Introduction

Two British professors of medicine have recently made what appears to be a revolutionary proposal - a "Polypill" with six ingredients that everyone 55 and older would take, cutting their risk of heart attack and stroke by over 80%. At present, these two conditions sooner or later kill roughly half the population in Britain. Of course, changes in lifestyle (improved diet, no smoking, more exercise) could probably produce similar benefits, but it's harder to get people to undertake them within a reasonable time frame. So let's look at the pill proposal carefully.

The idea

The plan involves attacking 4 major cardiovascular risk factors - low density lipoprotein (LDL) cholesterol, blood pressure, serum homocysteine, and platelet function - using medications that are widely accepted as safe and effective. But which drugs to choose, and how effective are they in lowering the risks?

Low density lipoprotein (LDL) cholesterol
Statins are the best sort of drug to lower LDL cholesterol levels. Out of 6 statins analyzed in over 200 studies, three - atorvastatin, simvastatin, and lovastatin - were selected as candidates for inclusion in the Polypill. In normally prescribed doses, they reduce LDL cholesterol by roughly 70 mg/dL (1.8 mmol/L), and cut coronary heart events (i.e. a heart attack or angina) at age 60 by 61%, and strokes by 17%.

Blood pressure
Five sorts of blood pressure medication were studied, using analyses of 350 clinical studies. They were: thiazide diuretics (water pills), beta-blockers, ACE inhibitors, angiotensin II receptor blockers (ARBs) and calcium channel blockers. All 5 types of drug produce similar blood pressure reductions. Using half the standard recommended dose, blood pressure lowering is about 80% of that obtained with the full standard dose. On the other hand, combining three drugs at half-dose strength is caculated to cause a reduction of 20 mm Hg in the top (systolic) number, and 10 mm Hg in the lower (diastolic) number.

Using a three-drug combination would reduce heart attack and angina by 46% and strokes by 63%. While these 'good' effects of high blood pressure drugs can be added together when drugs are combined (as there is only one target - raised blood pressure), the side effects reported are those of the individual drugs used, and usually different for each type of drug, and cannot be added together.

Serum homocysteine
Raised homocysteine levels are known to be associated with an increased risk of heart attack and stroke. Taking 0.8 mg/day of folic acid reduces homocysteine levels by about 25%, and is associated with a reduction in heart attacks and angina of 16%, and in strokes of 24%.

Platelet function
Platelets are likely to clump together if there is any underlying artery wall damage, producing a heart attack (coronary thrombosis, myocardial infarction or MI) or a stroke (cerebral thrombosis). Analyses of 15 clinical trials have shown that a 75 mg/day dose of aspirin is associated with a reduction in heart attacks and angina of 32% and in strokes of 16%.

The Polypill approach

We've outlined the reductions in cardiovascular events by medications acting on the four risk factors. The British professors calculated the effect of taking a pill containing the 6 drugs necessary to influence all four risk factors by multiplying the relative risks associated with each. (This approach has been shown to be valid in previous studies.) In this way, they calculated a theoretical reduction in heart attacks and angina of 88%, and in stroke of 80%.

Taking the Polypill from the age of 55 up to 85 would mean that 30 out of 100 men would avoid a heart attack, angina, or stroke, and would have an estimated 13 extra years of life. Out of 100 women, 24 would avoid these cardiovascular events, and would gain an average of 14 years of life.

The side effects produced by the Polypill would vary slightly, depending on which blood pressure lowering drugs were used. The three types with the lowest risk of side effects (thiazides, ARBs, and calcium blockers) would cause symptoms in about 8% of people on the Polypill. If, on the other hand, the three cheapest types of blood pressure lowering drugs were selected (thiazides, beta-blockers, and ACE inhibitors), side effects would be reported in about 15% of those taking the pill.

Comment

This is an exciting proposal. Millions of people are already taking different combinations of the various drugs that have been proposed, but doing so in response to a recognized increased risk e.g. high blood pressure, high LDL cholesterol, etc. However, the two professors believe that everyone over 55, as well as younger people with known arterial disease, should take the Polypill. They say that there's no need to measure the cholesterol, blood pressure, homocysteine, or platelet function before or during treatment, as the benefits have been calculated for whatever the initial levels of risk. Taking the Polypill should reduce heart attacks and strokes by over 80%, and only 1-2% of those taking it would need to stop because of side effects.

The size of the predicted benefits is remarkable. Only large reductions in smoking and obesity could achieve similar results. And using generic drugs throughout would keep the cost down to less than that of screening regularly for the 4 risk factors. In summary, if the project proves to be feasible (and there are many 'ifs' and 'buts'), the chances of making a big dent in cardiovascular disease look quite bright.