European Journal of Heart Failure (2010) 12, 181185

doi:10.1093/eurjhf/hfp193

Rationale and design of the b-blocker in heart

failure with normal left ventricular ejection
fraction (b-PRESERVE) study
Jingmin Zhou, Haiming Shi, Jian Zhang, Yongxin Lu, Michael Fu, and Junbo Ge* for
the b-PRESERVE Study Investigators
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Disease, Shanghai, China

Received 12 August 2009; revised 19 October 2009; accepted 4 November 2009

Downloaded from http://eurjhf.oxfordjournals.org/ by guest on January 7, 2012

Aims Chronic heart failure with normal left ventricular ejection fraction (HFNEF) is not only common, but also carries a
high risk of substantial morbidity and mortality. However, few studies have been conducted in this population and no
proven treatment is available. Although b-blockers are evidence-based first-line therapy in systolic heart failure, they
have not been well studied in HFNEF.
.....................................................................................................................................................................................
Methods This study is a multicentre, prospective, randomized, open-label, blinded endpoint (PROBE) trial. A total of 1200
patients will be randomized to either b-blocker (metoprolol succinate) or control (n 600 per group). The
primary endpoint is a composite of hospitalization for heart failure and cardiovascular death. The secondary end-
points include cardiovascular death, heart failure mortality or hospitalization, all-cause mortality, change in
New York Heart Association class, change in left ventricular ejection fraction, increase in NT-proBNP (by 50%
of the value at randomization), b-blocker tolerance, and premature termination of b-blocker therapy due to
adverse events. The follow-up period is a minimum of 2 years.
.....................................................................................................................................................................................
Conclusion This study will provide important evidence, for the first time to our knowledge, of the long-term efficacy of b-blocker
therapy in the management of HFNEF.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords b-Blocker Chronic heart failure Left ventricular ejection fraction NT-proBNP

65% at 5 years.4,5 Thus, there is obviously an urgent need to

Introduction
Chronic heart failure (CHF) is a major and growing cause of cardi-
ovascular morbidity and mortality throughout the world, particu-
larly in the elderly. Epidemiological studies over the last decade
have shown that 40 55% of heart failure patients have a normal
ejection fraction, and are designated as heart failure with normal
left ventricular ejection fraction (HFNEF). The prevalence of
HFNEF is increasing, not only due to the growing number of
patients with hypertension and diabetes but also due to ageing
of the population worldwide.1 The occurrence of clinical events
increases markedly once patients are hospitalized for HFNEF.2 5
Up to a third of HFNEF patients may be re-admitted due to
CHF exacerbation within a year. Similarly, once hospitalized, the
mortality for HFNEF may be as high as 22 29% at 1 year and
develop effective treatment for patients with HFNEF.
To date, few clinical studies have been conducted in this specific
patient population and therefore there is no proven therapy avail-
able. The clinical management of such patients has been largely
empiric. At present, the mainstay of treatment for HFNEF is the
control of symptoms and management of underlying comorbidities
that predispose to the condition, including hypertension, diabetes,
ischaemia, and arrhythmias. Up to now, inhibitors of the renin
angiotensin system have probably been the most extensively
studied. However, no benefit on mortality has been definitively
demonstrated. CHARM-Preserved, which was part of the
CHARM (Candesartan in Heart Failure Assessment of Reduction
in Mortality and Morbidity) programme of studies, evaluated can-
desartan in patients with HFNEF, but failed to show a significant

* Corresponding author. Tel: 86 21 64041990, Fax: 86 21 64223006, Email: ge.junbo@zs-hospital.sh.cn or jbge@zs-hospital.sh.cn

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2010. For permissions please email: journals.permissions@oxfordjournals.org.
182 J. Zhou et al.

