youtube.com/watch?vdB7eXTh6zdg
http://www.youtube.com/watch?v0J6Tf3cv8sg
http://www.rheumaticheartclub.org/

UNICEF, United Nations Childrens Fund; WHF, World Health Federation; WHO, World Health Organization.

highlighted as an opportunity to inform ministers of health


about RHD. The United Nations Childrens Fund has produced a document titled Facts for Life, with a series of
chapters on raising healthy children, that provides practical
tips for policy makers and health professionals. Other useful
tools exist: WHFs dedicated RHD website, RHDNet, provides resources, although all these resources should be more
dynamic and high prole in order to generate as much interest as possible (Table 3).
One suggestion was for an A4 factsheet of hard data to
distribute that would provide consistent, powerful messages required for global advocacy. Finally, all participants
supported ongoing advocacy efforts directed at the pharmaceutical and biomedical industry to improve the global

256

benzathine penicillin G supply and to consider low-cost


tertiary interventions. Industry partners also have skills
and experience relevant to broader disease control efforts.

Science and researchpriorities and translation


The following areas were identied as research priorities
(Table 4).

Interdisciplinary interaction to direct research


priorities More collaboration among members at all
levels (including scientists, healthcare workers, clinicians,
echo technologists, nurses, health educators, etc.) within
the RHD community will foster the exchange of ideas for
topics for research from basic research to knowledge

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gRECS

TABLE 4. Science and researchpriorities and translation


Coordination of
research

 Interdisciplinary interaction to direct


research priorities
 Registries as a research tool, especially in resource-poor countries
 Global collaboration

Applied science

 Screening interventions
 Treatment interventions
 Vaccine development

Basic sciences
research






GAS pharyngitis
Strep registries
M protein gene typing
Genetic studies

GAS, group A streptococcus.

translation. In particular, more contact between basic and


clinical sciences will steer efforts in providing answers to
questions arising from within the clinical environment.
A clear need exists for registries as a research tool,
especially in resource-poor countries, which will also
facilitate the development of country-specic priorities
for prevention. Furthermore, if similar protocols are
used, combining data across registries will allow for the
evaluation of the natural course of disease at a global
level. The research can also be extended to trials
involving multicenter institutions on the notication of
ARF. In addition, there is a need to have research
targeting the strengthening of health systems to ensure
adequate management of cases. There was a call for
assistance in setting up RHD programs where they
currently do not exist.

Global collaboration Participants strongly suggested


that investigators of programs emanating from more afuent
settings consider including units from less-developed
countries when planning research and applying for grants,
especially in screening for RHD. Sharing training
opportunities, for example, in echocardiography, will serve
to strengthen the global network in RHD research.

effective and innovative means of delivery while encouraging adherence. There is also a need for an evidence base
for current treatment strategies to be developed. This
should include further research on penicillin as a prophylactic drug, drugs being used for patients with heart
failure, and alternatives to the more expensive drugs
currently used. There was consensus that concerted efforts
should be directed at developing a vaccine for group A
streptococcus (GAS).

Basic sciences research More studies are needed on


ways of accurately identifying GAS in the absence of laboratory facilities, in other words, developing clinical prediction rules, given that many cases occur in rural areas devoid
of clinic facilities. The development of registries to record
streptococcal infection, especially in resource-poor settings,
will serve as a useful tool to document the epidemiology
of GAS-related infections. Studies on M protein gene
typing are also needed to inform the development of
potential M proteinebased vaccines. Genetic studies may
serve to identify indicators of RHD disease before the
onset of symptoms and the individuals most likely to
benet from a potential vaccine, thus reducing the overall
cost of vaccination.
Training and capacity building
A serious concern in combating RHD is the lack of sufcient training and health worker capacity in high prevalence areas. This was expressed by all participants in each
group. However, sensitizing all levels of healthcare workers
to RHD was the important initial step to raise awareness,
then to generate interest in training, and then nally to
offer appropriate training (Table 5).
Training requirements are complex, multilevel, and
should include denitions for each role (e.g., teachers,
nurses, community workers, general practitioners,
TABLE 5. Training and capacity-building priorities
Training

 Sensitizing healthcare workers


 Training at all levels with a wide range of
outputs
 Targets including heathcare workers,
communities, schools teachers, patients,
and families.
 Integration of ARF and RHD training in
existing health worker education programs
 Collaboration and networking
 Exchange programs

Capacitybuilding

 National algorithms and referral systems


 Sustainable models for low-cost
technology
 Sustainable models for cardiology and
surgical services

Development of effective screening and treatment


interventions There is a need to research and develop
screening interventions that will be effective in diagnosing
RHD in its early stages, especially in those resource-poor
settings where surgery is not an option. Screening-related
research should focus on: 1) identifying indicators of higher
risk in children characterized as borderline RHD by the
WHF criteria to answer the question of when to start
prophylaxis; 2) identifying more cost-effective interventions
(e.g., hand-held echo or nurse-led screening); 3) identifying
community-based approaches to improve the accuracy of
epidemiologic ndings; and 4) performing cost-effectiveness
analyses.
Given the concerns regarding adherence to secondary
prophylaxis, treatment-related research should focus on

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ARF, acute rheumatic fever; RHD, rheumatic heart disease.

257

gRECS

specialists) regarding expectations and desired outcomes.


In South Africa, a pilot workshop trained school nurses to
educate other nurses, teachers, and pupils using a locally
produced DVD. It was strongly recommended that a national committee be nominated to lead training and integrate ARF/RHD training into existing health workers
education programs. Practically, anaphylaxis training must
be a pre-requisite for all those involved in penicillin delivery and is critical to building condence in the program
among those instituting the delivery.
The need for human resources was well illustrated by the
example of Rwanda with a desperate shortage of skilled
workforce. Currently, there are only 2 pediatric cardiologists
for a population of 10 million; also, there is a dire shortage of
pediatricians. Existing options to address these realities
include task-shifting and integrated management models.
General practitioners are trained in RHD management and
have become the rst line of contact. A 1-year diploma in
cardiology is also being offered in Rwanda, and noncommunicable disease nurses are currently undergoing
echocardiography training. Other centers have trained radiographers or radiology technicians in echocardiography.
Another thought was to offer the WHF curriculum in a 1-year
diploma that could also be offered as distance learning.
Currently, RHD Australia has training modules online. There
is also a U.S. guideline for emergency echo.
Colleagues from Egypt highlighted that they were not
short of training nor doctors, but they urgently needed individuals with experience in data management, statistics, and
ethics. Research infrastructure was also generally insufcient,
resulting in decreased research capacity. All participants were
concerned that managing available resources was a priority,
but it was challenging without administrative staff and
nancial support.
One proposition was the expansion of exchange programs to up-skill clinicians and make available local and
overseas opportunities. These need not be the typical
north-south collaborative model; they could be southsouth coordinated training, intracontinental, or regional
(Table 3). It was clear that all the specialties needed to be
trained and informed (pediatrics, adult medicine, cardiology, infectious disease) using strategies appropriate for
different cadres of health workers. Surgeons in the groups
felt that many of their colleagues found ischemic heart
disease surgery more appealing than RHD work, but
others were keen to tackle the challenges of valve surgery.
Surgeons generally found the interface with the rest of the
health system challenging.
Finally, some practical concerns were debated. It was
felt that referral systems needed to be developed with national or regional algorithms promulgated. Sustainable
models for international normalized ratio (INR) monitoring
and the high costs of cardiovascular technology remain
concerning in low-income countries. For surgical services
to succeed, local interest must be generated to sustain
surgical programs and medico-surgical centers need to be
accountable to local and regional needs.

258

Practical issues in RHD control at a country level


Many of the points raised in the rst 3 groups were echoed
in this group discussion, which grappled with practical
issues on a country level (Table 6).

Penicillin
 Availability: The majority of the participants expressed
serious concerns regarding the availability, quality, and
safety of penicillin. In view of the evidence of efcacy of
benzathine penicillin, the realities of intermittent supplies
and the inadequate response of pharmaceutical companies
and governments to ensure regular, high-quality penicillin
is alarming. All countries report an even poorer supply of
oral penicillin, used when benzathine was unavailable or
not permitted, as in certain areas of India. Indian delegates
remarked on the suboptimal compliance with oral penicillin and an observed increased recurrence rate once benzathine penicillin was discontinued in their states (because
of concerns around anaphylaxis). All countries represented
had different dosage intervals and thus were variably
affected by poor supply.
Penicillin thus remains a critical issue for any
comprehensive RHD program and a major focus area to be
tackled over the next 5 years.
TABLE 6. Practical issues at a country level
Penicillin

 Benzathine penicillin remains


the most effective primary and
secondary preventive agent for
ARF/RHD.
 Serious concerns remain
regarding the availability, quality,
delivery, and safety of penicillin
from many areas of the world.

Treatment of sore
throat

 Sore throats are still


under-recognized and
undertreated.
 Need for local clinical prediction
rules.
 Streptococcal sore throat
programs needed.

Warfarin

 Point-of care INR is a critical


need in order to monitor
warfarin use.

National policy of
notiable diseases

 Governments should be
encouraged to make ARF/RHD
notiable and to support local
registries.

Surgical capacity

 Surgical capacity remains a


concern for those caring for
patients with advanced disease.

INR, international normalized ratio; other abbreviations as in


Tables 1 and 5.

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 Anaphylaxis: Deaths due to anaphylaxis, although rare,


have been followed by cessation of secondary prevention
programs using benzathine penicillin G in some settings.
There were a variety of approaches to preventing
anaphylactic deaths. One method was increasing the
availability of and training in the use of anaphylaxis kits,
whereas another was introducing regular skin testing. In
1 Indian center, RHD patients have skin tests prior to
each injection. In Nepal, these were performed with the
rst injection, each batch change, and each brand
change. New brand and constant batch changes were
challenges both in India and Pakistan and have resulted
in either skin tests or test doses with each injection. Two
other strategies were presented: 1) In Brazil, a family
history is taken prior to delivery of benzathine penicillin;
adrenaline is always pre-loaded; and the patient is
observed for 40 min after administration. In New Zealand, the rst injections are done in a hospital with the
rest delivered entirely by nurses in community settings.
In South Africa, primary healthcare nurses are routinely
involved in other benzathine penicillin delivery programs (such as treatment of syphilis). These units are
largely not equipped with anaphylaxis kits, although
nurses are taught anaphylaxis management.
Generally, it was felt that further research was needed
into the causes and mechanism of anaphylaxis and prevention of anaphylaxis events. Many feel that anaphylactic
events are often due to reactions to reagents or impurities
rather than to the penicillin itself, yet anaphylaxis has the
potential to entirely derail a functioning secondary prophylaxis program. This should be a keen priority research
area.
 Delivery: All participants agreed that the evidence indicated that 2-weekly penicillin doses were highly effective. However, such regular administration was
problematic in many areas of the world, and thus the
standard regimen in most groups was 4-weekly doses.
Compliance and adherence remain a major concern and
different strategies were outlined. One approach
included the situation in Perth, Australia, where nurses
visit schools and homes to administer penicillin. The
consensus was in favor of employing several strategies
depending on the environment and target population.
New models were reviewed with comparisons of successes and failures. Studies determining the barriers to
adherence are critically needed as is structured evaluation of successful programs. For those on oral prophylaxis, another suggestion was using the directly observed
therapy strategy used in tuberculosis management.
The role of the healthcare worker involved in benzathine
penicillin delivery was also strongly debated. Skilled health
workers are scarce in all regions with high RHD prevalence
and increased adherence will place extra demands on already
stressed health systems. Integration with coexisting benzathine programs, such as for syphilis treatment, may result in

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 253-261

shared costs and possibly improved adherence. Each region


should look at their adherence and recurrence rates and the
current staff providing penicillin delivery in order to adopt
the most successful model. The value of experienced, highly
skilled nurses cannot be overemphasized. Reducing the pain
of the benzathine injection is an important aspect of
increasing adherence; skills in this area should be taught to
all community and primary healthcare workers. Adjuncts
such as lignocaine, the use of separate needles, normal saline,
and slow injections should be practiced.
Simple, cheap, and innovative models are required to
support existing health systems to improve compliance.
These include delegating prescription authority from doctors to nurses for benzathine penicillin G and text message
reminders for benzathine penicillin G doses. A suggestion
was to provide small incentives for families to bring children for prophylaxis (e.g., offering a sibling an examination). The use of Internet and electronic records can
improve standardization, making the program delivery
safer and easier to monitor.

Treatment of sore throat The treatment of sore throat is


pivotal to reducing the burden of ARF and eventually RHD in
our communities. However, all participants agreed that sore
throats were untreated and under-recognized as the primer
to RHD. The Nepalese slogan of a sore throat can break
your heart accompanied by a stern picture of Dr. Prakash
Regmi, from the Nepalese Heart Foundation, has been
widely distributed throughout Nepal, with good effect. A
variety of similar strategies was deliberated, including the
use of community health workers or health posts to
diagnose and treat sore throats in Rwanda, Zambia, or
Nigeria. Although it was agreed that every sore throat
should be treated, the consensus was that at least 40%
were being missed.
Most regions were treating sore throats with benzathine penicillin, which once again raised many previously
mentioned concerns. The evidence for clinical prediction
rules was discussed, and the need for further research in
this area was mentioned. In addition, research on rapid
streptococcal test kits in developing countries is needed to
delineate its role, if any, to improve diagnostic yield and
treat strep throat.
Different strep throat programs were reviewed. Brazil
has a good national strep throat program with reasonable
awareness of streptococcal sore throat. This is a result of a
local university initiative with evidence-based guidelines
tailored to the region. The importance of awareness among
children and in schools was stressed and the importance
and previous success stories (Cuba) of mass education
cited [7]. Work continues in the Philippines, India, and
Pakistan focusing on awareness and education in smaller
group sessions.

Warfarin Another strongly expressed lack was for


warfarin and monitoring of warfarin use for those with
atrial brillation and/or mechanical prosthesis. Although
259

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most countries had warfarin available in the tertiary centers, this was not often the case in regional hospitals or
health posts. Access to INR monitoring was far less likely to
be available in remote or rural areas. Many participants
expressed a dire need for point-of-care INR testing, as they
all perceived this as a real problem. As a result, many
patients were commenced on aspirin only.

do have surgical capacity (some even free of charge or


heavily subsidized), but they also have extensive
waiting lists that include patients from other countries.
Advocacy efforts and increased awareness in India, the
Philippines, and Nepal have resulted in increased case
ascertainment and, subsequently, increasing demand for
surgery.

National policy of notiable diseases ARF is only

CONCLUSIONS

notiable in New Zealand, parts of Australia, and South


Africa. However, this was not without problems, despite the
obvious advantages [8]. The importance of burden of disease
estimates, recurrence monitoring, and case nding was
explored and reinforced. Many participants expressed their
frustration at the lack of data and the sense of not
knowing what is going on. It was clear, however, that
great strides have been made in terms of hospital registries.
In addition, registries compiled by organizations such as
the Nepalese Heart Foundation have been incorporated
into national control and prevention programs with input
from governments and departments of health. In Rwanda,
electronic integration of all chronic diseases has resulted
in a national chronic disease program (Table 3). The
importance of integrated programs in resource-poor
settings was emphasized while stressing the specic uses of
a local RHD registry.

