Healthy Skepticism Library item: 16111

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Publication type: news

Reddy SK.
Can polypill replace poly-policy for heart health?
The Hindu 2009 May 6
http://www.hindu.com/2009/05/06/stories/2009050655071000.htm

Abstract:

Rational combinations of proven life-saving drugs have a role in the secondary prevention of cardiovascular disease. But there is no acceptable substitute for creating social conditions that stimulate, support, and sustain healthy living habits across the lifespan.

Full text:

Considerable media interest has recently been evinced in the use of a ‘polypill,’ as a means of protection against heart attacks and strokes. The published results of an Indian ‘polycap’ trial provided the immediate source of excitement, even though the idea of a ‘combination pill’ or ‘polypill’ for protection against cardiovascular diseases (CVD) has been around for some years.

The rationale for a polypill evolved over the last two decades of the 20th century, when a series of large clinical trials demonstrated that four classes of drugs were highly effective in reducing the risk of recurrent heart attacks and death in persons who survived a first heart attack. These drugs (beta-blocker, aspirin, ACE-inhibitor and statin) were not only effective when given individually but also had incremental benefit when added to one another. It has therefore become the standard practice to prescribe all of these drugs to a post-heart attack patient for ‘secondary prevention’ of further adverse events.

The other dreaded cardiovascular event is a ‘stroke,’ or paralysing ‘brain attack.’ Although the clinical manifestation is neurological, the underlying cause lies in blocked blood vessels and impeded blood flow. One of the main causes of a stroke is high blood pressure that is unrecognised, untreated, or poorly controlled. Blood pressure-lowering drugs have been shown to reduce the risk of a stroke, heart attack, and death. Such drugs include diuretics, ACE inhibitors, and betablockers. Cholesterol-lowering statins have also been shown to reduce the risk of one major form of stroke (‘ischemic’ stroke produced by blood clotting). Aspirin is highly effective in reducing the risk of an ischemic stroke but increases the risk of a ‘haemorrhagic’ stroke, resulting from bleeding into the brain. Aspirin and statin are not helpful in preventing a haemorrhagic stroke, which is mainly linked to high blood pressure.

Even a first heart attack can be prevented by lowering blood cholesterol and pressure as well as by reducing the clotting ability of blood. However, it is not clear whether four or five drugs are collectively beneficial and needed, as clinical trials of ‘primary prevention’ have not employed such four or five drug combinations to assess impact on CVD or death. Indeed, while some primary prevention trials of aspirin suggested benefit in terms of reducing the risk of heart attack or death, others indicated that net harm may result from an increased risk of bleeding related strokes.

In 2001, a scientific meeting organised by the World Health Organisation and the Wellcome Trust called for the development of a ‘combination pill’ for secondary prevention of CVD. The rationale lay in the potential for improved patient adherence (‘one pill is easier to swallow than four’) and lower cost (anticipated but not estimated). The frequently observed under prescription of these life-saving drugs by doctors was also expected to be overcome by making the prescription simpler. Spurred on by this report, an Indian drug manufacturer set about developing a ‘red heart pill’ in 2002.

In 2003, Wald and Law published a landmark article in the British Medical Journal, in which they modeled the potential benefit of combining six drugs for ‘primary prevention.’ Folic acid was recommended for addition to aspirin, betablocker, ACE-inhibitor, statin, and a diuretic. It was argued that since these drugs could prevent the first heart attack or stroke in persons with predisposing risk factors, all persons above the age of 55 years should be administered this ‘preventive polypill.’ This, they said, would reduce the risk of CVD by 75 per cent.

This claim generated huge waves of interest as well as controversy. While folic acid was not shown to be protective against CVD in later trials, several efforts commenced to combine three or more of these six drugs. One of these involved a clever packaging of six drugs in a single capsule, avoiding the need to prepare blended tablets. This ‘polycap,’ prepared by an Indian firm, was tested for its efficacy in persons who did not have a prior heart attack or stroke but had at least one of several risk factors (ranging from hypertension to smoking). This ‘proof of concept’ trial did not test impact on major CVD events but observed reductions in blood pressure and blood fats (though to a lesser extent than predicated by Wald and Law). In the meanwhile, others from India, New Zealand, the U.K., Iran, and Spain have set out to develop blended pills, using different combinations, and are ready to launch major trials of ‘primary’ or ‘secondary’ prevention.

