The polypill: an emerging treatment alternative for secondary prevention of cardiovascular disease

Increasing need for secondary prevention of coronary heart disease and cardiovascular disease

Cardiovascular disease (CVD), defined as ischaemic heart disease, stroke and CHF, ranks as the major cause of death and a major cause of disability in the developed world. In addition, CVD engenders enormous healthcare costs for society, as well as significant burdens for the individual patient. One-hundred years ago, CVD accounted for less than 10% of all deaths worldwide, whereas today, the proportion of total deaths due to CVD is about 30%. Importantly, about 80% of the global burden of CVD death occurs in low- and middle-income countries. Two decades ago, Murray and Lopez [1] predicted that CVD will be the leading cause of death and disability worldwide by 2020, mainly because of the rapid increase in low- and middle-income countries. Since the mid-twentieth century, CVD has been the leading cause of death in the developed world,[2,3] and by 2001, CVD had emerged as the leading cause of death in the developing world, accounting for almost 50% of all deaths in high-income countries and 28% of deaths in low- and middle-income countries.[2] The emerging risk of developing a primary or secondary CVD event depends to a large extent on the increasing global prevalence of the most important risk factors, including tobacco use, high blood pressure, high blood glucose, lipid abnormalities, obesity and physical inactivity.

Over the past two decades, death rates have been significantly reduced and more patients survive their first myocardial infarction or cerebrovascular event. As a consequence, the numbers of patients, often elderly, who will be in future need of long-term secondary preventive measures, including both non-pharmacological and pharmacological treatment, is steadily growing. However, current experience from specialist outpatient units reveals that although most patients receive adequate treatment at discharge from hospital, some 50% of patients fail to reach their individually set treatment goals after 1 year of follow-up.[4,5]

Major therapies for secondary prevention are now generic

In the 1980s, a range of classes of powerful antihypertensive and lipid-lowering drugs were introduced, most importantly the angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins).[6,7] Over the past three to four decades, these therapies have been tested in large outcome trials, and proven to be effective in primary as well as secondary prevention of CVD. Interestingly, the introduction of these drug classes to general healthcare in Sweden, for example, coincided with a steady and sharp decline in cardiovascular mortality. However, despite the progress made over the past decades, there remains a need for improvement in implementing tighter control measures during long-term CVD management. Patents on the most important ACE inhibitors, ARBs, CCBs and statins have expired, and these compounds are now generic. As a result, prices have fallen sharply, bringing down treatment costs and increasing the availability of these important pharmacological agents to many CVD patients.

Undertreatment is still a problem

The steady reduction in CVD mortality that has been observed in developed countries, e.g. Sweden, during the past 20–30 years, has come to a halt. This is a concern, since secondary prevention remains suboptimal, and additional measures need to be taken to tighten the chain of detection–treatment–follow-up management.[6,7] A number of European countries, e.g. France, Portugal, the Netherlands, Spain, Luxemburg, Italy and Denmark, have implemented rational strategies for reducing CVD.[5] However, in other European countries there is a need for major improvements to ensure that patients reach their individual treatment goals. Specifically, there is an urgent need to address the problems of undertreatment and low adherence to therapy.

Long-term treatment adherence to many prescribed chronic medications remains poor, sometimes to levels below 50%, owing to social, cultural, psychological and economic issues, as well as other factors related to patients, healthcare providers and healthcare systems. Non-adherence to treatment has major health consequences since medication discontinuation is associated with higher rates of recurrent events and mortality in patients with established CVD.[8] Cost and affordability of medications are still major barriers, especially in elderly people. Although most drugs used in secondary prevention are considered to be cost effective, such drugs may still not be affordable to large segments of the population in middle- and low-income countries.[9]

Care providers need to increase efforts to achieve optimal targets for cardiovascular disease risk reduction

Approximately half of the decline in CVD mortality observed in developed countries during the past two decades is attributable to medical therapy. Aspirin [acetylsalicylic acid (ASA)], the statins, beta-blockers, ACE inhibitors and ARBs have all been shown to reduce CVD events in secondary prevention.[6,7] However, despite clear evidence of effectiveness, there remain large treatment gaps and multiple barriers to effective implementation of secondary prevention. Importantly, proven therapies are not prescribed to all patients who are likely to benefit. For example, the third European Action on Secondary Prevention through Intervention to Reduce Events (EUROASPIRE III) survey, carried out in nine European countries, found that the prevalence of smoking (17%), obesity (35%), uncontrolled hypertension (56%) and elevated cholesterol (25%) remains high among patients with ischaemic heart disease. Furthermore, the use of statins and ACE inhibitors/ARBs remains suboptimal since they are prescribed to only 71% and 78% of patients at risk, respectively.[10]

Pharmacoeconomic evidence favours further action to improve adherence

The overall direct and indirect costs for the management of CVD remain high in developed countries. The highest costs are associated with in-hospital patient care as well as direct and indirect costs for disability. In Sweden, health economic studies show that 7.5% of costs [11] during follow-up were related to physicians and 5.3% to nurses. Drug costs accounted for 6.3%, i.e. half the costs for outpatient follow-up by physicians and nurses.[11] One important reason for this is that costs for well-documented drugs are low because most of them are generic. Adherence issues, structured management and achieving treatment targets, not issues related to costs of treatment, are the major challenges for secondary prevention of CVD.

