Renin-angiotensin system inhibition and survival in elderly HFrEF with CKD: a target trial emulation

Abstract

Elderly patients with heart failure with reduced ejection fraction (HFrEF) and chronic kidney disease (CKD) are underrepresented in clinical trials. While ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB) are cornerstone therapies for HFrEF, concerns about renal deterioration lead to underuse in patients with advanced CKD. The STOP-ACEi trial showed no renal benefit from discontinuing these agents, but mortality effects remain uncertain. To quantify the association between ACEi/ARB use and all-cause mortality in elderly patients with HFrEF and moderate-to-advanced CKD. We conducted a target trial emulation using retrospective registry data. Patients aged ≥65 years with HFrEF (ejection fraction <40%) and CKD stage G3–G5 (eGFR <60 mL/min/1.73m², not on dialysis), without contraindications (hyperkalaemia or hypotension), were included. Overlap weighting balanced following covariates: age, sex, eGFR, potassium, ejection fraction, systolic blood pressure, diabetes, coronary artery disease, atrial fibrillation, hypertension, beta-blocker use, diuretic use, mineralocorticoid receptor antagonists use, and SGLT2 inhibitor use. Hazard ratios were estimated using weighted Cox regression. ACEi/ARB use was 59% overall but declined sharply with advancing CKD: 67% in G3a, 62% in G3b, and 33% in G4–G5 (p<0.001)—a pattern not explained by contraindication rates (9%). Over median 3.2-year follow-up, 135 deaths (35%) occurred. After overlap weighting achieving excellent covariate balance (all SMD <0.01), ACEi/ARB use was associated with significantly lower mortality (HR 0.60, 95% CI 0.38–0.96, p=0.032). Results were robust across sensitivity analyses: doubly robust estimation (HR 0.51, 95% CI 0.32–0.82), and after excluding sacubitril/valsartan users (HR 0.62, 95% CI 0.39–0.99). In elderly patients with HFrEF and CKD, ACEi/ARB therapy was associated with 40% lower hazard of mortality. Despite this benefit, treatment rates declined sharply with worsening kidney function independent of contraindications, revealing a treatment paradox. These findings support ACEi/ARB use in older HFrEF patients with moderate-to-advanced CKD when no contraindications are present.