Review

European Heart Journal (2006) 27, 16511656

doi:10.1093/eurheartj/ehi841

Benets, challenges, and registerability of the polypill

Peter Sleight*, Hubert Pouleur, and Faiez Zannad
Cardiac Department, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK
Received 29 August 2005; revised 3 March 2006; accepted 9 March 2006; online publish-ahead-of-print 7 April 2006

KEYWORDS

Guidelines for the management of cardiovascular disease (CVD) stress the importance of treating global
risk, rather than individual risk, factors. Patients at high cardiovascular (CV) risk, for example, benet
from a combination of aspirin, antihypertensive agents, lipid-lowering drugs, and possibly folic acid. As
the number of medications that a patient requires increases, adherence and compliance to therapy are
likely to decrease. The use of affordable, multiple-target, xed-combination polypills, which concomitantly reduce multiple risk factors without increasing the pill burden or the risk of adverse effects,
has the potential to improve CV risk factor management, thereby reducing the incidence of CVD. This
review discusses the benets of the polypill and the challenges and requirements for its success and
registerability. Discussions with regulatory bodies are required in order to obtain some balance
between an overcautious registration approach and the potentially large public health benets that
are likely to arise from the use of polypills.

Introduction
Cardiovascular disease (CVD) is the most common cause of
death in Western countries and will continue to be so in
2020.1 A correlation has been demonstrated between CVD,
stroke, and renal failure and a number of modiable risk
factors, including hypertension,2 dyslipidaemia,35 platelet
function,6 and homocysteine levels,7,8 although the risks
associated with the latter now seem to be of less importance.9 As cardiovascular (CV) risk factors commonly
co-exist,10 high-risk patients with hypertension, obesity,
and diabetes may well benet from a combination of
aspirin, antihypertensive agents, lipid-lowering drugs, and
possibly folic acid. This led Professor Walds group to
propose a six-component polypill for the primary prevention
of CVD in everyone over the age of 55 years.1113 We support
the polypill concept, however, we suspect that both the
healthcare professionals and the public will need a long
period of education and consultation before this is accepted
and suggest that it might be better to rst target secondary
prevention. As the most suitable drug combination depends
on a patients characteristics and co-morbidities, it may also
be better to be less ambitious and consider a series of polypills comprising three or four components.
Although the expectation might be that patients who
receive numerous therapies for secondary prevention will
be at higher risk than those who receive fewer therapies,
unpublished results from the Maximal Individual Therapy in
Acute Myocardial Infarction (MITRA) registry14 (n 6067)
demonstrate that post-myocardial infarction (MI) survival
is signicantly improved in patients who receive four

* Corresponding author. Tel: 44 186 576 0564; fax: 44 186 576 8844.
E-mail address: peter.sleight@attglobal.net

medications [aspirin, beta-blocker, angiotensin-converting

enzyme (ACE) inhibitor, and statin] when compared with
those who receive zero, one, or two agents (unpublished
results) (Figure 1). Similarly, a survey carried out in French
hospitals demonstrated consistently better 1-year survival
rates in patients with acute MI (n 2320) receiving triplecombination therapy than in those receiving single medications, irrespective of whether the treatment comprised
antiplatelet, lipid-lowering, or antihypertensive agents
(Figure 2).15 Increasing the number of medications,
however, can have a negative impact on compliance and/
or adherence to therapy16,17 and, as a result, multipletarget, xed-combination pills are being developed, which
have the potential to alter the delivery of CV treatment.

The CV polypill
In their controversial article published in 2003, Wald and
Law18 proposed that a single daily pill combining half-doses
(to minimize toxicity) of a beta-blocker, thiazide diuretic,
and an ACE-inhibitor, together with a statin, folic acid,
and aspirin, and taken by everyone aged .55, could
reduce the incidence of CVD by over 80%. Furthermore,
the authors claimed that approximately one in three
people would gain an average of 1112 years of heart
attack- and/or stroke-free life. The objective of the polypill
was to improve four key CV risk factors simultaneously:
LDL-cholesterol, blood pressure (BP), serum homocysteine
levels, and platelet function. The proposed benets
are based on a series of meta-analyses, which suggest
that statin use lowers mean LDL-cholesterol levels by
1.8 mmol L21 (69.7 mg dL21), thereby decreasing the risk
of ischaemic heart disease (IHD) and stroke by 60 and
17%, respectively. Furthermore, half-doses of multiple

& The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on January 3, 2017

Cardiovascular disease;
Polypill;
Hypertension;
Dyslipidaemia;
Registration

1652

P. Sleight et al.

specialist physicians will, therefore, be required to

improve physician acceptance of the polypill.

