Polypill for heart failure with reduced ejection fraction: the POLY

Abstract 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. Similar content being viewed by others Main 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 therapy3. 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 common4,5,6,7. 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 readmission8. Barriers to GDMT use involve both provider-level and patient-level factors. Provider-level factors include therapeutic inertia and concerns about adverse effects9. Patient-level barriers include polypharmacy burden, complex dosing regimens and high medication costs10. 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 improvement11,12,13,14. 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 medications15. Polypills have been evaluated for the primary or secondary prevention of atherosclerotic cardiovascular disease but not for HF16. 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. Results Study population 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. 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. Primary and secondary endpoints 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). 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; Pinteraction = 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 < 0.001) (Table 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). Sensitivity and subgroup analysis 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 (Pinteraction = 0.76); baseline use of all three polypill component classes (yes versus no; Pinteraction = 0.82); or age group (<60 versus ≥60; Pinteraction = 0.11; Extended Data Table 3). The treatment effect on the primary endpoint seemed similar across prespecified subgroups, including race (Black versus non-Black, Pinteraction = 0.61), sex (female versus male, Pinteraction = 0.15), ethnicity (Hispanic versus non-Hispanic; Pinteraction = 0.94) and HF chronicity (new onset versus chronic, Pinteraction = 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). Utilization of GDMT 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 < 0.001; Fig. 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 < 0.001). In the adjusted analysis, participants in the polypill arm were 68% more likely to achieve optimal GDMT at 6-month follow-up (adjusted rate ratio, 1.68; 95% CI: 1.13–2.50; 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). Safety outcomes 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 (<60 or ≥60 years; Extended Data Table 7). Discussion 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. Notably, we observed significant clinical benefit with the polypill even though participants randomized to the ‘usual care’ arm were prescribed GDMT at rates much higher than those observed in contemporary clinical and registry data6,17,18. Utilization of the four GDMT medications in the usual care arm was 78% at any dose and 42% at optimal doses. For comparison, the TITRATE-HF registry showed that although 66% of patients were prescribed quadruple GDMT at 6 months, only 14% received optimal doses of the medication19. These observations support the characterization of the control arm in the current trial as ‘enhanced usual care,’ made possible by active engagement of the study team along with the participants’ regular outpatient providers rather than passive observation of routine clinical practice. This design feature ensured a rigorous test of the polypill strategy’s incremental benefit. The clinical relevance of the 3.3 percentage point increase in LVEF at 6 months is supported by previous studies, which indicate that even more modest improvements in LVEF are associated with improved clinical outcomes20. The reduction in clinical events in the polypill arm compared with the enhanced usual care arm in the current study provides further corroboration. Given the well-established benefits of GDMT concerning cardiac remodeling and recurrent HF events, it is reasonable to assume that the observed benefits are a direct consequence of improved GDMT utilization21. Participants in the polypill arm had higher rates of GDMT use despite both arms having similar financial access to medications. Furthermore, the polypill strategy facilitated more rapid GDMT intensification, with differences in GDMT utilization evident at 1 month postrandomization. The polypill strategy was associated with a 60% reduction in the risk of recurrent HF and a nearly nine-point improvement in KCCQ-OSS. The magnitudes of benefit are similar to those observed in the STRONG-HF trial, which evaluated rapid uptitration of GDMT versus usual