Polypill Eligibility for Patients with Heart Failure with Reduced Ejection Fraction in the ASIAN-HF Registry: A Cross-Sectional Analysis

Background: The rates of guideline-directed medical therapy (GDMT) prescription for heart failure with reduced ejection fraction (HFrEF) in Asia remain sub-optimal. The primary objective of this study was to examine HFrEF polypill eligibility in the context of measured baseline prescription rates of individual components of GDMT among participants with HFrEF in Asia. Methods: A retrospective analysis of 4,868 patients with HFrEF from the multi-national ASIAN-HF registry was performed, and 3,716 patients were included in the final, complete case analysis. Eligibility for a HFrEF polypill, upon which patients were grouped and characterized, was based on the following: left ventricular systolic dysfunction (LVEF < 40% on baseline echocardiography), systolic blood pressure ≥ 100 mm Hg, heart rate ≥ 50 beats/minute, eGFR ≥ 30 mL/min/1.73 m, and serum potassium ≤ 5.0 mEq/L. Regression analyses were performed to evaluate associations of the baseline sociodemographic factors with HFrEF polypill eligibility. Results: Among 3,716 patients with HFrEF in the ASIAN-HF registry, 70.3% were eligible for a HFrEF polypill. HFrEF polypill eligibility was significantly higher than baseline rates of triple therapy prescription of GDMT across sex, all studied geographical regions, and income levels. Patients were more likely to be eligible for a HFrEF polypill if they were younger and male, with higher BMI and systolic blood pressure, and less likely to be eligible if they were from Japan and Thailand. Conclusion: The majority of patients with HFrEF in ASIAN-HF were eligible for a HFrEF polypill and were not receiving conventional triple therapy. HFrEF polypills may be a feasible and scalable implementation strategy to help close the treatment gap among patients with HFrEF in Asia.


INTRODUCTION
The burden of heart failure with reduced ejection fraction (HFrEF) in Asia is increasing. Guidelinedirected medical therapy (GDMT) is the cornerstone of treatment of patients with HFrEF and consists of beta-blockers (β-blockers), renin-angiotensin system inhibitors (RASi), mineralocorticoid receptor antagonists (MRA), and sodium glucose co-transporter 2 inhibitors (SGLT2i). A recent analysis demonstrated under-utilization of HFrEF GDMT (β-blockers, RASi, MRA) in 11 countries across Asia in the Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) registry [1].
The historical treatment algorithm for patients with HFrEF involves sequential initiation and titration of individual GDMT components over time. Previous work has suggested an additional reduction in mortality when GDMT components are used in combination compared with sequential initiation of these therapies [2]. As a result, the 2022 AHA/ACC/HFSA guideline for the management of heart failure recommends simultaneous initiation of GDMT, aligning with urgent recommendations by experts globally [3,4]. A HFrEF polypill is a fixed-dose combination of GDMT and a novel implementation strategy to simplify treatment and potentially improve GDMT adherence for untreated or undertreated patients with HFrEF [5]. The primary objective of this study is to examine HFrEF polypill eligibility in the context of measured baseline prescription rates of individual GDMT components among participants with HFrEF in the ASIAN-HF registry.

METHODS
A retrospective analysis of 4,868 patients with HFrEF (left ventricular ejection fraction (LVEF) < 40% on baseline echocardiography) from the multi-national ASIAN-HF registry was performed. Enrollment population as well as inclusion and exclusion criteria to the ASIAN-HF registry have been described previously [6]. Geographic blocs were grouped based on the United Nations Regional Groups. Regional income levels were categorized based on per capita income and corresponding World Bank classification [7]. Ethics approval was obtained from the local institutional review committee of each participating center, and all participants gave informed consent. The study conformed to the ethical guidelines in the Declaration of Helsinki.
A complete record of all medications was collected from each study participant at baseline. The following therapeutic classes of medications were included as GDMT for HFrEF based on guidelines during the recruitment period: β-blockers, ACEi/ARBs, and MRAs. Triple therapy was defined as being on all three therapeutic classes of medications. SGLT2i and ARNi data were not collected for this cohort, as data collection for the ASIAN-HF registry preceded the commercialization of SGLT2i and ARNi at study initiation.

