Preventing Cardiovascular Disease with One Pill?

Summarized by Robert W. Griffith, MD
July 25, 2003

Introduction

Two British professors of medicine have recently made what, on its face, appears to be a revolutionary proposal - a "Polypill" with six ingredients that would cut the rate of cardiovascular disease by over 80%. As heart attack, stroke and other preventable cardiovascular diseases sooner or later kill roughly half the population of Britain, it sounds like an idea to be taken seriously. Although changes in lifestyle (improved diet, no smoking, more exercise) can help reduce cardiovascular mortality, they are difficult to institute on a widespread scale within a reasonable time frame. This summary looks at the evidence collected by the proponents of the proposed Polypill.

The strategy

The approach taken was to simultaneously reduce 4 major cardiovascular risk factors - low density lipoprotein (LDL) cholesterol, blood pressure, serum homocysteine, and platelet function - using medications that are widely accepted as effective and safe, and having minimal side effects. Notably, pretreatment levels of these risk factor measures would be irrelevant.

Low density lipoprotein (LDL) cholesterol
Statins represent the drug class of choice for modifying LDL cholesterol levels. In a meta-analysis reported separately, the authors examined 164 short-term and 58 long-term randomized trials of six statins for their ability to reduce LDL cholesterol, ischemic heart disease (IHD) events, and strokes.¹ Three statins were selected - atorvastatin, simvastatin, and lovastatin - that, in normally prescribed doses, reduce LDL cholesterol by a mean of 70 mg/dL (1.8 mmol/L), IHD events at age 60 by 61%, and strokes by 17%.

Blood pressure
Five main categories of antihypertensives were studied, using analyses of 354 randomized trials.² They were: thiazide diuretics, beta-blockers, ACE inhibitors, angiotensin II receptor blockers (ARBs) and calcium channel blockers. The average 24-hour reductions in blood pressure were calculated for each drug at standard doses (i.e. the 'recommended' doses) and at half-standard and double-standard doses. All 5 categories of drug produced similar reductions, with averages of 9.1 mm Hg (systolic), 5.5 mm Hg (diastolic) at standard doses, and 7.1 mm Hg (systolic), 4.4 mm Hg (diastolic) at the half-standard doses.

Fifty trials compared drugs from two categories, separately and together; analyses showed that the efficacy of two drugs given together was additive. Although no trial has studied the effect of three drugs in combination, the additive effect of many combinations of two drugs suggests that the effect of three drugs in combination would also be additive. This is shown in the table, using half-standard dosing of each drug:

Blood Pressure Reduction (95% CI) *
	One Drug	Two Drugs	Three Drugs
Systolic (mm Hg)	6.7 (6.1 to 7.2)	13.3 (12.4 to 14.1)	19.9 (18.5 to 21.3)
Diastolic (mm Hg)	3.7 (3.1 to 4.3)	7.3 (6.2 to 8.3)	10.7 (9.1 to 12.4)

*Reductions in blood pressure adjusted to a usual pretreatment blood pressure of 150/90 mm Hg, the average blood pressure in people aged 50-69 years who have a stroke or ischaemic heart disease event.

The reductions in the incidence of IHD events and stroke with a triple combination are 46% and 63%, respectively.

As the side effects of different categories of antihypertensives are less than additive, and for most categories the side effects were dose-dependent, a combination of three drugs from different categories given at half-standard doses has a lower potential for side effects than the use of one or two drugs given at standard dosage.

Serum homocysteine
The dose of folic acid required to lower the serum homocysteine level was derived from a meta-analysis reported a year ago.³ It was found that 0.8 mg/day of folic acid reduces homocysteine levels by an average of 3 micromol/L (that's about 25%), and is associated with a reduction in IHD events of 16% (95% CI, 11 to 20) and in strokes of 24% (95% CI, 15 to 33).

Platelet function
As platelet function is difficult to quantify, the authors used data from randomized clinical studies of the effects of aspirin on cardiac events. A meta-analysis of 15 low-dose aspirin trials showed that a dose of 75 mg/day was associated with a reduction in IHD events of 32% (95% CI, 23 to 40) and in strokes of 16% (95% CI, 7 to 25).⁴

The Polypill approach

The reductions in cardiovascular events by drug-induced effects on the four selected risk factors have been outlined above. The effect of taking a pill containing the 6 drugs necessary to effect a change in all four factors was calculated by multiplying the relative risks associated with each. This yielded a reduction in IHD events of 88% (95% CI, 84 to 91) and in stroke of 80% (95% CI, 71 to 87).

Another calculation estimated the years of life gained without a heart attack or stroke if people without previous cardiovascular disease used a Polypill from age 55. Out of 100 men taking the Polypill for 30 years (i.e. up to age 85), 30 men would benefit by avoiding or delaying an IHD event or stroke, and would gain an average of 13 years of life. Out of 100 women, 24 would benefit in the same way within 30 years, and would gain an average of 14 years of life.

Adverse effects would vary slightly, according to which three antihypertensives are chosen. When selected from the three categories of antihypertensives with the lowest risk of adverse events, (a thiazide, an ARB, and a calcium channel blocker), about 8% of subjects would probably experience one or more side effects, mostly due to the aspirin component. Selection of one each from the three cheapest antihypertensive categories (a thiazide, a beta-blocker and an ACE inhibitor) would result in side effects in about 15% of subjects taking the pill.

Comment

The authors of the Polypill concept discuss the pros and cons of various ages and criteria for starting people on this preventive treatment, but come to the firm conclusion that one should treat everyone over 55 and younger people with known occlusive vascular disease. They point out that there is no need to measure the 4 selected risk factors before or during treatment, as the predicted benefits are calculated for whatever the initial levels of risk. Intervention in this way should reduce heart attacks and strokes by over 80%, and only 1-2% of those taking it would need to withdraw due to side effects.

As an accompanying editorial suggests, what is needed now is 'widespread debate on the new paradigm'. In favor of the Polypill is the fact that only large reductions in smoking and obesity could achieve as much benefit. Use of generic components would make the cost less than that of screening regularly for elevated risk factors.

In summary, the hopes of reducing cardiovascular disease seems a little bit brighter, thanks to this approach to prevention.

Source

• A strategy to reduce cardiovascular disease by more than 80%. NJ. Wald, MR. Law, BMJ, 2003, vol. 326, pp. 1419--1423

Footnotes
1. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. MR. Law, NJ. Wald, AR. Rudnicka, BMJ, 2003, vol. 326, pp. 1423--1427
2. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomized trials. MR. Law, NJ. Wald, JK. Morris, RE. Jordan, BMJ, 2003, vol. 236, pp. 1427--1431
3. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. DS. Wald, MR. Law, JK. Morris, BMJ, 2003, vol. 325, pp. 1202--1206
4. Collaborative meta­analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.  Antithrombotic Trialists Collaboration., BMJ, 2003, vol. 324, pp. 71--86

Related Links
How Useful is Homocysteine in Predicting Cardiovascular Disease Risk?
Age-Associated Cardiovascular Changes in Health and Disease
Are ARBs better than ACE-inhibitors?
Measures to Prevent Stroke

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