reduction in mortality although heart failure hospitalizations were needs to be further confirmed by prospective and randomized
significantly reduced.6 Similarly in PEP-CHF (Perindopril in clinical trials.15 The present study is, to our knowledge, the first
Elderly People with Chronic Heart Failure) which studied the effi- prospective and randomized trial to study the long-term efficacy
cacy of the ACE-inhibitor perindopril, there was no improvement of the b-blocker, metoprolol succinate, in patients with HFNEF.
in the primary outcome although there was a trend towards a
modest benefit for other endpoints.7 Recently, I-PRESERVE
(Irbesartan in Patients with Heart Failure and Preserved Ejection
Fraction) evaluated the effect of irbesartan in a total of 4128
Study design
patients aged 60 years or older with NYHA class IIIV heart Objectives
failure and an ejection fraction 45%. Over a mean follow-up
The objective of this trial is to study the long-term effects of
period of just over 4 years, there was no difference in the incidence
b-blocker treatment on morbidity and mortality in patients with
of the primary composite endpoint (all-cause mortality or cardio-
HFNEF.
vascular hospitalization) between treatment groups. Secondary
endpoints and subgroup analyses have also shown no benefit of
irbesartan over placebo in this patient group.8 Study population
b-Blocker treatment is a well established regimen for heart
Specific inclusion and exclusion criteria are listed in Tables 1 and 2.
failure patients with a depressed LVEF. However, it has not been
The definition of HFNEF is based on recently published guidelines
well studied in HFNEF despite the fact that several small studies
from the European Society of Cardiology.16 The most essential cri-

