Richard Smith: A gamechanger for the polypill?

Richard SmithIt is now some 15 years since the emergence of the idea and supporting evidence that combining antihypertensives and a statin into a single polypill and giving it to people daily could dramatically reduce morbidity and premature mortality from heart disease and stroke. Yet polypills are still not licensed in any high income country, although they are in India and some Latin American countries. Today JAMA publishes a paper that may prove a gamechanger.

Barriers to wider use of the polypill include lack of interest from major drug companies who are making lots of money from more expensive drugs, regulators being baffled, public health practitioners worrying about medicalisation, and clinicians, particularly cardiologists, assuming that a fixed dose pill must be inferior to titrated treatment.

It’s the last of these barriers that today’s paper attacks, and if more cardiologists begin to support the polypill then the other barriers might quickly crumble.

The new UMPIRE trial randomised 2004 people with established cardiovascular disease or at high risk of disease to either a fixed dose polypill containing two antihypertensives, a statin, and aspirin, or to usual care—that is titrated care. After a median follow up of 15 months those receiving the polypill had 30% better adherence and consequently significantly lower blood pressure and lipids. In the third of patients with very low adherence at baseline blood pressure and lipids were dramatically lowered in the group given the polypill. There was no difference in adverse events.

Importantly this trial was conducted in a group of patients where there is no argument about the evidence for prescribing antihypertensives, a statin, and aspirin. The argument continues about the benefits in those at lower risk.

For those who have studied adherence the results are not surprising. In short, adherence is horrible, with something like half of patients having low adherence or simply stopping the drugs. Clinicians perhaps like to deceive themselves about how much their patients take their drugs, but most know it’s poor. There are many complex and interrelated reasons for poor adherence, and a Cochrane review showed that most interventions to improve adherence have only a small effect. A 30% improvement is unusual.

Regulators are baffled by the polypill because they have never approved a drug with four components, but there are signals that they may be willing to license polypills on the basis of bioequivalence rather than clinical outcomes. We already have the bioequivalence data for many polypills. This new study showing a big improvement in adherence may be enough to nudge the regulators over the licensing line.

The UMPIRE study didn’t include any economic data, but polypills can be manufactured for a dollar for a month’s treatment. But the big savings come less from the cost of the drug than from the reduced need for visits to the clinician. Widespread use of the polypill could produce substantial savings in high income countries, but it’s low and middle income countries that would see the biggest benefits: 80% of heart attacks and strokes occur in people in those countries and at a younger age than people in high income countries.

Critics of the polypill perhaps forget that the problem that the polypill is trying to solve is that most people in the world with established cardiovascular disease do not get any treatment despite indisputable evidence of benefit. Even in high income countries half of those with coronary disease and two thirds of those with stroke are not treated.

The UMPIRE study shows the way to reduce the burden of the world’s major killers and causes of suffering.

Competing interest: RS has been an enthusiast for the polypill since the very beginning, participated in a polypill trial, and has been taking either the individual components or the polypill for five years. He can take a polypill, although it is not licensed in Britain, because of his participation in the trial. It costs him £12 a month. You could get it too by visiting RS receives no financial benefit from the polypill.

Richard Smith was the editor of the BMJ until 2004 and is director of the United Health Group’s chronic disease initiative.