POLY-HF Trial: Polypill Strategy Improves Heart Function and Reduces Hospitalizations in Heart Failure Patients

A novel polypill strategy combining three guideline-directed heart failure medications in a single daily dose significantly improved heart function and reduced hospitalizations compared to standard care, according to results from the phase 2 POLY-HF trial presented at the American Heart Association 2025 Scientific Sessions.

The randomized controlled trial enrolled 212 adults with heart failure with reduced ejection fraction (HFrEF), defined as left ventricular ejection fraction ≤ 40%, who were not receiving target doses of guideline-directed medical therapy. Participants were randomly assigned to receive either a once-daily polypill or the same medication classes as three separate pills over six months.

Polypill Composition and Study Design

The polypill contains metoprolol succinate (a β-blocker), spironolactone (a mineralocorticoid receptor antagonist), and empagliflozin (a sodium-glucose cotransporter 2 inhibitor). Both study groups continued taking the ARNI sacubitril/valsartan separately, as it requires twice-daily dosing and was not included in the polypill formulation.

"Heart failure is a serious condition that leads to frequent hospitalization and high risk of mortality," said Ambarish Pandey, MD, MS, FAHA, associate professor of internal medicine at UT Southwestern Medical Center and presenting author. "Four specific therapies have been shown to reduce mortality and cardiovascular hospitalizations and are the pillars of management of HFrEF. But the challenge has always been in implementation, and only 15% of patients with HFrEF actually get all the therapies."

Significant Clinical Improvements

The primary endpoint measured changes in left ventricular ejection fraction using cardiac magnetic resonance imaging. At six months, participants receiving the polypill demonstrated a 3.4 percentage point greater improvement in LVEF compared to usual care (39.9% vs. 36.5%; P = .024).

Secondary outcomes showed equally impressive results. Patients in the polypill group experienced 60% fewer heart failure hospitalizations and emergency department visits. Quality of life scores on the Kansas City Cardiomyopathy Questionnaire were 8 to 9 points higher among polypill patients, indicating reduced fatigue and fewer symptoms.

Therapeutic drug testing revealed fourfold greater odds of adherence in the polypill arm. By the end of six months, 71% of participants receiving the polypill achieved optimal doses of all four classes of guideline-directed medical therapy, compared with 42% in the enhanced usual-care group.

Diverse Patient Population

The study distinguished itself through its diverse enrollment, with approximately 54% of participants identifying as Black and 33% as Hispanic, with 20% primarily speaking Spanish. The research was conducted across two centers, including a safety-net hospital where nearly 70% of participants were uninsured or had county-sponsored coverage.

"Having team members who are from their background and being part of the clinical team that took care of these patients did help us have the trust and the rapport with the patients to enroll them," Pandey explained. "Because the burden of polypharmacy and because of the lack of being able to take GDMT is much higher and disproportionately greater in that population, we felt it was important to have the right representation of patients who bear the brunt of the polypharmacy-related nonadherence."

The mean age was 53.5 years in both groups, though only 22% of participants were women, which limits the generalizability of findings based on sex. The clinical heart failure burden was substantial, with a median baseline left ventricular ejection fraction of 26% and 85% having experienced a recent heart failure hospitalization.

Implementation Challenges and Future Directions

Despite the promising results, experts note several implementation considerations. Orly Vardeny, PharmD, professor of medicine at the University of Minnesota, highlighted important questions about long-term use: "How do changes in renal function, blood pressure or electrolytes necessitate coming off the polypill when used long-term? And lastly, how do we anticipate cost or insurance coverage challenges with polypills moving forward?"

Vardeny noted that 48% of participants were already prescribed quadruple guideline-directed medical therapy at baseline, meaning the trial focused more on adherence and treatment sustainability rather than initial therapy initiation.

Pandey and his team are planning expanded research to address these questions. "As for next steps, we are planning to do a longer follow-up and a multicenter trial for assessing the long-term benefits of a polypill-based approach on the risk of meaningful clinical endpoints of mortality and heart failure hospitalization," he said. "We also plan to undertake cost effectiveness studies and implementation studies that can facilitate the uptake and scaling of this intervention to improve guideline-directed therapy use in this population."

The POLY-HF trial represents a significant step toward addressing the implementation gap in heart failure care, where complex medication regimens often lead to poor adherence and suboptimal outcomes in vulnerable populations.