Review

Continuing Medical EducationNature Clinical Practice Cardiovascular Medicine (2009) 6, 101-110
doi:10.1038/ncpcardio1419  
Received 15 May 2008 | Accepted 23 October 2008 | Published online: 23 December 2008

Fixed-dose combination therapy and secondary cardiovascular prevention: rationale, selection of drugs and target population

Ginés Sanz* and Valentin Fuster  About the authors

Correspondence *Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernández Almagro 3, 28029 Madrid, Spain

Email
 gsanz@cnic.es

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Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit. Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide CME for physicians. Medscape, LLC designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To receive credit, please complete the post-test.

Learning objectives

Upon completion of this activity, participants should be able to:

  1. Describe the global burden of cardiovascular disease.
  2. Review the reasons for and the impact of nonadherence to medications for secondary prevention.
  3. Discuss how the use of a polypill could overcome existing limitations to secondary cardiovascular prevention.
  4. Identify outstanding issues that may affect the development and subsequent use of a polypill for secondary cardiovascular prevention.

Competing interests

The authors, the Journal Editor B Mearns and the CME questions authors A Del Negro and D Lie declared no competing interests.

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Summary

Ischemic heart disease and stroke are the leading causes of death worldwide. A large proportion of individuals at high 10-year risk of a cardiovascular event live in low-income and middle-income countries, and the large majority of all cardiovascular events occur in developing countries. A large amount of evidence supports the use of pharmacological treatment for the prevention of cardiovascular death in this population, including antiplatelet drugs, beta blockers, lipid-lowering agents and angiotensin-converting-enzyme inhibitors. However, the efficacy of cardiovascular prevention is hampered by several problems, including inadequate prescription of medication, poor adherence to treatment, limited availability of medications and unaffordable cost of treatment. Here we examine the use of fixed-dose combination therapy (a 'polypill'), and how this therapy could improve adherence to treatment, reduce the cost and improve treatment affordability in low-income countries.

Review criteria

The MEDLINE and PubMed databases were searched for original articles and reviews published between 1999 and 2008 that focused on fixed-dose combination therapy and cardiovascular secondary prevention. The search terms used were "polypill", "cardiovascular prevention", "fixed-dose combinations" and "adherence". All papers included were either English-language or Spanish-language, and all were full-text papers. We also searched the reference lists of identified articles for further papers. Books on treatment adherence and relevant WHO reports were also used.

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Introduction

In 2005, cardiovascular diseases caused 17.5 million deaths worldwide, which is 3.3 times more than AIDS, tuberculosis and malaria combined. In Europe, cardiovascular disease is the major cause of premature death in adults,1, 2 and data from the US show that in 2004, 869,700 people died as a result of cardiovascular and cerebrovascular diseases.3

The problem is even worse in low-income and middle-income countries; four-fifths of all cardiovascular-related events occur in these parts of the world.4 In addition, the global burden of cardiovascular disease is increasing steadily. Although cardiovascular-related mortality in high-income countries is projected to increase from 5 million in 2000 to 6 million in 2020, the corresponding figures for low-income and middle-income countries are set to rise from 10 million to a staggering 19 million.4, 5 Furthermore, a large proportion of deaths occur in the working-age population, particularly in developing countries.6, 7 However, even in countries in which cardiovascular mortality is declining, such as the US, the economic burden is increasing as the number of individuals living with these diseases increases, as reflected by the number of annual hospital discharges.8

Coronary heart disease accounts for a large proportion of cardiovascular deaths worldwide. As this condition is multifactorial, successful reduction of the huge effect it has on global health and the global economy requires effective control of risk factors and the appropriate use of medication. To date, unfortunately, most secondary prevention programs have shown only modest results. Research in this field and the development of new approaches to cope with the cardiovascular epidemic is, therefore, mandatory. The purpose of this Review is to discuss the problems faced by prevention of adverse cardiovascular events in clinical practice, and provide evidence for the need for fixed-dose combination drugs or 'polypills' in this setting. We feel that fixed-dose combination drugs will improve adherence, reduce costs and improve treatment affordability in low-income countries. Here we focus in particular on secondary prevention in the context of ischemic heart disease.

