By coincidence on Friday my new polypills arrived together with the results of a major study confirming that use of the polypill containing a statin and four antihypertensives in people without established disease can cut cardiovascular events by at least a third—and closer to half if people take the pill regularly.
The two arrive more than 17 years after The BMJ published a paper arguing that if everybody started taking the polypill at age 55 then heart attacks and strokes, still the world’s major killer, could be cut by 80%. I was the editor then and wrote a somewhat flippant “Editor’s choice” suggesting that this might be the most important issue of The BMJ for 50 years. The suggestion was greeted with scorn, but is remembered, probably because of its extravagance, but could still be true.
The new study published in the New England Journal of Medicine is a randomised trial of a polypill (a statin plus three antihypertensives) plus or minus aspirin in 5713 people with a mean age of 64 without established cardiovascular disease but some risk factors. In other words, these are like most people of that age in the world. Taking the polypill reduced cardiovascular events in the next 4.6 years by a fifth and by a third if the people took aspirin as well. The trial was conducted in nine countries (Bangladesh, Canada, Colombia, India, Indonesia, Malaysia, Philippines, Tanzania, Tunisia) with half of the patients coming from India, and problems of supplying the drug complicated by the pandemic meant that about a third of the patients were not taking the drugs all the time. The researchers calculated that those who took the polypill and aspirin all the time had a 40% reduction in cardiovascular events.
The trial started with 7534 patients, but 1821 were excluded after a run-in phase because of side effects attributed to the polypill and aspirin (715), not taking the pills regularly (560), or decline to be randomised (458). People were thus selected for not suffering from side effects and taking the pills regularly. Nevertheless, more patients taking the polypill (2.7%) or the polypill plus aspirin (3.1%) experienced hypotension or dizziness than in the placebo groups (1.1%, 1.5%).
These results join those of a pragmatic cluster-randomised trial reported in the Lancet of using a polypill (a statin, aspirin, and two antihypertensives) in 6838 people in Iran, some with and some without cardiovascular disease. That trial found a reduction of cardiovascular events of just over a third in those taking the polypill and of more than a half in those who took the polypill regularly.
The trials have comparable results, but they fall short of the 80% reduction predicted in The BMJ 17 years ago. One reason is obviously adherence, but the trial reported last week found that participants did not have the effect that the researchers expected from their pilot studies in reductions of blood pressure, heart rate, and blood lipids. Even in the pilot studies the researchers did not find the reductions The BMJ paper predicted—but the authors of The BMJ paper did find exactly the reductions they expected in a double-blind, cross-over trial in which I participated. The polypills have all used slightly different combinations of drugs, which may provide some of the explanation for the different results.
We seem now to have good evidence that the polypill can reduce cardiovascular events and deaths by at least a third and probably by half in those who take the polypill regularly. It also remains possible that even better results could be achieved with the optimal components of the polypill. But as 18 million people a year die from cardiovascular events (80% of the deaths in low and middle income countries) and millions more are disabled by the events, widespread use of the polypill would have a major impact.
Had the trial reported today been of a new and expensive drug manufactured by a major drug company then the results would have been beamed around the world and covered on the front page of newspapers and in all major news bulletins. In fact it’s raised hardly a squeak and merits no mention on the BBC. (I find it impossible not to contrast the coverage of this detailed 13-page report in a major journal with that of an unpublished trial of a new vaccine for covid-19).
Not only does the polypill, which could probably be made available for a dollar a month, not have the support of a major drug company, but it also threatens lucrative markets the companies already have. It also disturbs cardiologists who feel despite the evidence that tailored treatments that are regularly monitored must be better. Public health people don’t like the polypill because they feel that healthy lifestyles must be better—even when for many systemic reasons most people can’t achieve them. Plus randomised controlled trial evidence has been lacking for the benefits in those without established disease, providing an excuse to those who don’t like the idea of mass medication for whatever reason. That excuse is disappearing—may, indeed, have disappeared.
WHO has three times considered the polypill for the essential drugs list and turned it down every time. Although the list does include polypills for HIV infection and other infections, a pill with four or five components makes WHO nervous. Then there is the problem of exactly what they are approving—a concept, a strategy, or a particular combination of pills? I hope that this new evidence will mean the polypill does make it onto the essential drug list.
Meanwhile, I’ve been taking the polypill (or a version thereof) for more than a dozen years. I haven’t had a cardiovascular event—but I might not have done anyway. I did think that I had a cough caused by the polypill at the beginning, but I was challenged to stop and restart the pill to establish whether the cough was actually caused by the polypill. I discovered it wasn’t. I’ve not had any other side effects. I haven’t seen the cardiologist who started me on the polypill since the very beginning: I receive the pill (or pills) through the post every three months after completing a questionnaire reporting that I haven’t had any side-effects. I pay about £25 a month for the pills. Like many men, I wouldn’t take them if I had to go the doctor every three months to be tested.
Originally I did have just one polypill to take, but the company who made them stopped. Another company manufactured another polypill, but eventually it stopped as well. For years I’ve had to take three or four pills a night, which is why I’m excited to again to be back to one with last week’s delivery.
I don’t regret my flippant piece of 17 years ago, and I think that we will move to a place where everybody is offered the polypill at 55. The irony is that many people in their 60s and 70s end up taking most of the components of the polypill (separately and expensively) after they have had cardiovascular events.
And perhaps the most exciting thing about the polypill is that the concept—of combining cheap, off-patent drugs with different modes of action—can be effective in many other conditions, including diabetes, depression, asthma, chronic respiratory disease. Making cheap pills available to everybody is a better route for global health (but not business) than developing new, highly expensive drugs that only a few people can afford.
Richard Smith was the editor of The BMJ until 2004.
Competing interest: As this article makes clear, RS has long been an enthusiast for the polypill and his been taking it himself for more than a dozen years. He has also worked with authors of the new study and was director of the UnitedHealth part of the UnitedHealth/NHLBI Centres of Excellence programme that was one of the funders of the centre at St John’s Medical College, Bangalore, India, which is one of the leaders of the new study.