Abstract The cardiovascular polypill or fixed-dose combination pill, consisting of 3, 4, or more drugs in a single tablet (or capsule), has been proposed as an effective and convenient therapy in both secondary and primary prevention of cardiovascular disease (CVD). Each of the drugs in the combination has a documented ability to prevent CVD events. The combined effect has been estimated to reduce risk by 75% to 80%. Since the concept was introduced 15 years ago, several polypills are available and their effects on risk factors evaluated. Their effects on individual risk factors, such as hypertension and elevated low-density lipoprotein levels, are similar to the individual drugs separately. Enhancement of adherence of the polypill has also been shown compared to individual drugs given separately. Based on the reductions on the individual risk factors, the reductions in risk are estimated to be substantial. A few large long-term randomized controlled trials are ongoing and will be completed in the next 2 years. If the effects on CVD outcomes are as predicted, this would help the many millions of individuals who are currently not adequately treated or not treated at all. There are however considerable challenges in development and acceptance of the polypill. These include regulatory issues; intellectual property; perception by the public, patients, and physicians; and the role of health systems and societal approach to disease prevention. For the polypill to be accepted and achieve even a part of its potential, multiple barriers outlined in this review have to be overcome. blood pressure, cholesterol, CVD prevention, fixed-dose combination, polypill, risk factors The polypill or fixed-dose combination pill, defined as the combination usually of 3, 4, or more drugs in a single tablet (or capsule), each with a documented ability to prevent cardiovascular disease (CVD) events, has been proposed 15 years ago. This was based on 2 sets of observations. First, that aspirin, beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and statins each reduce the risk of CVD by about one quarter in secondary prevention and their collective use would likely reduce the risk by about 75% to 80%.1 Second, Wald and Law2 suggested that low doses (half doses) of different antihypertensive agents when given together would reduce blood pressure (BP) substantially and with few side effects and when given in conjunction with a statin, it could reduce CVD in primary prevention by as much as 80%.2 They had also suggested including folic acid to reduce homocysteine, but its value is not supported by most trials and so the idea of including it in a polypill has not been pursued vigorously. Wald and Law also suggested that the strongest risk predictor for CVD was an age over 55 years and proposed that the polypill be used in all over this age, irrespective of the level of any other risk factor.2 While this latter concept has considerable appeal (avoidance of screening, simplification of primary prevention), this aspect of the polypill has proven to be more controversial and the development of the polypill has been focussed largely in those with established vascular disease or certain high-risk groups such as those with hypertension or diabetes. It is now about 15 years since the concept of the polypill has been proposed, and despite its appeal there has been no polypill that has been in wide use worldwide. Why is this the case? In this article, we first briefly summarize the major trials of the polypill, the reasons why the polypill has not gained widespread acceptance, describe the ongoing major trials that may help overcome this gap and finally describe a bold new idea of continuing BP-lowering drugs at low doses (the quad pill). MAJOR COMPLETED STUDIES OF THE POLYPILL The initial trials of the polypill were designed to confirm the fact that combining 2 or 3 BP-lowering drugs at low or full doses were well tolerated and that these polypills would reduce BP and low-density lipoprotein to the degree that one would expect from the separate effects of each drug. This was confirmed in The Indian Polycap Study (TIPS) 1 and the TIPS 2 trials of the polycap3,4 (TIPS 1, one capsule containing ramipril 5 mg, hydrochlorothiazide 12.5 mg, atenolol 50 mg, aspirin 100 mg, and simvastatin 20 mg vs. placebo; TIPS 2 tested 2 polycap capsules vs. 1 capsule) and in trials of the Red Heart Pill (there are 2 versions: aspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg, atenolol 50 mg OR aspirin 75 mg, simvastatin 40 gm, lisinopril 10 mg, and hydrochlorothiazide 12.5 mg).5 These trials also showed an improvement in adherence compared to prescribing the individual components of the polypill separately. Similar results of improvement of adherence were documented by the trials involving Trinomia (with ramipril 2.5 mg, 5 mg, or 10 mg; aspirin 100 mg; atorvastatin 20 mg).6 The development of the Red Heart Pill was discontinued by its manufacturer Dr Reddy’s Laboratories. The Polycap is marketed in India and Zambia, and Trinomia is marketed in 22 Latin American and European countries up to 2016.7 The results of various polypills suggest that standard doses of 3 BP-lowering drugs, a statin and aspirin substantially reduce risk factors and in theory can reduce CVD risk by an estimated 60% to 70%, in those who take the medications regularly. It is likely that even with some reduction in adherence (say from the ideal of about 100% to a more realistic estimate of about 70% to 75% after many years), the benefits could be as large as about 50% relative risk reduction in CVD, which is substantial, especially in those with CVD or in those at high risk and without CVD, e.g., those with hypertension or diabetes. However, these theoretical estimates of large benefit need to be confirmed in prospective large trials which are currently underway. Large trials of the Polypill or the Polypill concept: a) Heart Outcomes Prevention Evaluation (HOPE) 3: HOPE 38,9 is large trial of 12,700 individuals at intermediate