Most secondary prevention patients are maintained on combination regimens, including an ACE inhibitor, statin and low-dose ASA. By systematically adding a combination of ACE inhibitor + statin + ASA to a beta-blocker regimen during secondary prevention, it is possible to achieve a further 71% relative risk reduction in mortality, which would translate into saving 17.9 million lives in Europe over 10 years.[12] This is the rationale for introducing pragmatic treatment regimens, such as the “polypill”, into routine secondary prevention.

Fixed-dose combination pills have been available for decades for the primary prevention of CVD and in the treatment of hypertension. Combinations of ACE inhibitors and ARBs with diuretics (hydrochlorothiazide or indapamide) are in routine use in clinical practice in most parts of the world. However, fixed combinations have not been commonly used in secondary prevention. This is surprising since the absolute benefits of improved adherence would be greater in secondary prevention and there is strong support for a fixed combination strategy from recent outcome studies.[13,14]

Combination treatment will be essential

From a societal as well as a patient perspective, suboptimal management of cardiovascular risk factors is associated with high direct and indirect costs for management of complications.[12] Therefore, it is important to develop effective approaches to optimize risk factor management in individual patients as well as in the population. This is particularly true in secondary prevention, where absolute risks are often higher since about 30% of all events are recurrent.[15]

Current guidelines recognize that monotherapies provide satisfactory reduction of CVD risk in only a limited proportion of the secondary prevention population and that the majority of these patients require combinations of effective drugs to achieve risk factor control and reduction of risk of future cardiovascular events.[16–18] The beneficial effects of statins, ASA and ACE inhibitors on the cardiovascular system have been shown in a variety of large studies.[19–22] There is also some evidence of synergistic effect of statins and ACE inhibitors in preventing new cardiovascular events in patients with established CVD.[23] Thus, European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines strongly recommend the combined use of ASA, statins, ACE inhibitors and beta-blockers be initiated early after a CVD event in order to prevent recurrences.[24]

Despite clear evidence of benefit, there is unacceptably low adherence to prescribed treatments..[8,9] Several high-quality secondary prevention registries have found that prescription of cardiovascular drugs for secondary prevention in general practice remains suboptimal. Further, nearly 10% of the CVD events in patients with established CVD in Europe have been shown to be due to the lack of adherence to secondary prevention medications.[25] This is unacceptable since CVD patients with good adherence have improved outcomes compared with patients who demonstrate poor adherence with prescribed therapies.[26,27] The current ESC/ESH guidelines have taken the position (evidence level IA) that it important to assess adherence in such patients and that reducing the number of tablets is the most effective single approach to enhance patient adherence.[24] The guidelines also argue that this may be achieved by a prescription of combination therapies, such as a polypill. In patients with a previous CVD, improvement in adherence has been shown after the administration of polypills with different components.[8,13,14] In secondary prevention, this translates into lower overall costs of care, as has been shown in recent publications.[28,29] While there is no evidence yet for improved cardiovascular outcomes after long-term polypill therapy, forthcoming randomized prospective studies will shed some light on this issue in the near future.[30,31,32]

The polypill: from a controversial idea to a pragmatic solution

From a global perspective, most health systems are underperforming in terms of implementing secondary prevention strategies after cardiovascular events. This is largely due to suboptimal adherence to effective drug treatments. All measures shown to be effective must be implemented to bring all countries up to the standards of the most advanced nations. The polypill concept offers several advantages to achieve the goal of optimal secondary prevention. First, it is a cost-effective strategy to improve outcomes. All relevant component drugs are off-patent and the costs of drugs account for only half the costs of physicians and nurse visits. Secondly, the polypill concept facilitates easy delivery of standard care. By avoiding complex and time-consuming sequential treatment algorithms, more at-risk individuals are likely to be treated. Thirdly, administration of a polypill also improves patient adherence. By taking only one pill versus several pills per day for secondary CVD prevention, adherence increases and preventive effects are augmented.

The polypill concept for secondary prevention is currently being introduced more widely in a number of European countries as well as the USA. It is time to treat larger groups of patients to goals set in guidelines, and to introduce the polypill concept to standard medical practice for secondary prevention.

Disclosure statement

TH, SEK, KN and SO are the editors of Blood Pressure and report no relevant conflicts of interest to disclose related to this Editorial.