Polypill Improved Ejection Fraction in HFrEF Trial

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 .

Heart failure (HF) represents a principal public health challenge, affecting more than 6 million Americans. Five-year mortality rates approach 50% 1 . Guideline-directed medical therapy (GDMT) improves clinical outcomes among patients with heart failure with reduced ejection fraction (HFrEF) 2 . Contemporary GDMT includes the use of four types of medication classes: beta-blocker, renin–angiotensin system inhibitor, sodium-glucose cotransporter 2 inhibitor (SGLT2i) and mineralocorticoid receptor antagonist (MRA). The use of these medications in combination reduces all-cause mortality by approximately 50% compared with conventional two-drug therapy 3 . Nonetheless, overall utilization of GDMT is low. Only 15% of patients hospitalized with HFrEF receive quadruple GDMT, and uptitration to optimal doses is even less common 4 , 5 , 6 , 7 . Recent evidence from the STRONG-HF trial underscores the clinical relevance of these implementation gaps. In that trial, achievement of optimal GDMT following HF hospitalization was associated with a 34% lower risk of all-cause death or HF readmission 8 .

Barriers to GDMT use involve both provider-level and patient-level factors. Provider-level factors include therapeutic inertia and concerns about adverse effects 9 . Patient-level barriers include polypharmacy burden, complex dosing regimens and high medication costs 10 . Several implementation strategies have been tested to improve use of GDMT, primarily targeting provider-level barriers through virtual consultations, clinician education, dedicated GDMT clinics and feedback reports with continuous quality improvement 11 , 12 , 13 , 14 . These interventions have demonstrated heterogeneous effects on GDMT uptake, with some having a modest increase and others showing no improvement. Furthermore, data regarding the impact of such interventions on clinical outcomes are lacking. In addition, most tested interventions do not adequately address patient-level barriers to GDMT, highlighting the need for new approaches.

A ‘polypill’ combines several medications into a single pill and may be a promising strategy for improving utilization of evidence-based medications 15 . Polypills have been evaluated for the primary or secondary prevention of atherosclerotic cardiovascular disease but not for HF 16 . Reasons that single-pill therapies have not been examined previously in HF might include concerns about reduced flexibility for dosing individual medications; the perceived risks of all-or-none treatment; and increased side effect profiles. Thus, there are limited prospective data on the safety and efficacy of a polypill strategy to initiate or optimize GDMT. Accordingly, we conducted a randomized controlled trial to evaluate whether a polypill-based strategy improves left ventricular ejection fraction (LVEF) compared with enhanced usual care in patients with HFrEF.

Between 2021 and 2025, we identified 475 patients who met eligibility criteria for the study (Fig. 1 ). From this group, 262 patients agreed to participate in a screening examination, and 212 were randomized to polypill therapy or enhanced usual care. A total of 190 participants (90%) attended all study visits, with similar completion rates in the polypill arm ( n = 95; 88%) and enhanced usual care arm ( n = 95; 91%). A follow-up cardiac magnetic resonance (CMR) scan at 6 months was obtained for 187 participants.

Flowchart illustrating study enrollment and randomization flowchart. EHR, electronic health record; ICD, implantable cardioverter defibrillator; MRI, magnetic resonance imaging.

Baseline characteristics were similar between treatment groups (Table 1 ). The median age was 54 years, 78% were male, 54% were Black and 33% were Hispanic. A total of 68% were uninsured or relied on county indigent health programs. Approximately half (53%) presented with new-onset HF and 79% had nonischemic cardiomyopathy. Median LVEF by CMR was 26% (interquartile range (IQR), 20–34) at baseline in the overall cohort, with no notable difference between the two treatment groups.

In modified intention-to-treat analysis, the primary endpoint was higher at 6 months in patients randomized to the polypill than in those randomized to enhanced usual care ( n = 187; LVEF, 40.4% versus 37.1%; adjusted between-group difference, 3.3 percentage points, 95% confidence interval (CI), 0.2–6.4; P = 0.039; Table 2 ). Individual-level LVEF at baseline and follow-up and participant-level changes from baseline to 6 months are shown in Extended Data Fig. 1 . Similar results were noted in intention-to-treat analysis, including all study participants, with a significantly higher LVEF on follow-up in participants randomized to the polypill than in those randomized to enhanced usual care (LVEF, 38.8% versus 35.6%; adjusted between-group difference, 3.2 percentage points; 95% CI, 0.2–6.2; P = 0.037; Table 2 ). Similar results were observed in the analysis excluding patients with improved LVEF (≥55%) on baseline CMR (Table 2 ). The significantly greater improvement in LVEF with polypill (versus enhanced usual care) was also observed in secondary analyses using echocardiographic LVEF measures (difference, 3.4 percentage points, 95% CI, 0.5–6.2; P = 0.021; Table 2 ).

Patients treated with the polypill had a lower risk of hospitalization or emergency department (ED) visit for HF than those in the enhanced usual care arm (37.0 versus 85.8 events per 100 person-years, adjusted rate ratio, 0.40, 95% CI, 0.18–0.88; P = 0.024). Similar benefit was observed in time-to-event analyses for HF events or mortality (adjusted hazard ratio (HR), 0.41; 95% CI, 0.20–0.83; P = 0.013; Fig. 2a ). The polypill strategy was also associated with a lower rate of all-cause hospitalization (adjusted rate ratio, 0.47; 95% CI, 0.24–0.91; P = 0.026).

a , Cumulative incidence of composite clinical HF events or death over 6 months of follow-up. The mean cumulative number of HF hospitalizations, ED visits or death per participant is shown, analyzed using the Andersen–Gill model for recurrent events. Numbers below the x axis indicate participants at risk at each timepoint. Adjusted HR, 0.41 (95% CI, 0.20–0.83); P = 0.013 (two-sided), with adjustment for age, sex, race, ethnicity, NYHA class, HF etiology, HF chronicity, eGFR and baseline NT-proBNP. b , KCCQ-OSS trajectories over 6 months by treatment group. Adjusted mean KCCQ-OSS scores with 95% CIs (dashed lines) at baseline and at 1, 3 and 6 months are shown, analyzed using linear mixed-effects models with maximum likelihood estimation. Higher scores indicate better health-related quality of life. Between-group comparison at 6 months: adjusted difference, 8.51 points (95% CI, 2.64–14.39); P = 0.005 (two-sided). c , Composite hierarchical endpoint calculated using the unmatched win ratio method with CIs derived from the log-transformed win ratio. The win ratio compares polypill versus enhanced usual care across a hierarchical composite: (1) all-cause death, (2) ≥5-point improvement in KCCQ-OSS, (3) total HF hospitalizations or ED visits, (4) ≥5% improvement in LVEF by CMR imaging, and (5) medication adherence by TDM. The overall win ratio is displayed alongside the percentage of wins, losses and ties for each component. Orange bars: polypill wins; blue bars: enhanced usual care wins; gray bars: ties. Overall win ratio, 1.72 (95% CI, 1.65–1.80); P n = 108 biologically independent participants in the polypill arm and n = 104 biologically independent participants in the enhanced usual care arm across all panels. All available KCCQ-OSS observations at baseline and at 1, 3 and 6 months were included in the linear mixed-effects model in b .

The Kansas City Cardiomyopathy Questionnaire-Overall Summary Score (KCCQ-OSS) at 6 months was 71.8 (95% CI, 60.4–83.2) in the polypill arm compared with 63.3 (95% CI, 51.9–74.7) in the enhanced usual care arm (adjusted difference, 8.5 points; 95% CI, 2.6–14.4; P = 0.005; Fig. 2b ). No significant differences were observed in 6-min walk distance (6MWD) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels between the two arms (Extended Data Fig. 2 ). NT-proBNP findings were similar when stratified by baseline quadruple GDMT status (yes versus no; P interaction = 0.76; Extended Data Table 1 ).

For the prespecified composite outcome, the polypill strategy was superior to enhanced usual care, with a win ratio of 1.72 (95% CI, 1.65–1.80; P 2 and Fig. 2c ). The treatment benefit was driven primarily by improvements in quality of life (KCCQ-OSS, 32.9% wins versus 15.6% losses) and hospitalizations or ED visits for HF (8.9% wins versus 5.1% losses). Loop diuretic use and dosing (expressed as furosemide equivalents) were similar between treatment groups at baseline and at all postrandomization timepoints (Extended Data Table 2 ).

Excluding participants with suboptimal short-axis images at baseline or follow-up also yielded similar results (LVEF difference, 3.1 percentage points, 95% CI, 0.1–6.2; P = 0.042). In responder analysis, a greater proportion of participants in the polypill arm achieved LVEF improvement at thresholds of ≥5% (71% versus 62%), ≥10% (45% versus 33%) and ≥15% (26% versus 17%). The treatment effect of polypill versus enhanced usual care on LVEF was not modified by quadruple GDMT utilization at baseline ( P interaction = 0.76); baseline use of all three polypill component classes (yes versus no; P interaction = 0.82); or age group ( P interaction = 0.11; Extended Data Table 3 ). The treatment effect on the primary endpoint seemed similar across prespecified subgroups, including race (Black versus non-Black, P interaction = 0.61), sex (female versus male, P interaction = 0.15), ethnicity (Hispanic versus non-Hispanic; P interaction = 0.94) and HF chronicity (new onset versus chronic, P interaction = 0.92; Extended Data Table 3 ). Findings for the primary outcome and key secondary outcomes were consistent in a post hoc sensitivity analysis refitting all linear mixed-effects models using restricted maximum likelihood estimation (Supplementary Table 1 ).