Pharmaceutical/formulation issues

Figure 1 Post-MI survival in German hospitals is signicantly improved in

patients who receive four medications (aspirin, beta-blocker, ACE-inhibitor,
and statin) when compared with those who receive zero, one, or two
(P-logrank , 0.0001). (Unpublished results from the MITRA registry.14
Reproduced with kind permission from Dr Anselm Gitt, Herzzentrum
Luwigshafen, Kardiologie, Luwigshafen, Germany.)

Not all drugs are suitable for use in combination products.

Candidate agents should be safe, well tolerated, effective
in sub-maximal doses, and physicochemically compatible
with the other components of the pill. The potential for
drugdrug interactions that affect the bio-availability and/
or efcacy of the individual agents must also be considered.

Cost

Registration

Figure 2 In French hospitals, patients with acute MI treated with singletarget, triple-combination therapy had signicantly better 1-year survival
rates when compared with those receiving single medications.15 (Reproduced
with kind permission from Dr Nicolas Danchin, Department of Cardiology,
Hopital Europeen Georges Pompidou, Paris, France.)

antihypertensive drugs can signicantly lower BP with fewer

side effects than the full dose and can reduce the risk of IHD
by 46% and stroke by 63%. Importantly, Wald and Law estimated that adverse events would only warrant discontinuation of the pill in 12% of patients and that fatal side
effects would occur in less than one in 10 000 users.
Despite these ndings, the concept of multiple-target combination products has met with numerous challenges, and
their development is still in its infancy.

Challenges and requirements for success

The success of any new agent, including a xed-dose,
multiple-action combination pill, depends on several
factors, including the following.

Physician acceptability
Physicians like to have the exibility to titrate individual
agents and, as a result, are often hostile to the concept of
xed-dose combination pills. In practice, however, physicians often manage unresponsive patients by prescribing
an alternative agent rather than titrating the dose.
Considerable re-education of both primary care and

If a combination product comprises drugs that are already

available, evidence of its likely efcacy and safety can
largely be obtained from existing large-scale clinical trials
and meta-analyses. Although the regulatory authorities
will require, at the very least, a demonstration of pharmacodynamic/pharmacokinetic efcacy using surrogate markers,
they will hopefully not require hard endpoint data.
Large-scale morbidity and mortality trials would be both
prohibitively expensive and ethically challenging.

Patient acceptability
This partly depends on the ease with which a treatment can
be administeredthe number of pills, the dosing time
and interval, and whether the pill is easy to swallow and
can be taken with food and drinkand the occurrence of
side effects. In the case of Wald and Laws hypothetical
polypill, the inclusion of aspirin (the uncoated form of
which is associated with dyspepsia) has the potential to
cause side effects that might lead to treatment discontinuation and hence loss of benet from the other drugs.
Similarly, the inclusion of a beta-blocker can cause severe
side effects in patients with unrecognized (or forgotten)
bronchospasm or asthma. The use of beta-blockers in
elderly patients with hypertension (except for post-MI
patients) is now increasingly questioned because of
adverse effects on glucose metabolism as well as poorer
effectiveness when compared with newer antihypertensive
agents.19,20
Table 1 summarises the pros and cons of multiple-action,
xed combination medication.

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on January 3, 2017

The eventual costs of a polypill are likely to be much greater

than the simple addition of the generic components.
Although combining multiple generic drugs in a single packaging should, in theory, be cost-effective, the individual
agents are often substantially more expensive than might
be expected. Furthermore, the pharmaceutical costs of
development and registration will not be trivial, and as
each additional component can cause a logarithmic increase
in the workload required to prove the safety and efcacy of
a product, cost-effectiveness is likely to decrease as the
number of components increases. The predicted return on
investment might, therefore, be surprisingly small.