care8. Furthermore, these results align with previous pooled analysis of GDMT trials that showed that quadruple GDMT is associated with a 50% reduction in the composite of cardiovascular death or HF hospitalization compared with dual therapy3. Treatment with the polypill was not associated with a significant reduction in NT-proBNP levels—one of the secondary endpoints. The overall high utilization of GDMT in both arms may have limited the potential for further NT-proBNP reduction. The neutral finding may also reflect inadequate statistical power to assess an outcome such as NT-ProBNP, given its considerable variance. Notably, the difference in SGLT2i utilization between the active and comparator arms in our study was larger than that observed for other GDMT classes, and a similar pattern is observed in trials of SGLT2i, in which the relative reduction in clinical events exceeds that in NT-proBNP levels or in LVEF improvement22. The polypill strategy had a favorable safety profile, with lower rates of serious adverse events compared with enhanced usual care. Expected side effects reflecting comprehensive GDMT were observed, including an increased incidence of genitourinary infections and lightheadedness in the polypill arm compared with enhanced usual care. On the other hand, clinically relevant hyperkalemia was not detected in the polypill group. The latter may reflect the fact that concurrent use of SGLT2i can mitigate the risk of hyperkalemia associated with MRA and RASi therapy23. Findings of the POLY-HF trial extend the existing literature on the role of polypill therapy in cardiovascular disease in several ways. Although previous trials such as SECURE and Poly-Iran have shown the efficacy of a polypill approach in atherosclerotic cardiovascular disease16,24, POLY-HF is the first trial to evaluate its use in HFrEF—a condition associated with complex medication regimens and individualized dose titration of several drugs. The overencapsulation approach used in the current study enables flexible dose adjustment and can be routinely implemented in conventional pharmacies. In the current trial, a certified pharmacy technician encapsulated a 30-day supply in approximately 15 min using a commercially available capsule-filling machine. Future implementation could leverage in-hospital or local pharmacy-based encapsulation to improve scalability. These findings establish that a polypill-based strategy is compatible with the complex therapeutic requirements of HFrEF and may offer benefits across several clinical domains. Our findings also add to the emerging body of evidence supporting a polypill approach for the management of HFrEF. The COMBO-HF-X trial (N = 35) evaluated the feasibility of an encapsulated polypill with individualized GDMT combinations in a safety-net population, incorporating all four GDMT classes within a single capsule, including sacubitril/valsartan, which necessitated a separate dose to accommodate twice-daily dosing25. The HFrEF Polypill Implementation Strategy in Sri Lanka trial (N = 40) evaluated a fixed-combination polypill containing bisoprolol, losartan, eplerenone and dapagliflozin, offering a once-daily quadruple GDMT polypill without sacubitril/valsartan that may be particularly suited to resource-limited settings26. Preliminary results from these trials demonstrate the feasibility of a polypill-based approach to improve adherence to HF GDMT across diverse patient settings, using different customizable polypill formulations and support the potential for scalability. Together with POLY-HF, these trials will further define the optimal composition, personalization and scalability of polypill strategies in HFrEF. The POLY-HF trial has several notable strengths. First, the trial was conducted in a diverse, high-risk population, with more than half the cohort identifying as Black race and one-third identifying as Hispanic ethnicity, including 20% who were Spanish-speaking, and most were uninsured or relying on indigent county-supported health programs. This population bears a disproportionate HF burden yet remains severely underrepresented in clinical trials27,28,29. Second, the primary outcome was measured using CMR—the gold standard for LVEF assessment—which has better reproducibility than echocardiography. Finally, the enhanced usual care comparator with active GDMT optimization achieved high GDMT utilization, substantially exceeding contemporary benchmarks. The polypill’s demonstrated efficacy against this rigorous comparator underscores the robustness of these findings. Several limitations warrant consideration. As a trial conducted primarily