Abstract
Introduction
I first encountered the idea of the polypill on a bus in France in 2002. Seven years later in Clapham, South London, I'm taking five of the components of a polypill every night, but I'm still waiting for the single polypill, although I know that several polypills are available in India. What is the story that has led me from France to Clapham, and where will we go next?
First encountering the concept of the polypill
The bus in France was taking a gaggle of editors from the BMJ [British Medical Journal] Publishing Group to a chateau for a two-day meeting. At that time I was the editor of the BMJ and the chief executive of the BMJ Publishing Group. I was sat next to Nick Wald, a professor of epidemiology and the editor of the Journal of Medical Screening, one of our journals.
Nick thinks differently from most people, as do many first rate scientists. He also loves to debate, believing in the Socratic method. If you say something silly, as I often do, he will be on to you in a shot, asking for your evidence. Some people find this difficult. I like him a lot.
I can't remember how the conversation began, but at some point Nick said something like: ‘If I told you that a pill with several components could prevent most heart attacks and strokes, could you guess the components?’ I had a go. A statin to reduce blood lipids certainly. Aspirin to reduce the chances of blood clotting, something that happens in a heart attack and most strokes, certainly. A diuretic and an angiotensin converting enzyme (ACE) inhibitor, which lower blood pressure, probably. Beyond that I wasn't sure. A professor of cardiology who was with us also had a go – and he simply thought the question was a tease. Once you've heard the basic idea and that there are several components, one can guess most of the components, although not the optimal combination.
Three papers in a ‘collector's issue of the BMJ’
After the bus ride I didn't think much about the polypill until we had three papers submitted to the BMJ in 2003 by Nick Wald and his colleague Malcolm Law. 1, 2, 3 One of these papers made the momentous claim that if everybody started taking a polypill every day at the age of 55 years then around three-quarters of heart attacks and strokes could be prevented. 1 It was momentous not only because it had such a dramatic impact on those conditions but also because those conditions kill about half of the population in developed countries and now a similar proportion in developing countries. Very few interventions in medicine will stop three-quarters of people dying of a condition: indeed, most of medicine is about patching people up. With many treatments the benefits only just outweigh the risks.
The polypill they proposed had six components: a statin, aspirin, three drugs to lower blood pressure (a thiazide diuretic, a beta blocker and an ACE inhibitor) all at half dose and folic acid. Nobody disputes that the first five drugs individually have the potential to reduce heart attacks and stroke, but the inclusion of folic acid is uncertain.
None of the three papers was a trial of using the polypill as Nick and Malcolm proposed – not least because the polypill did not exist. For many that was a problem. Their proposal was theory not fact. But two of the papers were reviews of the huge amounts of evidence already available from trials and other studies of the effects of statins and blood pressure lowering drugs on deaths from heart attacks and stroke. 2, 3 It wasn't a very big scientific leap to think that Nick and Malcolm were right. Many people, including me, might decide that the evidence was strong enough to begin to take such a pill if it was available. Indeed, they might be reluctant to enter a trial, where you might get the placebo rather than the polypill.
By 2002 others had also thought about the idea of a polypill. 4 One crucial point is that the drugs work in different ways and that their effect is additive. So some drugs reduce lipids, others blood pressure and others the tendency of the blood to clot.
The idea proposed by Nick and Malcolm did, however, go beyond what others had considered. First, they had shown in one of their studies that by combining several blood pressure drugs at half dose you could get most of the benefit with few of the side-effects. 3 That's very important if you are going to give the pill to people who feel healthy because they don't feel the benefit (of preventing a heart attack they might have in 10 years' time) but they will feel the side-effects.
Second, Nick and Malcolm proposed giving the polypill to everybody at 55 years without any testing. Conventionally, preventive treatment is given to people who have been determined to be at ‘high risk’ because they have raised blood pressure or lipids, smoke, are diabetic or have a family history. Most authorities – like our National Institute for Health and Clinical Excellence (NICE) in Britain – advise that you should have a 20% risk of having a heart attack or stroke in the next 10 years before you are treated. But for many people a one in five chance of experiencing an event that might kill or severely disable them might seem excessively high. Most vaccines, for example, are given to prevent a dramatically lower risk of death or disablement.
Nick and Malcolm have calculated that you have a 5% risk of a heart attack or stroke in the next 10 years simply through being 55 years old. Indeed, age is such a powerful determinant of your risk that little extra information is added by doing the other tests. Plus many of those who have heart attacks or stroke are at lower than a 20% risk. This seems paradoxical (and is in fact called ‘the prevention paradox’), but the explanation is that there are many more people at lower risk. For example, if there are 100 people at 20% risk then over the next 10 years 20 will have heart attacks or stroke. But if there are 500 people at 8% risk then 40 will have a heart attack or stroke.
A simple, radical and iconoclastic idea
I was excited by the simplicity and originality of the polypill concept, but I was most excited by its radical and iconoclastic nature. I must confess at this point to having an iconoclastic streak.