Benets, challenges, and registerability of the polypill

Table 1 Pros and cons of multiple-action, xed combination

medication

Regulatory guidelines for multiple-target,

xed-dose combination products
Before approving (registering) monotherapies, some believe
that the regulatory authorities, such as the American Food
and Drug Administration (FDA)21 and the European
Committee for Proprietary Medicinal Products (CPMP),22
will continue to require appropriately analysed data from
randomized, controlled clinical trials, which demonstrate
clear benet vs. placebo or another effective drug in
terms of quality and/or quantity of life. One hopes,
however, that this restrictive attitude will change. Once
approved, the authorities have little control over the
doses prescribed or whether a drug is taken alone or in combination with additional agents. In contrast, by registering a
xed-dose combination product, the regulatory authorities
are effectively advocating both the dose and the combination of two or more drugs. As a worse case scenario, for
such products to be approved, each active component
must contribute to the therapeutic effect of the combination product, e.g. the benets of specic doses of Drug
A plus Drug B must be greater than the effects of either
drug alone. In the case of a two-drug combination, a factorial trial testing ve doses per agent might require a
minimum sample size greater than 800. To complicate
matters further, the A plus B . A or B rule is only really

appropriate for xed-combination products, such as amlodipine besylate/benazapril hydrochloride (HCl), which have a
single therapeutic aim (reducing BP). The effects of combining agents with different therapeutic targets, such as lipid
and BP (atorvastatin/amlodipine, for example) or lipid and
platelet aggregation (pravastatin/aspirin), are harder to
assess unless wider endpoints, such as CV morbidity and/or
mortality, are used. One hopes, however, that the regulatory
authorities will be less demanding, as the cost of a complex
bio-equivalence study would effectively rule out the development of any polypill and, in any case, too many dose combinations would defeat the object of developing a simplied
combination therapy.
According to old guidelines from the FDA and CPMP,22,21
xed-combination products should not change medical practice simply because they are convenientthey must also
provide health benets. Three types of product labelling
are available according to whether a product is indicated
in rst-line therapy, second-line therapy, or as a convenience for patients who require simplied therapy.

First-line therapy
For a xed-combination product to be indicated in rst-line
therapy, a low-dose combination of Drugs A plus B must
be more effective than the respective high-dose monotherapies and have a similar side-effect prole or be similarly
effective but have fewer side effects. Examples are
amlodipine besylate/benazapril HCl and telmisartan/
hydrochlorothiazide.23,24

Second-line therapy
Fixed-combination products can be indicated in second-line
therapy in patients who fail to achieve a satisfactory
benet/risk ratio with monotherapy and require additional
agents or dose titration. In such cases, xed-dose combination products are recommended if one or more of the
components diminishes the dose-related side effects of
the other(s). For example, the ACE-inhibitor benazapril
reduces the incidence of ankle oedema in patients
treated with the third-generation calcium-channel blocker
amlodipine besylate.25

Convenience therapy
A xed-combination product can be indicated for convenience if it has the potential to simplify therapy by improving
the dosing strategy or pill burden. If a product achieves this
without providing additional health benets, the convenience claim should be restricted to non-prescription
(over-the-counter) products, which are fraught with problems. For example, the recent UK case of over-the-counter
licensing of a low dose of statin has been questioned in an
authoritative critique from the independent and highly
respected Drugs and Therapeutic Bulletin.26 Furthermore,
as reducing the pill burden has the potential to improve
compliance to therapy, it may be necessary for regulatory
authorities to relax their former guidelines and rethink
their current restrictions on product labelling.
The burden of proving the safety and efcacy of a combination product lies with the applicants rather than with the
regulatory authorities. Applicants must provide proof that
each product contains the appropriate drug ratios and

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on January 3, 2017

Pros
Growing general professional and healthcare support for the
polypill
Recognition that the individual titration of each component (as
in many guidelines) does not work on grounds of cost and/or
practicality
Costs are lower with generics
Easier patient compliance
Easier for elderly to understand dosing
Ensures that all the evidence-based medicines are given,
bypassing the likelihood that general practitioners will miss
one or more components
More widespread use
Potentially very large public health benets at affordable cost,
e.g. generic statins
Cons
Concerns that such a pill be too big to swallow
Problems with formulation, e.g. should the polypill include
aspirin?possible problems with enteric coating and, since
aspirin is likely to be the least-tolerated component,
benets of other well-tolerated components may be lost if
treatment is stopped due to dyspepsia (author favours giving
aspirin separately)
Need for testing of efcacy (probably on surrogatesBP/lipids/
platelets/C-reactive protein, but not major adverse cardiac
events)
Need for two (or more) sizes of the polypill for start- and
full-dose to get optimal effects with least side effects
Need for several polypills in order to cover different
patient proles, e.g. post-MI/hypertension/diabetes/chronic
heart failure, etc.
Need to educate regulatory bodies to be more exible in their
requirementsthe components have huge trial data already
Doses of the individual drugs in a polypill may be best for a
general population, but less optimal for an individual patient