Surgical capacity Finally, the focus turned to surgical


capacity in countries with overwhelming burden of disease. The group represented different levels of capacity
from mixed public and private surgical services with no
real limits (Australia, New Zealand, and Unites States) to
centers with no surgery (Nigeria and Zambia) and those
with only visiting surgical teams (Rwanda). The difculties
of balancing adult versus pediatric surgical programs,
building new surgical capacity within affected countries,
and needing to have surgery performed outside of the
countries (from Africa to India or Israel) were examined in
detail. Many participants bemoaned the fact that the major
crisis lay in healthcare manpower, whereas others discussed the realities of the brain drain and the attraction of
other climes on recently skilled physicians or surgeons. Of
those involved in visiting surgical teams, the frustration of
being able to do only a limited amount of surgery was
expressed. On the other hand, a major concern was that in
these situations, valve replacements were performed in
preference to valve repairs. The need exists for better
business models for effective low-cost technology without
affecting the patients care. In Brazil, prosthetic valves are
cheaper than mitral rings, which has increased the
amount of valve replacements rather than the preferred
valve repair. The inherent difculties in patient selection,
especially for surgery in other countries, were also
discussed.
In general, the reality was long waiting lists for valve
surgery with patients dying on these lists. Some emerging
country centers such as Nepal, Brazil, and South Africa

260

The second RHD forum was a remarkable event. Building


on the foundation of the rst RHD forum, over 150
interested participants were able to meet and discuss critical issues on the RHD landscape. Unique to this meeting
was a mixture of diverse backgrounds and disciplines,
all crucially important to the conversation of RHD control
and prevention. It is clear that new leadership is emerging
in the RHD space, as well as new focus points beyond
medical management to political and policy decisions
and interventions. The networking that occurred should
encourage new research collaborations and sharing of
resources and expertise. Some priorities have emerged: the
necessity for political intervention and policy change; the
need to increase the health force by incorporating teaching,
training, and task-shifting; the need to revitalize the
research agenda by merging basic, clinical, and translational research; and, nally, the desperate need for universal access to high-quality penicillin. There were also
requests for new resources; for those that already exist to
be further developed, improved, and shared across platforms; and for resources to be supported in nonmedical
arenas. Finally, the need to involve the patient community
in the ongoing discussion was highlighted.
The RHD forum has thus far convened at cardiology
congresses that focused attention on medical participants.
In the future, consideration should be given to include
patient and parent groups, as well as the nonclinical disciplines needed for comprehensive disease activism. It is
time to effect concrete change in RHD activities across the
world, and we hope that the RHD forum will be part of the
solution, rather than a reection of current problems.
Several important initiatives and champions, we envisage,
will be born out of these forums and continue to invigorate
RHD activities over the next years. The participants of both
the rst and second RHD forums represent a new, thriving,
growing community of RHD activists who should usher in
a new era of signicant improvements in RHD control and
prevention expanding beyond the borders of high-income
nations.

ACKNOWLEDGMENTS
The authors would like to thank all the participants of the
second RHD forum for their input, commitment, and
enthusiasm and their continued work for RHD patients
across the globe. Particular thanks to the chairs of the
4 working groups: Drs. Karthikeyan, Mayosi, Mocumbi,
Regmi, Sadiq, Saxena, Taubert, and Wilson.

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September 2013: 253-261

gRECS

REFERENCES
1. Marijon E, Mirabel M, Celermajer DS, Jouven X. Rheumatic heart
disease. Lancet 2012;379:95364.
2. Zhlke L. Successes, failures, challenges and ground-breaking research:
messages from the 6th World Congress of Paediatric Cardiology and
Cardiac Surgery. Cardiovasc J Afr 2013;24:935.
3. Remenyi B, Carapetis J, Wyber R, Taubert K, Mayosi BM. Position
statement of the World Heart Federation on the prevention and
control of rheumatic heart disease. Nat Rev Cardiol 2013;10:
28492.
4. Carapetis JR, Zhlke LJ. Global research priorities in rheumatic fever
and rheumatic heart disease. Ann Pediatr Cardiol 2011;4:412.

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 253-261

5. Rheumatic Heart Club. Home page. 2008. Available at: http://www.


rheumaticheartclub.org/. Accessed August 22, 2013.
6. Caring and Living as Neighbors. Nephrotic Syndrome Club Meeting,
Hanoi, Vietnam, February 2012 [video]. September 10, 2012. Available
at: http://www.youtube.com/watch?v3LBMXMITBvM. Accessed
August 22, 2013.
7. Nordet P, Lopez R, Duenas A, Sarmiento L. Prevention and control of
rheumatic fever and rheumatic heart disease: the Cuban experience
(1986e1996e2002). Cardiovasc J Afr 2008;19:13540.
8. Nkgudi B, Robertson KA, Volmink J, Mayosi BM. Notication of rheumatic fever in South Africaevidence for underreporting by health
care professionals and administrators. S Afr Med J 2006;96:2068.

261

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gREVIEW

Aiming at Strategies for a Complex Problem of


Medical Nonadherence
Jose M. Castellano*,y, Robert Copeland-Halperin*,y, Valentin Fuster*,y,z
New York, NY, USA; and Madrid, Spain
ABSTRACT
The deteriorating health of the population and the increasing prevalence of chronic diseases are global
problems whose causes are multifactorial and complex. The Western lifestyle does not promote healthy
living, and the consequences are most devastating when social inequalities, together with the economic and
population explosion of recent decades, are considered. The expansion of poor nutritional habits, obesity,
sedentarism, and hypertension are increasingly contributing to the development of a cardiovascular disease
epidemic. Recent data on the rates of compliance with lifestyle modication and adherence to prescribed
medication are alarming. Over 50% of patients, on average, decide to abandon the treatment prescribed,
and the objectives to improve their habits (quit smoking, lose weight, or engage in physical activity) are
met by an equal or lower percentage. Beyond the impact it has on individual health, it carries a huge
economic cost, as it is associated with a failure in achieving therapeutic goals, higher rate of
hospitalization, and death. Improving communication between doctors and patients, the active involvement
of other health professionals, and the development of combination drug formulations (polypill) are
potential strategies for improving adherence and reducing costs.
Cardiovascular therapy has seen a decade of exciting
new advances in efcacious drugs as well as sophisticated
devices that improve clinical outcomes. The costs of
developing these advances in the therapeutic milieu have
been immense, and the effects of such proven interventions
(whether they are drugs, devices, or lifestyle modications)
are often hindered by the fact that patients do not adhere to
the recommendations of their caregivers. In fact, despite
evidence of improved outcomes from adherence, the
average medication compliance rates in developed countries are estimated to be just 50% [1].
The global problem of nonadherence was recognized
more than 3 decades ago, and results in poor clinical
outcomes, unnecessary disease progression, increased cost
of care, as well as premature death (an estimated 125,000
deaths per year in the United States are attributed to
medication nonadherence) [2]. Nonadherence carries a
huge economic cost that is derived from both direct and
indirect costs. Failure to identify and improve low adherence often results in increased pharmacotherapy with
increased doses of medication (with the inherent increase
in the overall cost of treatment, risk of adverse side effects,
misdiagnoses, and, in certain situations, unnecessary
treatment) and increasing disease burden. Undesirable
outcomes resulting from nonadherence may lead to a loss
of work productivity on the part of patients and caregivers.
A recent World Health Organization (WHO) report
stated that because the magnitude of nonadherence and the
scope of its consequences are so alarming, more health
benets worldwide would result from improving adherence to existing treatments than by developing new ones

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 263-271

[3]. All strata involved in the health system (healthcare


providers, policymaking ofcials, scientists, the academic
community, consumers, and industry) have called for action in order to address medical adherence and reduce the
consequences of this growing public health issue.

WHAT IS ADHERENCE?
Medical adherence refers to the extent to which patients
follow medical instructions and implies an active patient
participation about the timing, dosage, and frequency of
taking drugs. Although most research has focused on
adherence to medication, adherence also encompasses
numerous health-related behaviors that extend beyond
taking prescribed pharmaceuticals. Medical compliance encompasses these processes, which imply a passive participation by the patient. These typically include lifestyle
modications or behavioral interventions and can uctuate
over time. For example, smoking cessation might be achieved for some time, but patients frequently relapse and
continue to smoke. Similarly, following a diet, losing
weight, or undertaking physical activity uctuate depending on the behavior of a patient at any given time. Medical
persistence refers to the duration of taking a medication and
is dened as the duration from the time of initiation to
discontinuation of therapy.
In 2003, WHO [4], recognizing the increasing clinical
and economic costs of nonadherence, issued the Adherence to Long-Term Therapies: Evidence for Action statement [3]. WHO dened nonadherence as the extent to
which a persons behaviortaking medication, following a

From the *Zena and


Michael A. Wiener Cardiovascular Institute, Icahn
School of Medicine at
Mount Sinai, New York, NY,
USA; yMarie-Jose and
Henry R. Kravis Cardiovascular Health Center, Icahn
School of Medicine at
Mount Sinai, New York, NY,
USA; zCentro Nacional de
Investigaciones Cardiovasculares (CNIC),
Madrid, Spain. Correspondence: J. M. Castellano
(jmcastellano.cardio@
gmail.com).
GLOBAL HEART
2013 World Heart
Federation (Geneva).
Published by Elsevier Ltd.
All rights reserved.
VOL. 8, NO. 3, 2013
ISSN 2211-8160/$36.00.
http://dx.doi.org/10.1016/
j.gheart.2013.06.001

263

gREVIEW

diet, and/or executing lifestyle changescorresponds with


agreed recommendations from a healthcare provider.
WHO also recognizes 2 distinct categories of nonadherencepreventable and nonpreventable (Table 1)
and recommends targeting tailored treatment interventions
for the former.

THE SCALE OF NONADHERENCE: A WORLDWIDE


REALITY
The Institute of Medicine has recently published a document that presents some of the key features directed to
promoting cardiovascular health in the world, with special
emphasis in low- and middle-income countries, where
cardiovascular disease (CVD) accounts for nearly 30% of all
deaths [5]. The increased prevalence of risk factors of CVD
and related chronic diseases in developing countries,
including tobacco use, unhealthy dietary patterns, reduced
physical activity, increasing blood lipids, and hypertension,
reects signicant global changes in behavior and lifestyle.
These changes now threaten once low-risk regions, a shift
that is accelerated by industrialization, urbanization, and
globalization. The Institute of Medicine document has
raised awareness on the fact the prevalence of CVD is
increasing not only in low- and middle-income countries,
but also worldwide, in relation to an increase in global
population associated to an increase in cardiovascular risk
factors such as pernicious nutritional habits and obesity,
which without question is having a detrimental impact on
global health [6]. We are facing a worldwide epidemic that
is very complex in nature, underlined by multifactorial
causality, and implicates various strata of society.
The Manhattan Project was carried out in 2004 in an
effort to quantify the various degrees of compliance and
adherence among a large U.S. population affected by
different chronic diseases. According to the results of this
study, 50% of patients were unable to comply with lifestyle
modication regarding smoking cessation and weight loss.
Medical adherence was alarmingly low, showing rates
lower than 60% in the case of antihypertensive, antidiabetic, and cholesterol-lowering drugs. More startling
perhaps are the results of the current guidelines recommendations on the actual use of aspirin, antihypertensive
medications, and statins, especially for secondary
TABLE 1. Preventable and nonpreventable reasons for discontinuation or nonadherence
Preventable
Low health literacy
No-ll of rst prescription
identied
Nonresponder or no clinical
evidence of effectiveness
of the medication
Cost prohibitive for the patient

264

Nonpreventable
Serious mental illness
Serious adverse effects
Polypharmacy

prevention in patients with CVD. Although results vary


depending on the pharmacologic regimen, medical
adherence averages around 60% [7]. For example, the
degree of adherence to treatment with salicylic acid was
found to be lower than 45% despite its use being recommended to the totality of this population (Table 2).
The PURE (Prospective Urban Rural Epidemiological)
study [8] set out to quantify the degree of medical adherence worldwide in the context of coronary artery disease
and cerebrovascular disease. This study included 153,996
patients, ages 35 to 70 years, from rural and urban areas of
countries around the world in an effort to study the impact
of middle-class income of each country in the real use of
drugs with proven efcacy in secondary prevention
(namely, antiplatelet drugs, beta adrenergic blockers,
angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and statins). The results indicate that
adherence to medical treatment is directly related to income and, although far from being acceptable in higherincome populations, it is particularly low in low-income
and rural areas. The conclusions of this and other studies
call for action on the urgent need to improve access to
treatment through the use and the development of more
efcient and cheaper treatments that guarantee adherence
to medical treatment in secondary prevention.
Different epidemiological studies have found that only
20% to 30% of patients achieve optimal cardiovascular risk
factor control. In a study to measure the degree of
compliance with the Sixth Joint National Committee
guidelines [9] for treatment of high blood pressure, only
37% of patients reported consistent adherence to their
antihypertensive regimens. Dailey et al. [10] studied
37,431 Medicaid-funded patients in the United States and
used pharmacy records to show that patients with type 2
diabetes averaged about 130 days per year of continuous
drug therapy, and that at the end of 1 year, only 15% of the
patients who had been prescribed a single oral medication
were still taking it regularly. Similar results have been
found in related clinical trials such as BARI 2D (Bypass
Angioplasty Revascularization Investigation 2 Diabetes)
[11] and COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) [12], in
which a tremendous effort was made to address lowadherence rates.
The available data suggest the healthcare system is
facing a critical challenge, with various implications and
consequences. The solution to this complex problem requires exploration of the responsibilities not only of the
patient who fails to comply with medical recommendations, but also of physicians, the healthcare system, and the
regulatory organizations. In this context, WHO published a
document in which it recognized low pharmacological
adherence as a complex, international problem that affects
especially those long-lasting therapeutic regimens for
chronic diseases, such as diabetes mellitus, hypertension,
asthma, cancer, human immunodeciency virus, and
tuberculosis among others [3]. The main conclusion of this

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TABLE 2. Current guideline recommendation and actual use of aspirin, antihypertensive medications, and statins among U.S. adults
55 years of age and those with a history of CVD
Age 55 yrs (n 2,554)
Recommended Use

Actual Use

84.2
60.1
63.7

31.6
47.8
37.3

Aspirin
Antihypertensives
Statins

History of CVD (n 592)


%
37.5
79.5
58.6

Recommended Use

Actual Use

100
69.3
88.3

44.5
61.0
57.0

%
44.5
87.8
64.0

Values are percentages. Based on data, used with permission, from Muntner et al. [7]. CVD, cardiovascular disease.

document was that patients must receive more support


from the healthcare system and a multidisciplinary
approach are required to offer tailored solutions to individual cases.

PAYING THE PRICE FOR POOR ADHERENCE


Adherence is the single most important modiable factor
that compromises therapeutic outcome. The consequences
of medication nonadherence are not only poor clinical
outcomes but also unnecessary healthcare costs. The total
cost estimates for nonadherence range from $100 billion to
$300 billion each year and include both direct and indirect
costs [13]. The costs of drug-related hospitalizations has
been estimated to be around $47 billion a year [14].
Furthermore, nonadherence to medication has been associated with and additional $2,000 a year per patient in
medical costs from visits to physicians ofces [15]. In the
specic case of heart failure, it has been shown that nonadherence plays a major role in preventable rehospitalizations [16]. Indirect costs include loss of productivity
derived from nonadherence to prescribed medical treatment, as well as higher costs for private managed care insurance benets. Furthermore, WHO predicts the problem
of nonadherence will grow as the burden of chronic diseases increases worldwide [3]. Available evidence suggests
that better adherence leads to improved clinical outcomes
and lower healthcare costs [17]. It is critical, therefore, that
the agenda of policymakers include the issue of improving
patient adherence as a pivotal way to address the escalating
costs of health care not only in the United States, but also
worldwide.

TIMING: A CRITICAL WINDOW OF OPPORTUNITY


Recent evidence shows that adherence to treatment of
certain chronic diseases decreases signicantly during the
rst 6 months after the prescription [18]. Furthermore,
patients who abandon treatment within this time frame are
less likely to go back into treatment [19]. Therefore, the
rst 6 months of treatment are a critical window of opportunity to act upon the problem of nonadherence. On
the other hand, good adherence to cardioprotective drugs
has demonstrated better outcomes and reduced mortality
in patients with coronary artery disease and diabetes mellitus [19]. In this context, a recent review found that

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September 2013: 263-271

improvements in guideline adherence, as measured by


performance indicators, have led to signicant reductions
in mortality [20]. Their ndings suggest that improving
quality achieves reductions in death in excess of those
observed for any new therapy. It is estimated that the use of
clinical guidelines for acute myocardial infarction could
prevent 80,000 deaths annually in the United States alone
[21]. Therefore, the potential global implications are signicant if effective ways to improve adherence to guidelines can be developed.

