Polypill and Polycap 

• Yusuf  hypothesized that a combination of 4 drugs (aspirin, a beta-blocker, a statin, and an angiotensin-converting enzyme [ACE] inhibitor) could reduce CVD (cardiovascular disease ) events by 75% in those with vascular disease.¹ However, most patients with CVD are not receiving these medication due to the sheer number of pills and its costs.²

• Other researchers have discussed the creation, feasibility, and utility of a Polypill which could lower one’s risk for developing CVD. The development of such a single pill would likely result in enhanced adherence to recommended cardiac treatments and the pill should have beneficial effects on lowering levels of blood pressure (BP), serum lipids, and platelet aggregation and should also have few side effects and an acceptable safety/tolerability ratio.

• Among people without existing CVD, the most discriminatory screening factor is age, because >90% of CVD deaths occur in people aged >55 years. Therefore, using a polypill in people aged 55 years, especially those with at least one additional risk factor (i.e., at moderate risk), could prevent the majority of CVD events in both high- and low-income countries.

• A meta-analysis of individual patient data from 29 trials of hypertensive individuals (mostly with BP >160/100 mm Hg) or those with preexisting CVD confirmed that lowering systolic BP by 5 mm Hg over 4 to 5 years reduced the risk of CAD  by 20%, stroke by 28%, and major CVD events by 22%, with additional reductions in heart failure.³ Larger reductions in BP led to greater benefits, and treatment was generally safe.

Theoretical Consideration

• Although drugs used in secondary prevention are cost-effective, these drugs are still not affordable to the majority of individuals in middle- and low-income countries, where the cost of a 1-month supply of standard generic secondary prevention drugs ranges from 2 to 18 days’ wages of government workers.

• Costs of a polypill using generic components (estimated at $1 a day in developed and 20 cents in developing countries) are likely to be much lower than the costs of individual drugs. Savings may be realized from reduced packaging, distribution, and marketing costs and fewer physician visits and laboratory tests.

• An example of potential cost savings is provided by the pricing of the Polycap used in The Indian Polycap Study (TIPS) trial in India, where it is currently approved for use and marketed at a substantially lower cost than its component drugs. 

• Moreover, use of a polypill would allow physicians to spend less time prescribing and monitoring multiple drugs and to allocate more time and resources to lifestyle counseling. 

Practical results

• Several studies have demonstrated that a Polypill or Polycap can be created to achieve the above objectives. Yusuf and associates ⁴ examined the effect of the Polycap on blood pressure, lipids, heart rate, and urinary thromboxane B2, and assessed its tolerability in a double-blind trial in 2053 individuals in 50 centers in India.

• The Polycap consisting of low doses of thiazide (12.5 mg), atenalol (50 mg), ramipril (5 mg), simvastatin (20 mg), and aspirin (100 mg) per day, or to eight other groups, each with about 200 individuals, were compared to patients taking aspirin alone, simvastatin alone, hydrochlorothiazide alone, three combinations of the two blood-pressure-lowering drugs, three blood-pressure-lowering drugs alone, or three blood-pressure-lowering drugs plus aspirin.

• Compared with groups not receiving blood-pressure-lowering drugs, the Polycap reduced systolic blood pressure by 7 mm Hg and diastolic blood pressure by 6 mm Hg, which was similar when three blood-pressure-lowering drugs were used, with or without aspirin. Reductions in blood pressure increased with the number of drugs used.

• Polycap reduced LDL cholesterol by 27 mg/dl which was less than that with simvastatin alone (33 mg/dl). According to the rule of six, this is equivalent to reducing the statin dose by half. Both reductions were greater than for groups without simvastatin.

• The reductions in heart rate with Polycap and other groups using atenalol were similar (7 beats per min), and both were significantly greater than that in groups without atenalol.

• Tolerability of the Polycap was similar to that of other treatments, with no evidence of increasing intolerability with increasing number of active components in one pill.

• This Polycap formulation could be conveniently used to reduce the risk of CAD by 62% and stroke by 48% only slightly less than the 80% reduction of CVD risk estimated in the original hypothesis.^{4, 5}

• In  another  randomized controlled trial (RCT), a four component Polypill was developed which contained relatively low doses of aspirin, an ACE inhibitor, a diuretic, and a statin.⁶ This pill contained 75 mg of aspirin, 10 mg of lisinopril, 12.5 mg of hydrochorthiazide, and 20 mg of simvastatin and was evaluated in 378 individuals in several countries. ⁶

• The results showed sizeable beneficial effects on blood pressure, blood lipids, and other CVD risk factors. During the three month trial, 23% of individuals randomly assigned to the Polypill group discontinued this therapy compared with 18% of those in the placebo group due to side effects.

• The excess of side effects were mainly attributable to the well known side effects of aspirin [gastric irritation and/or bleeding tendency] and of ACE inhibitor (cough and/or light headedness, dizziness or hypotension). ⁶

• Based on the estimated reductions in the risk of CVD observed, it was estimated that there would be an approximate 60% reduction in the risk of CAD and ischemic stroke, but a 50% increase in extra-cranial bleeding.⁶

• Therefore, the beneficial effects of this Polypill need to be balanced with the side effects documented and with the likely rates of adherence to taking this medication in persons at low to moderate risk for CVD.⁶ This excess risk is acceptable in people with documented CAD where the benefits of aspirin far outweigh the risk.

• In the TIPS trial, BP and cholesterol lowering were of lesser magnitude than projected. This finding raises many questions, such as the potential need for full doses of some BP-lowering drugs or the addition of a fourth BP-lowering drug (e.g., calcium channel blocker at half dose) and the use of simvastatin 40 mg or a more potent statin.

