Target-dose vs below-target-dose ACE inhibitors and lower risk of kidney failure and mortality in US Veterans with HFrEF

Abstract Aims In randomized controlled trials, target-dose angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) improved clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF), although the mortality reduction was not statistically significant. Target doses worsened kidney function, but kidney failure (KF) was not evaluated. We compared KF and mortality between below-target-dose and target-dose ACEIs and ARBs in patients with HFrEF, overall and stratified by advanced chronic kidney disease (CKD) status. Methods Of the 154 945 Veterans with HFrEF (left ventricular ejection fraction ≤ 40%) and no baseline KF, 134 046 were initiated on ACEIs (target-dose, n = 37 667), and 20 899 were initiated on ARBs (target-dose, n = 4017) during 2000–18. While remaining blinded to study outcomes, we assembled two propensity score-matched cohorts: ACEI (N = 70 860; target-dose, n = 35 430) and ARB (N = 7900; target-dose, n = 3950), balanced on 76 baseline characteristics. Hazard ratios [95% confidence intervals (CIs)] associated with target doses were estimated for 5-year KF and 5-year all-cause mortality, through 31 December 2023. Results In the ACEI cohort, target-dose was associated with an 18% (95% CI, 11%–25%) lower risk of KF and a 6% (95% CI, 3%–8%) lower risk of death. Subgroup and spline analyses showed that the KF association was significant among those with baseline estimated glomerular filtration rate < 35 mL/min/1.73 m2, whereas the mortality association was significant among those with estimated glomerular filtration rate ≥ 35 mL/min/1.73 m2. Target-dose ACEIs were associated with a 3% (95% CI, 1%–6%) higher risk of heart failure hospitalization and a 7% (95% CI, 0%–14%) higher risk of hospitalization due to acute kidney injury. In the ARB cohort, target-dose had no association with outcomes. Conclusion Among patients with HFrEF, target-dose (vs below-target-dose) ACEIs, but not ARBs, were associated with a lower risk of KF (despite a higher risk of AKI), which was limited to those with advanced chronic kidney disease. The survival benefit was modest and limited to those without advanced chronic kidney disease.