BARRIERS TO ADHERENCE
Several factors appear to be associated with poor adherence. Nonadherence to medications can be intentional or
unintentional. Intentional nonadherence is an active process whereby the patient chooses to deviate from the
treatment regimen [22]. WHO has categorized potential
reasons for medication nonadherence into 5 broad
groupings that include patient-, condition-, therapy-, socioeconomic-, and health systemerelated factors [3,23].
Although it is true that patients are ultimately in control of
the fashion in which they take their prescribed medications, there are various reasons why that can facilitate
nonadherent behavior.

Patient-related factors
Patient characteristics have been the focus of numerous
investigations of adherence. Age, sex, education, occupation, income, race, religion, ethnic background, and urban
versus rural living have not, however, been denitely
associated with adherence [24]. Similarly, attempts to
dene stable personality traits of a typical nonadherent
patient have been futile, as no single pattern of patient
characteristics predicts nonadherence [25]. With the
exception of extreme disturbances of functioning and
motivation, personality variables have not emerged as signicant predictors. Thus, contrary to previous belief, there
is no such thing as a nonadherent personality, and the
causes of failure to follow treatment are not associated with
certain personality traits of the patients [26].
Among the most common reasons patients do not take
their medicines is simply forgetfulness [1]. Practitioners
(and other health enablers) often assume that the patient is,

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gREVIEW

or should be, motivated by illness to follow a treatment


protocol.
The presence of psychological problems, particularly
depression [27], correlates with poor adherence to medication across a range of chronic diseases [25]. This is of
particular signicance when one takes into consideration
that depression is widely associated with heart disease (1 in
3 patients with congestive heart failure, recent myocardial
infarction, or acute coronary syndromes will meet criteria
for either major or minor depression) [28] and even mild
depression is sufcient to signicantly alter compliance
with essential therapy [4].
A patients motivation to adhere to prescribed treatment is inuenced by the value that he or she places on
following the regimen (cost-benet ratio) and the degree of
condence in his or her ability to follow it. Conversely,
when medications such as antidepressants and corticosteroids are slow to produce intended effects that are apparent
to the patient, there may be a tendency to believe the
medication is not working and to discontinue use.

Condition-related factors
Silent chronic conditions represent a signicant challenge
because of patients perception about the nature and the
severity of their illnesses. Adherence rates are typically
higher among patients with acute conditions, as compared
with those with chronic conditions; persistence among
patients with chronic conditions is disappointingly low,
dropping most dramatically after the rst 6 months of
therapy. Factors such as perceived susceptibility to illness,
perceived severity of illness, self-efcacy, and control over
health behaviors are more robust correlates [6]. For
adherence to occur, symptoms must be sufciently severe
to arouse the need for adherence, be perceived as being
resolvable and acute, and remedial action must effect a
rapid and noticeable reduction in symptoms. An internal
locus of control appears crucial for effective adherence.

Therapy-related factors
Medication-related factors can also act as a barrier to
adherence. The complexity of the regimen, concern about
medication side effects, and patients lack of condence in
the benet of treatment all play a role in the lack of
adherence.
The number of medications has a negative impact on
adherence, and elderly patients tend to take more prescription medicines than any other group [29]. Studies
evaluating dose frequency have shown rapid decreases in
adherence rates with increasing dose frequency (Table 3).
Simple dosing (1 pill, once daily) helps maximize adherence, particularly when combined with frequent reinforcing visits [30]. In fact, it has been shown that minimizing
the total number of daily doses is more important in
promoting adherence to antihypertensive regimens than
minimizing the total number of medications [31].

266

TABLE 3. Relations between dosing regimen and compliance


averaged from 76 studies using electronic monitoring
Dosing
Once daily
Twice daily
3 times daily
4 times daily

Took Most Doses (%)

Took on Time (%)

79
69
65
51

74
58
46
40

Based on data, with permission, from Garner [32].

Medication costs represent a key source of nonadherence in all elds of medicine, particularly in patients
with low or xed incomes, those with chronic medical
conditions, and those on disability [32]. One-third of
Americans report they did not ll a prescription or reduced
the dose in the past year because of out-of-pocket costs
[33]. The cost of medication and its relationship to
adherence has been the source of extensive studies.
Recently, Choudhry et al. [34] reported the results from
a controlled trial that assessed whether the elimination
of copayments for statins, beta-blockers, angiotensinconverting enzyme inhibitors, and angiotensin-receptor
blockers for recent survivors of an acute myocardial
infarction could improve adherence, reduce future cardiovascular events, and save costs. The elimination of
copayments signicantly increased adherence in the control group. However, an alarming nding of this study,
consistent with previous ndings [35], was that less than
one-half of patients in the full-coverage group were fully
adherent to prescribed medication. One can draw the
conclusion that in order to adequately address the solution
to low adherence, interventions must focus on other contributors to nonadherence other than drug costs.

Socioeconomic-related factors
Available evidence has shown that the strongest sets of
socioeconomic factors related to adherence are social
support and other related constructs such as living alone
and marital status. Presence of adequate social support,
living with others, and being married have been shown to
be associated with better adherence [16].

Health systemerelated factors


There is a total lack of communication between healthcare
providers and patients. Whereas 74% of healthcare providers believe their patients comply with their recommendations, 83% of patients fail to tell their healthcare
providers about medical adherence [36,37]. The amount of
time a physician spends going over new medications with
patients is scarce and certainly a cause for nonadherence.
The results of a survey conducted over more than 500
physicians revealed that among the central problems of
medical nonadherence is the time physicians spend going
over new medication with their patients. In this survey,
that time averaged 49 s [38,39]. Furthermore, patients

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demonstrate better adherence when they receive care from


the same provider over time [29].
Correlative studies revealed positive relationships between adherence of patients to prescribed treatment and
provider communication styles characterized by providing
information, positive talk, and asking patients specic
questions about adherence [40]. The clarity of diagnostic
and treatment advice has been correlated with adherence to
short-term but not to long-term regimens and chronic illnesses. Warmth and empathy of the clinician are central
factors. Patient satisfaction with the medical regimen affects
adherence favorably, so that when the patients level of
trust in the physician is low, patients are more likely to
forego the use of medications [41].
Another important barrier is inability to understand or
act on instructions for taking medication. In fact, 1 study
[2] found that 60% or more of patients could not correctly
report what their physicians told them about medication
use between 10 and 80 min after receiving the information.
Table 4 summarizes the various barriers to adherence.

TENETS OF LOW ADHERENCE TO MEDICATION:


AIMING AT NEW APPROACHES TO IMPROVE
ADHERENCE
The impact of adherence on clinical results has been the
focus of numerous studies over the past years. Although the
scope of the problem and the magnitude of the consequences
of nonadherence are well identied, solutions have not
always come across in a clear, concise manner, and too often
have been short-sided in placing most of the responsibility
on the patients. Moreover, evolving data have provided us
with more questions than solutions because of the complex
nature of the problem. The data provided so far has identied
various barriers to adherence (patient-related, conditionrelated, therapy-related, socioeconomic-related, and health
systemerelated factors) that account for the low levels of
adherence that are found today throughout the world.
However, it is the intricate relationship among patient,
provider, and health system that might explain the reasons
for, and should ultimately provide the solutions to, this
complex problem (Fig. 1). There are, in our view, 7 basic
tenets of low adherence that can serve as the basis to propose
mechanisms of correction:

1. The causes that lead to failure in adherence to treatment


are not related, as shown, to personality traits of the
patients, that is, there is not a characteristic nonadherent personality.
2. There is a total lack of communication between physicians and patients, and therefore, a very low concordance between the level of communication that doctors
perceive to have with their patients and the real information that patients transmit to their physicians.
3. Medication adherence shows little or no relationship
with medication compliance [42]. For example, smoking cessation or physical exercise are not associated with
a higher medical adherence, because the latter implies a
more rational and active decision on the patients part.
4. Patients sociodemographic characteristics have little
relationship with nonadherence and are more related
with other variables, such as disease type [43].
5. Patients want to know why they take prescription
drugs, the expected duration of the regimen, possible
adverse effects of drugs, the expected impact on their
lifestyle, and the consequences of nonadhering to the
recommended treatment [42,44,45].
6. Healthcare professionals communicate deciently with
their patients and provide little information about
medical prescriptions, which could give rise to misinterpretation by patients. Patients perceived lack of information contributes decisively to nonadherence.
7. Adherence to pharmacological treatment is a decisionmaking process in which the patient rationally and
actively decides to engage in the convenience of
following treatment after taking into account different
motivations. Professional support and the correct
communication with the physician can have a profound
impact, particularly in patient populations such as the
elderly, who often nd themselves in a situation of social isolation, emotional vulnerability, and economic
struggle [46].

Adherence cards
Among the interventions found to be most effective in
randomized clinical trials, successful interventions address
known barriers, regardless of whether the barrier is owned
by the patient, provider, community healthcare system, or

TABLE 4. Barriers to adherence


Patient-Related

Illness-Related

Psychiatric illness (depression)

Asymptomatic disease

Cognitive impairment

Medication side
effect
Complexity of treatment
Acute vs. chronic

Condence in benet of treatment


Insight into illness
Trust in provider
Satisfaction w/medical regimen

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 263-271

Provider-Related

System-Related

Adequate follow-up/
discharge planning
Warmth and empathy

Availability/accessibility of services

Poor communication
Continuity of care

Cost of treatment
Support for patient education
Data/information management
Community support
Training provided

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gREVIEW

print & web 4C=FPO

FIGURE 1. Tenets of low adherence and strategies aimed at improving adherence. HRP, high risk plaque initiative.
governmental agency [29]. There is no doubt that
communication between patients and healthcare professionals is one of the main variables that impact adherence, and that by simply improving the quantity and
quality of communication there can be a signicant
improvement on medical adherence. However, in the
current healthcare system, physicians lack the ability to
increase the time, and the already overloaded ofce visits
do not allow physicians to put in place a system of
continuous monitoring and regular follow-ups. Therefore,
alternative methods must be pursued that allow for an
increased level of communication that does not dramatically increase the time physicians spend on this matter.
One such method could be in the form of a questionnaire
that measures in an objective manner the expected level of
adherence for each patient. Such a questionnaire should
include simple and concise variables with which to obtain
information about the patients concerns regarding treatment, the degree of willingness to follow treatment, and
that patients economic solvency to adhere. Once the patient has gone over the questionnaire, the physician could
answer the concerns raised by the treatment. One such
questionnaire, the Adherence Estimator, has been tested
using 3 drivers of self-reported adherence: perceived concerns about medications; perceived need for medications;
and perceived affordability of medications [42]. By simple
summation of the weights assigned to the category responses of the 3 items, a total score was obtained and
patients were placed into 1 of 3 segments based on the total
scorelow, medium, and high risk for nonadherence.

268

Sensitivity was 88%: of the nonadherers, 88% would be


accurately classied as medium or high risk by the
Adherence Estimator. The 3 risk groups differed on theoretically relevant variables external to the Adherence
Estimator in ways consistent with the hypothesized
proximal-distal continuum of adherence drivers. The
Adherence Estimator is readily scored and is easily interpretable. Due to its brevity and transparency, it should prove
to be practical for use in everyday clinical practice and in
disease management for adherence quality improvement.
This system, however, should also involve nurses, physician
assistants, and nurse practitioners.

Simplied drug regimens


Modifying a patients drug regimen to reduce the number
of pills a patient is required to take at each dose is one way
to address adherence. One study found that among hypertension patients, those who took once-daily therapy had
11% better adherence (as dened by the percentage of
correct doses) than those who took twice-daily therapy.
Similar improvements were seen among patients with high
cholesterol. Patients prescribed to take their medication
twice daily had 10% better adherence than did patients
who had a 4-times-daily dosing schedule [47].

Polypill: toward achieving secondary prevention


Given the inverse relationship between complex regimens
and adherence, a different approach involves the concept
of the polypill (xed-dose combination drugs). Available

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evidence regarding the use of such treatments shows signicant increases in adherence rates, signicantly reduced
production and distribution costs, and improvement of
treatment availability, especially in low- and middleincome countries [48]. The results of a meta-analysis
[49] of such drugs showed a 20% relative reduction in
the rate of nonadherence compared with that of component drugs taken separately.
Regarding the potential clinical benets of the polypill,
Yusuf [50] published a review illustrating how aspirin,
beta-blockers, angiotensin-converting enzyme inhibitors,
and statins together could theoretically decrease worldwide
cardiovascular events by 75% in at-risk patients. In the case
of secondary prevention for patients with previous history
of coronary artery disease or cerebrovascular disease, the
use of a polypill could potentially decrease the incidence of
future events. In the United States alone, it has been
calculated that the use of a polypill (with efcacy-proven
compounds that are used alone), could prevent 3.2
million cardiovascular and 1.7 million cerebrovascular
events [7]. Data arising from the recently published PURE
study [51] further strengthens the case for a polypill in
secondary prevention, especially in low-income countries.
The study aimed to study the prevalence of unhealthy
lifestyles in 7,519 individuals with coronary heart disease
or stroke in various regions of the world with different
incomes. The results are worrisome, as the prevalence of
healthy lifestyle was low (18.5% continued to smoke, only
35.1% undertook physical activity, and 39.0% had healthy
diets), with the lowest prevalence of healthy lifestyles
taking place in low-income countries [51]. The rationale
for the use of the polypill in secondary prevention is that it
can reduce the cost of medication and also improve patient
adherence to treatment. Cost of medication is determined
mainly by the price of raw materials (generics) and the cost
of manufacturing, packing, and distribution [48]. In
addition, the process of packing and distribution of a
polypill containing several active drugs is less expensive
than the management of those drugs separately. In fact, the
price of the 1 commercially available polypill (Trinomia),
recently introduced in Central America, is less than 50% of
the price of its components purchased separately. The effect of the polypill on patient adherence to treatment is
unknown. However, there is some evidence in the literature that the use of xed-dose combination drugs in the
treatment of hypertension improves adherence by almost
25% [52]. Therefore, it can be anticipated that the polypill
will demonstrate a similar positive effect on patient
adherence in secondary prevention.
The polypill is, therefore, an interesting therapeutic
option to improve clinical outcomes, because it signicantly facilitates therapeutic regimens and considerably
reduces costs, both of which have been proven to be major
barriers to adherence. However, just as with conventional
treatments, its prescription must be accompanied by
adequate information and should not hinder the communication between patient and physician.

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September 2013: 263-271

The Grenada and Cardona studies: community and


communication
Recently, a novel approach to improve adherence has been
addressed, based on a program of communication and
community aid that involves adults helping other individuals, much in the way already existing organizations
(e.g., Alcoholics Anonymous). This method of reinforcing
healthy habits has successfully been implemented as a case/
control study on the island of Grenada and does not
require active involvement of healthcare professionals. In
this case, 100,000 individuals were divided into groups of
11 people who helped each other achieve certain lifestylerelated goals, such as change in diets, weight loss, achieve
blood pressure goals, and engage in physical exercise [6].
This model has allowed putting into practice an efcient
system of local control, which has shown an important
lesson about the changes needed to be undertaken to
control chronic disease. Similarly, the Cardona Project
(in the Spanish town of Cardona, with a population of
5,000 inhabitants and currently undergoing a major economic recession) is currently underway to study the impact
of communication among adults over 50 years of age in
controlling cardiovascular risk factors and healthy habits.
Together, the Cardona and Grenada experiences may serve
as a template for other communities around the world with
similar characteristics, which have proven that collaboration and reinforcement among individuals of the same
community striving to reach the same goal is a valuable
tool to reach better adherence and compliance.