within a safety-net system serving a predominantly young male population, generalizability to older adults and women may be reduced. Most participants were already receiving several GDMT components at baseline, and the trial therefore evaluated primarily consolidation and optimization rather than de novo initiation of all four GDMT classes simultaneously—an approach that warrants evaluation in future studies. However, subgroup analysis demonstrates consistent safety and efficacy of the polypill (versus enhanced usual care) across age and baseline GDMT use strata, highlighting the robustness of our study findings. With the open-label design, patient-reported outcomes such as the KCCQ-OSS may be particularly susceptible to bias. An imbalance in baseline KCCQ-OSS was observed that probably reflected chance variation. The analysis of KCCQ-OSS adjusted for baseline levels of the score, reducing the likelihood that a baseline difference influenced the results. The 6-month follow-up period limits conclusions regarding long-term outcomes and the durability of benefit. Therapeutic drug monitoring (TDM)-based adherence was assessed for metoprolol and spironolactone only and was not performed for other GDMT components; however, self-reported adherence assessed by the MMAS-8 suggests a broader improvement in medication adherence with the polypill strategy. Also, the polypill formulation did not include an ARNi and did not achieve maximum guideline-recommended doses for beta-blocker or spironolactone (fixed at 12.5 mg), which may have attenuated the magnitude of benefit. Furthermore, our threshold of ≥50% of target dose for ‘optimal GDMT’ reflects a pragmatic implementation benchmark based on previous studies rather than the guideline-recommended target of maximally tolerated dosing. In summary, a polypill strategy for patients with HFrEF improved cardiac function, quality of life and clinical outcomes compared with enhanced usual care over 6 months in the POLY-HF trial. The polypill approach facilitated improved utilization and adherence to GDMT by addressing structural barriers related to prescription complexity and pill burden. These findings support the use of polypill strategies to optimize GDMT implementation in patients with HF. Future multicenter studies are needed to evaluate the long-term effects of a polypill-based strategy and its applicability across different healthcare settings. Methods Trial design The POLY-HF trial was an open-label, randomized controlled trial conducted between November 2021 and October 2025. The trial protocol was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center (STU2020-1340) and monitored by an independent data safety and monitoring board. Details of the trial design have been published previously, and the trial was registered on ClinicalTrials.gov (NCT04633005)30. The study protocol and statistical analysis plan are provided as Supplementary Information. Setting and trial participants The study was conducted at two hospitals in Dallas, Texas: Parkland Hospital, a safety-net county hospital, and Clements University Hospital. Participants were recruited during hospitalizations for HF or at outpatient cardiology visits. Eligibility requirements included age ≥ 18 years, symptomatic HF with LVEF ≤ 40% on screening echocardiogram and not receiving the target doses of quadruple GDMT. Key exclusion criteria included serum creatinine >2.5 mg dl−1 for men or >2.0 mg dl−1 for women, contraindications to GDMT or inability to undergo CMR. All participants provided written informed consent. Randomization and treatment intervention Participants were randomly assigned 1:1 to polypill-based therapy or enhanced usual care using computer-generated block randomization stratified by acute versus chronic HF status and Black versus non-Black race. Polypills were created by overencapsulating the following individual medications in an inert gel capsule without chemical combination or compounding: empagliflozin 10 mg, spironolactone 12.5 mg and metoprolol succinate (25, 50, 100 or 150 mg). The rationale for polypill dosing and components has been detailed previously30. In brief, polypill dosing was informed by data from BIOSTAT-CHF demonstrating that achievement of at least 50% of target doses was associated with outcomes similar to 100% of target doses31. Spironolactone was included at 12.5 mg based on evidence of effective aldosterone blockade with a rate of hyperkalemia similar to placebo at this dose32. Four doses of metoprolol succinate were available to allow uptitration to the most commonly utilized doses. A renin–angiotensin system inhibitor