A once-daily polypill significantly improved ejection fraction compared to enhanced usual care in patients with heart failure (mean difference 3.3 percentage points; 95% CI 0.2-6.4; P=0.039).
RCT (n=212)
open-label
randomized
Yes
Does a once-daily polypill containing metoprolol, spironolactone, and empagliflozin improve ejection fraction in adults with heart failure with reduced ejection fraction compared to enhanced usual care?
A polypill strategy for HFrEF significantly improved left ventricular ejection fraction and medication adherence while reducing heart failure events compared to standard rapid uptitration.
Mean Difference: 3.3 (95% CI 0.2–6.4)
p-value: p=0.039
Heart failure with reduced ejection fraction carries a poor prognosis. Although guideline-directed medical therapy reduces morbidity and mortality, its real-world utilization is low. Accordingly, we conducted an open-label randomized trial (POLY-HF) at two centers enrolling a predominantly underserved population to test whether a polypill strategy improves cardiac function in heart failure. Adults with heart failure and left ventricular ejection fraction ≤40% were randomized to a once-daily polypill containing metoprolol succinate (25/50/100/150 mg), spironolactone 12.5 mg and empagliflozin 10 mg, or rapid uptitration of individual guideline-directed medical therapy medications (‘enhanced usual care’). Participants also continued treatment with a renin-angiotensin system inhibitor or sacubitril/valsartan as a separate pill. The primary endpoint was ejection fraction as assessed by cardiac magnetic resonance imaging at 6 months. Secondary endpoints included clinical outcomes and adherence. We randomized 212 patients (median age 54 years, 22% female, 54% Black). Follow-up magnetic resonance imaging data were available for 187 (88%) participants who were included in the modified intention-to-treat analysis. Polypill treatment was associated with greater improvement in ejection fraction compared to enhanced usual care (between-group difference, 3.3 percentage points, 95% confidence interval, 0.2–6.4; P = 0.039), meeting the primary outcome. Individuals randomized to the polypill also had a 60% lower rate of heart failure hospitalizations or emergency department visits (adjusted rate ratio, 0.40; 95% confidence interval, 0.18–0.88; P = 0.024). Adherence, assessed by blood concentrations of metoprolol and spironolactone, was higher with polypill treatment than with enhanced usual care (79% versus 54%, P = 0.001). The polypill was well tolerated, with fewer adverse events with polypill treatment as compared to enhanced usual care. A polypill for heart failure was associated with a significant improvement in cardiac function as compared with enhanced usual care. ClinicalTrials.gov registration: NCT04633005 .
“These data support that simplifying medication regimens through a polypill approach can substantially improve both clinical and patient-centered outcomes in heart failure with reduced ejection fraction. Future trials are needed to evaluate long-term effects on mortality and morbidity and assess implementation strategies to inform the adoption of polypills for management of heart failure in diverse healthcare settings.”
Published July 2026 with TCTMD, News-Medical, AJMC coverage; AHA 2025 presentation follow-up; high adherence signal (79% vs 54%).
Pandey et al. (2026) conducted an RCT in heart failure with reduced ejection fraction (n=212). polypill vs. rapid uptitration of individual guideline-directed medical therapy medications (enhanced usual care) was evaluated on ejection fraction as assessed by cardiac magnetic resonance imaging at 6 months (MD 3.3 percentage points, 95% CI 0.2-6.4, p=0.039). A once-daily polypill significantly improved ejection fraction compared to enhanced usual care in patients with heart failure (mean difference 3.3 percentage points; 95% CI 0.2-6.4; P=0.039).