A total of 79% of participants in the polypill arm were adherent (with detectable serum levels of all tested medications), compared with 54% in the enhanced usual care arm ( P = 0.001). In adjusted analyses, participants in the polypill arm were 50% more likely to be adherent to all tested medications (adjusted rate ratio, 1.50; 95% CI, 1.05–2.16; P = 0.027; Table 2 ). Self-reported adherence at 6 months, assessed by the Morisky Medication Adherence Scale-8 (MMAS-8), was numerically higher in the polypill arm than in enhanced usual care, with a trend toward significance (6.2 versus 5.8; adjusted difference, 0.45; 95% CI, −0.02 to 0.92; P = 0.06). The proportion of participants classified as highly adherent was also numerically greater in the polypill arm but was not significant (37% versus 25%, P = 0.09; Extended Data Fig. 3 ).

Utilization of individual GDMT classes by study group over time is illustrated in Extended Data Table 4 . At baseline, the utilization of quadruple GDMT at any dose was similar between groups (44% in the polypill arm versus 52% in the enhanced usual care arm). Following randomization, quadruple GDMT utilization increased over time in both arms, with the largest gains occurring within the first month (96% in the polypill arm versus 71% in enhanced usual care at 1 month). The polypill arm achieved and maintained significantly higher quadruple GDMT utilization at any dose at all postrandomization timepoints, including the 6-month follow-up (97% versus 78%; P 3 ). A similar pattern of results was noted for quadruple GDMT utilization at the optimal doses. Although baseline rates were low and comparable between groups (5.6% versus 5.8%), the polypill arm achieved and maintained significantly higher optimal GDMT utilization at all postrandomization timepoints, reaching 71% at 6-month follow-up, compared with 42% in enhanced usual care ( P P = 0.011). Similarly, the modified Heart Failure Collaboratory (mHFC) score demonstrated consistently greater improvement in the polypill arm at all postrandomization timepoints, increasing from a mean of 62.1 to 91.3 at 6 months, compared with an increase from 65.9 to 80.8 in the enhanced usual care arm ( P < 0.001).

a , Utilization of quadruple GDMT at any dose over 6 months by treatment group. The percentage of participants receiving all four GDMT classes (beta-blocker, RASi, MRA and SGLT2i) is shown at baseline and at 1, 3 and 6 months. Bars: proportion of participants receiving quadruple GDMT in each treatment arm; error bars: 95% CIs calculated using the Wilson score method. b , Utilization of optimal-dose quadruple GDMT over 6 months by treatment group. The percentage of participants receiving all four GDMT classes at optimal doses is shown, defined as ≥50% of target dose of beta-blocker and ACEi or ARB (or any dose of sacubitril/valsartan) and any dose of MRA and SGLT2i at baseline and at 1 month, 3 months and 6 months. Bars: proportion of participants receiving quadruple GDMT in each treatment arm; error bars: 95% CIs calculated using the Wilson score method. c , mHFC score over 6 months by treatment group. Mean mHFC scores are shown at baseline and at 1 month, 3 months and 6 months, with higher scores (range 0–100) indicating better medication optimization across the four GDMT components (beta-blocker, RASi, MRA and SGLT2i). Individual participant scores are overlaid. Datapoints represent biologically independent participants. Sample sizes (polypill, enhanced usual care) at baseline and 1 month, 3 months and 6 months were 108, 104; 103, 97; 97, 92; and 95, 95, respectively. Between-group comparisons were performed using the chi-squared test for a and b and the two-sample t -test for c ; all tests were two-sided, with no adjustment for multiple comparisons.

Serious adverse events were less frequent in the polypill arm compared with enhanced usual care. One death occurred in each arm (Extended Data Table 5 ). Serum creatinine and potassium at 6 months were similar between polypill and enhanced usual care (creatinine, 1.13 versus 1.11 mg dl −1 , P = 0.63; potassium, 4.20 versus 4.20 mEq l −1 ; P = 0.87; Extended Data Fig. 2 ). Physician-directed treatment discontinuations were infrequent. In the polypill arm, the polypill was discontinued in one participant (0.9%), and a renin–angiotensin system inhibitor (RASi) was discontinued in two (1.9%) participants. In the enhanced usual care arm, physician- or care team-directed discontinuations included beta-blockers in one participant (1.0%), renin–angiotensin system inhibitor in three participants (2.9%), SGLT2i in two participants (1.9%) and MRA therapy in one (1.0%) participant. The number of temporary treatment interruptions with successful rechallenge was similar between groups (Extended Data Table 5 ). The favorable safety profile of the polypill was consistent when adverse events were examined by number of baseline GDMT classes (Extended Data Table 6 ) and by baseline age ( 7 ).

In this randomized trial, a polypill-based strategy in patients with HFrEF led to greater improvement in cardiac function at 6 months compared with enhanced usual care. Furthermore, the polypill strategy resulted in a significant reduction in clinical HF events and improved quality of life. These benefits were associated with substantially higher utilization of GDMT without any increase in adverse events.