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Secondary prevention of ischemic heart disease

Conventional or traditional risk factors account for a large proportion of the population-attributable risk of ischemic heart disease. The INTERHEART study included more than 15,000 patients who had previously suffered an acute myocardial infarction from 52 countries, representative of all continents, and showed that the following nine risk factors account for 90% of population-attributable risk in men and 94% in women: smoking, hypertension, diabetes mellitus, obesity, dietary patterns, physical activity, consumption of alcohol, blood apolipoprotein levels and psychosocial factors. Despite some variations in the incidence of these risk factors in different geographic regions, their effect was consistent in both men and women, across different regions and ethnic groups. The correlation between these risk factors and events was even more striking in young people, which suggests that most premature myocardial infarctions are preventable (Figure 1).9

Figure 1 Distribution of cardiovascular events according to the number of risk factors in the INTERHEART study.9
Figure 1 : Distribution of cardiovascular events according to the number of risk factors in the INTERHEART study. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

 

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The reduction in cardiovascular mortality achieved in the US and other developed countries during the last decades underlines the importance of secondary prevention measures. Similar conclusions were made after analysis of the database of the Health Professionals Follow-up study. Chiuve et al.10 concluded that "62% of all coronary events may have been avoided had all men adhered to a low-risk lifestyle of not smoking, exercising regularly, eating prudently, consuming alcohol in moderation, and maintaining a healthy weight".

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Pharmacological therapy for secondary prevention

Lifestyle changes are undoubtedly important; however, in some high-risk individuals considerable residual risk remains. In addition to lifestyle changes, a large body of evidence supports the use of pharmacological treatment for the prevention of death in high-risk patients. Investigations suggest that approximately half of the reduction in cardiovascular mortality seen during the last few decades in the US and other developed countries could be attributable to medical therapy.11, 12 However, several problems hamper the use of medication for cardiovascular prevention, and the use of fixed-dose combination drugs has been proposed to improve therapy.

Problems with secondary prevention: rationale behind fixed-dose combination therapy

Although secondary prevention measures are a key component of any public-health strategy to reduce the burden of cardiovascular disease, a large proportion of potential candidates do not receive adequate treatment. Three crucial reasons for this treatment gap have been identified, most of which can be tackled by fixed-dose combination therapy: inadequate prescription of medication, poor adherence to treatment, and unaffordable cost of medication.

Prescription of medication

The problem of insufficient treatment in patients who have suffered a myocardial infarction has been documented by numerous registries and studies in different countries. For example, the European Action on Secondary Prevention through Intervention to Reduce Events (EUROASPIRE) II survey included patients from nine European countries, and demonstrated that the prevalence of smoking, obesity and uncontrolled blood pressure among patients with coronary artery disease was 20%, 33% and 53.9%, respectively.13 In addition, the use of angiotensin-converting-enzyme (ACE) inhibitors and statins was less than expected in this population—43% and 57.7%, respectively.13 Similar results have been observed in the EUROASPIRE III study,14 as well as the Global Registry of Acute Coronary Events (GRACE)15 and the Proyecto de Registro de Infarto Agudo de Miocardio Hospitalario (PRIAMHO) registries.16 Government-driven initiatives to improve prescribing practices have been launched in some European countries; in the UK, for example, GPs are paid for preventive efforts, and in Spain the government carries out periodic evaluation of prescriptions for the secondary prevention of cardiovascular disease in primary care.

The WHO study on Prevention of Recurrences of Myocardial Infarction and Stroke (WHO-PREMISE) has documented an even worse situation for secondary prevention in low-income and middle-income countries.17 In this cross-sectional survey of 10,000 patients with cardiovascular disease, the percentage of those with coronary heart disease who received beta blockers was 48.1%, ACE inhibitors 39.8% and statins only 20.8%.

Adherence

The efficacy of cardiovascular drugs in secondary prevention is also limited by poor adherence to treatment.18 Several studies have shown that compliance to treatment in chronic conditions approaches only 50%.19 However, poor adherence is frequently under-recognized as it is not often directly assessed by physicians.20 In 2008, a report indicated that 40% of the almost 45 million patients treated for hypertension in the US did not adhere to treatment, and a similar proportion was observed for those treated with lipid-lowering agents.21

Poor compliance to medication is related to sociodemographic, psychological, economic and clinical factors. Advanced age, psychiatric disorders and complexity of treatment have been repeatedly identified as predictors of poor compliance, which clearly correlates with the number of pills a patient needs to take daily.20 In this regard, taking only one tablet each day could improve adherence (see below).

