Progress With the Polypill

The prevalence and disease burden of cardiovascular disease (CVD) and thewidespread use ofmedications for its preventionand treatmenthave led to the concept that a singlepill containing several cardiovascular medications, a “polypill,” might be useful inmore effectively delivering pharmacologic interventions than the samemedicationsprescribedand taken separately. For about a decade and a half there have been active discussions of combination pills for primary or secondary prevention of CVD.1 The discussion is consistent with the widespread interest in the importance of noncommunicable diseases, particularly in lowandmiddle-income countries. The logic for the polypill seems sound. CVD is commonas are its major risk factors, and effective pharmacologic treatmentsareoftentakentogether.Combiningsomeof thesemedications into a single pill most likely will improve adherence, whichdeclineswith increasing numbers of medications, and a polypill might improvedistributionofmedication. It is alsopossible that costs could be lower because generic medications with a long history of use could be combined; for instance, several available blood pressure pills combine 2 antihypertensive medications.With this simple logic, the concept of providing combination therapy in a single pill has been embraced by prominent researchers andorganizations including theWorldHealth Organization. Yet for all the discussion, movement toward implementation has been slow. Why has what seems to be such a good idea still not been widely studied and implemented? There are several challenges tomake a successful combination pill. Technically the agents must be stable when combined. There must be no adverse interaction when the medications are taken together. Medications have to be able to be taken at the same time of the day. The combination pill might require regulatory approval. Itneeds tobeproduced,marketed,anddistributed;and itmustbeeconomically viable. This all requires substantial investment to ensure widespread uptake. Factors that could further complicate theuse of combination pills include the issue of adverse effects to one drug and theneed toproducemultiple pills if a numberof possibledose combinations are necessary. Adverse effects to one medication could result in cessation of all agents in a given polypill. Cliniciansmay not knowwhich polypill ingredient is causing the adverse effects. If just 2 doses each of 4 medications are used, 2 x 2 x 2 x 2 or 16 different dose combinationswould be needed to make all dose combinations available. Another consideration is identifying good candidates for the polypill. There are 3 settings in which this combination medication approach could beuseful. First, thepolypill could beusedbypatientswith knownCVDor those at high riskwho are already taking severalmedications, oftenat the same time. In this setting a polypill could improve medication adherence. Second, in lower-incomecountries a singlepill for either primary or secondary CVD prevention might lower cost and increase efficiencyby simultaneouslydeliveringmultiplepreventive interventions to appropriate higher-risk patientswho are not receiving these interventions. Third, the combination pill could be used to increase the number of people receiving preventive interventions if this approachwere promoted as a simpleway for those at risk for CVD to adopt an effective preventive intervention.WaldandLaw2havesuggested thatusing a polypill in everyone older than about 55 years for primary prevention could reduce CVD bymore than 80%. Many formulations for a CVD polypill have been proposed. Because hypertension and dyslipidemia are common and often coexist, most combinations contain at least 1 blood pressuremedicationand1 statin. Somecombinationagents include aspirin, andothers have suggested including certain vitamins and minerals. While there have been many proposed polypill combinations andseveral settings inwhich theycould be used, randomized trial data of specific polypills in specific settings are limited. Several short-term, randomized trials3-7 have evaluated variouspolypills containing from1to3antihypertensiveagents and a statin and some contained aspirin. These trialswere designed to determine the magnitude of change in blood pressure or lipid levels and whether this magnitude was consistent with what would be expected based on trials of single agents. When compared with placebo, the combination pills resulted in meaningful reductions in systolic and diastolic bloodpressure, and in total and low-density lipoprotein (LDL) cholesterol, but these reductions were less than what would have been expected from the component medications based on trials of these agents taken as single medications.8 In this issue of JAMA, Thom and colleagues,9 representing a group of international investigators, evaluated the utility of a polypill strategy in 3 European countries and India for deliveringmedication to patients with CVD or at high risk for CVDevents by presence ofmultiple risk factors. The 2004patientswere takingmultiplemedications for hypertension and dyslipidemiaprior to enrollment. In this randomized trial, the polypill group was given a combination of 2 blood pressure medications (lisinopril 10 mg, atenolol 50 mg), 1 lipidloweringmedication (simvastatin40mg), andaspirin (75mg), while the usual care group continued individual medication intake as per usual. Comparedwith patients in the usual care group, those in thecombinationpill grouphad improvedmedicationadherenceandmodest reductions inbloodpressure (2.6 Related article page 918 Opinion