Several scientific questions currently remain, especially with respect to primary prevention. Are three or four or five drugs required and will the increasing number provide incremental benefits that exceed the risks and are worth the cost? How will this drug combination compare with behaviour change involving healthy diets, regular exercise, and smoking cessation? Will only one or two drugs, along with behavioural interventions, equal a four or five drug combination in primary prevention, even if some drug therapy is required? Should poly-drug therapy be reserved for persons at a high ‘absolute’ risk of a future CVD event, usually because of multiple co-existing risk factors?

Practising physicians have been uncomfortable with the idea of a fixed dose combination. They wish to retain the freedom of ‘titrating’ each drug according to an individual’s clinical response. Trialists regard this as unwarranted caution and argue that trials have validated the effective dose of each drug, which then goes into a combo pill. It is conceivable, however, that several combo pills may emerge with different dose levels to permit a range of prescribing options.

The major criticism directed at the claim that the polypill will be the panacea for preventing CVD comes from the public health community who view it as a purely biomedical approach to a problem wherein deranged biology has many social determinants and behavioural causes. If those antecedent causes are not addressed, increasing numbers of individuals from each successive generation would have to be put on a pill at some stage of their lives. These critics also worry that the promised protection of a polypill may work against people giving up unhealthy habits like smoking or bad diets.

It is clear that the decline of CVD in developed countries over the past four decades has been the result of policies promoting healthier behaviours as well as improved clinical care. At least 50 per cent of the observed decline in CVD-related death in these countries has been ascribed to shifts in population risk profiles of diet and smoking. In the United Kingdom, 48.1 per cent of the total mortality decline observed during 1981-2000 has been attributed to a decline in smoking.

Finland was at the top of the global league table for coronary heart disease related deaths at the beginning of the 1970s. Major population-based programmes, involving community health education, tobacco control as well as marketing of food products with lowered salt and saturated fat, have sharply reduced coronary mortality and made Finland the poster child of CVD prevention in Europe.

The recent recommendations from the World Health Organisation, the World Bank, and several other international expert bodies estimate that tobacco control and reduction of salt in diet will save millions of lives over the next 10 years. If trans-fats are removed or reduced and saturated fat as well as sugar are reduced in processed foods, the gains will be even greater. Fruit and vegetables have been shown to be protective both against CVD and cancer. Policies that influence their production, processing, and pricing will affect the population risk of CVD. Similarly, urban design and transport policies can greatly enable physical activity by providing protected cycle lanes, safe pedestrian pathways, parks, and community sporting facilities.

Some countries have used fiscal policies, taxation, and regulation to advance these goals. When Mauritius substituted soya oil for palm oil as the subsidised ration oil in the public distribution system, the mean population level of blood cholesterol declined. Withdrawal of subsidies for animal foods and increased import of vegetable oils and fruit led to a sharp decline in CVD mortality in Poland in mid 1990s. The U.K.’s food and health agencies have prevailed upon the food industry to progressively lower salt in processed foods. Denmark has removed trans-fats from manufactured food products while New York has banned their use in restaurants, bakeries, and hotels. Following the U.S. precedent, soft drink manufacturers are responding to pressure from public health advocates by promising to remove sugar-rich beverages from schools around the world. The U.K. and the European Union are placing restrictions on advertising of junk foods to children. Tobacco taxes are being increased in many countries, to raise prices and reduce consumption.

It is worth noting that these regulatory measures are being taken even in free market countries, to make it easier for people to make and maintain healthy living choices. The libertarian outcry against a ‘nanny state’ trying to influence individual behaviour seems particularly misplaced at a time when the global economic crisis has reinstated the state’s role of a responsible regulator. It is imperative that governments facilitate the creation of social conditions that stimulate, support, and sustain healthy living habits across the lifespan. By preventing the augmentation or acquisition of risk in the first place, such policies will benefit future generations too.

The bottom-line? As a cardiologist, I welcome the availability of rational combinations of proven life-saving drugs in easily administered and cost-saving formulations, especially for the secondary prevention of CVD. As an epidemiologist and public health advocate, however, I would like to caution against proclaiming the polypill as the principal pathway to primary prevention of CVD. A poly-policy approach involving health education and multi-sectoral strategies for promoting healthy behaviour is the more rational, cost-effective, and sustainable approach for primary prevention. Poly-policy and pill are of course not mutually exclusive.