was not included in the polypill to facilitate preferential use of sacubitril/valsartan, which requires twice-daily dosing and is not suited for inclusion in a once-daily formulation. The United States Food and Drug Administration provided an Investigational New Drug exemption for the polypills used in this study. The polypill was assembled by an external pharmacy (Pharmacy Solutions). Encapsulation of a 30-day supply was performed by a certified pharmacy technician using a commercially available capsule-filling machine (ProFiller 1100, Torpac). At randomization, participants assigned to the polypill arm were switched from an individual beta-blocker, MRA and/or SGLT2i to a polypill containing these therapies. Participants received an initial 30-day polypill prescription at randomization. Participants continued a renin–angiotensin system inhibitor or sacubitril/valsartan therapy separately. In the enhanced usual care arm, the study team collaborated with participants’ primary care or cardiology providers to initiate and optimize individual GDMT components. This included providing GDMT initiation or uptitration recommendations, along with study visit blood pressures and heart rates, to participants’ physicians. A study physician provided prescriptions for GDMT for participants who had not yet seen an outpatient provider. Patients were provided beta-blockers, MRAs, and SGLT2i medications at no cost to minimize any financial barriers to GDMT in the enhanced usual care arm. Follow-up and assessments Participants attended in-person visits at months 1, 3 and 6. At each study visit, GDMT was assessed and uptitrated toward maximally tolerated doses. In the polypill arm, metoprolol succinate was uptitrated across the four available polypill doses based on clinical response and tolerability. In both arms, recommendations for renin–angiotensin system inhibitor or sacubitril/valsartan optimization were provided to participants’ providers. Participants received 30-day medication refills until maximally tolerated doses were achieved; 60- or 90-day supplies were then dispensed. At the 6-month visit, participants in the polypill arm were transitioned to equivalent doses of individual GDMT components to ensure continuity of care after trial completion. At each visit, vital signs and blood samples were obtained for measurement of the metabolic panel and NT-proBNP. Quality of life was assessed using the KCCQ, and functional capacity was measured using the 6-minute walk test. Medication adherence was assessed using therapeutic drug monitoring with quantitative liquid chromatography-tandem mass spectrometry to measure serum levels of metoprolol and spironolactone, as previously reported33,34. Self-reported medication adherence was assessed at each study visit using the MMAS-8, a validated eight-item questionnaire with scores categorized as high (8), medium (6 to <8), or low (<6) adherence35. CMR was performed at baseline and 6 months on a 3 T system (Achieva; Philips Medical Systems) at the Advanced Imaging Research Center, University of Texas Southwestern Medical Center. Short-axis imaging was used for primary LVEF analysis at baseline and follow-up. In participants with suboptimal short-axis images at either baseline or follow-up (n = 10), long-axis images were used for LVEF assessment. Images were analyzed and confirmed in a core laboratory using standardized software (CVI42, Circle Cardiovascular Imaging) by cardiologist with advanced training and board certification in CMR who was blinded to treatment assignment. Echocardiography was performed according to standard protocols in a core laboratory at baseline and 6 months. In a subset of participants who did not undergo protocol-specified baseline echocardiography, clinical screening echocardiograms obtained at index hospitalization were utilized for LVEF assessment. Outcomes The primary outcome was LVEF at 6 months assessed by CMR. Prespecified secondary outcomes included the following: HF hospitalization, ED visit for HF or all-cause mortality; HF hospitalization or ED visit for HF; LVEF by echocardiography; quality of life (KCCQ-OSS); exercise capacity (6MWD); measured and self-reported medication adherence; and NT-proBNP. We also calculated a win-ratio-based composite endpoint that included the following outcomes in hierarchical order: all-cause mortality; ≥5-point improvement in KCCQ-OSS; total HF hospitalizations or ED visits for HF; ≥5% improvement in LVEF from baseline to 6 months by CMR; and adherence by drug monitoring. Participants were classified as adherent if they had detectable serum levels of all tested medications