Meta-analysis compares mortality benefits of heart failure treatment combinations

In patients with heart failure with reduced ejection fraction, a combination of angiotensin receptor-neprilysin inhibitors (ARNIs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 (SGLT-2) inhibitors offers the most estimated aggregate benefit, a study found.

Researchers performed a meta-analysis of randomized controlled trials published between January 1987 and January 2020 to estimate and compare the benefit of pharmacological therapy for heart failure with reduced ejection fraction. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, MRAs, digoxin, hydralazine-isosorbide dinitrate, ivabradine, ARNIs, SGLT-2 inhibitors, vericiguat, and omecamtiv-mecarbil were compared. The primary outcome was all-cause death. Secondary outcomes included life-years gained in two heart failure populations. Results were published by JACC: Heart Failure on Dec. 8.

The meta-analysis included 75 studies with 95,444 participants. The combination of an ARNI, beta-blocker, MRA, and SGLT-2 inhibitor was most effective in reducing all-cause death (hazard ratio [HR], 0.39; 95% CI, 0.31 to 0.49), followed by the combination of an ARNI, beta-blocker, MRA, and vericiguat (HR, 0.41; 95% CI, 0.32 to 0.53) and an ARNI, beta-blocker, and MRA (HR, 0.44; 95% CI, 0.36 to 0.54). Results were similar for the composite outcome of cardiovascular death or first hospitalization for heart failure. The HRs were 0.36 (95% CI, 0.29 to 0.46) for an ARNI, beta-blocker, MRA, and SGLT-2 inhibitor; 0.44 (95% CI, 0.35 to 0.56) for an ARNI, beta-blocker, MRA, and omecamtiv-mecarbil; and 0.43 (95% CI, 0.34 to 0.55) for an ARNI, beta-blocker, MRA, and vericiguat. The estimated additional number of life-years gained for a 70-year-old patient on an ARNI, beta-blocker, MRA, and SGLT-2 inhibitor was 5.0 years (95% CI, 2.5 to 7.5 years) versus no treatment.

The study authors wrote, “[T]hese results highlight the substantial number of life-years saved with comprehensive medical therapy for HFrEF [heart failure with reduced ejection fraction], at a cost which is likely lower per number of life-years saved compared with commonly used treatment for patients with diseases that carry a similarly worse prognosis.”

An editorial said that sequencing and strategy trials to guide personalization of combined therapy for heart failure could improve treatment. “Although the complexity is most evident for HFrEF, combination therapies are endorsed and promoted across multiple domains, including type 2 diabetes, chronic kidney disease, and atherosclerotic cardiovascular disease. The charge now is to construct the best methods to determine the most efficacious, comprehensive, scalable, and patient-centered combination regimens,” the editorial stated.