1653

1654

Justication for xed-combination products

Justication for combining various active components in a
single pill must be based on valid therapeutic principles,
which take into account the potential advantages and disadvantages. The advantages of a combination product might
include simplication of therapy leading to improved
patient compliance and an improvement in the benet/
risk assessment due to the following.
(i) The addition or potentiation of a therapeutic benet,
i.e. a combination product is as effective as higher
doses of the individual components but has a better
safety prole or is more effective than a single substance with an acceptable safety prole.
(ii) An improvement in the side-effect prole of one drug
due to an interaction with another. This is only considered a valid benet, however, if the side effect
that is counteracted is serious or common and was
not created to discourage drug abuse. (The addition
of an antinausea agent to morphine, for example, is
unlikely to meet the approval of the regulatory
authorities.)
The degree of acceptance of xed-combination medications varies from country to country, with America and
Europe leading the eld, followed by countries such as
Canada and Australia, and then Japan. In the USA, numerous
single-target combination products have been approved, as
well as two mixed-target combination pills, atorvastatin/
amlodipine and pravastatin/aspirin. In contrast, the Japanese
regulatory authority will not, at present, consider applications for multiple-target combination pills and has yet to
approve many of the single-target combinations that are
registered in almost every other country. It is hoped,
however, that this attitude may change as a result of
current discussions.
Although it is agreed that most patients (even the simplest cases or those having only hypertension without any
other disease) require more than one drug, the implicit
notion that it is known, or has been demonstrated, that
having all of the medications in one pill have a measurable
effect on compliance and therefore would benet public
health is still a matter for debate.

A number of other challenges are still to be addressed.

The need for separate titration of individual ingredients
may be important in a number of situations. This may
require the design of pills of different strengths in order to
cover all of the possible doses of each of the titrated ingredients. Deciding on how many of such pills should be made
available is also an important challenge.

Discussion
It is estimated that 50% of all patients discontinue their
prescription medication within 1 year of initiation, and an
additional 35% discontinue their treatment after 2
years.27 Furthermore, because of poor adherence, 3050%
of prescriptions fail to produce the desired therapeutic
results in patients with chronic medical conditions.
Although it is generally accepted that reducing the pill
burden improves adherence and/or compliance to
therapy, very few data are available to support this
theory. This is largely because adherence and compliance
are difcult to quantify in normal clinical practice. Data
from clinical trials may not be applicable because of
improved monitoring and more compliant patients. In a retrospective cohort study evaluating 10 526 participants in a
US-managed care plan, patients receiving two or more
medications in addition to their BP- and lipid-lowering
agents were up to 45% less likely to adhere to their
therapy than those receiving zero to one additional medications (Figure 3).16 Similarly, a retrospective claims analysis using data from several managed-care organizations
during 19992000 demonstrated that the percentage of
patients adhering to concomitant BP- and lipid-lowering
therapies was signicantly less than the percentage adhering to either BP- or lipid-lowering therapy alone [32.9 vs.
54.7% (P , 0.005) and 42.0% (P , 0.005), respectively,
after 910 months].17 If future studies are able to demonstrate a signicant relationship between the simplication
of therapy and compliance, guidelines that currently
exclude convenience as sufcient justication for combination products may need to be revised. Many elderly
patients are confused and take their pills haphazardly
and/or in the wrong dosage. A polypill would be expected
to help this group of patients considerably.

Figure 3 Adherence to lipid- and BP-lowering therapy decreases as the

number of additional medications increases.16

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on January 3, 2017

minimal doses, that the product is safe and effective in a

signicant proportion of the target population, that the
benet/risk ratio is at least as good as that of the individual
agents, and pharmacodynamic and pharmacokinetic data to
assess drugdrug interactions. The applicant is also required
to assess any clinically benecial pharmacokinetic interactions in healthy subjects, patients, and high-risk subgroups (such as the elderly and those with diabetes and/or
renal disease). Thus, although drugdrug interactions are a
major concern for the development of combination products, thorough assessments have the potential to improve
the safety of these medications when compared with
more traditional single therapies, which are often used in
combinations that have not been formally tested.
For products that combine established drugs, often used
concomitantly (such as antihypertensive agents and statins),
well-founded bibliographic data can be used to provide a
rationale for the proposed doses, thereby minimizing the
number of new studies that must be carried out.