Withdrawal of secondary prevention treatment translates into increased morbidity and mortality, and is associated with a large economic burden. Bosworth suggested that a lack of adherence to therapy is responsible for almost 10% of all hospital admissions.20 Mukherjee et al.22 analyzed a series of 1,358 patients discharged from hospital after an acute coronary syndrome. Use of a combination of evidence-based medical therapies was independently and strongly associated with reduced 6-month mortality. This study group also observed that the use of adequate evidence-based pharmacological and nonpharmacological measures resulted in a reduced incidence of death, myocardial infarction and stroke in a smaller series of patients with peripheral vascular disease.23 Similar results were observed in a French registry that included 2,119 patients who had suffered a myocardial infarction; 1-year survival was 97% in patients who received aspirin, beta blockers and statins, compared with 88% in those who received none, one or two of these medications.24

Ho and coworkers25 analyzed the effect of medication discontinuation on mortality after a myocardial infarction in a series of 1,521 patients. Multivariable survival analysis found that discontinuation of secondary prevention therapy was independently associated with increased 1-year mortality (hazard ratio 3.81, 95% CI 1.88–7.72). Furthermore, Rasmussen et al.26 observed that adherence to statins and beta blockers correlated positively with survival; this effect could not be demonstrated with calcium-channel blockers, which is a drug class that has no definitive proven survival advantages in patients who have suffered a myocardial infarction.

Cost of secondary prevention and affordability in low-income countries

Secondary cardiovascular prevention that uses evidence-based therapies is cost-effective. Economists have estimated that the years of productivity gained through the prevention and treatment of cardiovascular diseases contributed US$1.5 trillion to the US economy each year from 1970 to 1990. As Mary Lasker pointed out, "if you think research is expensive, try disease".27

Franco et al.28 have suggested that to be cost-effective in terms of secondary prevention, the annual cost of a polypill should be no more than euro dollar400. Gaziano et al.29 analyzed the cost-effectiveness of a four-drug regimen for secondary cardiovascular prevention in several emerging countries. Incremental cost-effectiveness ratios per quality-adjusted life-year in secondary prevention were less than $400. As the WHO considers interventions to be cost-effective if this ratio is less than three times the gross national income per head, the authors concluded that a regimen containing aspirin, two antihypertensive drugs and one statin is cost-effective in the regions listed in Table 1.

Table 1 Cost-effectiveness analysis of cardiovascular disease prevention with a multidrug regimen.
Table 1 - Cost-effectiveness analysis of cardiovascular disease prevention with a multidrug regimen.
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The fact that secondary prevention medication is cost-effective does not, however, ensure affordability in middle-income and low-income countries. Figure 2, taken from a report by Mendis et al. in the WHO bulletin, nicely illustrates this point.30 Affordability, defined as the number of days' wages required for the lowest-paid government worker to purchase a 1-month supply of a generic, four-drug, secondary prevention regimen varied among low-income and middle-income countries, and reached 18 days in some. In addition, out-of-pocket expenditure on health is much higher in less developed countries than in developed nations.30

Figure 2 Affordability measured as the number of days' wages required for the lowest-paid government worker to purchase a 1-month supply of standard preventive medication for coronary heart disease in selected low-income and middle-income countries.
Figure 2 : Affordability measured as the number of days' wages required for the lowest-paid government worker to purchase a 1-month supply of standard preventive medication for coronary heart disease in selected low-income and middle-income countries. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

The standard medication includes generic equivalents for a daily combination of 100 mg aspirin, 100 mg atenolol, 10 mg angiotensin-converting-enzyme inhibitor and 20 mg statin. This Figure was adapted from Mendis S et al. (2007) Bull World Health Organ 85: 279–288, which is published under an open-access license by the World Health Organization.30

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Fixed-dose combination drugs for secondary prevention

The use of fixed-dose combination therapy, in the form of a polypill, for cardiovascular prevention was first proposed by Wald and Law in 2000.31 These authors developed the concept in a seminal paper published in 2003, which claimed that a polypill comprising six components and administered to each individual older than 55 years would reduce the incidence of cardiovascular disease by more than 80%.32 Since then, controversy has surrounded the true value of this idea.33, 34, 35, 36, 37 The potential benefits and drawbacks of this type of combined therapy were summarized in a review by Sleight and colleagues33 published in 2006. They concluded that the polypill has the potential to improve the management of cardiovascular risk factors. Detractors of the polypill argue that the estimated risk reduction could be too optimistic, that many patients will remain undertreated and that patients' and doctors' acceptability will be less than expected. An additional source of concern is the potential adverse effects related to some of the cardiovascular polypill components, such as aspirin (gastrointestinal complications) and ACE inhibitors (cough). Adverse effects from one or more of these drugs could lead to discontinuation of treatment and, therefore, the loss of benefit of all other drugs included in the formulation. Furthermore, the need for the efficacy of the polypill in primary prevention to be proven in adequate, large, randomized trials before it can be accepted in clinical practice has been repeatedly argued.