risk and no CVD and evaluated the roles of rosuvastatin 10 mg/day, combination of fixed doses of candesartan at 16 mg/d + hydrochlorothiazide 12.5 mg/day vs. their respective placebos. In addition, because the trial used a 2 × 2 factorial design, it also tested the impact of combination BP and lipid lowering vs. neither and so informs what a polypill of 3 drugs at low doses might do in primary prevention. The study showed that rosuvastatin reduced CVD by 26.5% but that BP lowering (BP reduction of 6.0/3.0 mm Hg) was only associated with a modest 7% Relative Risk Reduction (RRR) in CVD. However, in a prespecified subgroup analysis of those with SBP in the highest tertile (>143 mm Hg), there was a 27% RRR in CVD with BP lowering. Combination of statins + BP lowering reduced CVD events in those with elevated BP by 40% and by 30% in the overall population. If these results can be replicated in future trials with a polypill, then this would be a major advance in primary prevention. b) “TIPS 3”10 is designed to evaluate the effects of long-term treatment on clinical events of the standard-dose combination pill (atenolol 100 mg, ramipril 10 mg, hydrochlorothiazide 25%, and simvastatin 40 mg) vs. placebo in 5,700 individuals without documented CVD but at high risk of CVD events (1% or more per year) as assessed by the INTERHEART Risk Score. The primary outcome is the composite events of cardiac and vascular events. Given that the risk/benefit ratio of aspirin is uncertain in primary prevention of CVD, aspirin 100 mg or placebo was given by a factorial design so that aspirin can be evaluated separately. The trial has completed enrollment by August 2017, in India, Philippines, Columbia, Malaysia, Indonesia, Tunisia, Tanzania, and Canada, and results are expected in 2019 or 2020. The trial includes a high proportion of individuals with hypertension (66%) and diabetes or dysglycemia (32%), and so the results will be relevant to those at intermediate and high risk of, but no CVD. “PolyIran RCT” is an open-label cluster randomized trial designed to determine the effects of a combination pill [aspirin 81 mg, enalapril 5 mg (or valsartan 40 mg), atorvastatin 20 mg, and hydrochlorothiazide 12.5 mg] vs. minimal usual care on primary and secondary CVD prevention in 7,000 adults 50- to 79-year-old individuals from Iran. The primary outcome at 5 years is the time to first major cardiovascular event. Results are expected in 2018.11 The SECondary prevention of cardiovascUlaR disease in the Elderly (SECURE) Trial12 is an ongoing multicenter, international, randomized trial designed to evaluate the effects of the Trinomia polypill containing aspirin 100 mg, ramipril 2.5, 5, or 10 mg, and atorvastatin in secondary prevention of 3,206 patients >65 years within 8 weeks of myocardial infarction in reducing cardiovascular events (composite of cardiovascular death, nonfatal MI, nonfatal nonischemic stroke, and urgent revascularization). Support comes from the funds from the EU and follow up will be for a minimum of 2 years. Completion date is estimated to be April 2020. A recent small randomized placebo-controlled crossover RCT (Quadpill Trial) studied the effect of the quadpill, a single capsule containing 4 BP-lowering drugs, each at quarter dose (irbesartan 37.5 mg, amlodipine 1.25 mg, hydrochlorothiazide 6.25 mg, and atenolol 12.5 mg), in 55 patients, mean age 58 years, who had not received BP-lowering therapy previously.13 Compared to placebo, BP reduction due to active therapy was 22/13 mm Hg (office BP) and systolic BP monitored by 24 hours ambulatory BP was reduced by 19 mm Hg. There were no serious adverse events reported. This was a short-term trial of 4 weeks each with active and placebo, with a 2-week washout in between. The findings suggest that the benefits of quarter-dose combination therapy could be additive and might result in clinically important reduction in BP. Larger and longer trials of the quarter-dose or quadpill, ideally on hypertension, are needed. CHALLENGES IN DEVELOPMENT AND ACCEPTANCE OF POLYPILL There are unique challenges involved in the development and acceptance of a polypill into clinical practice. These include the following: a. Regulatory: The polypill does not use novel ingredients, but it is a fixed-dose combination of 4 or more drugs, each of which has been proven to reduce the risk of CVD. Fixed-dose combinations with so many active ingredients have never been approved before, even though the individual components are commonly used in the same patients in clinical practice. The acceptance of Trinomia (with 3 components) by several regulatory bodies is a positive step. Another positive step is the guidelines of the Food and Drug Administration (FDA) which has indicated that only pharmacokinetics (PK) and pharmacodynamics (PD) studies are needed for the approval of a drug in secondary prevention.14 Hopefully, this will spur the development of several new polypills using some of the newer statins and BP-lowering agents. b. Intellectual Property: One major concern for potential manufacturers of a polypill is protection of intellectual property. Large pharmaceutical companies have successfully followed a formula in developing innovative molecules and drugs which are effective in treating a common important disease such as hypercholesterolemia. These drugs are usually sold at relatively high costs until the drugs go off patent, after which the prices of the generic versions tend to be substantially lower, depending on the number of companies manufacturing them. With the polypill it is difficult to “protect” the intellectual property of any given combination, and this has been a deterrent to major pharmaceutical companies from developing or marketing a polypill. Hopefully, this will be overcome with many generic companies developing new polypills and their collective efforts can have a positive impact on the acceptance, availability, and use of polypills. c. Perception by the public, patients, and physicians The public and patients Surveys have