P. Sleight et al.

Benets, challenges, and registerability of the polypill

Conclusions
Guidelines for the management of CVD stress the importance of treating global risk, rather than individual risk,
factors.3234 Patients at high CV risk, for example, benet
from a combination of aspirin, antihypertensive, and
lipid-lowering agents.35,36 As the number of medications
increases, however, adherence and compliance to therapy
are likely to decrease.16,17 The use of multiple-target, xedcombination products, such as atorvastatin/amlodipine and
aspirin/pravastatin, which concomitantly reduce multiple
risk factors without increasing the pill burden or the risk
of adverse effects, has the potential to improve CV risk
factor management, thereby reducing the incidence of
CVD. Discussions with regulatory bodies are required in
order to obtain some balance between an overcautious
registration approach and the potentially large public
health benets that would arise from affordable combinations of well-proven therapies.

Acknowledgements
This manuscript is based on discussions at the 7th Cardiovascular
Clinical Trialists (CVCT) Workshop, Versailles, December 2004. This
workshop is organized annually by the Clinical Investigation
Center (CIC, INSERM-CHU) of Nancy, France, in collaboration with
the ESC Working Group on Cardiovascular Pharmacology and Drug
Therapy, the American College of Cardiology Foundation, and the
National Heart, Lung, and Blood Institute (NHLBI) of the National
Institutes of Health (NIH). The participants were E. Abadie,
C. Bernaud, J.S. Borer, A. Castaigne, L. Cloarec-Blanchard,
R. Collins, J. Cutler, G. Dagenais, B. Dahlo
f, N. Danchin, L. Fisher,
L. Friedman, N. Geller, M. Ghadanfar, C. Grines, S. Haffner, V.
Jamieson, D. Julian, S.E. Kjeldsen, M.A. Konstam, S. Kupfer,
M. Lievre, R. Lipicky, R.V. Luepker, A.P. Maggioni, P. Maillere, A.
Nathwani, E. Neuhart, C. OConnor, B. Pitt, S. Pocock, P. Poole
Wilson, H.P., M. Pressler, B. Roniker, L. Ruilope, F. Senatore,
P. Serruys, P.S., P.G. Steg, N. Stockbridge, K. Thygesen, D.
Throckmorton, H. Wedel, J. Wittes, F.Z., and B. Zuckerman together
with the authors.
Conict of interest: P.S. has received grant support for trials: ISIS
1-4, HPS, SEARCH, HOPE, ONTARGET/TRANSCEND from BHF, UK
MRC, Can. MRC, Ontario Heart & Stroke Foundation, AstraZeneca,
sano-aventis, Aventis, Boehringer-Ingelheim, BMS, GSK, Monarch,
MSD, Nat. Vit. E association, Roche, and has received speaker/
DSMB fees from Abbott, AstraZeneca, Aventis, Bayer, BoehringerIngelheim, Boehringer Mannheim, BMS, Genentech, GSK, Knoll,
Menarini, Merck, Monarch, MSD, Novartis, Organon, Pzer,
Pharmacia, Sano, Schering, Servier. H.B. is an employee of Pzer
Inc. F.Z. has received a grant for his group from Guidant, Novartis,
Pzer and Servier, and he also gives lectures and consults for
these companies.