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and post hoc analyses in patients with HFNEF have shown promis-
ing results. In a prospective study investigating the effect of propra-
nolol vs. no propranolol on the incidence of total mortality and of
total mortality plus non-fatal myocardial infarction in 158 older
patients with CHF and a LVEF .40%, Aronow et al. 9 reported a
35% reduction in total mortality and a 37% decrease in total mor-
tality plus non-fatal myocardial infarction during 32 months of
follow-up. In another study, Nodari et al.10 compared the effects
of 6 months administration of atenolol or nebivolol on resting
and exercise haemodynamic parameters and maximal exercise
capacity in 26 patients with hypertension and LVEF .50%. Both
atenolol and nebivolol administration were associated with a sig-
nificant decrease in the resting and peak exercise heart rate and
blood pressure, but an increase in peak transmitral E/A wave vel-
ocities (E/A) ratio. This latter effect was greater with nebivolol.
Moreover, nebivolol showed a smaller reduction in the cardiac
index, a greater increase in the stroke volume index, and a
decline in the mean pulmonary artery pressure and pulmonary
wedge pressure, both at rest and peak exercise.10 Furthermore,
the Swedish Doppler-Echocardiographic study demonstrated an
increase in E/A ratio after 6 months administration of carvedilol,
suggesting an improvement in diastolic function.11 In the
SENIORS (Study of the Effects of Nebivolol Intervention on Out-
comes and Rehospitalizations in Seniors with HF) trial, 752 (35%)
of the patients had an LVEF .35%. The primary outcome was a
composite of death or cardiovascular hospitalization. In the
overall SENIORS study, nebivolol was associated with a modest
14% reduction in the primary endpoint. A similar magnitude of
reduction was noted in the subgroup with EF .35%. It is note-
worthy to mention that despite being labelled as patients with
HFNEF in SENIORS, this subgroup of patients with an EF .35%
consisted of patients with both preserved and reduced LVEF, and
the proportion of patients with an EF 50% was less than 15%
of all of the patients in the trial.12,13 Recently, a prospective obser-
vational study reported on the association between b-blocker pre-
scription at discharge and mortality in a cohort of patients with
advanced HF and preserved LVEF.14 Results from this study
strongly suggest that heart failure with preserved LVEF in the
elderly may benefit from b-blocker treatment.14 However, this
teria for HFNEF in this trial are: heart failure symptoms, elevated
NT-proBNP 1500 pg/mL, and LVEF 50%. In addition, age
.40 years and a recent hospitalization for heart failure, but not
within 3 months prior to enrolment, are required.
Design
This outpatient study is a multicentre, prospective, randomized,
open-label, blinded endpoint design (PROBE) (Figure 1). Patients
must be consistent with current symptoms of NYHA II or higher
within 3 months prior to enrolment and will be randomized to
either b-blocker or control in a ratio of 1:1. Other medications
(diuretics, angiotensin converting enzyme inhibitors or angiotensin
receptor blockers, long-acting nitrates, cardiac glycosides, or com-
binations of these medications) are not restricted and can be given
to the patients in both groups.
Ethical considerations
This study will be conducted in accordance with the principles
stated in the revised Declaration of Helsinki (2000, Scotland).
The Ethics Committee of Zhongshan Hospital of Fudan University,
PR China, approved this study and the study protocol was also sub-
mitted to the ethics committee of each participating hospital.
Written informed consent must be obtained from every subject
before entry into the study. Chinese Clinical Trial Register
number: ChiCTR-TNC-00000144.
Table 1 Key inclusion criteria
Male or female aged 40 years
Left ventricular ejection fraction (LVEF) 50%
Consistent with current symptoms of NYHA II or higher within
3 months prior to enrolment
NT-proBNP 1500 pg/mL
Health status suitable for outpatient follow-up
Written informed consent obtained
b-Blocker in HFNEF
Table 2 Key exclusion criteria
Sick sinus syndrome, second- or third-degree heart block without
permanent pacemaker in situ; uncontrolled decompensated CHF
(e.g. severe symptomatic hypotension, severe fluid retention,
requiring intravenous inotropes)
Acute coronary syndrome or acute myocardial infarction or stroke
within 1 month
Prescription of b-blocker within the last month or a history of a
life-threatening adverse event (AE) induced by a b-blocker
Any life-threatening non-cardiac disease or bad health status, e.g.
infection with HIV, malignant tumour, alcohol or drug abuse,
and severe liver disease or kidney disease (serum creatinine
.3.0 mg/dL)
Heart failure caused by the following diseases: restricted
cardiomyopathy, severe primary valvular heart diseases, pericardial
diseases, or systemic diseases (e.g. thyroid dysfunction, amyloidosis)
Have been accepted or plan to accept invasive cardiac therapy, e.g.
coronary artery bypass graft (CABG), percutaneous coronary
intervention (PCI), implantable cardioverter defibrillator (ICD)
implantation, cardiac transplantation
Women of reproductive age who do not use reliable contraceptive
methods
Severe anaemia (haemoglobin ,6.0 g/dL)
Asthma or unstable chronic obstructive pulmonary disease
Enrolled in another clinical study
Poor compliance
Figure 1 Study design.
Dosage of b-blocker