Despite criticism, the potential value of applying the polypill concept for secondary prevention has been recognized by different expert panels, including the WHO and the Combination Pharmacotherapy and Public Health Research Working Group. Research in this area is seen by these panels as an important breakthrough.4, 34, 35

Although the polypill concept has not been proved in cardiovascular secondary prevention, the efficacy of fixed-dose combination therapy has been demonstrated in populations of patients with other conditions such as AIDS, tuberculosis and hypertension. In this regard, a meta-analysis published in 2007 by Bengalore et al.38 of four hypertension trials showed that fixed-dose combination therapy decreased the risk of medication noncompliance by 24% compared with conventional treatment (relative risk 0.76, 95% CI 0.71–0.81, P <0.0001; Figure 3). Furthermore, two retrospective analyses have also shown a 29% improvement in treatment adherence with a fixed-dose combination drug in patients with hypertension39 and 13% in those with diabetes.40

Figure 3 Effect of fixed-dose combinations on treatment adherence in patients with hypertension.
Figure 3 : Effect of fixed-dose combinations on treatment adherence in patients with hypertension. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

Permission obtained from Elsevier Ltd © Bangalore S et al. (2007) Am J Med 120: 713–719.38

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In addition to improving patients' adherence to treatment, the polypill could offer advantages such as reduced cost, ease of use for the elderly and easier prescription by general practitioners. However, as pointed out in the Second World Health Organization and Wellcome Trust Workshop on Secondary Prevention of Cardiovascular Disease in Low and Middle Income Countries, direct proof of the polypill effect on treatment adherence is still lacking in patients at high risk of myocardial infarction and coronary heart disease.

Fixed-dose combination therapy: selection of drugs

The pharmaceutical development of a cardiovascular polypill presents several unique challenges, including the selection of components and doses, the type of pharmaceutical formulation and regulatory problems. From a formulation development standpoint, an almost linear relationship exists between the number of active components in a polypill and the technical problems of formulation development. The association of different drugs in a single pharmaceutical dosage form may have an effect on the physicochemical properties of each and every individual component. In fact, an increase in the number of active components in a polypill also increases the likelihood of interactions between them (as discussed in an accompanying Review by Guglietta and Guerrero in Nature Clinical Practice Cardiovascular Medicine). In addition, if the drug is too specific, owing to inclusion of many components, key subgroups of patients might be excluded. The selected fixed-dose combination pill should, therefore, balance galenic difficulties and therapeutic usefulness. Aspirin, statins, ACE inhibitors and beta blockers are routinely administered in all patients recovering from an acute myocardial infarction who do not have contraindications to these drugs. These agents should, therefore, be considered as potential components for a fixed-dose combination pill designed for secondary cardiovascular prevention.

Antiplatelet agents

Aspirin is a key component of cardiovascular prevention and should be included in any fixed-dose combination pill designed for secondary prevention therapy. Figure 4 displays data from the well-known meta-analysis performed by the Antithrombotic Trialists' Collaboration group. The graphic shows the effect of antiplatelet treatment in patients after a myocardial infarction. Antiplatelet treatment significantly reduced the incidence of any new events. For every 1,000 patients treated with an antiplatelet medication, 18 nonfatal reinfarctions, 5 nonfatal strokes and 14 vascular deaths are prevented.41 Data from the same study also confirmed the absence of significant differences in efficacy between high versus low doses of aspirin; the vascular event rates were 14.1% and 14.5% for 500–1500 mg aspirin and 75–325 mg aspirin, respectively. At the present time, guidelines recommend 75–162 mg of aspirin for patients after a myocardial infarction; this recommendation is classified as class I, with an A level of evidence in the AHA and ACC guidelines.42

Figure 4 Incidence of cardiovascular events according to antiplatelet treatment status.
Figure 4 : Incidence of cardiovascular events according to antiplatelet treatment status. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