been conducted of patients receiving prevention drugs, whether in the form of a combination pill or not.7,15 The responses have generally been positive, particularly by simplification of the drug treatment regimens. However, some individuals were put off by the need to take all these many drugs. Indeed, anecdotally, some patients have expressed the desire for discontinuation of all or some of the drugs, especially when they believe that they do not have any CVD. Continuing education of the purpose and effects of the drugs, reassurance of their safety, and explanation of the need for such preventive treatment need to be initiated and maintained. Physicians While the majority of physicians surveyed support the concept of the combination pill, several concerns have been raised.7,15 First is the concern that the use of combination therapy would replace efforts to promote healthy lifestyles and that entire populations may be unnecessarily “medicalized”. This concern may be based on the presumption that prescribing drugs in apparently healthy people is undesirable. In practice, lifestyle modification should remain an integral and primary component in CVD prevention. However, successful and sustained lifestyle modification is achieved in only a fraction of patients. It would be unwise to wait to discover whether lifestyle counseling has been successful before initiating to evidence-based drug therapy in high-risk individuals. The 2 approaches (lifestyle modification and a polypill) are complementary and together will have the greatest benefits. The second concern arises from the beliefs by physicians that they should individually select and tailor dosages of medications rather than prescribe a fixed-dose, fixed-component combination pill. While some contraindications exist for each drug, e.g., dyspepsia and gastric bleeding for aspirin and asthma for beta-blockers, the number of individuals having any of these conditions are relatively few and alternative formulations could be made to accommodate these situations. In secondary prevention, the benefits of the typical combination of pills are clear and consistent in all the subgroups examined irrespective of the level of individual risk factors. A statin is effective irrespective of lipid level and an angiotensin-converting enzyme inhibitor and/or beta-blocker is effective irrespective of BP levels. In a majority of individuals, a combination pill (perhaps available in low and standard doses) can be used without the need for further customization. Health systems and societal approach Studies have reported significant evidence of practice gaps in primary and secondary CVD care in most countries. As demonstrated by the PURE study of 180,000 individuals from 20 high-, middle-, and low-income countries, these gaps can be explained as barriers at the patient, health care provider, and health system levels.16 In PURE, only 46.4% of those with hypertension were aware of having elevated BP, 40.6% were on pharmaceutical treatment, and only 13.1% had BP controlled. Only 12.5% of treated individuals were taking 2 or more drugs. Routine screening of hypertension in middle-aged adults did not occur in most countries.17 In PURE, of the approximately 8,000 participants who had coronary heart disease or stroke, 25.3% were taking antiplatelet agents, 17.4% beta-blockers, 19.5% angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and 14.6% statins approximately 5 years after their event. In participating low-income countries, the use of these drugs was very low at 3–9%, but only moderate rates of use in high-income countries (40–67% in Canada, Sweden, and United Arab Emirates).16 The data reported in PURE may be due to the gaps due to poor drug adherence and poor access, among other reasons. At the patient level, adherence decreases after 30 days, falling to as low as 50% at 6 months after discharge, with further declines over time.18 Such discontinuation of therapy has been shown to be associated with increased mortality in patients with coronary artery disease. Reasons for nonadherence are multiple and include, among others, the relatively high drug costs when multiple drugs (even when generics are used), lack of knowledge that these drugs for prevention need to be taken lifelong, lack of systematic follow-up and costs and inconvenience associated with repeated physician visits. Combination therapy using low-cost, accessible medications may help overcome patient-level barriers, which however do not occur in isolation. Barriers to care at the health care provider and health system level often overlap. One solution may be to re-imagine the health system approach using existing resources, e.g., by using nonphysician health workers for systematic screening and initiation of combination-drug therapy, augmented by ongoing treatment and life style education and reminders. Physicians only need to be involved when there are adverse effects or in patients with complications, The WHO Task Shifting-Global Recommendations and Guidelines have been designed to help this strategy.19 Routine screening and follow-up, and use of an affordable combination pill, could lead to a significant reduction in current global treatment gaps. CONCLUSION The cardiovascular combination pill or polypill represents an innovative approach to ensure individuals at high risk of subsequent or new events receive appropriate and sustained therapy at affordable costs. This approach would help the many millions of individuals who are currently not adequately treated or not treated at all. However, to be accepted and achieve even a part of its potential, multiple barriers outlined in this review have to be overcome. DISCLOSURE The authors declared no conflict of interest. REFERENCES 1. Yusuf S. Two decades of progress in preventing vascular disease. Lancet 2002; 360: 2– 3. 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American Journal of Hypertension – Oxford University Press
Published: Mar 15, 2018
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