In the b-blocker arm, metoprolol succinate will be initiated at
12.5 mg once daily immediately after randomization and the dose
will be doubled every 2 weeks, to gradually achieve the target
dose of 200 mg/day or the maximum tolerated dose. Patients
will be maintained at the target dose or the maximum tolerated
dose until the end of the study. Blood pressure, heart rate, and
183
ECG will be monitored at rest during the follow-up period and
will be documented together with other vital parameters. The
drop out criteria concerning blood pressure and heart rate are
symptomatic systolic blood pressure ,100 mmHg, heart rate
,55 b.p.m. or both. Patients will be followed up in the heart
failure outpatient clinic at each centre every 48 weeks. Blood
sampling, ECG, and echocardiography will be performed every
12 months.
Study endpoints
The primary endpoint is a composite of cardiovascular death and
admission to hospital due to worsening HF. The secondary end-
points include cardiovascular death, heart failure mortality or hos-
pitalization, all-cause mortality, change in New York Heart
Association (NYHA) class, change in LVEF, increase in NT-proBNP
(by 50% of the value at randomization), b-blocker tolerance, and
the rate of premature termination of b-blocker therapy due to
adverse events (AEs). Any hospitalizations, unscheduled visits to
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clinic or the emergency room, changes in medication and AEs
will be recorded. Changes in left atrial diameter (LAD) and
NT-proBNP will also be recorded. Outcomes will be assessed
by the endpoint committee who are blinded to the allocated
group.
Sample size estimation
On the basis of the data from our pilot study and previous studies,
we estimated that a composite rate of hospitalization for CHF and
cardiovascular death will occur in 15% of patients with HEPEF at
2 years follow-up. The clinical trial was designed to prove that
the primary endpoint event rate in the b-blocker group was
about 10%. In order to have at least 80% power to detect a differ-
ence between the control and the b-blocker groups at a signifi-
cance level of 0.05, a total of 1080 patients (540 patients in each
group) will be necessary. Given a 10% loss to follow-up, 1200
patients are needed in this study.
Randomization and blinding
Central randomization will be conducted with SAS 8.2. Randomiz-
ation will be stratified by screening centres and enrolment date
intervals to ensure a similar sample constitution between two
groups and to improve comparability within the different date
intervals. The randomization will be blinded to the Data Manage-
ment & Statistical Analysis Centre but not to the primary investi-
gator (PI) of each centre.
Statistical analysis
An independent Data Management & Statistical Analysis Centre
will be responsible for the data management and statistical analysis.
The safety population is defined as all eligible patients who enter
the study and receive at least one dose of b-blocker. The
changes in physical signs and results of all examinations as well
as AEs will be used for the safety analysis. The analyses of
primary endpoints, secondary endpoints, and other endpoints
will be performed according to the intention to treat principle,
and with reference to the per-protocol analysis. Baseline charac-
teristics will be compared using one-way ANOVA or x2 test or
Fishers exact test. The primary outcome will be presented by
184
Kaplan Meier curves for the treatment group followed by the
stratified log-rank test using the stratification variables. Logistic
multivariable analysis will also be used to compare the endpoints
between two groups adjusting for other variables including sex,
age, major cardiovascular (CVD) risk factors, and screening
centres. For repeated measures data, the mixed effects model
will be used for quantitative data, and the generalized estimating
equations approach will be used for repeated measures categorical
data, to fit the logistic regression analysis. For missing data, last
observation carry forward will be used. Because the sample size
is assessed based on the primary endpoints, the rates of AE will
be mostly descriptively analysed. The hypothesis test will just be
used for exploratory study. For all tests, a P-value , 0.05 is con-
sidered statistically significant. Statistical analysis will be performed
using SAS version 8.0.
Study organization and administration
This is an investigator-initiated clinical trial and is solely organized
by the Department of Cardiology, Zhongshan Hospital of Fudan
University, Shanghai, PR China. The screening centres and PIs of
each centre are listed in the Appendix. The executive steering
committee will be responsible for overall supervision of the
study, policy decisions, protocol amendments, publications, and
presentations. Subcommittees of the executive committee
include (i) an independent central adjudication committee for adju-
dicating cause of death and cause of hospitalizations; and (ii) a data
and safety monitoring board responsible for monitoring the overall
conduct of this study, receiving and reviewing reports of serious
AEs, reviewing periodic reports of safety data, and establishing
stopping rules for the trial for safety reasons only.
Discussion
Heart failure with normal left ventricular ejection fraction constitu-
tes nearly half of all heart failure patients and is associated with high
morbidity and mortality. Epidemiological studies have shown that
the prevalence of HFNEF is growing and that it generally occurs