and nonadherent if any tested medication was undetectable. We characterized use of GDMT in several ways: quadruple GDMT utilization (prescription of all four GDMT classes at any dose); optimal GDMT utilization (prescription of all four GDMT classes with beta-blocker ≥50% of target doses, ACEi or ARB at ≥50% of target dose or any dose of sacubitril/valsartan, any dose of SGLT2i and any dose of MRA; and the mHFC score4,36. These thresholds for defining ‘optimal GDMT’ were selected to mirror the definition used in GDMT implementation studies and registries5,37. Current ACC/AHA/HFSA guidelines recommend titration to maximally tolerated doses, and the ≥50% threshold for ‘optimal GDMT’ reflects a pragmatic benchmark for assessing GDMT implementation rather than a substitute for the guideline-recommended target2. Safety outcomes included serious adverse events, hyperkalemia (serum potassium >5.5 mM and >6.0 mM), systolic blood pressure <90 mmHg, all-cause hospitalizations or death. A complete list of all prespecified outcomes is provided in the study design manuscript30. Statistical analysis We estimated that a sample size of 175 participants would provide >90% power to detect a five-percentage point difference in LVEF between treatment groups at 6 months at a two-sided significance level of 0.05. Assuming 15% loss to follow-up and a 6% rate of inadequate MRI quality, we enrolled 212 participants to maintain adequate power. The primary outcome was analyzed using a modified intention-to-treat approach among participants with available CMR data at baseline and follow-up (excluding 25 participants who lacked follow-up CMR imaging scans). We also performed an intention-to-treat analysis that included all 212 randomized participants, with the last observation was carried forward for participants with missing follow-up CMR data. Participants with missing MRI data on follow-up were censored at the 6-month visit. Three participants had improved LVEF ≥ 55% on baseline CMR, and an additional analysis was performed excluding these participants. For the primary outcome (LVEF by CMR) and echocardiographic LVEF, treatment group differences were assessed using a linear mixed- effects model with maximum likelihood, with treatment group, timepoint (baseline, 6 months) and treatment group by time interaction as fixed effects, and participant as a random effect with adjustment for age, sex, race/ethnicity, NYHA functional class, HF etiology (ischemic, nonischemic), HF chronicity (acute, chronic), eGFR and baseline NT-proBNP. For KCCQ-OSS, 6MWD and MMAS-8, the same modeling approach was used with timepoints at baseline and at 1, 3 and 6 months. Treatment effects are presented as least-squares mean differences with 95% CIs. The composite outcome was analyzed using win-ratio methodology, with each participant in the polypill group compared with each participant in the enhanced usual care group in a pairwise fashion according to the prespecified hierarchy. Clinical endpoints were analyzed using the Andersen–Gill model for recurrent events with robust variance estimation accounting for within-subject correlation. Both unadjusted and adjusted models were fitted, with covariate adjustment similar to that for the primary outcome. Results are presented as HRs with 95% CIs. The rate of HF hospitalization or ED visit was also analyzed using Poisson regression models with person–time as an offset. Person–time was calculated from the randomization date to the final study visit for participants who completed the study, to the date of loss to follow-up (defined as the date they missed their scheduled follow-up visit), or to the date of death for those who died. Poisson model assumptions were formally assessed using simulation-based residuals; a dispersion test identified significant overdispersion (φ̂ = 2.34, P = 0.02). Accordingly, quasi-Poisson regression was used as the primary analytic approach, a semiparametric correction that retains identical Poisson point estimates while providing conservative, overdispersion-corrected s.e. without requiring additional parametric assumptions about the variance structure. Both unadjusted and adjusted models were fitted, with a similar adjustment as the primary outcome. Results are presented as rate ratios with 95% CIs. Among other outcomes, NT-proBNP was analyzed using a linear mixed-effects model with timepoints at baseline, 1, 3 and 6 months, with log-transformed values. Results are presented as geometric means with 95% CIs. Between-group comparisons were expressed as geometric mean ratios. Medication adherence, as assessed by drug levels (adherent versus