Permission obtained from BMJ Publishing Group Ltd © Antithrombotic Trialists' Collaboration group (2002) BMJ 324: 71–86.41

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LDL-lowering therapy

Strong evidence that supports clinical efficacy is also available for statins. Figure 5 has been constructed with data from a meta-analysis published in 2003 by Law and coworkers.43 A 1.5 mmol/l reduction in LDL cholesterol level results in a 20% to 50% reduction in cardiovascular events.44 Importantly, such an LDL cholesterol level reduction can be achieved with most statin regimens. The Prospective Studies Collaboration group published a meta-analysis in 2007 that included 61 prospective studies and 55,000 vascular deaths. In this study, total cholesterol level was positively associated with mortality related to ischemic heart disease, and the authors state that the evidence is conclusive that statins can reduce both coronary events rates and stroke rates.45 We believe, therefore, that statins should also be considered a cornerstone component of a fixed-dose combination pill for secondary cardiovascular prevention therapy.

Figure 5 Reduction in the risk of ischemic heart disease events according to LDL cholesterol level and years in treatment.
Figure 5 : Reduction in the risk of ischemic heart disease events according to LDL cholesterol level and years in treatment. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

Data obtained from Law et al.43 The columns represent reduction in the risk of ischemic heart disease events according to duration of treatment and the mean reduction in LDL cholesterol achieved in each trial.

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Blood-pressure-lowering therapies

Observational studies have demonstrated that blood pressure levels correlate with the risk of cardiovascular disease and stroke. Drugs designed to lower blood pressure reduce the risk of these two conditions, not only in patients with hypertension, but also in those at high risk who have normal blood pressure.46, 47 With regard to ACE inhibitors, two meta-analyses with similar results were published in 2006, one by Dagenais and coworkers48 and another by Danchin et al.49 Dagenais et al. included three large trials in their analysis—the Heart Outcomes Prevention Evaluation (HOPE) and Prevention of Events with Angiotensin-Converting-Enzyme Inhibition (PEACE) studies, and the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA)—and almost 30,000 patients, half of whom had a history of myocardial infarction. ACE inhibitors reduced all-cause mortality from 8.9% to 7.8%, a 14% statistically significant reduction (odds ratio 0.86, 95% CI 0.79–0.94). The subgroup analysis also demonstrated that these drugs were effective even when administered in addition to other medications, such as antiplatelet and lipid-lowering agents, which is a key consideration in the development of combination therapies (Figure 6). Present AHA and ACC guidelines, therefore, recommend ACE inhibitors in the treatment of patients who have suffered a myocardial infarction, even in those without left ventricular dysfunction as a class I indication (level of evidence A).42

Figure 6 Effect of angiotensin-converting-enzyme inhibitors on mortality in different subgroups of high-risk patients.
Figure 6 : Effect of angiotensin-converting-enzyme inhibitors on mortality in different subgroups of high-risk patients. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

Permission obtained from Elsevier Ltd © Dagenais GR et al. (2006) Lancet 368: 581–588.48

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Beta blockers

Long-term treatment with beta blockers after acute myocardial infarction reduces total mortality by about 20% and sudden death by 34%.50 Several trials that tested atenolol, metoprolol tartrate, propranolol hydrochloride or timolol maleate have demonstrated that the beneficial effect is maintained for approximately 2 years after myocardial infarction. No differences in efficacy have been demonstrated among this diverse class of agents; however, those with appreciable intrinsic sympathomimetic activity provide more benefit than those without.50 Although the potential adverse effects of beta blockers are numerous, discontinuation of treatment is not necessary in most cases, as negative effects can be overcome by changing the beta blocker used, or adjusting the dose. As dose titration is an important method to avoid adverse effects, the inclusion of a beta blocker in a fixed-dose combination pill requires an increase in the number of formulations, and thus increases the complexity of pharmaceutical development.

