Revisiting Optimal Medical Therapy in HFrEF: Do Men and Women Need Different Doses? Evidence from KorAHF III registry
M Kim, S M Park, E J Kim, S W Han, I C Kim, M C Cho, H S Ahn, M S Shin, J O Jeong, J J Kim, J O Choi, H J Cho, B S Yoo, S M Kang, D J ChoiAbstract
Background
Current guideline-directed medical therapy (GDMT) for HFrEF is based on clinical trials with male-dominant cohorts. Because of sex-related differences in body size and pharmacokinetics, women might be exposed to higher effective drug concentrations and greater susceptibility to adverse effects at standard doses. However, sex-specific data on optimal dosing remain scarce, especially in Asian patients. This study investigated sex differences in the dose–response relationship of renin–angiotensin system (RAS) blockers and beta-blockers to identify sex-specific dose–response patterns and optimal dosing in Asian patients.
Methods
This study analyzed data from the KorAHF III registry, a nationwide, prospective, multicenter cohort enrolling patients hospitalized with acute heart failure in Korea. We included patients with HFrEF (LVEF≤40%) and assessed outcomes over a 12-month follow-up period. The primary outcome was a composite of cardiovascular death and heart failure hospitalization. Multivariable Cox models with polynomial terms were used to identify optimal dosages for each sex.
Results
A total of 4,155 patients (M/F: 2,718/1,437) were analyzed. Women were significantly older (69.8 vs. 63.0 years, p<0.001) and had slightly lower BMI (24.0 vs. 24.8 kg/m2, p<0.001) than men. The proportions of reaching the target dose were significantly lower in women for ARNI (11.9% vs. 17.9%, p = 0.003) and beta-blockers (2.7% vs.5.2%, p = 0.005), while no significant difference was observed for ACEi/ARB (3.6% vs. 2.8%, p=0.653). During the 12-month follow-up, the incidence of the primary outcome was not different between sexes (37.4% in women vs. 34.2% in men, p = 0.153). Nonlinear dose-response analysis revealed that for RAS blockers (ACEi/ARB and ARNI), both sexes derived clinical benefits from even low-dose initiation, while men demonstrated incremental benefits with further titration, women reached a therapeutic plateau at lower dose levels. For beta-blockers, men showed a continuous risk reduction with increasing doses, meanwhile women exhibited a J-shaped pattern, with maximal risk reduction occurring at approximately 20% of the target dose and an increased risk at higher doses.
Conclusion
Optimal dosing for HFrEF medications appears to differ by sex. Our findings support a shift from a uniform target-dose strategy toward a sex-specific, Asia-tailored approach, emphasizing that while low-dose initiation is effective for both sexes, optimal maintenance doses differ significantly by sex.Relative risk of the PO of medicationsFor image description, please refer to the figure legend and surrounding text.