STATISTICAL METHODS
Eligibility for a HFrEF polypill was based on the following clinical and laboratory criteria for initiation of combination GDMT: left ventricular systolic dysfunction (LVEF < 40% on baseline echocardiography), systolic blood pressure ≥ 100 mm Hg, heart rate ≥ 50 beats/minute, eGFR ≥ 30 mL/min/1.73 m, and serum potassium ≤ 5.0 mEq/L [3,8,9]. Patients with HFrEF were grouped and characterized according to their eligibility for a HFrEF polypill. Differences between the two groups were tested with Student's t-test, Wilcoxon rank-sum test, or the Chi square test for continuous and categorical variables, respectively.
Mixed effects logistic regression analyses were performed to evaluate the associations of the baseline sociodemographic factors with eligibility for a HFrEF polypill, including adjustments for age, sex, and body mass index. A random effect was also added to these models to account for within-study site clustering. Patients with incomplete data on the eligibility criteria for the HFrEF polypill were excluded from the analysis. STATA 14.0 (Stata Corp, College Station, TX, USA) was used for the statistical analyses.

RESULTS
The participant flowchart is shown in Supplement: Figure 1, and baseline characteristics and HFrEF polypill eligibility are reported in Supplement: Table 1 for a HFrEF polypill. More than 90% of patients were eligible based on heart rate ≥ 50 beats per minute and serum potassium < 5.0 mEq/L, while 88.7% (3,295/3,716) were eligible based on an eGFR ≥ 30 mL/min/1.73 m 2 , and 86.2% (3,205/3,716) were eligible based on a systolic blood pressure ≥ 100 mm Hg. Table 1 Figure 1 shows that HFrEF polypill eligibility was significantly higher than baseline rates of triple therapy GDMT prescription across sex, all studied geographical regions, and income levels. HFrEF polypill eligibility was also higher than rates of individual ACEi, ARB, and BB adherence for the low-income level. Supplement: Figure 2 shows the treatment 'gap' for polypill eligibility, defined as those who are eligible for HFrEF polypill but not receiving triple therapy. The proportion of patients in the treatment 'gap' was greatest in those from South Asia (46.56%; p < 0.001) or the lower income region (47.09%; p < 0.001) but not different between sexes (male 41.05% versus female 38.79%; p = 0.251).

Figure 1
Prescription of individual and combined components of guideline directed medical therapy, triple therapy, and eligibility for HFrEF polypill by sex (a), geographic bloc (b), regional income level (c). 5 Vijay et al. Global Heart DOI: 10.5334/gh.1215 Table 2 shows the comparison of characteristics among individuals who were and were not eligible for a HFrEF polypill. Patients who were eligible for a HFrEF polypill were younger (age 60.8 years ± 13.0 vs. 62.1 ± 13.1, p = 0.005), more likely to be male (79.9% vs. 75.0%), had a higher BMI (24. 3

DISCUSSION
In this study of patients with HFrEF from 10 different regions across Asia, 70.3% of participants were eligible for a HFrEF polypill. HFrEF polypill eligibility was significantly higher than baseline rates of triple therapy GDMT prescription across sex, all studied geographical regions, and income levels. The treatment 'gap,' which may indicate populations most likely to benefit from a polypill, was greatest in those from India or the lower income regions. These findings support previous research demonstrating more than 80% of patients with HFrEF in India were eligible for a HFrEF polypill [9].  Table 2 Association of sociodemographic and geographic factors with HFrEF polypill eligibility.
*Adjusted for age and sex, and site-level clustering using a random effect. This study found that patients were more likely to be eligible for a HFrEF polypill if they were younger and male and less likely to be eligible if they were from Japan and Thailand. This may be due to the demonstrated differential drug clearance as well as differential baseline SBP based on sex, age, and ethnicity, which has been previously demonstrated [10]. Key considerations, as HFrEF polypills are implemented in target populations, include availability of multiple HFrEF polypill doses to prioritize safety and tolerability through low-dose initiation with subsequent titration to higher dose HFrEF polypills, and potential customization of dose combinations [5].
Limitations of this analysis include that laboratory data used to determine HFrEF polypill eligibility were obtained at the time of hospital admission, and that renal function frequently changes during hospitalization in many HFrEF patients, which may influence HfrEF polypill eligibility. Key components of GDMT, including SGLT2i and ARNi compounds, were not included in this analysis due to limited data availability in the ASIAN-HF registry. Finally, more than 1,000 people were excluded from the analysis due to data completeness; however, it is uncertain how this would influence the estimates provided.

CONCLUSION
Polypills may improve adherence by up to 44% as compared to a multi-drug regimen [11]. This study indicated that 7 out of every 10 patients were eligible for HFrEF polypill therapy in a representative cohort of patients with HFrEF across Asia. Given sub-optimal rates of GDMT prescription and potential adherence in Asia, HFrEF polypills may be a feasible and scalable implementation strategy to help to close the treatment gap among HFrEF patients in undertreated populations.

DATA ACCESSIBILITY STATEMENT
Data is available upon request from the corresponding author and the ASIAN-HF committee.

ADDITIONAL FILE
The additional file for this article can be found as follows: