NEW ORLEANS — A polypill containing a beta-blocker, a mineralocorticoid antagonist, and an SGLT2 inhibitor produced a substantial improvement in compliance to guideline-directed medical therapy for heart failure along with measurable improvements in heart failure control, according to data from a randomized trial.

Compared with usual care, the polypill was associated with increases in adherence and left ventricular ejection fraction (LVEF) as well as a reduction in hospitalizations over a 6-month period, said senior trial investigator Ambarish Pandey, MD, an associate professor of internal medicine in the Division of Cardiology and Geriatrics at UT Southwestern Medical Center, Dallas.

In this investigator-initiated study, the drugs were delivered by “over encapsulation,” meaning that the three pills were simply placed in a single large capsule for ingestion.

First Randomized Trial of Heart Failure Polypill

“This is the first randomized evidence of the efficacy of a polypill in heart failure,” said Pandey, who presented the results of the POLY-HF trial in a late-breaking session at American Heart Association (AHA) Scientific Sessions 2025.

At two centers in Dallas, Pandey and colleagues randomly assigned 212 participating patients with heart failure and reduced ejection fraction to the polypill or to usual care. In the control group, the patient’s cardiologist or primary care physician prescribed the same medications. Patients in both groups received a renin-angiotensin blocker, which was offered separately in the polypill group.

For the primary outcome of LVEF at 6 months, LVEF increased from a baseline of approximately 29% in both groups, but it increased by a statistically significant 3.4% in the polypill group (39.9% vs 36.5%; P = .024).

The outcome is consistent with the greater improvement in adherence in the polypill group at 6 months (79.3% vs 54.3%), which was monitored via blood levels, according to Pandey. The proportion of patients on guideline-directed medical therapy at optimal doses was significantly greater in the polypill group at 1 month (21% vs 12%), 3 months (54% vs 29%) and 6 months (71% vs 42%; P < .05 for all).

Researchers noted improvement in several secondary outcomes, including a 60% reduction in heart failure hospitalizations, emergency department visits, and death over the course of follow-up among those taking the polypill vs those taking their medications separately. They also observed a greater improvement in quality of life, which was measured by the Kansas City Cardiomyopathy Questionnaire, with the polypill. At 6 months the between-group difference in the KCCQ was 8.5 points (P = .005) favoring the polypill, which exceeds the five points widely regarded as clinically meaningful, according to Pandey.

There were four formulations of the polypill differentiated by the dose of the beta-blocker metoprolol. While each pill contained 10 mg of the SGLT2 inhibitor empagliflozin and 12.5 mg of the mineralocorticoid spironolactone, it could have 10 mg, 50 mg, 100 mg, or 150 mg of metoprolol.

The improvement in adherence and outcome was particularly notable because enrollment was focused on an urban population that is often underserved. Of those enrolled, 68% were completely uninsured or relied on county-sponsored health programs. Forty-two percent were experiencing food insecurity and 32% were experiencing housing instability. Twenty-two percent were women, 54% were Black individuals, and 33% were Hispanic individuals.

Even though relatively young, with a median age of 54 years, the study population had a high median comorbidity burden, according to Pandey. Many had a recent hospitalization for heart failure, and adherence to heart failure medications at baseline was moderate-to-low in 73% of patients.

Polypill Is Produced With No Special Technology

Guideline-directed medications for heart failure were provided to patients in both groups at no cost. The polypill was formulated at Pandey’s center.

“This did not require any special technology,” Pandey explained in an interview with Medscape Medical News. He said that by placing standard doses of the drugs into a single pill, there was no need for pharmacokinetic studies.

“Anyone could do this,” he said.

This might be true, but Dorairaj Prabhakaran, MBBS, DM, MSc, executive director of the World Health Organization’s Centre for Chronic Disease Control in New Delhi, India, is not certain that most would. Rather, he suggested that a financial incentive would be appropriate to entice production of a commercially available heart failure polypill.

The POLY-HF trial is “an important study with exciting results,” according to Prabhakaran, who served as a discussant for the trial. He believes there is an urgent unmet need for “bold new approaches” to overcome nonadherence to guideline-directed medical therapy for heart failure, a risk that he does not think is adequately appreciated by patients.

Juxtaposing heart failure to cancer, for which 5-year relative survival rate for all forms combined is 69%, Prabhakaran pointed out that this is closer to 50% for patients with heart failure. In India, the median survival is closer to 3 years, he said.

To optimize survival in heart failure, it is not enough to take just some of the guideline-directed medical therapy agents or lower doses when full doses are tolerated. Each agent adds an incremental mortality reduction, according to Prabhakaran.

Both he and Pandey pointed out that most studies show less than half of heart failure patients on optimized doses of all guideline-directed medical therapy. It is not clear that a polypill is the only or best answer to this chronic problem, but Prabhakaran said POLY-HF supports the polypill as “an attractive option.” 

“These are particularly encouraging results while we wait for hard endpoint trials,” he said.

The trial of the polypill was an investigator-initiated study without industry funding. Pandey reported financial relationships with Abbott, Accorai, Alleviant, Anumana, Axon, Bayer, Cytokinetics, Edwards Lifesciences, Idorsia Pharma, iRhythm, Kardigan, Merck, Novartis, Novo Nordisk, Pfizer, Roche, Sarfez, Science37, and Ultraomics. Prabhakaran reported no potential conflicts of interest.