Elsevier

The Lancet

Volume 373, Issue 9672, 18–24 April 2009, Pages 1341-1351
The Lancet

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Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial

https://doi.org/10.1016/S0140-6736(09)60611-5Get rights and content

Summary

Background

The combination of three blood-pressure-lowering drugs at low doses, with a statin, aspirin, and folic acid (the polypill), could reduce cardiovascular events by more than 80% in healthy individuals. We examined the effect of the Polycap on blood pressure, lipids, heart rate, and urinary thromboxane B2, and assessed its tolerability.

Methods

In a double-blind trial in 50 centres in India, 2053 individuals without cardiovascular disease, aged 45–80 years, and with one risk factor were randomly assigned, by a central secure website, to the Polycap (n=412) consisting of low doses of thiazide (12·5 mg), atenolol (50 mg), ramipril (5 mg), simvastatin (20 mg), and aspirin (100 mg) per day, or to eight other groups, each with about 200 individuals, of aspirin alone, simvastatin alone, hydrochlorthiazide alone, three combinations of the two blood-pressure-lowering drugs, three blood-pressure-lowering drugs alone, or three blood-pressure-lowering drugs plus aspirin. The primary outcomes were LDL for the effect of lipids, blood pressure for antihypertensive drugs, heart rate for the effects of atenolol, urinary 11-dehydrothromboxane B2 for the antiplatelet effects of aspirin, and rates of discontinuation of drugs for safety. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00443794.

Findings

Compared with groups not receiving blood-pressure-lowering drugs, the Polycap reduced systolic blood pressure by 7·4 mm Hg (95% CI 6·1–8·1) and diastolic blood pressure by 5·6 mm Hg (4·7–6·4), 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 (2·2/1·3 mm Hg with one drug, 4·7/3·6 mm Hg with two drugs, and 6·3/4·5 mm Hg with three drugs). Polycap reduced LDL cholesterol by 0·70 mmol/L (95% CI 0·62–0·78), which was less than that with simvastatin alone (0·83 mmol/L, 0·72–0·93; p=0·04); both reductions were greater than for groups without simvastatin (p<0·0001). The reductions in heart rate with Polycap and other groups using atenolol were similar (7·0 beats per min), and both were significantly greater than that in groups without atenolol (p<0·0001). The reductions in 11-dehydrothromboxane B2 were similar with the Polycap (283·1 ng/mmol creatinine, 95% CI 229·1–337·0) compared with the three blood-pressure-lowering drugs plus aspirin (350·0 ng/mmol creatinine, 294·6–404·0), and aspirin alone (348·8 ng/mmol creatinine, 277·6–419·9) compared with groups without aspirin. 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.

Interpretation

This Polycap formulation could be conveniently used to reduce multiple risk factors and cardiovascular risk.

Funding

Cadila Pharmaceuticals, Ahmedabad, India.

Introduction

Aspirin,1 β blockers,2 angiotensin-converting-enzyme inhibitors,3 and statins4 reduce cardiovascular disease. One combination pill including all the above drugs could potentially reduce recurrent vascular events in people with cardiovascular disease by about 75%.5 Wald and Law extended this hypothesis in several ways.6, 7, 8 First, a combination of three agents to decrease blood pressure at low doses was estimated to reduce blood pressure substantially (11 mm Hg diastolic) in individuals with average blood pressure values, with few adverse effects. Second, they proposed addition of folic acid to reduce homocysteine to reduce cardiovascular disease. Third, they advocated giving this so-called polypill to individuals 55 years and older, irrespective of previous cardiovascular disease or risk factors. Wald and Law estimated that such a polypill would reduce cardiovascular disease by more than 80%. Of the various components they proposed, lowering homocysteine does not reduce cardiovascular disease,9 whereas all other components have been proven to reduce myocardial infarction and stroke. Therefore, the combination of blood-pressure-lowering drugs (ramipril, atenolol, and hydrochlorthiazide), simvastatin, and aspirin is likely to substantially reduce stroke and myocardial infarction.

Before large trials of a polypill are undertaken to reduce cardiovascular events, we addressed several questions. First, can one pill (or capsule) be formulated that can deliver an effect similar to the additive effect from each component provided separately? Second, what degree of reduction in blood pressure and LDL cholesterol can be achieved in people with normal levels of risk factors? Third, will a polypill with five components be tolerated? Fourth, do unexpected interactions arise when these drugs are given in a single pill? Fifth, does aspirin reduce the blood-pressure-lowering effects of ramipril, atenolol, and hydrochlorthiazide? We therefore designed The Indian Polycap Study (TIPS) to address the above questions.10 Additionally, we calculated the potential risk reductions in stroke and cardiovascular heart disease from the Polycap with data for the observed effect on risk factors recorded in TIPS.

Section snippets

Study design and population

Since we were testing the effects of five active pharmacological components (three agents to lower blood pressure, statin, and aspirin: Polycap [Cadila Pharmaceuticals, Ahmedabad, India]), a full factorial design would require 32 cells. Such a design was not practical. Therefore, we identified five questions (see above) that were most relevant and could be addressed by randomly assigning individuals to one of nine groups (figure 1, table 1). For blood-pressure lowering, we used

Results

Figure 1 shows the trial profile. 412 individuals were randomly assigned to the Polycap group and about 200 to each of the other eight groups. Table 1 shows the baseline characteristics.

The final scheduled follow-up was not available in 326 individuals, mainly because some participants perceived little benefit by participating in the trial. However, at least one recording of blood pressure after randomisation was available in 1971 (96%) patients. We obtained fasting blood samples at the last

Discussion

Our study has shown that the Polycap is non-inferior to its individual components in lowering blood pressure and heart rate (an indicator of β blockade). It lowers LDL cholesterol and urinary 11-dehydrothromboxane B2 substantially, but to a degree that is slightly less than that with simvastatin or aspirin alone. The differences in effect of the Polycap on lipids compared with simvastatin is of borderline significance, but is consistent with unpublished pharmacokinetic data (Khamar B, Cadila,

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