Polypill ─ Future Direction

• It is anticipated that two different polypills with and without aspirin would be developed for use in primary and secondary prevention.

• Ultimately, as with any therapy, the polypill may not be suitable for all. Patients at extremely high risk (e.g., those with very aggressive manifestations of atherothrombotic disease) or those with side effects to multiple medications may still require individualized therapy, and therefore the polypill should be considered as a complementary strategy.

• Although the Polycap used in TIPS is a suitable candidate for evaluation of its impact on clinical outcomes in large trials, it is important to evaluate whether a preparation without aspirin or a “full-strength” Polycap can be developed. If tolerability and a significantly greater impact on risk factors of a full-strength Polycap can be established, then such a formulation may lead to substantially greater benefit.

• The TIPS investigators have initiated an additional trial, The Indian Polycap-K Study (TIPS-K), to compare the current formulation of the Polycap with 2 capsules of the Polycap (daily doses of aspirin 200 mg, thiazide 25 mg, ramipril 10 mg, atenalol 100 mg, and simvastatin 40 mg) with or without the addition of low-dose potassium. The aforementioned drugs (other than potassium) at the full doses are clinically recommended in secondary prevention, and this study is therefore particularly relevant for secondary prevention.

• The ongoing Heart Outcomes Prevention Evaluation (HOPE)-3 trial is evaluating the concept of combined BP and cholesterol lowering in individuals without vascular disease and with average BP and cholesterol levels. The trial is conducted in 256 centers in 22 countries in North and South America, Europe, Africa, Asia, and Australia. It will soon complete enrollment of 12,500 individuals at moderate risk (men aged >55 years and women aged >65 years with 1 risk factor or women aged >60 years with 2 risk factors; expected annual placebo event rate of 0.9% to 1%/y) randomized to rosuvastatin 10 mg/d alone, a fixed-dose combination of candesartan 16 mg/d hydrochlorothiazide 12.5 mg/d alone, both, or neither (2×2 factorial design) for 5 years.

• All participants receive structured lifestyle advice. The main outcomes include major CVD events and changes in cognitive and renal function. The study has high power to detect relative risk reductions of 25% to 30% for each of the cholesterol- and the BP-lowering arms and of 35% to 40% for the combination versus double placebo.

• The TIPS-3 trial expected to start recruitment in early 2011 will evaluate a preparation of the Polycap without aspirin (either the doses used in the first TIPS trial or enhanced doses based on results of the TIPS-K trial) versus placebo over 5 years in 5000 individuals without CVD and with an estimated risk of major CVD of 1%/y in India and China. Both of these trials will include health economic analyses and will conduct passive follow-up for an additional 5 years beyond the active trial phase as additional benefits beyond the actual duration of treatment may emerge.

The Polypill as a Global Strategy to reduce the CVD Burden  

• On the basis of available data on the individual component drugs, the polypill could potentially be widely used in secondary prevention and in selected high-risk individuals without CVD (e.g., those with severe hypertension or diabetes with additional risk factors). In such individuals, a 50% to 75% proportional reduction in risk can be anticipated from prolonged therapy. By contrast, in individuals without CVD and not at high risk, large trials are needed to quantify the benefits, potential risks, and cost-effectiveness of the polypill. If such trials will provide clear evidence that the polypill reduces the risks of major CVD events by at least 40% to 50% in moderate-risk individuals (e.g., a reduction in 10-year risk from 10% to 5%) with good safety, tolerability, and cost-effectiveness, then it could become a key component of both primary and secondary CVD prevention globally.

• However, the polypill should not be considered in isolation but as an integral part of a comprehensive CVD prevention strategy that includes efforts to reduce tobacco use, increase physical activity, and increase consumption of heart-healthy diets. Such a 4-pronged approach could substantially reduce CVD by >80% to 90% globally in a highly cost-effective manner. Even if the uptake of these measures is only 50% of an “ideal” target, a substantial reduction in CVD by half globally is possible within the next 2 decades. If this can be achieved, it will represent a major scientific, clinical, and public health advance that would have resulted from systematic research being translated into improved human health. ^{7, 8}

• The beneficial effects of polypill should not, however, negate the tried and proven approaches to coronary risk reduction including initiating and maintaining a regular program of physical activity, eating a calorically balanced, low sodium, heart healthy diet with plenty of fruits and vegetables, to not begin smoking cigarettes, or stop smoking if one smokes, maintain one’s optimal weight, and have a positive outlook on life.

• The polypill may also be perceived as a threat to the traditional role of physicians in many countries and to the perceived superiority of the individualized, titrated, target-driven approach to CVD prevention, but new data may alleviate such concerns.

Sources

1. Yusuf S. Two decades of progress in preventing vascular disease. Lancet. Jul 6 2002;360(9326):2-3.

2. Yusuf S, Islam S, Chow CK, et al. Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and low-income countries (the PURE Study): a prospective epidemiological survey. Lancet. Aug 26 2011.

3. Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. Nov 8 2003;362(9395):1527-1535.

4.Yusuf S, Pais P, Afzal R, et al. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet. Apr 18 2009;373(9672):1341-1351.

5. 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. Jun 28 2003;326(7404):1427.

6. An international randomised placebo-controlled trial of a four-component combination pill (“polypill”) in people with raised cardiovascular risk. PLoS One. 2011;6(5):e19857.

7. Lonn E, Bosch J, Teo KK, Pais P, Xavier D, Yusuf S. The polypill in the prevention of cardiovascular diseases: key concepts, current status, challenges, and future directions. Circulation. Nov 16 2010;122(20):2078-2088.

8. Lonn E, Yusuf S. Polypill: the evidence and the promise. Curr Opin Lipidol. Dec 2009;20(6):453-459.