Target Versus Below-Target Dose ACE Inhibitors in U.S. Veterans with HFpEF: Differential Outcomes by CKD Status

Target-dose angiotensin-converting enzyme inhibitors (ACEIs), compared with below-target doses, have been associated with lower risks of death and kidney failure (KF) in patients with heart failure with reduced ejection fraction (HFrEF). We examined these associations in heart failure with preserved ejection fraction (HFpEF).

Among 96,473 Veterans with HFpEF (EF ≥ 50%) newly initiated on ACEIs (2000-2018), 32,728 received target doses recommended for HFrEF. Propensity scores for receiving target-dose ACEIs were used to assemble an outcome-blinded matched cohort of 61,160 patients (target-dose, n=30,580), balanced on 76 baseline characteristics. Outcomes were 5-year all-cause mortality, incident KF, and HF hospitalization.

Compared with below-target-dose ACEIs, target-dose ACEIs were associated with a lower KF risk (HR, 0.89; 95% CI, 0.83-0.97), no mortality difference (HR, 0.99; 95% CI, 0.97-1.02), and a higher risk of HF hospitalization (HR, 1.08; 95% CI, 1.04-1.12). Among 16,735 patients with chronic kidney disease (CKD; eGFR 15-59 mL/min/1.73 m2), target-dose ACEIs were associated with a lower risk of KF (HR, 0.82; 95% CI, 0.75-0.90) and mortality (HR, 0.93; 95% CI, 0.89-0.96) without a higher HF hospitalization risk (HR, 0.95; 95% CI, 0.90-1.01). Each association differed significantly from those in patients with eGFR ≥ 60 mL/min/1.73 m2 (interaction p<0.001).

In HFpEF, target-dose ACEIs were associated with a lower risk of KF, a higher risk of HF hospitalization, and no association with mortality. These associations were consistently more favorable in the subgroup with CKD. These findings underscore the importance of evaluating treatment strategies within biologically coherent HFpEF phenotypes.