Heart failure ‘polypill’ improves cardiac function, cuts hospitalization risk

Treatment with a “polypill” that combines multiple medications into a single daily dose significantly enhanced cardiac function and reduced hospitalizations for patients with heart failure, according to a study led by Michigan Medicine and UT Southwestern Medical Center.

Patients who took the polypill experienced greater improvements in left ventricular ejection fraction, a standard measure of the heart’s pumping ability, than those on standard treatment with multiple medications. 

Those taking the polypill also had a 60% lower rate of heart failure-related hospitalizations or emergency department visits.

The findings, published in Nature Medicine, suggest a new treatment approach that could help more heart failure patients receive optimal therapy.

“A polypill method may increase utilization of therapies that significantly improve outcomes for heart failure yet are only utilized by a small fraction of patients,” said lead author Ambarish Pandey, M.D., a cardiologist at the University of Michigan Health Frankel Cardiovascular Center, Professor of Internal Medicine and the Director of the Cardiometabolic Research Center at U-M Medical School. 

“Our promising results from the POLY-HF trial bring us closer to that reality.”

Heart failure affects more than 6 million Americans. Despite advances in treatment, around 50% of patients die within five years of diagnosis. 

For patients who have heart failure with reduced ejection fraction, or HFrEF, current guidelines recommend treatment with four types of medication classes: beta-blockers, renin–angiotensin system inhibitors, sodium-glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonists. 

While the combination of treatments reduces heart failure deaths by 50% compared to conventional two-drug therapy, only 15% of patients hospitalized with HFrEF receive all four medications.

In the study, conducted at UTSW between 2021 and 2025, adults with a left ventricular ejection fraction of 40% or lower randomized into two groups. 

The first took a daily polypill containing three of the four medications, and a second renin-angiotensin system inhibitor pill. The other group received each drug in separate doses.

Researchers assessed the patients after six months to test cardiac function. The polypill group had a greater improvement in ejection fractions, 3.3 percentage points over the standard care group.

When the researchers checked whether patients were taking their medication, nearly 80% of those taking the polypill had all four drugs detected in their blood, compared with just over half of those taking separate pills. 

While polypill therapy has found success in trials for atherosclerotic disease, the POLY-HF trial is the first to test the approach in heart failure.

“POLY-HF shows that simplifying how these drugs are delivered can close that gap, and the principle could extend to many other conditions that depend on complex daily regimens,” said senior author Thomas J. Wang, M.D., Dean of the University of Michigan Medical School and Josiah Macy, Jr. Professor, who formerly served as Chair of Internal Medicine at UT Southwestern.

Additional authors: See all additional authors online.

Funding/disclosures: This work was funded by a grant from the National Institute on Minority Health and Health Disparities of the National Institutes of Health (R01MD017529).

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Pandey is a coinventor on a Polypill for Heart Failure US provisional patent application (63/912,172) filed November 2025. Wang is named as a coinventor on a Polypill for Heart Failure US provisional patent application (63/912,172) filed November 2025 and another application related to technologies for producing combination pills. The other authors declare no competing interests.

Paper cited: “Polypill for heart failure with reduced ejection fraction: the POLY-HF randomized trial,” Nature Medicine. DOI: 10.1038/s41591-026-04504-5