“Whatever happened to the polypill?” my colleagues ask me when told about the status of fixed-dose combination therapy for cardiovascular disease prevention. While the concept has always seemed straightforward, the implementation of this apparently simple concept has proved more challenging than anticipated. More than a decade after the concept was introduced, the state of the science has moved considerably forward, but perhaps not as brightly as initially projected.
The promise and a brief history of the polypill
A polypill, or fixed-dose combination therapy, is a familiar strategy for multidrug delivery for anyone who has ever taken a multivitamin. Combinations of drugs are widely available to treat a variety of diseases, including HIV, tuberculosis, and raised blood pressure, among others [1].
In 2001, Professor Richard Peto and others first outlined the concept of using the fixed-dose combination of aspirin, a statin, an angiotensin-converting enzyme (ACE) inhibitor, and a beta blocker for cardiovascular disease secondary prevention in low- and middle-income countries [2].
However, it was not until 2003 that the modern concept of the Polypill was born. There was a brilliant BMJ cover, almost like a movie poster, as well as the catchy name and the tantalizing models by Professors Nicholas Wald and Malcolm Law that promised the prevention of more than 80% of all cardiovascular disease deaths [3].
No longer just for poor countries, the concept was hailed as a panacea. It was going to be cheaper, simpler, and plain better than what had been used before, just like any great innovation. All that needed to be done was to give the Polypill to everyone over 50 years old. However, critics quickly argued that polypills would medicalize whole populations, detract from individual-level health behaviors and population-level interventions, and even widen health disparities [4]. The next step was to move from models to trials to evaluate the effects of polypills.
Since 2009, there have been 13 trials (n = 8,898) of fixed-dose combination therapy including at least one statin and one blood pressure lowering drug for cardiovascular disease prevention reported [5]. Designed as pharmacokinetic and pharmacodynamic studies, none of these initial trials were powered to detect a difference in outcomes, and no differences in fatal or nonfatal events have been demonstrated. Six different formulations have been included in these trials, including combinations without aspirin.
Like other fixed-dose combinations, these trials demonstrate a robust and consistent effect on improving adherence across diverse settings. Among the four trials (n = 3,338 participants) of multiple fixed-dose combinations that measured adherence [6–9], fixed-dose combination increased adherence by 44% (95% CI: 26% to 65%) compared with usual care in patients with prevalent cardiovascular disease or high risk for cardiovascular disease (Table 1), though substantial heterogeneity (I2 = 79%) was present [10].
Data from the Single Pill to Avert Cardiovascular Events (SPACE) individual participant data meta-analyses demonstrate that individuals with low baseline adherence had the greatest improvements in adherence, from 17% at baseline to 74% at trial end (relative risk [RR] = 4.46 [95% CI: 3.72 to 5.36]), compared with participants who were already adherent at baseline (86% to 90%; RR = 1.04 [1.01 to 1.07]) [11].
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Table 1. Differences in adherence between the intervention and control groups in fixed-dose combination therapy trials that report adherence [10]. doi:10.1371/journal.pmed.1001862.t001
Adverse events were more common in participants who were randomized to fixed-dose combination therapy (30% versus 24%, RR = 1.20 [95% CI: 9% to 30%]), but some comparator groups included participants receiving placebo or usual care [5].
The three most common adverse events were elevated liver enzyme levels, cough, and myalgias. Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework, the quality of the overall evidence supporting fixed-dose combination therapy to improve adherence is high based on the consistency and precision of effect, low risk of bias (including reporting bias), and indirectness of evidence [10].
The level of recommendation would be strong based on the quality of evidence, the balance between desirable and undesirable effects, uncertainty between values and preferences, and cost.
Current availability and regulatory Status
The current availability and regulatory approval of fixed-dose combinations that include aspirin, a statin, and at least one blood pressure lowering drug are detailed in Table 2. Approval of a polypill has yet to be granted by the Food and Drug Administration or European Medicines Agency, though the Food and Drug Administration’s Cardiovascular and Renal Drugs Advisory Committee met publicly in September 2014 to discuss the potential utility of fixed-dose combinations of aspirin, a statin, and blood-pressure-lowering drugs for secondary prevention of cardiovascular disease.
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Table 2. Manufacturers and regulatory status of fixed-dose combinations for cardiovascular disease prevention [10]. doi:10.1371/journal.pmed.1001862.t002
Even combination blood-pressure-lowering therapy has received regulatory approval based on pharmacokinetic and pharmacodynamics studies, yet the bar seems higher for polypills. In fact, two recent (2012 and 2014) applications to add fixed-dose combination therapy to the WHO’s Model List of Essential Medicines for secondary prevention of cardiovascular diseases have been unsuccessful because of the lack of outcome data [10,12].
However, the use of different thresholds for acceptance of combinations of drugs to the Model List is inconsistent and concerning, particularly for drugs that are widely approved and used to prevent and control the leading cause of death globally.
Pragmatic steps to increase polypill availability and uptake
Despite being approved and available in more than 20 countries, widespread penetration of the polypill has not been reported. Five near-term, pragmatic issues should be readily addressed by clinicians, researchers, public health experts, industry, patients, and guideline writers to help increase the availability and uptake of fixed-dose combination therapy.
- Forsake the age-only screening and mass treatment approach outlined by Wald and Law and focus on secondary prevention
While the promise of the Polypill as proposed by Wald and Law [3] was captivating, the age-only screening and mass treatment approach does not have the scientific or sociopolitical capital to proceed. The effect of ongoing advocacy for this radical approach is uncertain, particularly given concerns about mass medicalization.