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Is the polypill realistic?

Dr Irene Chung and Professor Gregory Lip review the available evidence and ask...

Coronary heart disease and stroke are major problems in the UK. CHD is the biggest killer, accounting for 124,000 deaths each year2. Its prevalence is 3-7 per cent of the population, making it a major public health problem3,4 and conferring significant economic cost5. There are some 60,700 stroke deaths each year. Clearly, a more aggressive approach is needed to relieve such a burden.

The idea of taking one pill to substantially reduce cardiac and stroke risk would surely be welcomed by many patients. Wald and Law have suggested the use of a polypill that would do just this (see box above). A low-cost polypill could use generic components and would surely make economic sense. Is it really realistic?

Research evidence

Blood pressure-lowering agents Wald and Law's meta-analysis of more than 200 studies shows the use of statins can lower LDL cholesterol by 1.8mmol/l, which could reduce the risk of IHD by 60 per cent and stroke by 17 per cent6. Their review of 354 randomised controlled trials found that giving a combination of blood pressure-lowering drugs at half the standard dose can significantly lower blood pressure, which in turn would reduce the risk of stroke by 63 per cent and IHD by 46 per cent7.

However, the effect of such triple therapy at 'half doses' has not been tested in prospective randomised controlled clinical trials. In the Prospective Studies Collaboration8, involving an analysis of one million adults, each increase of 20mmHg usual systolic blood pressure

was associated with a more than twofold increase in stroke, as well as an increase in IHD death rate.

Other trials such as the Hypertension Optimal Trial (HOT)9 study suggest the maximum benefit of treatment lies between a blood pressure of 130 and 140mmHg systolic and 80-85mmHg diastolic. For diabetic or renal patients more intensive blood pressure control to below 130/80mmHg has been advised10. In many cases, a combination of all agents of the polypill is not necessarily required, nor may this be the most suitable combination.

ACE inhibitors For the secondary prevention of cardiovascular disease there is overwhelming evidence that the use of ACE inhibitors significantly reduces cardiovascular mortality and morbidity (for example, trials such as HOPE11, EUROPA12 and PROGRESS13) and that ACE inhibitors may have benefits beyond that of blood pressure-lowering effects alone.

There is some evidence (in heart failure, at least) that using the optimal full dosage of ACE inhibitors is better than low doses (or half doses, as in the polypill). Similarly, ACE inhibitors or angiotensin receptor blockers are usually first-line antihypertensive agents in diabetic or renal patients, unless contraindicated, and optimal doses of this class of drug similar to that used in the trials should be administered.

Folic acid The authors also claim lowering serum homocysteine by 3µmol/l can reduce IHD events by 16 per cent and stroke by 24 per cent ­ however, this is based on the findings from 46 genetic studies and 16 cohort studies. To our knowledge there is only one placebo-controlled randomised tria · 14, of only 205 patients taking folic acid (1mg), B6 (10mg) and B12 (400µg), which showed a significant reduction in coronary artery re-stenosis

(19.6 per cent versus 37.6 per cent) following percutaneous coronary angioplasty.

Therefore, good trial evidence for folic acid in treating cardiovascular disease is actually quite weak. Indeed, large clinical trials have yet to confirm the use of folic acid in both primary and secondary prevention of IHD and stroke, and the emphasis on folic acid in the polypill still needs some justification from stronger evidence than that derived from cross-sectional studies.

Aspirin Wald and Law5 also analysed 15 randomised trials using low-dose aspirin (50-125mg) and suggested IHD events could be reduced by 32 per cent and strokes by 16 per cent. But an analysis from Sanmuganathan and colleagues15 suggests aspirin treatment for prevention is safe and beneficial only if the coronary event risk is 1.5 per cent/year, is safe but of limited value at a coronary risk of 1 per cent/year, and probably unsafe at a coronary event risk of 0.5 per cent/year. Therefore, women under 65 without other risk factors would probably not benefit from it. Many patients with concomitant conditions such as atrial fibrillation would not derive adequate thromboprophylaxis from aspirin, and if warfarin were added, the risk of bleeding would be higher with concomitant aspirin use.

Other limitations

The polypill may not be suitable for asthmatics or people with heart block and gout because of the presence of ?-blocker and diuretic. The authors claim the doses used have a fairly good safety profile but this has yet to be proven in clinical trials.

Wald and Law5 conclude that any

individual over 55 or diabetic or with any history of cardiovascular disease should take

the polypill. This then leads to the question of cost-effectiveness.

Given limited NHS resources it is vitally important we allocate them correctly. It is crucial to assess and address each individual's risk profile with the necessary and clinically proven drugs in a rational way. Statistical methods and meta-analyses of population data can only adjust for some, but not all, biological processes in the individual patient.