References
1. Ezzati M, Hoorn SV, Rodgers A, Lopez AD, Mathers CD, Murray CJ.
Estimates of global and regional potential health gains from reducing
multiple major risk factors. Lancet 2003;362:271280.
2. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specic relevance of usual blood pressure to vascular mortality: a meta-analysis
of individual data for one million adults in 61 prospective studies.
Lancet 2002;360:19031913.
3. Randomised trial of cholesterol lowering in 4444 patients with coronary
heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet
1994;344:13831389.
4. 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;285:24862497.
5. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin
in 20,536 high-risk individuals: a randomised placebo-controlled trial.
Lancet 2002;360:722.
6. Collaborative meta-analysis of randomised trials of antiplatelet therapy
for prevention of death, myocardial infarction, and stroke in high-risk
patients. BMJ 2002;324:7186.
7. Eikelboom JW, Lonn E, Genest J Jr, Hankey G, Yusuf S. Homocyst(e)ine
and cardiovascular disease: a critical review of the epidemiologic
evidence. Ann Intern Med 1999;131:363375.
8. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease:
evidence on causality from a meta-analysis. BMJ 2002;325:12021209.
9. Clarke R, Daly L, Robinson K, Naughton E, Cahalane S, Fowler B,
Graham I. Hyperhomocysteinemia: an independent risk factor for
vascular disease. N Engl J Med 1991;324:11491155.
10. Wilson PW, Kannel WB, Silbershatz H, DAgostino RB. Clustering of metabolic factors and coronary heart disease. Arch Intern Med
1999;159:11041109.
11. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more
than 80%. BMJ 2003;326:14191428.
12. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination
treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ 2003;326:14271434.

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on January 3, 2017

In addition to reducing the pill burden, combination products have the potential to improve compliance by allowing
some patients to achieve their therapeutic goals more
quickly than they might with monotherapy. This is especially
important in patients with asymptomatic conditions, such as
hypertension and dyslipidaemia, who may be tempted to
discontinue their medication unless a measurable benet
is achieved within the rst few months of treatment.
Furthermore, the recent Valsartan Antihypertensive LongTerm Use Evaluation trial demonstrated a signicant CV
benet of more rapid BP control.28
Multiple-target combination products can also improve CV
risk management by encouraging physicians to treat global
risk, rather than individual risk, factors. This is essential
because CV risk factors, such as hypertension and dyslipidaemia, frequently co-exist and interact in a multiplicative,
rather than additive, manner.29 On the basis of this knowledge, many large-scale CV outcome trials, such as the
Antihypertensive and Lipid-Lowering treatment to prevent
Heart Attack TrialLipid-Lowering Arm30 (n 10 355) and
the Anglo-Scandinavian Cardiac Outcomes TrialLipidLowering Arm31 (n 10 305), have included both antihypertensive agents and statins. Although some argue that
additional studies are required to determine the optimal
dose combination and the exact indications for each
product, others believe that existing large-scale clinical
trials are sufcient proof of safety and efcacy and that
the development of combination pills should focus on drug
delivery and packaging.
In terms of safety, potential risks are associated with
hiding active components in a single pill. If the name of
the combination product does not reect its active components, users may not be aware which drugs they are
taking. As a result, they are less likely to inform their physician or pharmacist of their current medication(s) and are
more likely to take additional agents that interact
with their combination drug and lead to adverse effects.
The hidden inclusion of beta-blockers in a combination
product, for example, may be of concern for any patient
with bronchospasm. Thus, detailed product labelling is
essential to ensure that all patients are adequately informed
about their combination products.

1655

1656

27. Sasich LD, Wolfe SM, Pearson C, Swankin DA, Levin AA, Beard J. The
National Council on Patient Information and Education. JAMA
1997;278:14911492.
28. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T,
Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B, Zanchetti A,
VALUE Trial Group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the
VALUE randomised trial. Lancet 2004;363:20222031.
29. Wilson PW, Kannel WB, Silbershatz H, DAgostino RB. Clustering of metabolic factors and coronary heart disease. Arch Intern Med
1999;159:11041109.
30. ALLHAT Ofcers and Coordinators for the ALLHAT Collaborative Research
Group. The Antihypertensive and Lipid-lowering Treatment to Prevent
Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel
blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment
to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:29812997.
31. Sever PS, Dahlo
f B, Poulter NR, Wedel H, Beevers G, Cauleld M, Collins R,
Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, OBrien E,
Ostergren J, ASCOT Investigators. Prevention of coronary and stroke
events with atorvastatin in hypertensive patients who have average
or lower-than-average cholesterol concentrations, in the AngloScandinavian Cardiac Outcomes TrialLipid Lowering Arm (ASCOT-LLA):
a multicentre randomised controlled trial. Lancet 2003;361:11491158.
32. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr,
Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ, National
Heart, Lung and Blood Institute, Joint Committee on Prevention,
Detection, Evaluation and Treatment of High Blood Pressure, National
High Blood Pressure Education Programme Coordinating. The Seventh
Report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.
JAMA 2003;289:25602572.
33. Whitworth JA. 2003 World Health Organization (WHO)/International
Society of Hypertension (ISH) statement on management of hypertension.
J Hypertens 2003;21:19831992.
34. 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;285:24862497.
35. Frilling B, Schiele R, Gitt AK, Zahn R, Schneider S, Glunz HG, Gieseler U,
Jagodzinski E, Senges J, Maximal Individual Therapy in Acute Myocardial
Infarction Study Group. Too little aspirin for secondary prevention after
acute myocardial infarction in patients at high risk for cardiovascular
events: results from the MITRA study. Am Heart J 2004;148:306311.
36. Hanania G, Cambou JP, Gueret P, Vaur L, Blanchard D, Lablanche JM,
Boutalbi Y, Humbert R, Clerson P, Genes N, Danchin N, USIC 2000
Investigators. Management and in-hospital outcome of patients with
acute myocardial infarction admitted to intensive care units at the
turn of the century: results from the French nationwide USIC 2000 registry. Heart 2004;90:14041410.

