Evaluation of Clinical Outcomes of Selective Versus Nonselective Beta-Blockers Among Patients With Heart Failure With Reduced Ejection Fraction Receiving Sacubitril/Valsartan

Background: Beta-blockers, selective (metoprolol succinate or bisoprolol) and nonselective (carvedilol), and angiotensin receptor-neprilysin inhibitors (ARNIs) are the first-line guideline-directed medical therapy for heart failure with reduced ejection fraction (HFrEF). Concomitant use of carvedilol and ARNI (sacubitril/valsartan) may result in additive vasodilatory effects, which may increase the risk of hypotension and limit dose titration of sacubitril/valsartan. Objective: This study examines differences in clinical endpoints between selective and nonselective beta-blocker therapy among patients with HFrEF receiving sacubitril/valsartan. Methods: This retrospective cohort study utilized TriNetX Research Collaborative real-world data. Patients receiving sacubitril/valsartan concomitantly with carvedilol were identified as the intervention cohort, while those receiving metoprolol succinate or bisoprolol served as controls. The primary endpoint was a composite of all-cause mortality or all-cause hospitalization during the 3-year follow-up. Propensity score matching (PSM) balanced confounders. Kaplan-Meier analyses were used to estimate event-free survival, and hazard ratios (HRs) were calculated using Cox proportional hazards models for time-to-event outcomes. Sensitivity analyses were conducted to evaluate the robustness of the findings. Results: Overall, 75 230 patients received carvedilol and 21 587 received metoprolol/bisoprolol. After PSM, 20 939 patients were included in each group. Carvedilol was associated with a higher risk of the primary composite endpoint compared with those taking metoprolol or bisoprolol (52.32% vs 46.29%; HR: 1.21; 95% CI, 1.17-1.24; P < .0001). Carvedilol was also linked to increased hospitalization risk (HR: 1.32; 95% CI, 1.28-1.36; P < .0001) but a modest reduction in mortality (HR: 0.92; 95% CI, 0.87-0.97; P = .0011). In addition, carvedilol was associated with higher risks of hypotension, end-stage renal disease, and bradycardia. Sensitivity analysis results were consistent for the primary endpoint. Conclusion and Relevance: Our results suggest that carvedilol may be associated with a higher risk of the composite endpoint, health care utilization, and adverse events but lower all-cause mortality compared with metoprolol or bisoprolol in patients with HFrEF taking sacubitril/valsartan.