Alternative strategies

There may be more proven strategies to reduce heart attacks and strokes. Indeed, Capewell and colleagues16 studied the decline in CHD mortality in Scotland between 1975 and 1994. They concluded 40 per cent of the benefit was due to 'active' treatments (including initial treatment for acute MI 10 per cent, hypertension 9 per cent, secondary prevention 8 per cent, heart failure 8 per cent, aspirin for angina 2 per cent and revascularisation 2.1 per cent), while 51 per cent of the reduction was down to risk-factor management (smoking 36 per cent, cholesterol 6 per cent, blood pressure 6 per cent and changes in deprivation 3 per cent).

Although the remaining 9 per cent reduction in CHD mortality was due to other unquantified factors it seems clear that smoking may be the most important risk factor to be tackled. A similar finding was observed with regard to the decline in CHD mortality in New Zealand between 1982 and 199317. Therefore, smoking cessation should be an important part of the strategy to reduce cardiovascular disease.

Another example of a simple, proven strategy to reduce cardiovascular and stroke risk is the detection, treatment and control of hypertension. High blood pressure is probably the most important risk factor for cardiovascular disease, and by achieving the target of systolic <140mmhg there="" would="" be="" a="" reduction="" of="">

28-44 per cent in stroke and 20-35 per cent in ischaemic heart disease, depending on age. This would prevent some 21,400 stroke deaths and 41,400 ischaemic heart disease deaths each year.

These translate to approximately 42,800 strokes and 82,800 ischaemic heart diseases saved, making a total of 125,600 events saved per year in the UK18. These numbers ­ or the lack of effort to do anything about it ­ makes depressing reading, even to the most cynical of epidemiologists and statisticians.


1 Wald NJ, Law MR. A strategy to reduce

cardiovascular disease by more than 80 per cent.

BMJ 2003;326:1419-24

2 Coronary heart disease statistics. BHF Statistics Database 2002

3 Brady AJB et al. Secondary prevention in 24,431 patients with coronary heart disease: survey in primary care. BMJ 2001;322:1463-6

4 Nanchahal K et al. Analysis of predicted coronary heart disease risk in England based on Framingham study risk appraisal models published in 1991/2000. BMJ 2002; 25:194-5

5 Liu JL et al. The economic burden of coronary heart disease in the UK. Heart 2002;88:597-603

6 Law MR et al. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart and stroke: systemic review and meta-analysis.

BMJ 2003;326:1423-7

7 Law MR et al. Value of low dose combination treatment with blood pressure lowering drugs.

BMJ 2003;326:1427-31

8 Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for

one million adults in 61 prospective studies.

Lancet 2002;360:1903-13

9 Hansson L et al. Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension; principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;51:1755-62

10 European Society of Hypertension. European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003;21:1011-53

11 Heart Outcomes Prevention Evalution (HOPE) Study investigators. Effect of ramipril on cardiovascular events in high-risk patients.

N Engl J Med 2000;42:145-53

12 The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril on reduction of cardiovascular events among patients with stable coronary coronary artery disease: randomised,

double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003;362:782-8

13 PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with

previous stroke or transient ischaemic attacks.

Lancet 2001;358:1033-41

14 Schnyder G et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001;345:1593-600

15 Sanmuganathan PS et al. Aspirin for prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials. Heart 2001;85:245-6

16 Capewell S et al. Contribution of modern cardiovascular treatment and risk factor changes to the decline in coronary disease mortality in Scotland between 1975 and 1994. Heart 1999;81:380-6

17 Capewell S et al. Explanation for the decline in coronary heart disease mortality rates in

Auckland, New Zealand, between 1982/93. Circulation 2000;26:1511-6

18 He FJ, MacGregor GA. Cost of poor pressure control in the UK: 62,000 unnecessary deaths per year.

J Human Hypertens 2003;17:455-7

What is the polypill?

In a recent BMJ Wald and Law came up with a revolutionary idea to address the scourge of CHD and stroke, by the formulation of a 'polypill'1.

This was meant to be a combination drug that included a statin (for example atorvastatin 10mg or simvastatin 40mg), three blood pressure-lowering drugs (such as a thiazide, a ?-blocker and an angiotensin-converting enzyme inhibitor, each at half-standard dose), folic acid (0.8mg) and aspirin (75mg).

They claimed the polypill (if taken, and, more importantly, tolerated) could reduce ischaemic heart disease events by 88 per cent and stroke by up to 80 per cent.

They even advised that everyone aged over 55 or with existing cardiovascular disease would benefit from it, even without requiring risk factors to be measured.

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