Discharge counseling
Patients who receive counseling immediately preceding
and/or following a discharge from the hospital are more apt
to adhere. Interventions often include in-hospital discharge
counseling by a pharmacist or nurse, as well as postdischarge home visits to provide pharmaceutical counseling. One study found that among elderly patients with
more than 3 medications, adherence improved by 43%
among patients who received counseling from a pharmacist
before and after hospital discharge, compared with patients
who did not receive the intervention [53]. Another successful intervention to improve adherence is counseling by
community pharmacists. The details of the counseling may
vary, but would likely include a review of the medication
list, assessment of patient knowledge about their condition
and medications, education on adherence strategies, and
suggestions for lifestyle changes to decrease symptoms.
One study of patients with heart failure found that among
patients who received monthly pharmacist counseling,
nonadherence (dened as a percentage of missed daily
doses) was less than one-half of that observed among the
usual care patients [54]. Similarly, another study of patients with heart failure found that pharmaceutical counseling combined with dose simplication increased
adherence by 46% (adherence was dened as medication
possession ratios between 80% and 120%) [55].

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SUMMARY
There are both enormous challenges and opportunities
associated with addressing the public-health crisis of
medication adherence. The multifactorial basis of nonadherence calls for a multifaceted solution. Ultimately, the
economic force behind the continuing rise in the cost of
health care will leave policymakers no choice but to deeply
revise, and come up with, efcient solutions to improve
medical adherence. In a healthcare system that is continually becoming more complex, where efcacious drugs and
sophisticated devices continue to improve clinical outcomes, part of the focus should be placed back on the
mechanisms that allow patients to follow and adhere to
medical recommendations, which in turn will improve
health outcomes and reduce costs.

REFERENCES
1. Bosworth HB, Granger BB, Mendys P, et al. Medication adherence: a
call for action. Am Heart J 2011;162:41224.
2. Gottlieb B. Medical nonadherence: nding solutions to a costly
medical problem. Drug Benet Trends 2000;12:5762.
3. De Geest S, Sabat E. Adherence to long-term therapies: evidence for
action. Eur J Cardiovasc Nurs 2003;2:323.
4. Gehi A, Haas D, Pipkin S, Whooley MA. Depression and medication
adherence in outpatients with coronary heart disease: ndings from
the Heart and Soul Study. Arch Intern Med 2005;165:250813.
5. Fuster V. Promoting Cardiovascular Health in the Developing World:
A Critical Challenge To Achieve Global Health. Washington, DC:
Institue of Medicine; 2010.
6. Fuster V, Kelly BB, Vedanthan R. Promoting global cardiovascular
health: moving forward. Circulation 2011;123:16718.
7. Muntner P, Mann D, Wildman RP, Shimbo D, Fuster V, Woodward M.
Projected impact of polypill use among US adults: medication use,
cardiovascular risk reduction, and side effects. Am Heart J 2011;161:
71925.
8. Yusuf S, Islam S, Chow CK, et al, for the PURE Study Investigators. Use
of secondary prevention drugs for cardiovascular disease in the
community in high-income, middle-income, and low-income countries (the PURE Study): a prospective epidemiological survey. Lancet
2011;378:123143.
9. Cheng JW, Kalis MM, Feifer S. Patient-reported adherence to guidelines of the Sixth Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure. Pharmacotherapy
2001;21:82841.
10. Dailey G, Kim MS, Lian JF. Patient compliance and persistence with
antihyperglycemic drug regimens: evaluation of a Medicaid patient
population with type 2 diabetes mellitus. Clin Ther 2001;23:131120.
11. Holper EM, Brooks MM, Kim LJ, et al, for the BARI Investigators.
Effects of heart failure and diabetes mellitus on long-term mortality
after coronary revascularization (from the BARI Trial). Am J Cardiol
2007;100:196202.
12. Shaw LJ, Berman DS, Maron DJ, et al, for the COURAGE Investigators.
Optimal medical therapy with or without percutaneous coronary
intervention to reduce ischemic burden: results from the Clinical
Outcomes Utilizing Revascularization and Aggressive Drug Evaluation
(COURAGE) trial nuclear substudy. Circulation 2008;117:128391.
13. Senst BL, Achusim LE, Genest RP, et al. Practical approach to determining costs and frequency of adverse drug events in a health care
network. Am J Health Syst Pharm 2001;58:112632.
14. Johnson JA, Bootman JL. Drug-related morbidity and mortality: a
cost-of-illness model. Arch Intern Med 1995;155:194956.
15. Ernst FR, Grizzle AJ. Drug-related morbidity and mortality: updating
the cost-of-illness model. J Am Pharm Assoc (Wash) 2001;41:1929.

270

16. Wu JR, Moser DK, Lennie TA, Burkhart PV. Medication adherence in
patients who have heart failure: a review of the literature. Nurs Clin
North Am 2008;43:13353. viieviii.
17. Dunbar-Jacob J, Erlen JA, Schlenk EA, Ryan CM, Sereika SM,
Doswell WM. Adherence in chronic disease. Annu Rev Nurs Res 2000;
18:4890.
18. Gadkari AS, McHorney CA. Medication nonfulllment rates and
reasons: narrative systematic review. Curr Med Res Opin 2010;26:
683705.
19. Ho PM, Magid DJ, Masoudi FA, McClure DL, Rumsfeld JS. Adherence
to cardioprotective medications and mortality among patients with
diabetes and ischemic heart disease. BMC Cardiovasc Disord 2006;6:
48.
20. Mehta RH, Peterson ED, Califf RM. Performance measures have a
major effect on cardiovascular outcomes: a review. Am J Med 2007;
120:398402.
21. Wagner GS, Bahit MC, Criger D, et al. Moving toward a new denition
of acute myocardial infarction for the 21st century: status of the ESC/
ACC consensus conference. European Society of Cardiology and
American College of Cardiology. J Electrocardiol 2000;33(Suppl):579.
22. Lowry KP, Dudley TK, Oddone EZ, Bosworth HB. Intentional and unintentional nonadherence to antihypertensive medication. Ann
Pharmacother 2005;39:1198203.
23. Bardel A, Wallander MA, Svrdsudd K. Factors associated with
adherence to drug therapy: a population-based study. Eur J Clin
Pharmacol 2007;63:30714.
24. Ingersoll KS, Cohen J. The impact of medication regimen factors on
adherence to chronic treatment: a review of literature. J Behav Med
2008;31:21324.
25. Grenard JL, Munjas BA, Adams JL, et al. Depression and medication
adherence in the treatment of chronic diseases in the United States:
a meta-analysis. J Gen Intern Med 2011;26:117582.
26. Hevey D, McGee HM, Horgan J. Relationship of initial level of distress
to changes in health-related quality of life during cardiac rehabilitation or usual care. Psychosom Med 2007;69:7937.
27. van Servellen G, Chang B, Garcia L, Lombardi E. Individual and system
level factors associated with treatment nonadherence in human
immunodeciency virus-infected men and women. AIDS Patient Care
STDS 2002;16:26981.
28. Jiang W, Glassman A, Krishnan R, OConnor CM, Califf RM. Depression
and ischemic heart disease: what have we learned so far and what
must we do in the future? Am Heart J 2005;150:5478.
29. Osterberg L, Blaschke T. Adherence to medication. New Engl J Med
2005;353:48797.
30. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther
2001;23:1296310.
31. Eisen SA, Miller DK, Woodward RS, Spitznagel E, Przybeck TR. The
effect of prescribed daily dose frequency on patient medication
compliance. Arch Intern Med 1990;150:18814.
32. Garner JB. Problems of nonadherence in cardiology and proposals to
improve outcomes. Am J Cardiol 2010;105:1495501.
33. Rector TS, Venus PJ. Do drug benets help Medicare beneciaries
afford prescribed drugs? Health Aff (Millwood) 2004;23:21322.
34. Choudhry NK, Avorn J, Glynn RJ, et al, for the MI FREEE Trial Investigators. Full coverage for preventive medications after myocardial infarction. New Engl J Med 2011;365:208897.
35. Choudhry NK, Setoguchi S, Levin R, Winkelmayer WC, Shrank WH.
Trends in adherence to secondary prevention medications in elderly
post-myocardial infarction patients. Pharmacoepidemiol Drug Saf
2008;17:118996.
36. Lapane KL, Dube CE, Schneider KL, Quilliam BJ. Misperceptions of
patients vs providers regarding medication-related communication
issues. Am J Manag Care 2007;13:6138.
37. Goldberg AI, Cohen G, Rubin AH. Physician assessments of patient
compliance with medical treatment. Soc Sci Med 1998;47:18736.
38. Tarn DM, Paterniti DA, Kravitz RL, et al. How much time does it take
to prescribe a new medication? Patient Educ Coun 2008;72:3119.

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 263-271

gREVIEW

39. Tarn DM, Heritage J, Paterniti DA, Hays RD, Kravitz RL, Wegner NS.
Physician communication when prescribing new medications.
ArchIntern Med 2006;166:185562.
40. Hall JA, Roter DL, Katz NR. Meta-analysis of correlates of provider
behavior in medical encounters. Med Care 1988;26:65775.
41. Piette JD, Heisler M, Krein S, Kerr EA. The role of patient-physician
trust in moderating medication nonadherence due to cost pressures. Arch Intern Med 2005;165:174955.
42. McHorney CA. The Adherence Estimator: a brief, proximal screener
for patient propensity to adhere to prescription medications for
chronic disease. Curr Med Res Opin 2009;25:21538.
43. DiMatteo MR. Variations in patients adherence to medical recommendations: a quantitative review of 50 years of research. Med Care
2004;42:2009.
44. Ziegler DK, Mosier MC, Buenaver M, Okuyemi K. How much information about adverse effects of medication do patients want from
physicians? Arch Intern Med 2001;161:70613.
45. Bailey BJ, Carney SL, Gillies AH, McColm LM, Smith AJ, Taylor M.
Hypertension treatment compliance: what do patients want to know
about their medications? Prog Cardiovasc Nurs 1997;12:238.
46. Williams SL, Haskard KB, DiMatteo MR. The therapeutic effects of the
physician-older patient relationship: effective communication with
vulnerable older patients. Clin Interv Aging 2007;2:45367.
47. Brown BG, Bardsley J, Poulin D, et al. Moderate dose, three-drug
therapy with niacin, lovastatin, and colestipol to reduce low-

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 263-271

48.
49.
50.
51.

52.

53.

54.

55.

density lipoprotein cholesterol <100 mg/dl in patients with hyperlipidemia and coronary artery disease. Am J Cardiol 1997;80:1115.
Sanz G, Fuster V. Polypill and global cardiovascular health strategies.
Semin Thorac Cardiovasc Surg 2011;23:249.
Glass G. Cardiovascular combinations. Nat Rev Drug Discov 2004;3:
7312.
Yusuf S. Two decades of progress in preventing vascular disease.
Lancet 2002;360:23.
Teo K, Lear S, Islam S, et al, for the PURE Investigators. Prevalence of
a healthy lifestyle among individuals with cardiovascular disease in
high-, middle- and low-income countries: the Prospective Urban
Rural Epidemiology (PURE) study. JAMA 2013;309:161321.
Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose
combinations improve medication compliance: a meta-analysis. Am J
Med 2007;120:7139.
Lipton HL, Bird JA. The impact of clinical pharmacists consultations
on geriatric patients compliance and medical care use: a randomized
controlled trial. Gerontologist 1994;34:30715.
Bouvy ML, Heerdink ER, Urquhart J, Grobbee DE, Hoes AW,
Leufkens HG. Effect of a pharmacist-led intervention on diuretic
compliance in heart failure patients: a randomized controlled study.
J Card Fail 2003;9:40411.
Varma S, McElnay JC, Hughes CM, Passmore AP, Varma M. Pharmaceutical care of patients with congestive heart failure: interventions
and outcomes. Pharmacotherapy 1999;19:8609.

271

ORIGINAL RESEARCH

gSCIENCE

Associations of Obesity With Lipoprotein Subfractions in


Japanese American, African American, and Korean Men
Nobutaka Hirooka*, Chol Shiny, Kamal H. Masakiz, Daniel Edmundowiczx, Jina Choojj,
Emma J. M. Barinas-Mitchell{, Bradley J. Willcoxz, Kim Sutton-Tyrrell{, Aiman El-Saed#, Iva Miljkovic-Gacic{,
Takayoshi Ohkubo**, Katsuyuki Miura**, Hirotsugu Ueshima**, Lewis H. Kuller{, Akira Sekikawa{, for the
ERA JUMP Study Group
Pittsburgh, and Philadelphia, PA, USA; Honolulu, HI, USA; Ansan, Republic of Korea; Seoul, South Korea;
Riyadh, Kingdom of Saudi Arabia; and Otsu, Japan
ABSTRACT
Background: Both indices of obesity and lipoprotein subfractions contribute to coronary heart disease risk.
However, associations between indices of obesity and lipoprotein subfractions remain undetermined across
different ethnic groups.
Objective: This study aims to examine the associations of indices of obesity in Japanese Americans, African
Americans, and Koreans with lipoprotein subfractions.
Methods: A population-based sample of 230 Japanese American, 91 African American, and 291 Korean men
ages 40 to 49 was examined for indices of obesitythat is, visceral and subcutaneous adipose tissue (VAT and
SAT, respectively); waist circumference; and body mass indexand for lipoprotein subfractions by nuclear
magnetic resonance spectroscopy. Multiple regression analyses were performed in each of the 3 ethnic groups
to examine the associations of each index of obesity with lipoprotein.
Conclusions: VAT had signicant positive associations with total and small low-density lipoprotein (LDL) and
a signicant negative association with large high-density lipoprotein (HDL) in all 3 ethnicities (p < 0.01). SAT,
waist circumference, and body mass index had signicant positive associations with total and small LDL in
only Japanese Americans and Koreans, whereas these indices had signicant inverse associations with large
HDL in all ethnic groups (p < 0.01). Compared with SAT, VAT had larger R2 values in the associations with
total and small LDL and large HDL in all 3 ethnic groups. VAT is signicantly associated with total and small
LDL and large HDL in all 3 ethnic groups. The associations of SAT, waist circumference, and body mass index
with lipoprotein subfractions are weaker than the associations of VAT in all 3 ethnic groups.