The polypill potentially upset everybody. It upset doctors because it showed clearly how their traditional practice of ‘diagnose and treat’ simply did not work – because most people who have heart attacks or strokes have never been treated. It upset public health people because of the implication that it could be an alternative to adopting a healthy lifestyle: no need to exercise, stay thin and eat a healthy diet if you could simply pop a pill. There is, of course, no reason why taking a pill and living a healthy lifestyle should not go together. Indeed, it is likely that the health conscious will do both. One public health leader in Britain has suggested that the polypill is like a vaccine – an intervention that has very low risk but substantial protective benefits.
Drug companies are upset by the polypill because a very low cost drug potentially destroys billion dollar markets. It now seems that the polypill can be made for something like a $1 a month, meaning both that preventive treatment becomes available to people in the developing world to whom it had been unaffordable and that drug company profits are destroyed. Pfizer, the world's biggest drug company, has pulled out of developing cardiovascular drugs partly because of the polypill. The implications may be even more profound for drug companies. Their traditional business model has been to invest heavily in research to develop drugs that meet unmet needs and have substantial benefit. Increasingly, however, they are spending huge sums to produce drugs that have only marginal benefit – for example, in people near the end of their lives with cancer – at high cost. The traditional model is collapsing, and they may need to try something new.
Then many people were upset by the ‘medicalization’ implied by everybody over 55 years taking a pill every day. This was a tricky one for me because I have railed against the medicalizing of birth, death, sexuality and other normal parts of life. It made me reflect on what is meant by medicalizing, and I see it as mostly falling into the hands of doctors and other health professionals. If it is that, the polypill is essentially demedicalizing – because you don't have to go to doctors to be tested and then keep visiting to be re-tested and have the doses of your drugs titrated.
So you can see that my radical and iconoclastic streaks were much excited by the polypill, and prompted my enthusiastic introductory remarks to the issue of the BMJ that included the three papers: ‘I suggest, gentle (or even angry) reader, that you keep this issue of the BMJ. It may well become a collector's item. It's perhaps more than 50 years since we published something as important as the cluster of papers from Nick Wald, Malcolm Law and others.’ 5
A scornful reaction
Perhaps partly because I'd got excited, but more because of the radical nature of the ideas, there was a huge response to the articles. And most of it was scornful. For many people the concept was ludicrous and even dangerous. ‘Undoubtedly a collector's item; the issue has been published on a date other than the intended 1st April, Either that, or the BMJ has been deceived by the last gasps of the oxymoronic academic clinical epidemiologists,’ wrote a rheumatologist from New Zealand. ‘The most important issue for 50 years? Yes, in the sense that the editorial board of the BMJ should consider resigning after publication of this issue,’ wrote a neurologist from the Netherlands.
It is interesting for me to look back on those responses for the first time in six years, and generally the reaction now is very different – although not perhaps from those doctors who believe that the true mission of medicine is to treat disease rather than prevent it. One curious feature of the polypill is that many people in their late 60s and older actually end up taking most of the components of the polypill but often when they have disabling disease. Surely it makes more sense to take the pills to stop you developing disease rather than wait until it is well-established.
After the initial burst the polypill story went quiet. Nick Wald and Malcolm, who have a patent on the polypill in Europe, began to try and find ways of bringing the pill to market. But they are not business men and things went slowly. Meanwhile, several manufacturers of generic drugs in India began trying to make the polypill.
Meeting the polypill again in a new role
I left the BMJ in July 2004 and joined UnitedHealth Europe, a subsidiary of an American company that worked with the NHS in the UK. I met with Nick every so often and even arranged a conversation with a health entrepreneur familiar with venture capitalists. I was also invited to a meeting of the Centre for Disease Control in Atlanta to discuss the polypill with a collection of leading international epidemiologists and cardiologists. Some were convinced by the concept of the polypill, although wary of the idea that everybody should be offered the pill without testing. Others were skeptical, but most during the meeting moved to being supportive of the polypill. There was universal agreement that something more was needed than the prevailing strategy of ‘diagnose and treat’ and encourage healthy living. I learnt too at the meeting that a trial was proposed. But the Food and Drug Administration was generally not impressed.
Towards the end of 2006 I became involved with an initiative led by Ovations, part of the UnitedHealth Group, to create centres in low- and middle-income countries to counter heart disease and other chronic diseases. In May 2007 running the initiative became my main job, and I oversaw a process of selecting centres from around the world. Two of the centres we selected – in Bangalore and Delhi – were both planning polypill trials, and a young cardiologist from Harvard, Tom Gaziano, who helped us in our work, was also pursuing the idea of the polypill. I was then contacted by Anthony Rodgers from New Zealand, who had been working with Dr Reddy's Laboratories in India for several years to develop the polypill.
The polypill re-entered my life in a big way. There are perhaps five groups in the world working on the polypill, and I now have close contact with four of them. After some reflection, I decided that I shouldn't tie myself to any one group but should be open with all of them – telling them not to tell me anything that they don't want the others to know.
