Polypill approach shows promise in HFrEF

A once-daily polypill containing three medications (metoprolol succinate, empagliflozin, and spironolactone) is associated with improved outcomes in patients with heart failure with reduced ejection fraction (HFrEF), according to the POLY-HF trial presented at AHA 2025.

“In recent decades, there have been important, effective treatment advances for patients with HF; however, the use of these treatments remains disappointingly low, with only 15 percent of patients receiving all guideline-directed medical therapies (GDMTs) at any dose for HF after hospitalization,” said lead author Dr Ambarish Pandey from the University of Texas Southwestern Medical Center in Dallas, Texas, US.  

“In our study, we focused on socially disadvantaged populations to demonstrate the positive impact of an easier-to-follow medication regimen with only one pill vs three pills daily, and we found significant improvements even after 6 months. Our findings provide the first evidence that a polypill approach could be effective for patients with HF,” he noted.

The POLY-HF trial enrolled 212 adults (mean age 54 years, 78 percent male) with HFrEF, defined as left ventricular ejection fraction [LVEF] ≤40 percent, who were not on target doses of GDMT. Participants were randomly assigned to either a once-daily polypill regimen containing metoprolol succinate 25/50/100/150 mg, empagliflozin 10 mg, and spironolactone 12.5 mg (n=108) or to enhanced usual care, where the same medications were administered as three separate pills (n=104).

At 6 months, a significant improvement in LVEF, assessed by cardiac MRI, was observed in the polypill group (from 29.7 percent to 39.9 percent) compared with the usual care group (from 28.9 percent to 36.5 percent), resulting in a between-group difference of 3.4 percent (p=0.02). [AHA 2025, abstract 4392990]

Patients treated with the polypill also experienced a 59-percent reduction in HF-related hospitalizations or emergency department visits than those receiving enhanced usual care.

Additionally, those on the polypill regimen achieved a better quality of life, as shown by a higher KCCQ-OSS* score at 6 months (71.8 vs 63.3 points), representing an increase of 8.5 points (p=0.005) over those receiving usual care.

There was also a significantly higher level of medication adherence observed in the polypill group than in the enhanced usual care group (79.3 percent vs 54.3 percent; rate ratio, 1.50; p<0.03).

No statistically significant differences in NT-proBNP** levels or 6MWD*** were observed between the polypill and usual care groups. Nonetheless, the absolute differences were numerically favourable for the polypill group, Pandey noted.

“Overall, these data support that simplifying medication regimens through a polypill approach can substantially improve both clinical and patient-centred outcomes in HFrEF,” said Pandey.

“Future trials are needed to evaluate long-term effects on mortality and morbidity and assess implementation strategies to inform the adoption of polypill for management of HF in diverse healthcare settings,” he added.

Safety

In terms of safety, fewer patients in the polypill group experienced kidney dysfunction (>30 percent eGFR decrease) and hyperkalaemia (serum potassium >5.5 mmol/L) than those in the usual care group (5 percent vs 11 percent and 0 percent vs 4 percent, respectively).

Lightheadedness or dizziness (16 percent vs 6 percent) and genitourinary infections (4 percent vs 0 percent) occurred more frequently in the polypill vs usual care group, but permanent treatment discontinuation was less common in the polypill group (4 percent vs 18 percent).

“The polypill approach that combines multiple medications into a single pill has proven successful in primary and secondary prevention of atherosclerotic cardiovascular disease,” according to Pandey. However, he noted during the AHA media briefing that “the challenge of using this polypill approach in HF is that HF requires complex, individualized medication dosing, patients can face a high risk of adverse outcomes, and it’s difficult to fit the management into a one-size-fits-all pill.”