Heart Failure With Reduced Ejection Fraction Polypill Implementation Strategy in Sri Lanka: A Randomized Clinical Trial

Guideline-directed medical therapy (GDMT) consisting of 4 medication classes (β-blockers, renin-angiotensin-system inhibitors, mineralocorticoid receptor antagonists, and sodium glucose cotransporter 2 inhibitors [SGLT2i]) reduces mortality and morbidity in heart failure with reduced ejection fraction (HFrEF). Despite this evidence, global GDMT uptake remains low with less than 45% prescribed 3 medication classes and even fewer prescribed all 4 medication classes, including SGLT2i, in low-income and middle-income countries (LMIC).¹ Polypills combining 4 GDMT classes in 1 pill are a promising implementation strategy to bridge this gap by addressing multilevel barriers, including medication adherence, clinical inertia, and supply chain complexity.² This proof-of-concept pilot randomized clinical trial assessed the feasibility, effect on medication adherence, and safety of a novel fixed-dose polypill compared with usual care in Sri Lanka.³

Methods |

This multicenter, parallel-group, type 1 hybrid, open-label, pilot randomized trial enrolled adults with HFrEF (left ventricular ejection fraction ≤40%, New York Heart Association class II to IV) at 2 public hospitals in Colombo, Sri Lanka (NCT06831864). Ethics approval was obtained from University of Kelaniya and the National Medicines Regulatory Authority (Sri Lanka) and Washington University in St Louis. All participants provided written informed consent. Full study rationale, design, and methods appear in the published protocol in Supplement 1, and the eMethods and CONSORT flow diagram appear in Supplement 2.³ Participants were randomized 1:1 in REDCap, stratified by site, to a once-daily HFrEF polypill (over-encapsulated bisoprolol, losartan, eplerenone, and dapagliflozin in 3 escalating fixed-dose strengths) or usual care for 4 weeks.

The coprimary implementation outcomes were feasibility of recruitment (target 4 participants per week) and completion of study procedures, including screening, randomization, drug allocation, follow-up, retention, and outpatient transition from HFrEF polypill to individual GDMT. Prespecified secondary outcomes were 4-week GDMT adherence measured by 2 complementary methods, the medication possession ratio (MPR) and pill count adherence ratio (PCAR), and safety. Implementation and safety outcomes were summarized as mean (SD), median (IQR), or counts (%). Adherence outcomes were analyzed with generalized linear mixed-effects models with a random intercept for participants nested within site, adjusted for baseline values.

Results |

From January to May 2025, 43 participants were screened and 40 were randomized (21 to HFrEF polypill; 19 to usual care). Median (IQR) age was 61 (55-70) years, 7 were female (18%) and 33 were male (82%), most had ischemic cardiomyopathy (n = 35 [88%]), and median (IQR) ejection fraction was 35% (30%-40%). The mean (SD) weekly recruitment rate was 6.7 (2.5) participants per week, 165% of the prespecified target of 4 participants per week (Table). Thirty-nine of 40 participants (97%) completed both the 1-week and 4-week visits and 19 in the HFrEF polypill arm were transitioned to individual GDMT drugs at the final study visit. All polypill participants received the lowest of the 3 fixed-dose strengths with no structured uptitration, although some received add-on bisoprolol and losartan.

Table.

Primary Implementation Outcomes by Site and Allocation

Outcome by site	Overall (n=40)	Site 1 (n=20)	Site 2 (n=20)
Participants screened, No.	43	20	23
Participants enrolled, No.	40	20	20
Screen failure, %	7	0	13
Weekly recruitment rate, mean (SD)	6.7 (2.5)	3.3 (0.8)	3.3 (2.1)
Target recruitment rate achieved, %	165	165	165
Outcome by allocation	No. (%)
	Overall (n=40)	HFrEF polypill (n=21)	Usual care (n=19)
Participants randomized	40	21 (100)	19 (100)
Allocation of HFrEF polypill	21	21 (100)	0
Participants completed 1-wk follow-up	39	20 (95)	19 (100)
Participants completed 4-wk follow-up	39	20 (95)	19 (100)
Participants dropped out of study	1	1 (5)	0
Participants on HFrEF polypill transitioned to individual drugs of GDMT at study end	19	19 (90)	0
Study time, median (IQR), d
Time from screening to enrollment	0 (0-3)	0 (0-2)	0 (0-4)
Time from enrollment to randomization	2 (1-5)	2.5 (1-5)	2 (1-2)
Time from randomization to 1-wk follow-up visit	10 (8-13)	10 (7-13)	11 (8-13)
Time from randomization to 4-wk follow-up visit	32 (29-34)	30 (29-34)	33 (29-34)

Abbreviations: GDMT, guideline-directed medical therapy; HFrEF, heart failure with reduced ejection fraction.

The mean (SD) MPR of 80% or more of prescribed 4-drug GDMT was 1.00 (0) in the HFrEF polypill arm vs 0.75 (0.44) in usual care arm (mean difference, 0.25; 95% CI, 0.12-0.39; P < .001). The mean (SD) PCAR of 80% or more adherence to 1 or more GDMT class by pill count was 0.85 (0.37) in the HFrEF polypill arm vs 0.47 (0.51) in the usual care arm (mean difference, 0.38; 95% CI, 0.09-0.66; P = .01) (Figure). Total pills dispensed per participant was lower in the HFrEF polypill arm (mean [SD], 45 [20]) than usual care (mean [SD], 127 [50]) (mean difference, −82; 95% CI, −107 to −58; P < .001). No participant withdrew due to an adverse event in either arm. There was 1 (5%) treatment-unrelated serious adverse event in the HFrEF polypill arm and 2 (11%) serious adverse events in usual care (exacerbations bronchial asthma and heart failure).

Figure. Funnel Graph of Adherence to Guideline-Directed Medical Therapy (GDMT).

This figure shows adherence to GDMT by arm, as measured by the medication possession ratio and the pill count adherence ratio. HFrEF indicates heart failure with reduced ejection fraction.

Discussion |

In this multicenter, type 1 hybrid pilot randomized trial of an HFrEF polypill conducted in an LMIC, an over-encapsulated 4-drug fixed-dose combination was feasible to implement, achieved higher composite GDMT adherence than usual care across multiple measurement methods, and was associated with no treatment-related serious adverse events and no treatment-related study withdrawals. The polypill arm dispensed approximately one-third of the total pill burden of usual care. Our findings suggest potential advantages of a single once-daily HFrEF polypill in initiating quadruple GDMT simultaneously and improving medication adherence with a single-pill combination, aligned with the POLY-HF randomized trial⁴ and the COMBO-HF-X pilot trial,⁵ collectively advancing the science of HFrEF polypill therapy. The main limitations of this trial are the small sample size with a low proportion of female patients, short follow-up, and limited generalizability, as this pilot trial was designed to assess feasibility in preparation for a large-scale HFrEF polypill clinical outcomes trial in Sri Lanka (NCT07569640). This approach may hold promise for achieving improved outcomes for patients with HFrEF globally and especially in LMICs where the burden of heart failure is high and growing.

Data Sharing Statement:

See Supplement 3.