Revisiting Optimal Medical Therapy in HFrEF: Do Men and Women Need Different Doses? Evidence from KorAHF III registry

초록

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.