Beginning to take the ‘polypill’
By now I was 55, and I decided that I ought to demonstrate my commitment to the idea by starting to take the polypill. I can't get access to a polypill, but I can get access to the individual components. I went to see David Wald, Nick's son and a cardiologist. He has established a practice of prescribing the individual components to those who want them. You receive the drugs through the post from a pharmacist in Oxford and have to pay. It costs me £12 a month, and I've been taking them now for about a year.
Nick and Malcolm hold the view that, on present evidence, aspirin should not be part of a polypill for those who have no evidence of established disease because although it will reduce heart attacks and strokes caused by clots it increases the risk of a bleed into the brain or gastrointestinal tract. The lives that would be saved maybe virtually cancelled out by the lives that are lost through bleeds, and – crucially – the bleeds might happen without warning, whereas the side-effects of the other five drugs are milder and come on slowly, meaning that people can stop taking the pill.
In people with established disease, however, the benefits of aspirin are greater – because the risks of a heart attack or a stroke are greater – whereas the risks remain the same, meaning that aspirin is included in the polypill for them.
Once a week I prepare my five pills by placing them into a pill box with a container for each day of the week. Into each container I put the folic acid, the statin (simvastatin) and the ACE inhibitor (lisinopril). Then I have to take my pill-cutter and cut in half the thiazide diuretic (bendroflumethiazide) and the calcium channel antagonist (amlodipine). This is awkward and messy because the pills are crumbly. I put half of each of the pills into each container. At night I swallow down the pills as I get into bed. Remarkably I've hardly missed a day, despite doing a lot of travelling.
The only common side-effects of these pills is the cough that can come from the lisinopril. I did have something of a cough at the beginning, but it was never really troublesome. Something like 10% of people are supposed to get the cough, but Nick thinks that almost everybody does – but most people are not bothered by it. If you are bothered you can switch to another – and more expensive – angiotensin receptor blocker.
David is, I believe, treating nearly 200 people in his programme – including himself (despite being under 40), Nick and Muir Gray, one of Britain's health leaders and visionaries – and the vast majority find it easy and keep going. It would, however, be much easier to take just one pill and avoid the weekly chopping session. What are the chances?
A plethora of polypills
There are now several polypills – including the polypill of Nick and Malcolm, the Red Heart Pill of Dr Reddy's Laboratories and the Polycap of the Bangalore Group. All the pills have been manufactured in India, and it has not been a straightforward process. Importantly the Bangalore group has published a trial in The Lancet in March 2009 showing that people will take the polypill, that it does reduce blood pressure, blood lipids, blood stickiness and heart rate, and that it has few side-effects. 6 The Polycap was used in this study, and it was not quite as effective as the pills individually or as Nick and Malcolm predicted – meaning that it might reduce heart attacks and stroke by 50% rather than 80%, still a remarkable reduction. There are, however, various technical reasons for think that the ‘true’ figure may be nearer to 80%.
This study and other similar but unpublished trials may mean that the regulatory authorities in Europe and the US may license the polypill to be taken by those with established heart or cerebrovascular disease – because these drugs, including aspirin, should be prescribed anyway for these people. Once the polypill is licensed for one use doctors are free to prescribe it for other uses if they believe there is benefit. It might thus be that I could start taking a polypill in 18 months – before I'm 60.
Remaining barriers
But the polypill may not be widely available in Europe and the US for several years for a variety of reasons.
First, the regulatory authorities may not license the polypill for use in people without established disease (including me) until they have the results of a trial showing that it does reduce heart attacks and strokes. Such a trial is now planned in India, but it is a major undertaking that will need thousands of patients and at least three years' follow-up. The trial will cost over £5 m and will be funded by the Wellcome Trust.
Even when this trial is completed there will be continuing debates over whether the pill should include aspirin, at what level of risk people should be treated, whether it can be acceptable to treat people simply on the basis of age and whether the pill can be off-prescription. It is likely to be at least 10 years until the concept of Nick and Malcolm will be implemented.
A second barrier to making the polypill widely available is the attitude of some prominent doctors. Cardiologists in particular prefer ‘bespoke treatments’ where patients' risk factors are regularly measured and drugs titrated accordingly. This strategy might be better for some individuals, but it will be very expensive and will not have the same overall impact because many people will remain untreated.
The final barrier – and perhaps the most important one – is the business barrier. If a major drug company were interested in the polypill then they might rapidly overcome many of the barriers, but they are not interested because the profit margin is so low. It is generic manufacturers who are interested in the polypill, but they do not have the funds to conduct major trials, are unfamiliar with getting new drugs onto the market, and lack the marketing power that will be needed to persuade millions of doctors to prescribe the polypill. It is impossible for these companies to produce credible business plans that will show an acceptable rate of return on investment. It is thus hard for them to keep going despite their commitment to the idea.
So the story is incomplete. I remain convinced that the polypill concept is brilliant and will prevail. What I do not know is how long it will take.
Footnotes
DECLARATIONS
Footnotes
Acknowledgements
This article was written as the foreword to a book on the polypill written by Shaun Holt, a New Zealand GP. The book [Miracle pill]: Will you take the polypill? was published by Star Books in June 2009