Coronary heart disease (CHD) is the leading cause of


death in the United States [1] and worldwide [2]. Thus,
preventing CHD is of great interest from both a clinical and
a public health perspective. Current clinical practice
guidelines, such as those by the National Cholesterol Education Program Adult Treatment Panel, recommend
measuring standard lipids to assess CHD risk and stratify
risk categories [3]. Our ability to estimate the risk of
developing CHD is limited, however, and intense efforts
have been made to determine whether additional examination would improve the accuracy of CHD risk estimation
[4,5]. Such efforts include measuring lipoprotein
subfractions.
Lipoprotein subfractions can be quantied by nuclear
magnetic resonance spectroscopy [6,7]. Some subfractions
are reported to be associated with CHD. Total low-density
lipoprotein (LDL) number and small LDL particles, for

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 273-280

example, are strong predictors of CHD. Small high-density


lipoprotein (HDL) is positively associated with CHD,
whereas large HDL is inversely associated [8,9].
Many epidemiological studies have demonstrated
strong associations of indices of obesity, such as visceral
adipose tissue (VAT), subcutaneous adipose tissue (SAT),
waist circumference (WC), and body mass index (BMI),
with CHD and its risk factors [10e12]. Evidence suggests
body fat distribution, such as VAT, is more strongly associated with CHD than BMI or WC are [11,13].
Recently, several studies have examined the associations between indices of obesity and lipoprotein subfractions. In these studies, VAT is more strongly associated
with risk factors and lipoprotein subfractions than SAT is
[11,14]. We have reported that VAT and SAT are associated with higher particle concentrations of total, large, and
medium very low-density lipoprotein (VLDL), small LDL,

This research was supported by grants HL68200


and HL071561 from the
National Institutes of
Health, Korea Centers for
Disease Control and Prevention (budget codes
2004-E71001-00, 205E71001-00), as well as B
16790335 and A 13307016,
17209023, and 21249043
from the Japanese Ministry
of Education, Culture,
Sports, Science and
Technology.
From the *Family Medicine
Faculty Development
Fellowship, University of
Pittsburgh, Pittsburgh, PA,
USA; yDepartment of Internal Medicine, Korea
University Ansan Hospital,
Ansan, Republic of Korea;
zDepartment of Geriatric
Medicine, John A. Burns
School of Medicine, University of Hawai`i, Honolulu, HI, USA; xDepartment
of Medicine, Temple University, Philadelphia, PA,
USA; jjCollege of Nursing,
Korea University, Seoul,
South Korea; {Department
of Epidemiology, Graduate
School of Public Health,
University of Pittsburgh,
Pittsburgh, PA, USA; #College of Public Health and
Health Informatics, King
Saud bin Abdulaziz University for Health Sciences,
Riyadh, Kingdom of Saudi
Arabia; **Department of
Health Science, Shiga University of Medical Science,
Otsu, Japan. Correspondence: A. Sekikawa (akira@
pitt.edu).
GLOBAL HEART
2013 World Heart
Federation (Geneva).
Published by Elsevier Ltd.
All rights reserved.
VOL. 8, NO. 3, 2013
ISSN 2211-8160/$36.00.
http://dx.doi.org/10.1016/
j.gheart.2013.07.001

273

gSCIENCE

and large HDL in a population-based sample of U.S. white


and Japanese middle-aged men [15]. Our study also indicates the associations of VAT with lipoprotein subfractions are stronger than those for SAT. However,
few studies have investigated associations between indices
of obesity (i.e., VAT, SAT, WC, and BMI) and lipoprotein
subfractions among different ethnicity groups from a
community-based population. This study examined
the association between indices of obesity and lipoprotein
;subfractions for Japanese Americans (JA), African Americans (AA), and Koreans from a community-based sample.

METHODS
Study participants
During 2002 to 2006, 712 men ages 40 to 49 were
randomly selected: 303 JA men from a representative
sample of offspring to fathers who participated in the
Honolulu Heart Program, Honolulu, Hawaii, USA [16];
107 AA men from Allegheny County, Pennsylvania, USA
[17]; and 302 Korean men from Ansan, Gyeonggi-do,
South Korea. JA men were the third or fourth generation
of JA without ethnic admixture. All the participants were
without clinical cardiovascular disease or other severe
diseases [17]. Men in Honolulu were randomly selected
from the offspring of the members of the Honolulu Heart
Program [18]. Men in Allegheny County, Pennsylvania,
USA, were randomly selected from the voter registration
list. The voter registration list is very complete. Men in
South Korea were randomly selected from the Korean
Health and Genome Study, an ongoing population-based
prospective cohort study [19]. The rate of participation
was about 50% at each site. This rate of participation
is much higher than for the MESA (Multi-Ethnic Study
of Atherosclerosis) [20] and is comparable with the CARDIA (Coronary Artery Risk Development in Young Adults)
[21] and the CHS (Cardiovascular Health Study) [22].
Of the original sample, we excluded men taking lipidlowering medications (n 83) and individuals with
missing values (n 17). The nal sample was 612 subjects
(230 JA, 91 AA, and 291 Koreans). Written informed consent was obtained from each participant. The study was
approved by the institutional review boards of the following
institutions: the Kuakini Medical Center, Honolulu, Hawaii,
USA; the University of Pittsburgh, Pittsburgh, Pennsylvania,
USA; and Korea University, Seoul, South Korea.
All participants underwent a physical examination and
laboratory assessment and completed a lifestyle questionnaire (e.g., smoking and alcohol consumption), as
described previously [17]. Venipuncture was performed
after a 12-h fast, early in the morning of the clinic visit.
Samples were stored at 80 C and shipped on dry ice to
the University of Pittsburgh to determine lipids, glucose,
and other factors. Serum lipids were determined using
standardized methods by the Centers for Disease Control
and Prevention. Intra-assay coefcients of variation for total
cholesterol, triglycerides, and HDL-C were 1.8%, 1.8%,

274

and 3.5%, respectively. Serum glucose was determined by


an enzymatic assay. An intra-assay coefcient of variation
for glucose was 1.8%. Data collection was standardized
across the research centers.

Body mass index and abdominal adiposity indices


BMI was calculated using body weight and height (kg/m2).
WC was measured twice at the umbilical level using a
measuring tape while the participant was standing upright
in underwear. An average of the 2 measurements was used.
VAT and SAT were determined as previously described
[23]. Briey, VAT and SAT areas were measured at the level
between the fourth and fth lumbar vertebrae using
computed tomography images obtained with the same
apparatus at each site (GE-Imatron C150; GE Medical
System, South San Francisco, California, USA). All
computed tomography images were read at the Cardiovascular Institute, University of Pittsburgh, using image
analysis software by 1 trained reader (AccuImage; AccuImage Diagnostic Corporation, San Francisco, California,
USA).

Lipoprotein measurement
Nuclear magnetic resonance spectroscopy (LipoScience,
Inc., Raleigh, North Carolina, USA) was performed to
quantify serum lipoproteins of different sizes [24]. Particle
concentrations of the following lipoproteins were determined: VLDL (large: >60 nm; medium: 35e60 nm; small:
27e35 nm); LDL (intermediate-density lipoprotein:
23e27 nm; large: 21.3e23 nm; small: 18.3e21.2 nm);
and HDL (large: 8.8e13.0 nm; medium: 8.2e8.8 nm;
small: 7.3e8.2 nm) [8]. Weighted average particle sizes
were calculated from the subclass levels.

Statistical analyses
Values of lipoprotein subfractions were positively skewed
and log-transformed to approximate the normality. To
examine the correlations among obesity indices, we used
the Spearman rank correlation. To examine the association
of each obesity index BMI, WC, SAT, and VAT (a primary predictor variable)with each lipoprotein (an
outcome variable), multiple linear regression analyses were
performed. In the regression model, values of lipoprotein
were log-transformed to approximate the normality, and
age, pack-year smoking, and amount of alcohol consumption per day were adjusted. Statistical signicance
level was considered to be 0.01. All statistical analyses were
performed with IBM SPSS Statistics (version 20, IBM,
Armonk, New York, USA).

RESULTS
The baseline characteristics of study subjects are presented
in Table 1. Mean BMI (kg/m2) differed signicantly
among the 3 groups: 27.3 for JA; 29.6 for AA; and 24.7 for
Koreans. JA had signicantly higher VAT and serum

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September 2013: 273-280

gSCIENCE

TABLE 1. Basic characteristics of the study participants during 2002 to 2006 (N 612)
Japanese Americans

African Americans

Koreans

230
91
291
n
Age, yrs
46.0  2.9 (45.7, 46.4)
44.7  2.8 (44.1, 45.2)
44.8  2.8 (44.4, 45.1)
BMI, kg/m2
27.3  4.0 (26.8, 27.8)
29.6  5.9 (28.4, 30.8)
24.7  2.7 (24.4, 25.0)
WC, cm
92.2  10.2 (90.8, 93.4)
98.9  13.4 (96.1, 101.6)
83.4  7.1 (82.6, 84.2)
VAT, cm2
97.5  39.0 (92.3, 102.5)
79.7  36.7 (72.1, 87.4)
77.9  28.5 (74.6, 81.2)
SAT, cm2
131.0  56.6 (123.4, 138.2) 168.1  91.2 (149.1, 187.1) 82.8  31.6 (79.1, 86.4)
Systolic BP, mm Hg
126.5  12.1 (124.9, 128.0) 127.1  16.5 (123.6, 130.5) 121.8  14.1 (120.1, 123.4)
Diastolic BP, mm Hg
76.8  8.7 (75.7, 78.0)
75.4  12.5 (72.8, 78.0)
76.3  11.1 (75.0, 77.6)
Type 2 DM
7.4 (17)
8.8 (8)
9.6 (28)
Smoking, pack-years
4.5  9.3 (3.3, 5.8)
4.8  7.6 (3.3, 6.4)
14.1  14.1 (12.5, 15.8)
Alcohol, g/day
16.6  28.3 (12.9, 20.3)
14.0  22.8 (9.3, 18.8)
21.7  32.6 (17.9, 25.4)
Total cholesterol, mmol/l
5.49  0.93 (5.36, 5.59)
5.35  1.20 (5.10, 5.60)
4.99  0.87 (4.90, 5.10)
Triglycerides, mmol/l
1.99  1.44 (1.80, 2.17)
1.52  0.85 (1.34, 1.69)
1.83  1.19 (1.69, 1.97)
LDL-C, mmol/l
3.31  0.84 (3.20, 3.40)
3.33  1.08 (3.10, 3.56)
2.99  0.81 (2.90, 3.09)
HDL-C, mmol/l
1.31  0.32 (1.27, 1.35)
1.32  0.41 (1.24, 1.41)
1.19  0.30 (1.15, 1.22)
Lipoprotein subfractions, log-transformed
VLDL particle
Total, nmol/l
1.99  0.22 (1.96, 2.02)
1.81  0.29 (1.75, 1.87)
1.82  0.26 (1.79, 1.85)
Large, nmol/l
0.57  0.43 (0.52, 0.63)
0.49  0.33 (0.42, 0.56)
0.37  0.42 (0.33, 0.43)
Medium, nmol/l
1.60  0.37 (1.55, 1.65)
1.29  0.49 (1.20, 1.40)
1.27  0.57 (1.22, 1.35)
Small, nmol/l
1.66  0.25 (1.62, 1.69)
1.59  0.25 (1.53, 1.64)
1.53  0.30 (1.50, 1.57)
Average size, nm
1.69  0.06 (1.69, 1.70)
1.71  0.06 (1.70, 1.72)
1.66  0.08 (1.65, 1.67)
LDL particle
Total, nmol/l
3.13  0.14 (3.10, 3.14)
3.15  0.14 (3.11, 3.17)
3.05  0.14 (3.03, 3.06)
IDL, nmol/l
1.53  0.70 (1.45, 1.63)
1.64  0.54 (1.52, 1.75)
0.99  0.73 (0.91, 1.08)
Large, nmol/l
2.38  0.46 (2.31, 2.43)
2.60  0.33 (2.52, 2.67)
2.59  0.28 (2.56, 2.62)
Small, nmol/l
2.87  0.51 (2.80, 2.93)
2.86  0.42 (2.76, 2.94)
2.64  0.61 (2.58, 2.72)
Average size, nm
1.33  0.02 (1.33, 1.34)
1.34  0.02 (1.33, 1.34)
1.34  0.02 (1.34, 1.34)
HDL particle
Total, nmol/l
1.56  0.12 (1.56, 1.57)
1.50  0.09 (1.48, 1.52)
1.46  0.08 (1.45, 1.47)
Large, nmol/l
0.79  0.23 (0.77, 0.83)
0.76  0.25 (0.71, 0.81)
0.71  0.22 (0.69, 0.74)
Medium, nmol/l
0.45  0.35 (0.41, 0.50)
0.22  0.27 (0.17, 0.28)
0.15  0.25 (0.12, 0.18)
Small, nmol/l
1.44  0.12 (1.43, 1.45)
1.40  0.10 (1.38, 1.42)
1.36  0.10 (1.35, 1.38)
Average size, nm
0.99  0.02 (0.99, 0.99)
0.99  0.02 (0.98, 0.99)
0.99  0.02 (0.99, 0.99)

p Value
<0.001*y
<0.001*yz
<0.001*yz
<0.001*y
<0.001*yz
<0.001*z
NS
NS
<0.001*z
<0.05z
<0.001*z
<0.01y
<0.001*z
<0.001*z

<0.001*y
0.001*yz
<0.001*y
<0.001*
<0.001*z
<0.001*z
<0.001*z
<0.001*y
<0.001*z
<0.001*y
<0.001*yz
<0.001*
<0.001*y
<0.001*yz
NS

Values are means  SD for continuous variables and percentages for categorical variables. The p values for continuous variables were obtained from
analysis of variance and for categorical variables were from chi-square test. The 95% condence intervals are shown in parentheses for continuous
variables. BMI, body mass index; BP, blood pressure; DM, diabetes mellitus; HDL-C, high-density lipoprotein cholesterol; IDL, intermediate-density
lipoprotein; LDL-C, low-density lipoprotein cholesterol; SAT, subcutaneous adipose tissue; VAT, visceral adipose tissue; VLDL, very low-density
lipoprotein; WC, waist circumference.
*Signicant between Japanese Americans and Koreans.
ySignicant between Japanese Americans and African Americans.
zSignicant between Koreans and African Americans.

triglyceride levels. AA had signicantly higher BMI and


SAT. AA also had signicantly lower serum triglyceride
levels. Koreans had signicantly lower BMI, WC, and SAT.
Koreans also had signicantly lower serum total cholesterol, LDL cholesterol, and HDL cholesterol levels. Average
concentrations or sizes of all the lipoprotein subfractions,
except for HDL cholesterol size, were signicantly different
among the 3 groups (Table 1).

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 273-280

Correlations among VAT, SAT, WC, and BMI


Correlations among indices of obesity within the 3 groups
are shown in Table 2. In each of the 3 groups, SAT,
compared with VAT, was more highly correlated with BMI
and WC; the correlation between VAT and SAT was
weaker compared with the correlations of other combinations; the correlation between BMI and WC was the
strongest in JA and Koreans.

275

gSCIENCE

TABLE 2. Spearman rank correlations among indices of obesity for Japanese American, African American, and Korean men (N 612)

r (p < 0.001 for all)


Japanese Americans (n 230)
VAT
SAT
WC
BMI

African Americans (n 91)

Koreans (n 291)

VAT

SAT

WC

BMI

VAT

SAT

WC

BMI

VAT

SAT

WC

BMI

1.00

0.60
1.00

0.73
0.83
1.00

0.66
0.78
0.89
1.00

1.00

0.66
1.00

0.72
0.93
1.00

0.63
0.84
0.90
1.00

1.00

0.56
1.00

0.66
0.74
1.00

0.64
0.69
0.80
1.00

Abbreviations as in Table 1.

Associations of LDL subfractions with VAT, SAT,


WC, and BMI
In each of the 3 groups, VAT was signicantly and positively associated with total and small LDL particle concentrations; VAT was signicantly and negatively
associated with LDL size (Table 3). However, the associations of SAT, WC, and BMI with LDL subfractions were
varied among the 3 groups. SAT, WC, and BMI were
signicantly associated with total and small LDL particle
concentrations in JA and Koreans, but no signicant associations were found in AA. In JA and Koreans, R2 values
for the associations of indices of obesity with total and
small LDL lipoprotein subfractions were different. BMI had
the largest R2 values (R2 0.14, 0.12, 0.08, and 0.08 for
BMI, WC, VAT, and SAT) with total LDL particle concentrations. VAT had the largest R2 values (R2 0.14,
0.14, 0.11, and 0.10 for VAT, WC, BMI, and SAT) with
small LDL particle concentrations in JA. However, VAT
had the largest R2 values (R2 0.19, 0.10, 0.09, and 0.07
for VAT, BMI, WC, and SAT with total LDL particle concentrations; R2 0.14, 0.06, 0.06, and 0.05 for VAT, BMI,
WC, and SAT with small LDL particle concentrations) in
the associations with both total and small LDL particle
concentrations in Koreans (Table 3).

