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