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Polypill projects: The CNIC project

Despite the initial interest in the polypill concept for secondary prevention of cardiovascular disease, only a few research groups are currently working in this field. This discrepancy relates mainly to the lack of financial support from the pharmaceutical industry for a product that is associated with such a low profit margin. In addition to our project outlined below, at least two other companies based in India are developing fixed-dose combination pills for cardiovascular disease prevention, including Dr Reddy's Laboratories Ltd (Hyderabad) and Cadila Pharmaceuticals (Ahmedabad; see the accompanying Viewpoint by Xavier et al. in Nature Clinical Practice Cardiovascular Medicine). Several trials aimed to test the polypill concept, mainly for primary prevention, are now being prepared or are underway and recruiting patients. These trials include the Programme to Improve Life and Longevity (PILL) Pilot,51 the Improving Adherence using Combination Therapy (IMPACT) trial, and trials at Tehran University of Medical Science and Wake Forest University.52

A fixed-dose combination drug for cardiovascular prevention has been developed by our study group at the CNIC (Centro Nacional de Investigaciones Cardiovasculares or National Center for Cardiovascular Research), which is a public center located in Madrid whose mission is to prevent cardiovascular diseases and promote health. The project is being developed on the basis of three principles. First, the polypill is a key element of a complete program of cardiovascular prevention, which will also include patients' and physicians' education about changes in lifestyle. Second, we propose a three-component polypill, which comprises aspirin, a statin and an ACE inhibitor, for secondary prevention in patients who have already suffered an acute myocardial infarction. Finally, the end product is delivered at a price that ensures it is accessible to patients in low-income countries.

Although Wald and Law31 originally proposed a pill that combined half-doses of three antihypertensive drugs, together with a statin, folic acid and aspirin, to target primary prevention, our polypill will include 100 mg uncoated aspirin, 40 mg simvastatin and ramipril at three different doses (2.5 mg, 5 mg and 10 mg) to facilitate dose titration. Our fixed-dose combination therapy differs from that proposed by Wald and Law because we focus on patients treated after a myocardial infarction, as they constitute a high-risk population and should have already received these agents, as recommended by various different guidelines. Although beta blockers should be routinely administered in patients recovering from a myocardial infarction, we decided not to include these agents in our polypill; the addition of a beta blocker would increase the difficulties in galenic formulation and bioequivalence. Furthermore, a four-component combined therapy would narrow the target population and increase the difficultly of dose titration.

Epidemiological studies have demonstrated that aspirin, even at daily doses lower than 300 mg, is associated with a twofold increase in the risk of upper gastrointestinal tract complications. Although coated aspirin can reduce the incidence of minor lesions in the upper gastrointestinal tract, several meta-analyses have demonstrated that this formulation does not prevent serious gastrointestinal events.53 We decided, therefore, to include uncoated aspirin in our polypill to reduce formulation complexity.

The project is a private–public venture with Ferrer-Internacional, which is a Spanish pharmaceutical company based in Barcelona with experience in the development and launching of international projects. The new formulation will be available in 2010. We hope that the low cost and worldwide distribution of this three-component polypill will enable affordable secondary prevention in developing countries, and at the same time improve adherence to treatment.

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Conclusions

Cardiovascular disease, including ischemic heart disease and stroke, is the leading cause of death in both developed and developing countries. Patients with several key risk factors, and those who have a history of acute myocardial infarction, are at high risk of new coronary events. The efficacy of secondary cardiovascular prevention therapy in these high-risk populations is well-documented. However, the effectiveness of secondary prevention is hampered by several problems, such as inadequate prescription of medication, poor adherence to treatment, limited availability of medications, and unaffordable cost of treatment. We believe that the use of fixed-dose combination drugs could circumvent these problems, though controversy about the true value of the polypill concept still remains. We believe that a polypill (such as the one we are currently developing), delivered at a low price could improve adherence to treatment, reduce the cost and make treatment affordable in low-income countries. Success in this area of prevention could lead to the development of polypills for several other diseases, such as diabetes and stroke.36, 54

Key points

  • In 2005, cardiovascular diseases caused 3.3 times more deaths worldwide than AIDS, tuberculosis and malaria combined
  • Of all cardiovascular events that occur worldwide, four-fifths occur in low-income and middle-income countries
  • Although the efficacy of medication for secondary prevention of cardiovascular disease has been clearly demonstrated, a large proportion of potential candidates for therapy do not receive adequate treatment
  • Poor adherence to treatment and cost of medication are largely responsible for the discrepancy between evidence-based recommendations and actual treatment
  • Complexity of treatment is the main cause of patients' lack of adherence
  • Fixed-dose combination therapy (a 'polypill') might improve secondary prevention owing to a reduction in treatment complexity, and could provide medication at an affordable cost in developing countries

Acknowledgments

Ariana Del Negro, Medscape Cardiology, New York, NY and Désirée Lie, University of California, Irvine, CA, are the authors of and are solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Competing interests

The authors declared no competing interests.

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Subject areas under which this article appears: Public health