28 Sep, 12 | by BMJ Group
The idea of combining antihypertensive drugs, a statin, and sometimes aspirin into a polypill to prevent heart attacks and strokes is now a dozen years old, but still no drug is licensed in a high income country. This week researchers, funders, regulators, policymakers, and drug manufacturers gathered together in Hamilton, Canada, to review and perhaps accelerate progress.
The problem that the polypill may help to reduce is the huge “treatment gap.” Only a small proportion—perhaps 10%—of the people in the world who already have cardiovascular disease or are at high risk of it receive the drugs that evidence shows unequivocally will help them. Many people are not diagnosed. Of those who are diagnosed many are not treated because of “therapeutic inertia,” unavailability or unaffordability of drugs, and poor health systems. Then most of those who are treated are not treated adequately, which is partly because doctors treat individual “diseases” like hypertension or diabetes rather than the risk of heart attacks and stroke.
Another problem that was emphasised at the summit and is probably underappreciated is the low rate of adherence to treatment. Around half of people prescribed long term drugs have stopped taking them within a year, and most of those who stop do so within the first six months. A third of people may stop after the first prescription.
All this amounts to a huge problem with many more people dying young of cardiovascular disease than die of AIDS. Indeed, since the wide availability of antiretroviral drugs people with AIDS are more likely to die of cardiovascular disease than from AIDS—not least because antiretroviral drugs, particularly protease inhibitors, dramatically increase the risk of cardiovascular disease. Yet there is not political will to combat the “silent epidemic” of cardiovascular disease.
Widespread availability of the polypill won’t on its own solve this problem, but it could probably help considerably because of including all the drugs necessary to reduce risk, ease of use, improved compliance, and low cost. It would have to be accompanied, however, by public health interventions to reduce tobacco consumption and promote healthier diets and physical activity. In most of the world it will also be necessary to strengthen health systems, and, as was said repeatedly, in many places that means extensive use of non-physician providers and mobile technology.
Several different polypills are available from India and Latin America, and there have now been almost 10 trials showing how polypills can as expected reduce blood pressure, lipids, and platelet stickiness. Many more multicentre trials are underway, and an important one, UMPIRE, conducted in Britain and India will report in November. Polypills have low rates of side effects and discontinuation, and the trials have shown reasonable adherence, although most are short term. None of the trials as yet have included clinical outcomes, and debate rages over the importance of outcome studies. An emerging consensus, which even seems to include the Food and Drug Administration (FDA) in the US, is that outcome studies are not needed for licensing of polypills for secondary prevention.
It seems that the FDA may well accept pharmacokinetic, pharmacodynamic, and safety studies to approve polypills for secondary prevention. As was pointed out, getting polypills licensed is an essential step for their development. But polypills present new problems for regulators. The FDA has approved 44 two drug combinations and a couple of three drug combinations but never a four drug combination, which is usually the case with polypills. Although they have not been licensed in high income countries, they have been licensed in Argentina, Mexico, and Guatemala, and at the summit policymakers from Colombia and Brazil expressed enthusiasm for the polypill. (Why, I wonder, should Latin Americans be keener than other countries?)
The pandemic of deaths from cardiovascular disease cannot, however, be addressed simply through secondary prevention. Data from the US showed that only 4% of the adult population has a history of heart attack or stroke and account for only 11% of major acute cardiac events (MACE). Most heart attacks and strokes happen in people at low risk because there are so many more of them.
Regulators almost certainly will want trials with clinical outcomes to approve drugs for primary prevention, and such trials are underway in India, China, the Philippines and other countries. It will be some years before they report, and what is especially difficult is having to do a trial to prove that a fourth drug provides value over three. Such a trial would need huge numbers and probably be unaffordable, and it seems that regulators may not insist on such trials if there is convincing evidence of greater effectiveness over usual care. (An amusing aside occurred in this discussion when I referred to the “thicket” of regulations in Europe, but the Dutch regulator thought that I’d called regulators “thick headed.” We resolved the confusion.)
Getting drugs licensed is one major barrier to widespread use of polypills but another is the attitude of doctors, particularly cardiologists, who believe that they would be doing their patients a disservice by giving them a fixed dose combination rather than titrating the drugs against their blood pressure and blood lipids. We were told how an expert committee of doctors in India were unanimously against the use of the polypill. This, it was argued, was a clear case of the best being the enemy of the good, and the summit included many distinguished cardiologists who support the use of the polypill, although always emphasising the need for accompanying public health action and lifestyle advice.
The other major barrier, which was discussed less at the summit, is the business problem. Big pharmaceutical companies, which could fund big trials, shepherd the drugs through licensing, and market them energetically once licensed, have not been interested in polypills—probably because they don’t fit their familiar “blockbuster business model” (developing new drugs that are sold with very high margins). That model does, however, seem to be ending, and there are stories of big companies becoming more interested.
At the moment, however, the polypills are made by generic companies with little experience of getting drugs licensed and few marketing resources. They can’t see how they can get a return on their investment. Ideally a major health system—like the NHS or the Veterans’ Administration—would commit to a major purchase, but that hasn’t happened so far, although Kaiser Permanente in the US has encouraged use of combination therapy (in blister packs). Several people suggested that a public private partnership would be needed.
Patents might present another barrier, and we were told that there are hundreds of patents surrounding polypills. This is in part because of “patent trolls,” and the advice to those at the summit was to ignore patents. Another issue is that the word “polypill” has been trademarked by a pharmacist in Florida. As is so often the case, we don’t know what to call polypills. It may be better to talk about “fixed drug combinations” or “multidrug treatment.”
Considerable barriers remain to widespread use of the polypill to help close the treatment gap, but there is undoubtedly progress. Despite our impatience we know that it takes on average some 20 years for important innovations to diffuse through health systems—so we are roughly on track. “The polypill will take off. I’m not worried,” said one of the lead researchers, a cardiologist.
For those who would like to know more about what happened at the summit all (or most) of the many presentations will be available on the Population Heath Research Centre website and many Tweets, including about 50 from RS, can be seen at the hashtag
#polypillsummit on Twitter.
Competing interest: UnitedHealth, RS’s employer, helped sponsor the summit, and RS was on the planning committee. He has long been an enthusiast for the polypill, participated in a recent trial, and takes the polypill every night.
Richard Smith was the editor of the BMJ until 2004 and is director of the United Health Group’s chronic disease initiative.