nonadherent), and achievement of optimal GDMT at 6-month follow-up (yes or no) were evaluated using Poisson regression with a log link. Results are presented as rate ratios with 95% CIs. Sensitivity analyses were performed to assess the robustness of the study findings for the primary outcome. Participants with poor-quality short-axis MRI scans at baseline and/or follow-up (n = 10) were excluded. Secondary analyses were performed for the primary endpoint and for NT-proBNP, with stratification for baseline quadruple GDMT utilization (yes versus no); for the primary outcome by baseline use of all three polypill component classes (beta-blocker, MRA and SGLT2i; yes versus no) and by age group (<60 versus ≥60 years). Treatment effect modification was assessed using a three-way treatment × time × subgroup interaction term. In a post hoc sensitivity analysis, the primary linear mixed-effects models for the primary outcome (LVEF by CMR), echocardiographic LVEF, KCCQ-OSS, 6MWD, MMAS-8 and NT-proBNP were refit using restricted maximum likelihood estimation in place of maximum likelihood estimation. All analyses were conducted using R version 4.4.1 (R Foundation for Statistical Computing). Statistical significance was defined as a two-sided P value <0.05. The study was monitored by an independent data safety and monitoring board. Reporting summary Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. Data availability The deidentified individual participant data underlying the results reported in this article, including baseline characteristics, primary and secondary outcomes, medication utilization and adherence data, and adverse event data, are available from the corresponding author upon reasonable request. Data will be available beginning 6 months after publication and ending 5 years after publication. Data will be shared with researchers who provide a methodologically sound proposal to conduct analyses related to the trial’s research questions, subject to approval by the Principal Investigators (A.P. and T.J.W.) and execution of a data use agreement consistent with the data sharing policies of the University of Texas Southwestern Medical Center. Proposals should be directed to the corresponding author; requests will be acknowledged within 30 days and reviewed within 90 days of receipt. References Fonarow, G. et al. Heart failure epidemiology and outcomes statistics an updated 2025 report from the Heart Failure Society of America. J. Card. Fail. 32, 439–498 (2026). Heidenreich, P. A. et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 79, e263–e421 (2022). Vaduganathan, M. et al. 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Insights From DAPA-HF. JACC Heart Fail. 10, 543–555 (2022). Fiuzat, M. et al. Assessment of limitations to optimization of guideline-directed medical therapy in heart failure from the GUIDE-IT trial: a secondary analysis of a randomized clinical trial. JAMA Cardiol. 5, 757–764 (2020). Acknowledgements We thank the Advanced Imaging Research Center team for CMR image acquisition. We would also like to thank the Data Safety Monitoring Board members D. Lanfear, M. Keebler and P. Levy for their contribution to the trial. Funding A.P., Z.L.C., C.A., D.K.G., M.H.D., V.G.Z. and T.J.W. disclose support for the research of this work from the National Institute on Minority Health and Health Disparities (R01MD017529). The other authors received no specific funding for this work. Author information Authors and Affiliations Contributions All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication, approved the submitted version and agreed to be accountable for all aspects of the work. A.P. and T.J.W. conceptualized the study. A.P., N.K., S.K.R., Z.L.C., C.A., D.K.G., J.T.T., M.H.D. and T.J.W. were responsible for the design of the study. A.P., N.K., S.K.R., J.D.C., M.B.-R., K.Y., F.K., A.C. and V.G.Z. managed the day-to-day operations of the study. F.K. and K.Y. performed CMR analysis with the supervision of V.G.Z. and M.T.H. N.K., J.D.C., M.S.U., M.B.