Associations of HDL subfractions with VAT, SAT,


WC, and BMI
VAT was signicantly and negatively associated with large
HDL and HDL size in each of the 3 groups (Table 4). SAT,
WC, and BMI were signicantly and negatively associated
with large HDL concentration and size of HDL in the 3
ethnicities. R2 values in the association between indices of
obesity with HDL lipoprotein subfractions were varied
among the ethnicities. For example, VAT had the larger R2
values in the associations of both large HDL concentration
and HDL size compared with those for SAT, WC, and BMI
in AA (R2 0.22, 0.17, 0.15, and 0.11 for VAT, BMI, WC,
and SAT with large HDL particle concentrations; R2
0.15, 0.13, 0.11, and 0.11 for VAT, WC, BMI, and SAT
with HDL size) and in Koreans (R2 0.15, 0.14, 0.12, and
0.12 for VAT, BMI, SAT, and SAT with large HDL particle
concentrations; R2 0.23, 0.17, 0.16, and 0.12 for VAT,
BMI, WC, and SAT with HDL size). However, WC had

276

larger R2 value than BMI, VAT, and SAT did (R2 0.19,
0.18, 0.17, and 0.11 for WC, BMI, VAT, and SAT with
large HDL particle concentrations; R2 0.29, 0.27, 0.25,
and 0.19 for WC, BMI, VAT, and SAT with HDL size) in JA
(Table 4).

Associations of VLDL subfractions with VAT, SAT,


WC, and BMI
In each of the 3 groups, VAT was signicantly associated
with large VLDL (Table 5). Varied but signicant associations of SAT, WC, and BMI with large VLDL were found
among the 3 groups. SAT, WC, and BMI were signicantly
and positively associated with large VLDL in JA and AA,
but only BMI was signicantly associated with large VLDL
in Koreans. SAT, WC, and BMI were variedly associated
with other VLDL lipoprotein subfractions. In the association with large VLDL, VAT had the largest R2 value among
the indices of obesity in the 3 ethnicities (Table 5).

DISCUSSION
In the 3 ethnicities of middle-aged men, lipoprotein particle concentrations and size measured by nuclear magnetic
resonance spectroscopy were signicantly associated with
VAT. This result is consistent with our previous results in
U.S. white and Japanese middle-aged men [15]. Another
study also reported a similar association between lipoprotein and VAT in diabetic patients [25]. We also found that
the associations between SAT and lipoprotein subfractions
were less strong than the association between VAT and
lipoprotein subfractions was.

Associations of lipoproteins with SAT compared to


VAT
Only a few studies have examined the association of lipoprotein particles with SAT versus with VAT. Although it is
not completely clear how SAT, compared with VAT, is
associated with CHD risk factors, increasing evidence
points to weaker associations between SAT and lipoprotein
particle concentrations, compared with those associations
for VAT. Fox et al. found SAT had a weaker correlation
with metabolic factors than VAT in Framingham cohorts
[14]. This weaker association with SAT versus VAT was
also shown in white and AA patients with type 2 diabetes

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 273-280

LDL size

LDL small

LDL
intermediate
LDL large

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 273-280

Multiple linear regression model is adjusted for age, pack per year smoking, and alcohol consumption. For the model, the outcome variable is log-transformed lipoprotein concentration or size; primary predictor
variable is each index of obesity (VAT, SAT, WC, and BMI). Abbreviations as in Table 1.
*p < 0.01.

0.33*
(0.104)
0.27*
(0.078)
0.18*
(0.030)
0.24*
(0.058)
0.33*
(0.112)
0.31*
(0.092)
0.27*
(0.076)
0.13
(0.013)
0.25*
(0.060)
0.28*
(0.083)

WC
SAT

0.27*
(0.069)
0.25*
(0.059)
0.06
(0.000)
0.22*
(0.045)
0.21*
(0.048)
0.44*
(0.190)
0.32*
(0.104)
0.22*
(0.045)
0.38*
(0.139)
0.42*
(0.183)

VAT
BMI

0.22
(0.038)
0.02
(0.035)
0.02
(0.020)
0.24
(0.021)
0.16
(0.025)
0.25
(0.052)
0.01
(0.034)
0.03
(0.019)
0.30*
(0.050)
0.17
(0.029)
0.10
(0.001)
0.04
(0.034)
0.06
(0.014)
0.23
(0.010)
0.10
(0.008)
0.29*
(0.071)
0.03
(0.033)
0.13
(0.001)
0.37*
(0.098)
0.31*
(0.095)

WC
SAT
VAT

0.33*
(0.140)
0.17*
(0.018)
0.19*
(0.031)
0.31*
(0.114)
0.32*
(0.114)

H (adjusted-R2)

BMI
WC

0.30*
(0.119)
0.16
(0.014)
0.19*
(0.030)
0.35*
(0.144)
0.33*
(0.124)
0.23*
(0.083)
0.16
(0.016)
0.16
(0.020)
0.28*
(0.098)
0.28*
(0.094)

SAT
VAT

0.26*
(0.098)
0.17
(0.018)
0.24*
(0.050)
0.35*
(0.139)
0.37*
(0.150)
LDL total

Koreans

H (adjusted-R2)

African Americans

B (adjusted-R2)

Japanese Americans

TABLE 3. Multivariate-adjusted associations between adiposity indices and log-transformed LDL for Koreans, African Americans, and Japanese Americans (N 612)

BMI

gSCIENCE

mellitus [25]. Our ndings build on the increasing evidence that SAT is less strongly, but signicantly, associated
with lipoprotein particle concentrations and numbers.

Associations of triglyceride-rich lipoproteins with


VAT
Our ndings on the association between indices of obesity
and lipoprotein support the hypothesis that VAT has an
impact on the altered metabolism of triglyceride-rich lipoprotein. Investigators have tried to explain the mechanism for the associations between indices of obesity and
lipoprotein by looking at whether lipoprotein metabolism
is inuenced by regional body fat, such as VAT, through
lipid metabolism in the liver. VAT favors access to the liver,
which enhances lipolytic activity in the liver and causes fat
accumulation [26]. Then, increased fat in the liver activates
cholesterol ester transport protein, which leads to an
increased exchange of triglycerides from VLDL to LDL and
HDL. Subsequently, the triglyceride-rich LDL and HDL are
converted into small and dense LDL and HDL, respectively, by hepatic lipase. In this study, we found that VAT
was signicantly and positively associated with higher
particle concentrations of total and large VLDL and small
LDL, as well as signicantly inversely associated with large
HDL in the 3 ethnicities. We also observed the association
of VAT with lower average size of LDL (positively) and
HDL (inversely). Our results are consistent with the
triglyceride-rich lipoprotein metabolism theory in the 3
ethnicities.

Associations of triglyceride-rich lipoproteins with


WC, BMI, and SAT
We also found similar associations of WC and BMI with
large VLDL, small LDL, and lower average size of LDL and
HDL as seen in the associations of VAT with triglyceriderich lipoprotein subfractions in the 3 ethnicities in the
associations of SAT, WC, and BMI with triglyceride-rich
lipoprotein subfractions. Similar to VAT, SAT, WC, and
BMI support the notion that altered metabolism of
triglyceride-rich lipoprotein is affected by indices of
obesity, except in AA. AA showed signicant associations
of only WC and BMI with large VLDL, small LDL, and
large HDL. SAT did not show signicant associations with
the triglyceride-rich lipoprotein subfractions in AA. This
may be due to the smaller sample size of AA. Another
possibility is the difference in fat tissue distribution. Effect
of SAT on lipoprotein subfractions appears to be different
from that of VAT. The Framingham Heart Study reported
that increased SAT was signicantly associated with lower
triglyceride levels among the individuals who had high
VAT, whereas increased SAT was signicantly associated
with higher triglyceride levels among the individuals who
had low VAT [14]. The 3 ethnicities had signicantly
different fat tissue distributions. Therefore, AA, who had a
signicantly larger VAT, could explain the different associations between triglyceride-rich lipoprotein subfractions

277

278

HDL size

HDL
medium
HDL small

HDL large

Multiple linear regression model is adjusted for age, pack per year smoking, and alcohol consumption. For the model, the outcome variable is log-transformed lipoprotein concentration or size; primary predictor
variable is each index of obesity (VAT, SAT, WC, and BMI). Abbreviations as in Table 1.
*p < 0.01.

0.00
(0.071)
0.35*
(0.137)
0.04
(0.031)
0.17*
(0.041)
0.42*
(0.167)
0.01
(0.071)
0.32*
(0.117)
0.05
(0.032)
0.18*
(0.044)
0.41*
(0.160)

WC
SAT

0.15
(0.090)
0.36*
(0.145)
0.09
(0.038)
0.33*
(0.120)
0.48*
(0.228)

0.09
(0.076)
0.32*
(0.121)
0.05
(0.032)
0.08
(0.017)
0.36*
(0.124)

VAT
BMI

0.22
(0.120)
0.38*
(0.173)
0.23
(0.037)
0.02
(0.000)
0.29*
(0.111)

WC

0.23
(0.123)
0.34*
(0.145)
0.20
(0.023)
0.01
(0.000)
0.32*
(0.125)
0.22
(0.104)
0.31*
(0.113)
0.22
(0.028)
0.01
(0.009)
0.29*
(0.106)

SAT
VAT
BMI

0.16
(0.047)
0.36*
(0.176)
0.02
(0.005)
0.01
(0.002)
0.46*
(0.273)

WC
SAT

0.09
(0.028)
0.24*
(0.106)
0.05
(0.006)
0.05
(0.004)
0.35*
(0.188)

VAT

0.10
(0.030)
0.35*
(0.173)
0.06
(0.008)
0.03
(0.002)
0.44*
(0.254)

0.16
(0.048)
0.38*
(0.194)
0.01
(0.005)
0.01
(0.002)
0.48*
(0.294)

0.23
(0.112)
0.44*
(0.218)
0.11
(0.006)
0.01
(0.009)
0.36*
(0.154)

Koreans

H (adjusted-R2)
H (adjusted-R2)

H (adjusted-R2)

African Americans
Japanese Americans

TABLE 4. Multivariate-adjusted associations between adiposity indices and log-transformed HDL for Korean, African American and Japanese American (N 612)

BMI

gSCIENCE

HDL total

and SAT. However, further investigations are needed to


explain how SAT, WC, and BMI are associated with
triglyceride-rich lipoprotein metabolism.

Study strengths
We included population-based samples from 3 different
ethnicities, which allowed us to look at the cross-ethnic
consistency in the associations between each index of
obesity and lipoprotein subfractions. The measurements
for lipoprotein subfractions and for VAT, SAT, WC, and
BMI were standardized across the research centers. This
provided higher precision and accuracy in the measurements. In addition, indices of obesity included multiple
variables: VAT, SAT, WC, and BMI, from the 3 different
ethnic groups. By comparing the associations among the
different indices of obesity, this study allowed us to analyze
the relative magnitude of associations among the different
indices of obesity.

Study limitations
The smaller sample size for AA, compared with that of JA
and Koreans, gave the associations between indices of
obesity and lipoprotein subfractions less statistical power.
Although we randomly selected our study samples, our
samples may not necessarily be representative of the populations. This also inuenced the comparison of the
magnitude of associations among the ethnic groups. We
measured blood samples only at 1 time point and did not
take intraindividual variation [27] into account. Thus, it is
possible that the actual difference in lipid variables is
smaller than we reported. The study is cross-sectional in
design, which prevented the assessment of causality.
Clinical signicance of those differences among the ethnic
groups would be of interest for future studies. Our study
included only men and only individuals ages 40 to 49
years. Thus, the results may not be generalizable to other
age groups or women.

CONCLUSIONS
All 3 ethnic groups showed signicant positive associations
of VAT with large VLDL and small LDL and a negative
association of VAT with large HDL. This study has further
expanded the evidence that VAT is signicantly associated
with both atherogenic and atheroprotective lipoprotein
particle concentrations to middle-aged JA, AA, and Korean
men. Our results also expanded the evidence that the associations of SAT with lipoprotein subfractions are weaker,
compared with those of VAT, in these ethnic groups.

ACKNOWLEDGMENT
The authors especially would like to thank Jessica White, MS,
MLS, for her assistance in editing the English in this paper.

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 273-280

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 273-280

Multiple linear regression model is adjusted for age, pack per year smoking, and alcohol consumption. For the model, the outcome variable is log-transformed lipoprotein concentration or size; primary predictor
variable is each index of obesity (VAT, SAT, WC, and BMI). Abbreviations as in Table 1.
*p < 0.01.

VLDL size

VLDL
medium
VLDL small

VLDL large

BMI
WC

0.14
(0.015)
0.25*
(0.121)
0.09
(0.017)
0.11
(0.002)
0.15
(0.066)
0.10
(0.004)
0.19*
(0.097)
0.06
(0.010)
0.07
(0.005)
0.12
(0.057)

SAT
VAT

0.33*
(0.102)
0.35*
(0.186)
0.27*
(0.079)
0.11
(0.002)
0.20*
(0.084)
0.21
(0.019)
0.35*
(0.078)
0.20
(0.014)
0.097
(0.013)
0.14
(0.029)

BMI
WC

0.21
(0.019)
0.34*
(0.070)
0.21
(0.015)
0.10
(0.013)
0.09
(0.017)
0.15
(0.004)
0.30*
(0.042)
0.17
(0.004)
0.04
(0.024)
0.09
(0.021)

SAT
VAT

0.34*
(0.093)
0.44*
(0.155)
0.37*
(0.113)
0.18
(0.007)
0.06
(0.017)
0.19*
(0.046)
0.34*
(0.138)
0.16
(0.038)
0.06
(0.011)
0.28*
(0.088)

BMI
WC

0.16
(0.039)
0.36*
(0.150)
0.16
(0.041)
0.017
(0.014)
0.33*
(0.119)
0.15
(0.034)
0.25*
(0.084)
0.17
(0.042)
0.01
(0.015)
0.21*
(0.052)

H (adjusted-R2)
H (adjusted-R2)

SAT
VAT

0.19*
(0.048)
0.40*
(0.177)
0.20*
(0.055)
0.03
(0.014)
0.30*
(0.096)
VLDL total

Koreans

H (adjusted-R2)

African Americans
Japanese Americans

TABLE 5. Multivariate-adjusted associations between adiposity indices and log-transformed VLDL for Koreans, African Americans, and Japanese Americans (N 612)

0.22*
(0.042)
0.27*
(0.136)
0.15
(0.031)
0.10
(0.001)
0.16*
(0.069)

gSCIENCE

REFERENCES
1. Lloyd-Jones D, Adams RJ, Brown TM, et al. Heart disease and stroke
statistics2010 update: a report from the American Heart Association. Circulation 2010;121:e46215.
2. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and
regional burden of disease and risk factors, 2001: systematic analysis
of population health data. Lancet 2006;367:174757.
3. Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. Executive Summary of the Third Report of the
National Cholesterol Education Program (NCEP) Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in
Adults (Adult Treatment Panel III). JAMA 2001;285:248697.
4. Blumenthal RS, Michos ED, Nasir K. Further improvements in CHD
risk prediction for women. JAMA 2007;297:6413.
5. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA 2007;
297:6119.
6. Kathiresan S, Otvos JD, Sullivan LM, et al. Increased small low-density
lipoprotein particle number: a prominent feature of the metabolic
syndrome in the Framingham Heart Study. Circulation 2006;113:
209.
7. Mora S, Otvos JD, Rifai N, Rosenson RS, Buring JE, Ridker PM. Lipoprotein particle proles by nuclear magnetic resonance compared
with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women. Circulation 2009;119:9319.
8. Freedman DS, Otvos JD, Jeyarajah EJ, et al. Sex and age differences in
lipoprotein subclasses measured by nuclear magnetic resonance
spectroscopy: the Framingham Study. Clin Chem 2004;50:1189200.
9. Robertson TL, Kato H, Gordon T, et al. Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan,
Hawaii and California: coronary heart disease risk factors in Japan
and Hawaii. Am J Cardiol 1977;39:2449.
10. Ding J, Visser M, Kritchevsky SB, et al. The association of regional fat
depots with hypertension in older persons of white and African
American ethnicity. Am J Hypertens 2004;17:9716.
11. Goodpaster BH, Krishnaswami S, Resnick H, et al. Association between regional adipose tissue distribution and both type 2 diabetes
and impaired glucose tolerance in elderly men and women. Diabetes
Care 2003;26:3729.
12. Nagaretani H, Nakamura T, Funahashi T, et al. Visceral fat is a
major contributor for multiple risk factor clustering in Japanese
men with impaired glucose tolerance. Diabetes Care 2001;24:
212733.
13. Klein S. The case of visceral fat: argument for the defense. J Clin
Invest 2004;113:15302.
14. Fox CS, Massaro JM, Hoffmann U, et al. Abdominal visceral and
subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation 2007;
116:3948.
15. Nakata K, Choo J, Hopson MJ, et al. Stronger associations of sagittal
abdominal diameter with atherogenic lipoprotein subfractions than
waist circumference in middle-aged US white and Japanese men.
Metabolism 2010;59:174251.
16. Kagan A, Harris BR, Winkelstein W Jr, et al. Epidemiologic studies of
coronary heart disease and stroke in Japanese men living in Japan,
Hawaii and California: demographic, physical, dietary and biochemical characteristics. J Chronic Dis 1974;27:34564.
17. Sekikawa A, Ueshima H, Kadowaki T, et al. Less subclinical atherosclerosis in Japanese men in Japan than in white men in the United
States in the post-World War II birth cohort. Am J Epidemiol 2007;
165:61724.
18. Kagan A, McGee DL, Yano K, Rhoads GG, Nomura A. Serum cholesterol and mortality in a Japanese-American population: the Honolulu
Heart program. Am J Epidemiol 1981;114:1120.
19. Shin C, Abbott RD, Kim J, Lee H, Kimm K. Prevalence and correlates of
orthostatic hypotension in middle-aged men and women in Korea:
the Korean Health and Genome Study. J Hum Hypertens 2004;18:
71723.

