The use of preventive medications in people at high risk of cardiovascular disease is conceptually straightforward and yet in practice the adoption is disappointingly low and there is wide international variation. There are several barriers that might explain this shortfall and variation. The simplicity and economy of a polypill strategy might overcome some of these barriers.
The “Use of a Multidrug Pill In Reducing cardiovascular Events” (UMPIRE) trial assesses whether a polypill strategy (combining aspirin, a statin and two blood pressure lowering agents) will improve adherence to guideline-indicated therapies and lower blood pressure and cholesterol in people with established cardiovascular disease.
UMPIRE is running in India and in three countries in Europe (England, Ireland and the Netherlands). The trial is open, randomised, controlled and designed to include 1000 participants in India and 1000 in Europe with follow-up of 15 months. Participants are randomised to one of two versions of the polypill or to usual care. The primary outcomes are self-reported use of aspirin, a statin and at least two blood pressure lowering agents as well as changes in blood pressure and cholesterol. Secondary outcomes include cardiovascular events, reasons for stopping medications, serious adverse events and changes in quality of life. Interpretation will be enhanced by health economic and process evaluations.
UMPIRE is registered with the European Clinical Trials database, EudraCT: 2009-016278-34 and the Clinical Trials Registry, India: CTRI/2010/091/000250. The trial is part of the “Single Pill Against Cardiovascular Events” (SPACE) collaboration which encompasses the “IMProving Adherence using Combination Therapy” (IMPACT) and “Kanyini Guidelines Adherence with the Polypill” (Kanyini-GAP) trials.
Global patterns of cardiovascular disease (CVD) are changing with a fall in coronary mortality and event rates among higher income countries. In part this decline is attributable to effective drug measures both in risk factor treatment and improving case fatality. Whilst the burden of CVD has moved to low and lower-middle income countries (LMIC) this transition has not been paralleled by the availability of effective and affordable preventive drugs. People with established cardiovascular disease (people who have had a stroke or heart attack) need secondary prevention that addresses multiple risk factors. The delivery of proven preventive treatments to patients with CVD is a high public health priority.
However complexity, pill burden & cost confer particularly difficult barriers to uptake of treatment; recovery from a stroke or heart attack typically requires prescription of multiple medications for cholesterol, blood pressure and platelet function. A pill burden of 6 or more pills per day is not uncommon, especially with co-morbid problems such as diabetes. The number of pills prescribed is inversely related to adherence and low adherence negates prevention. In many countries the separate components of such a tablet cocktail are simply not available; in others the monthly cost of even a single generic component is a considerable portion of a month’s wages.
A combination once daily pill, a cardiovascular “polypill”, based on a combination of established generic drugs, may address these issues. A low-cost, fixed-dose, once-daily combination polypill, the Red Heart Pill, has been formulated by Dr Reddy’s Laboratories. This Red Heart Pill has 4 ingredients - aspirin, 2 blood pressure-lowering medicines and a cholesterol-lowering medicine.
In 2009 the European Commission called for improved treatment of chronic diseases in developing countries. Specifically they invited a treatment strategy “that combines existing safe and effective drugs for treating chronic diseases in a single daily pill”; stipulating that “this fixed-dose-combination pill should be low-cost and suitable for production and widespread use in resource-poor countries” and that the work should “address two major challenges of effective secondary prevention and treatment of chronic diseases: adherence to treatment and access to treatment in developing countries”.
The importance of these questions was also voiced by the US Centre for Disease Control and Prevention. The UMPIRE (Use of a Multidrug Pill In Reducing cardiovascular Events) trial was designed in response to this funding call.
UMPIRE will assess whether people prefer taking medication for the prevention of heart attacks and strokes as a single pill or as several separate tablets (adherence to medications) and if it improves blood pressure and cholesterol control and clinical outcomes (the risk of having further cardiovascular events) among high-risk patients in Europe (UK, Ireland and Netherlands) and India. The results will be used to develop recommendations for equitable access to cardiovascular preventive therapy.
The UMPIRE trial primary objective is to assess whether provision of a polypill-based cardiovascular preventive treatment strategy compared to usual medications improves adherence to indicated therapy and whether it induces changes in two major cardiovascular risk factors (blood pressure and LDL-cholesterol) in people at high risk of cardiovascular events.
Results will be compared between baseline and the end of the trial. Secondary objectives are assessing barriers to adherence, quality of life, safety, cardiovascular events and comparison of results between the participating countries. Economics and process evaluations of the polypill strategy are planned. A total of 2004 subjects have been randomised into the trial (1000 in Indian and 1004 in Europe) and the average follow-up period is expected to be 15 months (minimum 12 months).
Final trial subject visits will be completed by end of July 2012 and the results will be analysed for publication and dissemination in late 2012.
The polypill is a repackaging of effective preventive drugs in a combination pill; all of the groups outlining the potential of such an intervention have noted that it is not a panacea for CVD and it does not displace the importance of measures such as not smoking, healthy nutrition and regular exercise. The approaches are complementary. The major challenge lies in defining and implementing the most effective delivery strategy.
If adopted, it has the potential to bring effective CVD prevention within economic reach of individuals and governments in poorer countries. This is of particular priority in low and middle income countries, where 80% of the cardiovascular burden lies, the vast majority of individuals currently receive little or no long-term medical preventive care and, when even available, is often unaffordable.