Monday, December 7, 2020

The polypill: promise & perils

 - Jennifer Middleton, MD

The promise of a simple "polypill" to reduce cardiovascular disease (CVD) morbidity and mortality has been tantalizing researchers for decades. A 2012 analysis suggested that "[p]olypill use by US adults age ≥ 55 years is projected to potentially prevent 3.2 million CHD events and 1.7 million strokes over 10 years." The third iteration of an international research effort examining a combination of 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril known as TIPS-3 (The International Polycap Study 3) demonstrates promise, but a significant minority of enrollees struggled to tolerate it.

TIPS-3 enrolled over 7500 adults identified at intermediate to high risk of CVD using a 2x2x2 factorial design. Most of the participants were from the Philippines or India. Enrolled men were at least 50 years old, and enrolled women were at least 55 years old. Participants were predicted to be at intermediate or high risk of CVD events by their INTERHEART risk score. They completed a 3 to 4 week run-in period, during which time researchers assessed their adherence to lower doses of the full regimens. Notably, 9.5% of initially enrolled participants did not complete the run-in due to complaints of side effects, and another 7.4% could not achieve the minimum 80% adherence required to be randomized into the trial. 

The primary outcome differed by group: for the polypill and polypill + ASA groups, it was a composite of CVD death, myocardial infarction (MI), CVA, cardiac arrest, heart failure, and/or cardiac revascularization; for the ASA group, the primary outcome was only a composite of CVD death, MI, and/or CVA. Participants in the polypill vs placebo group had a hazard ratio (HR) of its primary outcome of 0.79 (95% confidence interval [CI] 0.63, 1.00). The ASA vs placebo group had an HR of its primary outcome of 0.86 (95% CI 0.67, 1.10), and the polypill + ASA group had a HR for its primary outcome of 0.69 (95% CI 0.50, 0.97). The researchers had intended to continue their enrollment and data analysis through 2020, but the COVID-19 pandemic forced a halt to their plans.

The TIPS-3 results are promising, but future research should focus on overcoming this study's shortcomings. Participants who did not experience disabling side effects and were able to adhere to their regimen lowered their risk of CVD events, but it's concerning that more than 1 in 6 enrolled participants could not get past the run-in period to enter the full trial. Physicians should exercise caution extrapolating results from this study to patients deemed at intermediate to high risk of CVD events using a different tool than INTERHEART (for example, the ASCVD calculator is used far more often in the United States). Lastly, a longer study period and larger number of participants may result in a better-powered study with more convincing confidence intervals; the HR of both polypill groups had wide confidence intervals perilously close to non-significance. With its lower HR, the polypill + ASA group appears to have been more effective than the polypill alone, but the confidence intervals of both groups overlap; this finding also conflicts with recent robust evidence showing that ASA is ineffective for primary CVD prevention among both average and higher risk persons. 

You can read more at the AFP By Topics on Coronary Artery Disease/Coronary Heart Disease and Stroke and TIA along with this review of an earlier polypill benefit analysis by Dr. Kenny Lin.