279

gSCIENCE

20. Bild DE, Detrano R, Peterson D, et al. Ethnic differences in coronary


calcication: the Multi-Ethnic Study of Atherosclerosis (MESA). Circulation 2005;111:131320.
21. Friedman GD, Cutter GR, Donahue RP, et al. CARDIA: study design,
recruitment, and some characteristics of the examined subjects.
J Clin Epidemiol 1988;41:110516.
22. Tell GS, Fried LP, Hermanson B, Manolio TA, Newman AB,
Borhani NO. Recruitment of adults 65 years and older as participants
in the Cardiovascular Health Study. Ann Epidemiol 1993;3:35866.
23. Kadowaki T, Sekikawa A, Murata K, et al. Japanese men have larger
areas of visceral adipose tissue than Caucasian men in the same
levels of waist circumference in a population-based study. Int J Obes
(Lond) 2006;30:11635.

280

24. Otvos JD. Measurement of lipoprotein subclass proles by


nuclear magnetic resonance spectroscopy. Clin Lab 2002;48:
17180.
25. Sam S, Haffner S, Davidson MH, et al. Relationship of abdominal
visceral and subcutaneous adipose tissue with lipoprotein particle number and size in type 2 diabetes. Diabetes 2008;57:
20227.
26. Desprs JP. Is visceral obesity the cause of the metabolic syndrome?
Ann Med 2006;38:5263.
27. Marcovina SM, Gaur VP, Albers JJ. Biological variability of cholesterol,
triglyceride, low- and high-density lipoprotein cholesterol, lipoprotein(a), and apolipoproteins A-I and B. Clin Chem 1994;40:
5748.

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September 2013: 273-280

EDITORIAL VIEWPOINT

gOPINION

Visceral Adipose Tissue: At the Intersection of


Lipoprotein Associated CV Risk
Robert S. Rosenson
New York, NY, USA
Obesity is a global epidemic that increases the risk of
type 2 diabetes, cardiovascular disease, and other medical
conditions that lead to premature mortality and more years
lived with disability [1]. However, obesity is a heterogeneous disorder in which the fat distribution confers differential cardiometabolic risks [2]. In most studies,
anthropometric measures of abdominal fat are superior
measures of incident coronary heart disease events than is
total adiposity estimated by the body mass index (BMI) is
[3e10]. Associations between coronary heart disease risk
factors and events are stronger when visceral adipose tissue
(VAT) is measured directly by computerized tomography
or magnetic resonance imaging than by indirect measures
of central adiposity such as the waist circumference or the
waist-hip ratio or estimated by BMI [11e15]. High VAT
area has also been more strongly associated with characteristics of vulnerable plaque than low VAT area or other
body compositional measures that included subcutaneous
adipose tissue area, waist circumference, and BMI [16].
Specically, VAT was associated with noncalcied plaque
burden as assessed by computerized tomography angiography, as well as the presence of noncalcied plaque with
positive remodeling and spotty calcium that represent
other characteristics of vulnerable plaque.
VAT is more metabolically active than subcutaneous
adipose tissue is, which results in increased ux of
nonesteried fatty acids into the portal circulation. The
nonesteried fatty acids serve as substrates for triglyceride
production, which is incorporated into large very lowdensity lipoprotein (VLDL) particles. Overproduction of
large VLDL particles and impaired catabolism in insulinresistant individuals results in transfer of core triglyceride
into LDL and high-density lipoprotein (HDL) particles.
Triglyceride-enriched LDL and HDL particles are substrates
for lipases that hydrolyze the triglyceride resulting in
smaller LDL and smaller HDL particles. Small LDL particles
are considered more atherogenic than large LDL particles
because of reduced clearance by LDL receptors and
increased oxidative susceptibility per particle.
High concentrations of large VLDL particles and
small LDL particles and low concentrations of large HDL
particles are associated with higher rates of coronary
artery disease in men [17] and predict future risk of
incident type 2 diabetes in previously healthy women
[18]. High LDL particle concentrations, particularly small
LDL particles, predict incident and recurrent cardiovascular events in population-based cohorts [19,20] and
among coronary heart disease patients treated with lipid-

GLOBAL HEART, VOL. 8, NO. 3, 2013


September 2013: 281-282

lowering therapy [21]. Low HDL particle concentrations


are associated with increased cardiovascular events in
population-based studies [22,23] and clinical trials of
lipid-modifying therapies in multivariate models [21,24].
The reported associations from these prospective studies
and clinical trials that examine cardiometabolic risk and
lipoprotein subclasses were signicant in multivariate
models that included indirect measures of adiposity such
as BMI; however, none of the reports measured adiposity
directly.
In this issue of Global Heart, Hirooka et al. [25]
investigated the association between multiple measures of
adiposity (computerized tomography and anthropometric)
and nuclear magnetic resonanceemeasured lipoprotein
subclasses from a population-based sample of middle-aged
men of Japanese, Korean, and African American ancestry.
VAT was more strongly associated with high concentrations of total LDL and VLDL particles and small LDL
particles and lower concentrations of large HDL particles
than subcutaneous adipose tissue, waist circumference,
and BMI in multivariate analysis that adjusted for age,
smoking, and alcohol consumption. The association of
VAT with these lipoprotein subclasses was similar regardless of ancestry. Unfortunately, the investigators did not
report whether these lipoprotein subclass associations were
different than those for plasma triglycerides and HDL
cholesterol, which are measures that have been correlated
with VAT in other studies [11,12] and incorporated into
the visceral adiposity index [2].
It is important to ask what clinically relevant information has been learned from the current study and
what information is required from future studies. VAT is
more strongly associated with cardiometabolic risk factors in several studies including this report from Hirooka
et al. [25], and thus future reports that investigate the
cardiometabolic risk of adiposity will require VAT measurements. Yet, it remains uncertain whether VAT and
certain lipoprotein abnormalities (high VLDL particle
concentration, high LDL particle concentration, or low
levels of large HDL particle concentration) considered in
isolation or in aggregate provide incremental information
concerning the risk of type 2 diabetes, atherosclerosis, or
cardiovascular events. Prospective studies will be
required to address the interactions of VAT and lipoprotein subclasses and their functional properties on
incident type 2 diabetes and cardiovascular disease in
ethnically and racially diverse populations of men and
women [26].

Dr. Rosenson is a stockholder in LipoScience, Inc.,


and he has participated in
Advisory Boards for LipoScience, Inc. Due to these
potential conicts of interest, he was not involved in
review of the manuscript
for which this editorial was
written.
From the Department of
Cardiometabolic Disorders,
Mount Sinai Heart, Icahn
School of Medicine at
Mount Sinai, New York, NY,
USA. Correspondence: R. S.
Rosenson (robert.
rosenson@mssm.edu).
GLOBAL HEART
2013 World Heart
Federation (Geneva).
Published by Elsevier Ltd.
All rights reserved.
VOL. 8, NO. 3, 2013
ISSN 2211-8160/$36.00.
http://dx.doi.org/10.1016/
j.gheart.2013.08.002

281

gOPINION

REFERENCES
1. Murray CJ, Abraham J, Ali MK, et al., for the U.S. Burden of Disease
Collaborators. The state of US health, 1990e2010: burden of diseases, injuries, and risk factors. JAMA 2013 Jul 10 [E-pub ahead of
print].
2. Amato MC, Giordano C, Galia M, et al., for the AlkaMeSy Study
Group. Visceral Adiposity Index: a reliable indicator of visceral fat
function associated with cardiometabolic risk. Diabetes Care 2010;33:
9202.
3. Larsson B, Svrdsudd K, Welin L, Wilhelmsen L, Bjrntorp P,
Tibblin G. Abdominal adipose tissue distribution, obesity, and risk of
cardiovascular disease and death: 13 year follow up of participants
in the study of men born in 1913. Br Med J (Clin Res Ed) 1984;288:
14014.
4. Lapidus L, Bengtsson C, Larsson B, Pennert K, Rybo E, Sjstrm L. Distribution of adipose tissue and risk of cardiovascular disease and death:
a 12 year follow up of participants in the population study of women in
Gothenburg, Sweden. Br Med J (Clin Res Ed) 1984;289:125761.
5. Donahue RP, Abbott RD, Bloom E, Reed DM, Yano K. Central obesity
and coronary heart disease in men. Lancet 1987;1:8214.
6. Prineas RJ, Folsom AR, Kaye SA. Central adiposity and increased risk
of coronary artery disease mortality in older women. Ann Epidemiol
1993;3:3541.
7. Rexrode KM, Carey VJ, Hennekens CH, et al. Abdominal adiposity and
coronary heart disease in women. JAMA 1998;280:18438.
8. Visscher TL, Seidell JC, Molarius A, van der Kuip D, Hofman A,
Witteman JC. A comparison of body mass index, waist-hip ratio and
waist circumference as predictors of all-cause mortality among the
elderly: the Rotterdam study. Int J Obes Relat Metab Disord 2001;25:
17305.
9. Oppert JM, Charles MA, Thibult N, Guy-Grand B, Eschwge E,
Ducimetire P. Anthropometric estimates of muscle and fat mass in
relation to cardiac and cancer mortality in men: the Paris Prospective
Study. Am J Clin Nutr 2002;75:110713.
10. Yusuf S, Hawken S, Ounpuu S, et al., for the INTERHEART Study
Investigators. Obesity and the risk of myocardial infarction in 27,000
participants from 52 countries: a case-control study. Lancet 2005;
366:16409.
11. Desprs JP, Nadeau A, Tremblay A, et al. Role of deep abdominal fat
in the association between regional adipose tissue distribution and
glucose tolerance in obese women. Diabetes 1989;38:3049.
12. Bergstrom RW, Leonetti DL, Newell-Morris LL, Shuman WP, Wahl PW,
Fujimoto WY. Association of plasma triglyceride and C-peptide with
coronary heart disease in Japanese-American men with a high
prevalence of glucose intolerance. Diabetologia 1990;33:48996.
13. Nakamura T, Tokunaga K, Shimomura I, et al. Contribution of visceral
fat accumulation to the development of coronary artery disease in
non-obese men. Atherosclerosis 1994;107:23946.
14. Fujimoto WY, Bergstrom RW, Boyko EJ, et al. Visceral adiposity and
incident coronary heart disease in Japanese-American men: the

282

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

10-year follow-up results of the Seattle Japanese-American Community Diabetes Study. Diabetes Care 1999;22:180812.
Nicklas BJ, Penninx BW, Cesari M, for the Health, Aging, and Body
Composition Study. Association of visceral adipose tissue with incident myocardial infarction in older men and women: the Health,
Aging and Body Composition Study. Am J Epidemiol 2004;160:7419.
Ohashi N, Yamamoto H, Horiguchi J, et al. Association between
visceral adipose tissue area and coronary plaque morphology
assessed by CT angiography. JACC Cardiovasc Imaging 2010;3:
90817.
Freedman DS, Otvos JD, Jeyarajah EJ, Barboriak JJ, Anderson AJ,
Walker JA. Relation of lipoprotein subclasses as measured by proton
nuclear magnetic resonance spectroscopy to coronary artery disease.
Arterioscler Thromb Vasc Biol 1998;18:104653.
Mora S, Otvos JD, Rosenson RS, Pradhan A, Buring JE, Ridker PM.
Lipoprotein particle size and concentration by nuclear magnetic
resonance and incident type 2 diabetes in women. Diabetes 2010;59:
115360.
Mora S, Otvos JD, Rifai N, Rosenson RS, Buring JE, Ridker PM. Lipoprotein particle proles by nuclear magnetic resonance compared
with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women. Circulation 2009;119:9319.
van der Steeg WA, Holme I, Boekholdt SM, et al. High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: signicance for cardiovascular risk: the IDEAL and
EPIC-Norfolk studies. J Am Coll Cardiol 2008;51:63442.
Otvos JD, Collins D, Freedman DS, et al. Low-density lipoprotein and
high-density lipoprotein particle subclasses predict coronary events
and are favorably changed by gembrozil therapy in the Veterans
Affairs High-Density Lipoprotein Intervention Trial. Circulation 2006;
113:155663.
Kuller LH, Grandits G, Cohen JD, et al., for the Multiple Risk Factor
Intervention Trial Research Group. Lipoprotein particles, insulin,
adiponectin, C-reactive protein and risk of coronary heart disease
among men with metabolic syndrome. Atherosclerosis 2007;195:
1228.
Mackey RH, Greenland P, Goff DC Jr, Lloyd-Jones D, Sibley CT, Mora S.
High-density lipoprotein cholesterol and particle concentrations,
carotid atherosclerosis, and coronary events: MESA (Multi-Ethnic
Study of Atherosclerosis). J Am Coll Cardiol 2012;60:50816.
Parish S, Offer A, Clarke R, et al., for the Heart Protection Study
Collaborative Group. Lipids and lipoproteins and risk of different
vascular events in the MRC/BHF Heart Protection Study. Circulation
2012;125:246978.
Hirooka N, Shin C, Masaki KH, et al. Associations of obesity with lipoprotein subfractions in Japanese American, African American, and
Korean men. Glob Heart 2013;8:27380.
Rosenson RS, Brewer HB Jr, Ansell B, et al. Translation of HDL function
into clinical practice: current prospects and future challenges. Circulation 2013. In press.

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PERSPECTIVES FROM NHLBI

gWATCH

A New Global Heart Series


The National Heart, Lung, and Blood Institute
(NHLBI) is one of 27 institutes and centers that make up
the U.S. National Institutes of Health (NIH), the largest
source of funding for biomedical research in the world.
The mission of the NHLBI is to provide global leadership
for a research, training, and education program to promote
the prevention and treatment of heart, lung, and blood
diseases and enhance the health of all individuals so that
they can live longer and more fullling lives [1]. In
particular, the NHLBI stimulates fundamental discoveries
in basic, clinical, and population science research; enables
the translation of scientic discoveries into clinical and
public health practice; fosters training and mentoring of
emerging scientists and clinicians; and communicates
research advances to the public [1]. Beginning with this
issue of Global Heart, the NHLBI will use the gWATCH
section of the journal to share and communicate current
perspectives on its activities, initiatives, and research advances with the global cardiovascular health community.
In this issue, the institutes perspectives on its new
collaborative partnership model for developing clinical
cardiovascular practice guidelines and its current emphasis
on implementation science and translation research are
presented.