more often in the elderly, in women, and in those with hyperten-
sion or diabetes. Given the ageing of the population worldwide and
the growing prevalence of hypertension and diabetes, HFNEF is
becoming a growing public health problem, yet it is still an under-
studied area.
Large clinical trials in the HFNEF population including CHARM-
preserved, PEP-CHF, and I-PRESERVE6 8 have failed to show a
reduction in mortality. Up to now, b-blockers have not been
studied in large clinical trials. But available short-term trials and
observational studies have shown promising results.9 14
The present study represents a continuation of this effort and to
our knowledge is the first large multicentre randomized clinical
trial to assess the long-term efficacy of a b-blocker in HFNEF.
The primary objective of this study is to assess the effect of the
b-blocker metoprolol succinate on morbidity and mortality out-
comes. To improve the statistical power, a composite endpoint
(hospitalization for HF and cardiovascular death) will be adopted
as the primary endpoint. Other measures of cardiac performance
(LVEF, NYHA class, 6 min walk distance) will be used as secondary
endpoints. It is well known that patients with HFNEF mostly suffer
J. Zhou et al.
from ventricular diastolic dysfunction, which can lead to left atrial
enlargement (increased LAD) and thus the occurrence of atrial
fibrillation and increased NT-proBNP levels. Therefore, LAD,
atrial fibrillation, and NT-proBNP may also reflect the severity of
HF in patients with HFNEF. Several studies have shown that
these variables are independent predictors of prognosis in patients
with HFNEF. Consequently, these variables will also be included as
secondary endpoints.
Another important feature of this study is the requirement for
NT-proBNP measurements at enrolment. Although the cut-off
value for diagnosing acute heart failure set by recent guidelines is
above 2000 pg/mL, the value for diagnosing chronic and stable
HFNEF remains undetermined, so we are using a cut-off value of
1500 pg/mL. The requirement for NT-proBNP measurement in
the present study is unique compared with all other HFNEF
studies; it has been included to increase diagnostic accuracy for
HFNEF in view of the difficulties encountered in previous
HFNEF clinical trials and in our daily clinical practice. NT-proBNP
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will also be used during follow-up to provide prognostic
information.
In conclusion, HFNEF represents a large branch of CHF, yet
there is no proven effective treatment. This study, using
NT-proBNP measurement as a part of the enrolment criteria, is
designed to examine the long-term effect of metoprolol succinate
for reducing morbidity and mortality in HFNEF, in a multicentre
and randomized manner.
Funding
This study is supported by a grant from National Basic Research
Program in China. In addition, the metoprolol succinate is provided
by AstraZeneca China, and the NT-proBNP measurements are sup-
ported by Roche Diagnostics (Shanghai) Limited.
Conflict of interest: none declared.
Appendix
Study management team
Executive steering committee
Junbo Ge: Zhongshan Hospital of Fudan University, Shanghai;
Junren Zhu: Zhongshan Hospital of Fudan University, Shanghai;
Jian Zhang: Fuwai Hospital, Beijing; Yongxin Lu: Wuhan Union
Hospital, Wuhan; Michael Fu: Sahlgrenska University Hospital,
Goteborg, Sweden.
Data management and statistical analysis
centre
Xuejuan Jin, Hong Jiang: Shanghai Institute of Cardiovascular Dis-
eases, Shanghai.
Central laboratory
Yunzeng Zou: Shanghai Institute of Cardiovascular Diseases,
Shanghai.
b-Blocker in HFNEF
Independent central adjudication
committeem
Jingmin Zhou, Naisheng Cai: Zhongshan Hospital of Fudan University,
Shanghai; Yong Li: Huashan Hospital of Fudan University, Shanghai;
Fengru Zhang: Ruijin Hospital, Shanghai Jiaotong University,
Shanghai.
Data and safety monitoring board
Naisheng Cai: Zhongshan Hospital of Fudan University, Shanghai;
Yong Li: Huashan Hospital of Fudan University, Shanghai; Kefei
Dou: Fuwai Hospital of Chinese Academy of Medical Sciences
and Peking Union Medical College, Beijing; Yuhua Liao: Wuhan
Union Hospital, Wuhan; Zhiming Ge: Qilu Hospital of Shandong
University, Jinan.
Principal investigators at each screening
centre
Jingmin Zhou: Zhongshan Hospital of Fudan University, Shanghai;
Haiming Shi: Huashan Hospital of Fudan University, Shanghai; Jian
Zhang: Fuwai Hospital of Chinese Academy of Medical Sciences
and Peking Union Medical College, Beijing; Yongxin Lu: Wuhan
Union Hospital, Wuhan; Meng Wei: Shanghai Sixth Peoples Hos-
pital, Shanghai; Yun Zhang: Qilu Hospital of Shandong University,
Jinan; Lianglong Chen: Union Hospital of Fujian Medical University,
Fujian; Changsheng Ma: Beijing Anzhen Hospital of Capital Medical
University, Beijing; Xinchun Yang: Beijing Chaoyang Hospital of
Capital Medical University, Beijing; Jianhua Zhu: the 1st Affiliated
Hospital of Zhejiang University, Hangzhou; Mingzhong Zhao:
Shanghai Tongji Hospital of Tongji University, Shanghai; Yigang Li:
Xin-Hua Hospital affiliated to Shanghai Jiao Tong University,
Shanghai; Guoping Lu: Ruijin Hospital Affiliated to Shanghai
Jiaotong University, Shanghai; Ben He: Renji Hospital Affiliated to
Shanghai Jiaotong University, Shanghai; Guosheng Fu: Sir Run Run
Shaw Hospital of Zhejiang University, Hangzhou; Zhimin Du: the
First Affliated Hospital of Sun Yat Sen University, Guangzhou.
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