Richard Smith: The polypill and the long journey to major impact

richard_smith_2014You’ve no doubt heard the saying that it takes 18 years for an innovation to be widely adopted in health systems. That should mean that time is up for the polypill (or fixed dose combination in current jargon) to prevent cardiovascular disease to be having a major impact, as the idea was floated in the late 90s or early 2000s, depending on who you think advanced it first. But, as a recent meeting at the London School of Hygiene and Tropical Medicine heard, progress remains slow, although one polypill, Trinomia, is licensed in 21 countries but not widely used.

There are multiple business, regulatory, manufacturing, and cultural blocks to the widespread use of the polypill, but one central one is the refusal of the World Health Organization (WHO) to allow the polypill onto the essential medicines list despite three applications in recent years. The first application was rejected for being unclear on the indication (both primary and secondary prevention); the second for being a concept with too many variants of three and four drug combinations; and the third for having neither a guideline nor an adequate strategy to support its widespread use. The rejections strike enthusiasts for the polypill as deeply unfair as polypills (fixed dose combinations) for HIV, TB, and malaria have all been allowed onto the list with what the cardiovascular polypill enthusiasts see as much less evidence.

A great strength of the meeting was that it included not just enthusiasts for the polypill, but also the secretary and one of the cochairs of the committee which meets every two years and decides which drugs will be allowed onto the essential medicines list. Also there were people from the worlds of HIV, TB, and malaria to discuss why they had been successful when the polypill enthusiasts had failed.

Two moments in what was a long and with luck productive meeting stood out for me. One was Martin Rosas-Peralta from Mexico explaining that the public health system in Mexico had agreed to pay for the polypill because it was “a strategy not just a pill.” What he meant was that use of the the polypill is part of a strategy that includes how it will be provided, promoted, delivered, and prescribed to solve the major problem that many Mexicans were dying of heart attacks and strokes without ever having received treatment.

The second moment was a short video made by Médecins Sans Frontières in which a patient from rural South Africa explained that she had long been taking one drug (a polypill) for her HIV but now had to take nine drugs as she had developed hypertension and diabetes. We know that multimorbidity is common in both high and low income countries and that many people in Britain, for example, are also taking nine drugs. Polypills could help, and there is strong evidence from trials that patients like polypills for the simple reason that they reduce the number of drugs they have to take. GPs are also coming round to them, but many cardiologists remain against them, clinging to their “measure and titrate” strategy, which, as Diederick Grobbee from the European Society of Cardiology said, simply doesn’t work in public health terms in that most people in the world at risk (at least 80%) remain undetected or untreated.

Nicola Magrini, the secretary of the essential medicines list committee (a full time position), picked up on the comment by Rosas-Peralta and said that the applications for the cardiovascular polypill had failed because there was no strategy to support its widespread adoption. Plus simply listing it without clear guidance of how it should be used and how it improves the current approach of treating individual risk factors (high blood pressure, hyperlipidaemia, etc) could cause confusion. How would the polypill reach the people who needed it most? How would it have impact on a major scale? How would its use relate to current guidelines and programmes on treating individual risk factors with separate drugs?

In contrast, polypills for HIV, TB, and malaria had been admitted to the list because there were clear strategies showing the need and the programmes that would be used to get the polypills to the people who needed them. Tackling the infections was a target in the Millennium Development Goals (MDGs), WHO and UNAIDS had programmes, and there was funding from the Global Fund for AIDS, TB, and Malaria and PEPFAR (President’s Emergency Plan For AIDS Relief).

Non-communicable disease (NCD), including cardiovascular disease, was not included in the MDGs but is included in the Sustainable Development Goals—albeit along with more than 150 other targets. Funding has been hard to come by for responding to NCD despite it accounting for two thirds of global deaths, and WHO in Geneva, as the meeting heard, has only one person working on cardiovascular disease. The polypill should be part of a new strategy for reducing death and suffering from cardiovascular disease based on assessing risk of cardiovascular disease and treating overall risk. With adequate guidance and resources a billion people might be helped. (Ironically the bold and much criticised strategy proposal in The BMJ in 2003 of offering the polypill to everybody above a particular age might be simpler to implement at scale than more complicated strategies of assessing risk or prescribing the polypill for those who have established disease.)

Getting a polypill or polypills onto the essential medicines list will not solve all the problems of making polypills widely available, but it’s a necessary if not sufficient step for the polypill being used in low and middle income countries where most of the patients are and most are untreated. High income countries pay little attention to the essential medicines list, but low and middle income countries rarely adopt a drug that is not on the list.

The challenge to polypill enthusiasts is not to produce more evidence of polypills’ effectiveness or even cost effectiveness, but to develop and test a strategy of how polypills can be delivered to the people who need them the most with the full support of all stakeholders, including those like cardiologists who are currently sceptical. WHO and those who work on the essential medicines list will help in this effort because everybody in the room shared the aim of reducing deaths from NCD by 30% by 2030.  

It’s unlikely that such an ambitious target can be achieved without widespread use of the polypill for cardiovascular disease.

Richard Smith was the editor of The BMJ until 2004.

Competing interest: RS was the editor of The BMJ when it published key articles on the polypill in 2003, remains an enthusiast for the polypill, and takes the “polypill,” although he’s disappointed that he has to take three separate pills rather than a polypill. He has no financial interest in the polypill.