-R. and A.K.J. collated the data. A.P., N.K., K.Y., M.W.S., A.K.J., A.C. and V.G.Z. accessed and verified all data. M.W.S. conducted the statistical analysis. A.P., N.K. and T.J.W. drafted the manuscript. All authors provided critical intellectual input and revised the manuscript for important scientific content. Corresponding author Ethics declarations Competing interests A.P. has received research funding (to the institution) from American Heart Association, Applied Therapeutics, Roche, Ultromics, Gilead Sciences, Bayer and AstraZeneca; has received honoraria as an advisor, consultant or speaker for Tricog Health Inc., Lilly, Rivus, Roche Diagnostics, Axon Therapies, Edward Lifesciences, Science37, Novo Nordisk, Bayer, Medical AI, AstraZeneca, Baylor Scott and White Research Institute, Boehringer Ingelheim, iRhythm Technologies, Tourmaline Bio, Merck, Sarfez Pharmaceuticals, Ultromics, Kardigan, Tenax Pharma, Alnylam, Abbott, Kilele Health, Anumana, Acorai, Novartis and Antlia Biosciences. A.P. is a coinventor on a Polypill for Heart Failure US provisional patent application (63/912,172) filed November 2025. N.K. has received consultant fees from Heart Test Laboratories, Tricog Health, Idorsia Pharmaceuticals and Science37. M.W.S. reports nonfinancial support from Merck, honoraria outside the present study from Idorsia and Otsuka, is an advisor for AccurKardia, is on the executive board for descendantsDNA and is the founder of ReCODE Medical. A.C. has received grant funding outside the present study from Novo Nordisk, Lilly USA and Sarfez Pharmaceuticals. Z.L.C. reports grants from AstraZeneca and personal fees from Abiomed, Vectorious, Kestra Medical Technologies, Reprieve Cardiovascular, WhiteSwell and Lexicon Pharmaceuticals. D.K.G. has received honoraria as an advisor to Novo Nordisk and research support from the NHLBI (R01HL153607, R01HL145293, R01HL133860). M.T.H. has served as a consultant for Imricor Medical Systems Inc. T.J.W. 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. Peer review Peer review information Nature Medicine thanks Jonathan Davis, Sheldon Litwin and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Michael Basson, in collaboration with the Nature Medicine team. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Extended data Extended Data Fig. 1 Individual-Level Changes in Left Ventricular Ejection Fraction From Baseline to 6 Months by Treatment Group. Individual-level changes in left ventricular ejection fraction (LVEF) by treatment arm. (A) Spaghetti plot depicting individual patient trajectories in LVEF (%) from baseline to 6 months for the Usual Care (red) and Polypill (blue) arms. (B) Waterfall plot of change in LVEF (ΔLVEF) from baseline to 6 months for each participant, ordered by magnitude of change and color-coded by treatment arm. The dashed line indicates the +15% super-responder threshold. Data are derived from n = 187 biologically independent participants with complete LVEF data at both baseline and 6 months (polypill, n = 93; enhanced usual care, n = 94). Extended Data Fig. 2 Biomarker and Safety Laboratory Trajectories by Treatment Group. Longitudinal trajectories of (A) NT-proBNP (pg/mL), (B) log-transformed NT-proBNP, (C) serum creatinine (mg/dL), and (D) serum potassium (mEq/L) from baseline to 6 months in the polypill (blue) and enhanced usual care (red) groups. Points represent unadjusted mean values at each time point (baseline, 1 month, 3 months, and 6 months), and shaded bands represent 95% confidence intervals. Data are derived from n = 108 biologically independent participants in the polypill arm and n = 104 biologically independent participants in the enhanced usual care arm, with all available observations at each time point included in linear mixed-effects models with maximum likelihood estimation. Extended Data Fig. 3 Self-Reported Medication Adherence by Treatment Group at Baseline and 6 Months. Distribution of self-reported medication adherence categories at baseline and 6 months in the enhanced usual care and polypill groups. Adherence was assessed using the 8-item Morisky Medication Adherence Scale (MMAS-8), with scores categorized as high (score = 8), medium (score 6 to <8), or low (score <6). Stacked bars represent the proportion of participants in each adherence category at each time point. Data are derived from n = 108 biologically independent participants in the polypill arm and n = 104 biologically independent participants in the enhanced usual care arm at baseline; at 6 months, data were available for n = 95 in the polypill arm and n = 95 in the enhanced usual care arm. Supplementary information Supplementary Information (download PDF ) Supplemental Table 1, Final study protocol and final study analysis plan. Sensitivity analysis of primary and secondary outcomes using restricted maximum likelihood estimation. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. About this article Cite this article Pandey, A., Keshvani, N., Rizvi, S.K. et al. Polypill for heart failure with reduced ejection fraction: the POLY-HF randomized trial. Nat Med (2026). https://doi.org/10.1038/s41591-026-04504-5 Received: Accepted: Published: Version of record: DOI: https://doi.org/10.1038/s41591-026-04504-5