COLLABORATIVE MODEL FOR PRACTICE


GUIDELINES DEVELOPMENT
On June 19, 2013, coincident with a public meeting of the
NHLBI Advisory Council (NHLBAC), the NHLBI
announced a new 2-step collaborative partnership model
for the development of current and future clinical cardiovascular practice guidelines [2], in alignment with
recent recommendations from the Institute of Medicine
[3,4]. In the rst step of this model, the NHLBI refocuses
its agenda on facilitating the generation of rigorous systematic evidentiary reviews in support of the highest
quality clinical practice guidelines worthy of the public
trust. Results of these rigorous reviews will be made
available free as a global public resource. In the second
step of this model, the NHLBI will collaborate with organizations that are on the frontlines of direct patient care to
prepare and issue the related clinical practice guidelines
informed by the rigorous evidentiary reviews. To implement this model, the NHLBI is partnering with stakeholder
or professional organizations including primary care and
cardiovascular specialty organizations, other federal
agencies, and international associations to ensure the

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September 2013: 283-284

completion and dissemination of these guidelines to reach


health care providers on the front lines of preventive care
and the general public [5]. In future issues of the journal,
the NHLBI will share concrete plans for future systematic
evidentiary reviews; the process for internal evaluation and
continuous improvement; strategies to facilitate sustained
adoption and implementation of guidelines; and the
identication of evidence gaps to inform and guide
research investments in order to maximize public health
impact.

IMPLEMENTATION SCIENCE AND THE


TRANSLATION OF RESEARCH DISCOVERIES INTO
PRACTICE
The NHLBI has been the global leader in heart, lung, and
blood research advances and has funded major basic and
clinical research as well as landmark epidemiological investigations that have led to effective diagnostic, preventive, and therapeutic interventions in the last half-century
[1,6]. It is well-recognized, however, that much of these
research advances is often lost in translation [7] and that
the fraction of discovery science that reaches patients in
clinical practices and real world settings remains very low.
For example, Westfall et al. [8] commented that it takes an
average of 17 years for only 14% of new scientic discoveries to enter day-to-day clinical practice, and that
Americans receive, on average, only half of recommended
preventive, acute, and long-term quality health care. In
fact, Naderi et al. showed more recently that nearly onethird of patients with a history of myocardial infarction
and about one-half without do not adhere to effective
evidence-based treatments [9].
Recognizing the enormity of the research translation
gap, the NHLBI held a series of internal leadership retreats
in May and June earlier this year that led to a commitment
of renewed emphasis on T4 translation research, including
dissemination and implementation research (Fig. 1) as one
approach to maximize the clinical and public health impact
of its research discoveries. In this conceptualization,
implementation research is interpreted to include rigorous
hypotheses testing and formal exploration of the processes
and factors that inuence the successful and sustained
adoption and integration of evidence-based interventions
within specic settings such as schools, work sites, communities, and other public health settings in order to
improve population health [10,11].

The perspectives expressed


in this article do not
necessarily represent the
views of the National Institutes of Health, Department of Health and Human
Services, or any other government entity.
Senior Advisor, Ofce of
the Director, National
Heart, Lung, and Blood
Institute, National Institutes of Health. Correspondence: G. A. Mensah
(george.mensah@nih.gov).
GLOBAL HEART
2013 Published by
Elsevier Ltd. on behalf of
World Heart Federation
(Geneva).
VOL. 8, NO. 3, 2013
ISSN 2211-8160/$36.00.
http://dx.doi.org/10.1016/
j.gheart.2013.08.014

283

gWATCH

FIGURE 1. The 4 steps (T1, T2, T3, and T4) involved in the translation of fundamental discovery science into clinical
and public health impact in real-world settings. T1, the rst translational stepbench to bedside or animal studies to
humans; T2, the second translational steptranslating science discovery to patients with specic diseases; T3, the third
translational steptranslating clinical insights to service delivery in clinical practices; T4, the fourth translational step
translating effective interventions to real-world settings. Based on and informed by the models of Khoury et al. Genet
Med 2007;9:665-74, and the Harvard Catalyst; The Harvard Clinical and Translational Science Center, available at: http://
catalyst.harvard.edu/pathnder/. Accessed August 28, 2013.
The diseases and risk factors addressed by NHLBI are
among the major contributors to global mortality and
disability. Thus, renewed emphasis on T4 translation
research in this arena can go a long way to maximize the
population impact of related biomedical research advances
made so far. In future issues of this journal, the NHLBI will
share information on funding opportunities to accelerate
T4 translation research in heart, lung, and blood diseases
and their risk factors.

George A. Mensah
Bethesda, MD, USA

4.

5.

6.

7.
8.

REFERENCES
1. National Heart, Lung, and Blood Institute. NHLBI Strategic Plan.
National Institutes of Health. Available at: http://www.nhlbi.nih.gov/
about/strategicplan/index.htm; 2007. Accessed August 28, 2013.
2. Gibbons GH, Shurin SB, Mensah GA, Lauer MS. Refocusing the
agenda on cardiovascular guidelines: an announcement from the
National Heart, Lung, and Blood Institute. Circulation 2013 Jun 19
[Epub ahead of print].
3. Institute of Medicine. Finding what works in health care: standards
for reviews. National Academy of Sciences. Available at: http://

284

9.

10.

11.

www.iom.edu/Reports/2011/Finding-What-Works-in-Health-CareStandards-for-Systematic-Reviews.aspx; 2011. Accessed August


28, 2013.
Institute of Medicine. Clinical practice guidelines we can trust.
National Avademy of Sciences. Available at: http://www.iom.edu/
Reports/2011/Clinical-Practice-Guidelines-We-Can-Trust.aspx; 2011.
Accessed August 28, 2013.
Gibbons GH, Harold JG, Jessup M, Robertson RM, Oetgen W. Next
steps in developing clinical practice guidelines for prevention.
Circulation 2013 Aug 8 [Epub ahead of print].
Nabel EG, Lauer MS. The cardiovascular programs of the National
Heart, Lung, and Blood Institute: from vision to action to impact.
J Am Coll Cardiol 2009;53:10823.
Lenfant C. Shattuck lectureclinical research to clinical practicelost
in translation? N Engl J Med 2003;349:86874.
Westfall JM, Mold J, Fagnan L. Practice-based researchBlue
Highways on the NIH roadmap. JAMA 2007;297:4036.
Naderi SH, Bestwick JP, Wald DS. Adherence to drugs that prevent
cardiovascular disease: meta-analysis on 376,162 patients. Am J Med
2012;125:8827.
Lobb R, Colditz GA. Implementation science and its application to population health. Annu Rev Public Health 2013;34:
23551.
Rabin BA, Brownson RC, Haire-Joshu D, Kreuter MW, Weaver NL. A
glossary for dissemination and implementation research in health. J
Public Health Manag Pract. 2008;14:11723.

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LETTER TO THE EDITOR

gMAIL

Rebuilding the Rheumatic Heart Disease Program in Sudan


This is a story of my country. I became a pediatric
cardiologist to help the children in Sudan. I was trained in
Saudi Arabia and had a good job, a good salary, and a big,
nice apartment, but I wanted to come back to Sudan and
help the children here. When I came back, I was focusing
on high-tech thingswe set up the center here with
echocardiography and interventional cardiac catheterization. We always considered rheumatic heart disease
(RHD) as a chronic pain with no remedy! The only program for RHD control in 1986 was a World Health Organization campaign involving 16 countries including
Sudan that was conducted in collaboration with the
Ministry of Health (MOH). The campaign was aimed at
screening and raising awareness with an emphasis on
secondary prophylaxis. Screening of 13,322 children was
done, and 146 cases of RHD were reported in Khartoum
Town. In this campaign, secondary prophylaxis coverage
was found to be 72%. Phase II was planned to extend the
program to other states; however, more nancial and
technical support was needed in terms of logistics, surveillance, and basic research. Therefore, this program
stopped in 2000.
When I attended the 2012 World Congress of Cardiology in Dubai, it was to present a paper about pediatric
arrhythmias. However, I happened to meet the World
Heart Federation RF/RHD Working Group, and this
meeting has changed my concepts about RHD to a disease that attracts the attention. I found myself part of a
big family caring about RHD.
In fact, some of us were trying to forget RHD! We go
to other countries and learn about all of these fancy
cardiac technologies and we come back home only to nd
these hopeless, pitiful cases. We collect a lot of money to
get these patients surgeryvalve replacement costs
about $5,000but they come back a few months later
with a hemorrhage, because the anticoagulant levels
were not controlled, or a stroke, because they did not
take the anticoagulants at all. Moreover, after a
marvelous repair by our surgeon, the disease recurs in the
same or other valves. In the end, it is just untreatable.
I was fascinated when I was in Dubai and met the
RHD group there. Right after the meeting all that I was
doing was writingI was writing the proposal for a RHD
control program in Sudan. The program is mainly based
on the ASAP Program proposed by the Pan African Society of Cardiology.
When I came back to Sudan, I talked to everyone, and
I got help from many people, including my colleagues and
our scientic societies (Sudan Heart Society and Sudanese
Association of Pediatricians) as well as the MOH ofcialswe wanted to join all efforts to make a strong case.
We presented the proposal to the MOH Advisory Council
on Cardiology 2 months after Dubai, and they gave input

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September 2013: 285-286

FIGURE 1. Brochure in Arabic for public awareness.

and accepted it and then passed it to the vice minister of


Health for his review.
We started collecting some money through our
charity groupThe Sudanese Childrens Heart Society
[1]and started publishing brochures for public awareness (Fig. 1). We distributed them through medical students when they made their rural rotations. As the
program was inserted in their academic courses, students
were very keen to share; many of them had chosen to
conduct their fth-year research on RHD awareness. We
also utilize the website of our society as a resource for
health education for both parents and physicians about
RHD.
Once the vice minister had accepted the proposal,
Khartoum state organized its rst training workshop for
50 health professionals in the MOH, including primary
care physicians and pharmacists in February 2013. We
met with the school health department in Khartoum
state. They have a health education program for teachers.

GLOBAL HEART
2013 World Heart
Federation (Geneva).
Published by Elsevier Ltd.
All rights reserved.
VOL. 8, NO. 3, 2013
ISSN 2211-8160/$36.00.
http://dx.doi.org/10.1016/
j.gheart.2013.07.002

285

gMAIL

FIGURE 2. Flow chart included in manual for secondary


care physicians.

We developed a manual for teachers and the ministry


inserted a 2-h session on RHD into that course; 200
teachers have taken it so far.
We talked to the World Health Organization ofce
here, and at the last minute, they integrated the RHD

286

program into their PEN (Package of Essential NCD interventions for primary care in low-resource settings)
pilot for Darfur. They were very helpful. In June 2013, the
ministry had the rst train-the-trainer course for 20
physicians from Darfur, using the manuals we developed
for primary and secondary care (Fig. 2). These trainers will
in turn train fellow physicians and nurses. They were also
given special manuals in Arabic made to train paramedical staff.
We also have trainee doctors to deliver lectures on RHD
at secondary and tertiary hospitals around Khartoum and
distribute the manuals there. They are also gathering information on the level of knowledge of health professionals,
and they are nding that it is very low because there has
been no active program for RHD in the last 12 years.
Very recently, we sat with the director of Therapeutic
Medicine Department at the MOH, and we planned the
roll-out of the program to the remaining states: train-thetrainer workshops for 20 physicians in each state. After
that, we need an awareness campaign. We have made
some broadcasts here and there but not really a full
campaign.
Sudan Heart Institute has started a simple register
based on RHDnet [2]. We need someone to do data entry;
we physicians have collected about 400 cases so far, and
although the data are not complete, it is a start. Sometimes it is hard for us to be patient because we are
thinking only about RHD, and the MOH has many other
things to think about, but the ministry has really listened
and things are moving. We are making good progress!
Sulafa K. M. Ali, Khartoum, Sudan
Correspondence: S. K. M. Ali (sulafaali2000@gmail.com)
REFERENCES
1. Sudanese Childrens Heart Society. Available at: http://sudankidsheart.
com/en/index.html. Accessed September 3, 2013.
2. World Heart Federation. Available at: http://www.world-heart-federation.
org/what-we-do/rheumatic-heart-disease-network. Accessed September
3, 2013.

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September 2013: 285-286

Ofcial Journal of the World Heart Federation

WORLD HEART FEDERATION INTERNATIONAL HEADQUARTERS


World Heart Federation
7, Rue des Battoirs
Case Postale 155
1211 Geneva 4, Switzerland
Tel: (+41 22) 807 03 20
Fax: (+41 22) 807 03 39
admin@worldheart.org
www.worldheart.org
CHIEF EXECUTIVE OFFICER
Johanna Ralston
johanna.ralston@worldheart.org

WORLD HEART DAY MANAGER


Cynthia Haro
cynthia.haro@worldheart.org

CHIEF OPERATING OFFICER


Sarah Ramsey
sarah.ramsey@worldheart.org

CONGRESS MANAGER
Sabrina Adolf
sabrina.adolf@worldheart.org

CAMPAIGNS AND COMMUNICATIONS


MANAGER
Lna Hssig
lena.hassig@worldheart.org

MEMBERSHIP AND ACCOUNT


MANAGER
Emilie Russell
emilie.russell@worldheart.org

PROJECT MANAGER
Sanni Hiltunen
sanni.hiltunen@worldheart.org

CHIEF SCIENCE OFFICER


Kathryn Taubert
kathryn.taubert@worldheart.org

PROGRAMME MANAGER
Lucy Keightley

PROGRAMME ADVISOR
Judith Watt

STRATEGIC ADVISOR
Kathy Cahill
DEPUTY DIRECTOR, CORPORATE
RELATIONS
Alan Cole
alan.cole@worldheart.org
MANAGER OF DEMONSTRATION
PROJECTS
Alice Grainger-Gasser
alice.graingergasser@worldheart.org

CONGRESS AND OPERATIONS


COORDINATOR
Heidi Lake
heidi.lake@worldheart.org

WORLD HEART FEDERATION BOARD MEMBERS 2013


PRESIDENT
K. Srinath Reddy India

SECRETARY
Nooshin Bazargani UAE

CONTINENTAL REPRESENTATIVE, AHN


Habib Gamya Tunisia

VICE-PRESIDENT
Deborah Chen Jamaica

TREASURER
Pierre Poncet Switzerland

CONTINENTAL REPRESENTATIVE, PASCAR


Bongani Mayosi South Africa

PRESIDENT ELECT
Salim Yusuf Canada

CHIEF EXECUTIVE OFFICER


Johanna Ralston Switzerland

VICE-PRESIDENT ELECT
Kingsley K. Akinroye Nigeria

CONTINENTAL REPRESENTATIVE, APSC


Kui-Hian Sim Malaysia

PAST PRESIDENT
Sidney C. Smith Jr. USA
PAST VICE-PRESIDENT
Hans Stam Netherlands
CHAIR, SCIENTIFIC POLICY AND
ADVOCACY COMMITTEE
Ann Bolger USA

CONTINENTAL REPRESENTATIVE, APHN


Tony Duncan New Zealand
CONTINENTAL REPRESENTATIVE, ESC
Michel Komajda France
CONTINENTAL REPRESENTATIVE, EHN
Dan Gaita Romania

CONTINENTAL REPRESENTATIVE, IASC


Marcia Barbosa Brazil
CONTINENTAL REPRESENTATIVE, IAHF
Eduardo Morales Briceno Venezuela
AT-LARGE MEMBER
Dayi Hu China