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on January 3, 2017

13. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low
density lipoprotein cholesterol, ischaemic heart disease, and stroke:
systematic review and meta-analysis. BMJ 2003;326:14231430.
14. Schuster S, Koch A, Burczyk U, Schiele R, Wagner S, Zahn R, Glunz HG,
Heinrich F, Stuby K, Berg G, Voigtlander T, Gieseler U, Jakob M,
Hauptmann P, Senges J. Early treatment of acute myocardial infarct:
implementation of therapy guidelines in routine clinical practice,
MITRA pilot phase. Z Kardiol 1997;86:273283.
15. Danchin N, Cambou JP, Hanania G, Kadri Z, Genes N, Lablanche JM,
Blanchard D, Vaur L, Clerson P, Gueret P; USIC 2000 Investigators.
Impact of combined secondary prevention therapy after myocardial
infarction: data from a nationwide French registry. Am Heart J
2005;150:11471153.
16. Chapman RH, Benner JS, Petrilla AA, Tierce JC. Adherence with concomitant antihypertensive and lipid-lowering therapy. Circulation 2003;
108:IV-757.
17. Schwartz JS, McLaughlin T, Grifs D, Arnold A, Pettitt D. Adherence to
chronic therapy among patients treated for hypertension, dyslipidemia,
or both. J Am Coll Cardiol 2003;41:526.
18. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more
than 80%. BMJ 2003;326:14191428.
19. Williams B, Poulter NR, Brown MJ, Davis M, McInnes GT, Potter JF,
Sever PS, Thom SM, BHS Guidelines Working Party, for the British
Hypertension Society. British Hypertension Society guidelines for hypertension management 2004 (BHS-IV): summary. BMJ 2004;328:634640.
20. Poulter NR, Wedel H, Dahlo
f B, Sever PS, Beevers DG, Cauleld M,
Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, OBrien E,
Ostergren J, Pocock S, ASCOT Investigators. Role of blood pressure and
other variables in the differential cardiovascular event rates noted in
the Anglo-Scandinavian Cardiac Outcomes TrialBlood Pressure
Lowering Arm (ASCOT-BPLA). Lancet 2005;366:907913.
21. Food and Drug Administration (FDA). Guidance for industry and FDA current
good manufacturing practice for combination products. http://www.
fda.gov/cder/guidance/OCLove1dft.htm# _ftn2 (20 March 2006).
22. Committee for Proprietary Medicinal Products (CPMP). Note for guidance
on xed-combination medicinal products. http://www.emea.eu.int/pdfs/
human/ewp/024095en.pdf#search5note%20for%20guidance%20on%
20xed%20combination%20medicinal%20products (20 March 2006).
23. Lacourciere Y, Martin K. Comparison of a xed-dose combination of 40 mg
telmisartan plus 12.5 mg hydrochlorothiazide with 40 mg telmisartan
in the control of mild to moderate hypertension. Am J Ther
2002;9:111117.
24. Giles TD. Rationale for combination therapy as initial treatment for
hypertension. J Clin Hypertens 2003;5:411.
25. Fogari R, Malamani GD, Zoppi A, Mugellini A, Rinaldi A, Vanasia A, Preti P.
Effect of benazepril addition to amlodipine on ankle oedema and subcutaneous tissue pressure in hypertensive patients. J Hum Hypertens
2003;17:207212.
26. Simvastatin over-the-counter. Drug Ther Bull 2005;43:2528.

P. Sleight et al.