Revisiting the Polypill: Does it Improve Adherence and Reduce Cardiovascular Risk?

Adherence to recommended preventative therapies is low among patients with cardiovascular disease (CVD).¹  In light of this well recognized problem, the World Health Organization (WHO) recommended in 2002 that fixed-dose combination (FDC) drug therapy formulations be developed and evaluated with the goal of overcoming poor adherence and inadequate dosing.²

In 2003, a polypill comprised of six components – a fixed-dose of a statin, three antihypertensive agents, folic acid, and aspirin – was first described.  It was claimed that such a pill could reduce the risk of cardiovascular events — including ischemic heart disease and strokes — by 80%.  Moreover, the polypill approach would (hopefully) result in fewer adverse events when compared to treatment strategies that required dose titration of multiple products.³   The UMPIRE (Use of a Multi-drug Pill in Reducing Cardiovascular Events) trial was designed to formally test the notion that a FDC product would significantly improve medication adherence and thereby reduce cardiovascular risk.

The UMPIRE study was a randomized, open-label, blinded-end-point clinical trial comparing FDC-based therapy to usual care in patients with established CVD or who’s calculated 5-year CVD risk was 15% or greater. This multisite study was performed in India, England, Ireland, and the Netherlands. The primary objective was to assess whether an FDC product compared with usual care improves medication adherence, lowers systolic blood pressure (SBP), and reduces low-density lipoprotein cholesterol (LDL-C). This is the first randomized, controlled trial to compare the long-term use of an FDC product with usual care in patients with CVD.

A total of 2,004 patients were randomized in a 1:1 ratio. Those randomized to usual care continued to receive standard treatments from their primary care physician. Those randomized to FDC therapy were prescribed 1 of 2 FDC formulations chosen by the trial physician. The FDC was taken once daily and was dispensed free of charge. Participants in the usual care group acquired their medications subject to local payments or exemptions.

Patients attended clinic visits at randomization, 12 months, and at the end of the study. Telephone or clinic visits were conducted at 1 month, 6 months, and 18 months. Adherence was self-reported and defined as taking the medication for at least 4 days during the week preceding the visit.

These results are encouraging and favored the FDC group but there were several potential study limitations that the authors acknowledge.  First, the sample population (80% male and 50% recruited from India) may not be representative of the general population.  Second, the FDC formulations were provided to participants free of charge (this was not the case in the usual care group) and this could have impacted adherence rates.  And third, the study did not measure cardiovascular events, only surrogate markers of cardiovascular risk.  Only 85 cardiovascular events occurred during the trial and the study was not sufficiently powered to detect differences between the two treatment strategies.

While statistically significant differences were seen in all three primary end points, one has to question the clinical importance of these findings.  Adherence was defined as taking the prescribed medications for at least 4 days during the week preceding the visit.  Thus, an “adherent” patient could have been taking only 57% of the prescribed dose (in the week preceding the visit)!  Moreover, self-reported medication taking behaviors are influenced by social desirability bias as well as inaccurate patient recall. Electronic prescription refill data is one of the most frequently used methods for measuring adherence and patients who fill their medications in a timely manner 80% of the time are generally categorized as adherent.⁴  Thus, this study failed to implement rigorous methods for measuring medication adherence and it is unknown what percentage of the participants took >80% of their prescribed doses.  In addition, those randomized to FDC therapy were provided medication at no cost and it is well documented that patients’ out-of-pocket cost for medication significantly influences adherence rates.  Were the observed improvements in medication adherence in the FDC group due to regimen simplification?  Or lower out-of-pocket cost?

Before we routinely use FDC formulations in practice, clearly more questions need to be answered. What happens when patients need a dose adjustment to one or more of the FDC components? If a FDC had four medications, each with two dose options, 16 different dose combinations would be necessary.  This would likely only increase patient (and prescriber) confusion and errors.  What happens when a patient experiences an adverse effect? How do you know which medication caused that adverse effect?  The FDC concept has perhaps more appeal now that we’ve eliminated LDL-C treatment targets but titrating medications to achieve blood pressure targets will likely remain a standard of care for the foreseeable future.

The UMPIRE trial leaves us with more questions than answers.  The results do not provide us with compelling evidence that FDC products improve adherence.  The root cause of poor medication adherence in most cases probably isn’t regimen complexity (e.g. multiple pills).  Although the primary outcomes of the trial were generally positive, we don’t know if this treatment strategy will reduce cardiovascular events.  While treatment simplification remains a potentially attractive strategy, larger studies are needed to assess the impact of FDC on cardiovascular outcomes.  What do you think?  Is the polypill strategy a credible approach worth continued study … or should we use our time and money to explore other approaches?