Combination of ARNI, BB, MRA, and SGLT2i most effective in reducing outcomes in HFrEF
A Systematic Review and Network Meta-Analysis of Pharmacological Treatment of Heart Failure With Reduced Ejection Fraction
Introduction and methods
Aim of the study
A systematic network meta-analysis was performed to estimate and compare the effects of combinations of different pharmacological therapies for HFrEF.
Randomized clinical trials that investigated the treatment effects of digoxin, isosorbide dinitrate and hydralazine (H-ISDN), ACEi, ARB, BB, MRA, ivabradine, ARNI, SGLT2i, vericiguat, or omecamtiv-mecarbil in adult patients with HFrEF in an outpatient setting or after stabilization after HF hospitalization were considered for inclusion. A total of 75 trials, with a total of 95,444 participants (23% women) were included in the analysis.
The primary outcome was all-cause death. Secondary outcomes were a composite of CV death and hospitalization for HF, CV death, and likelihood of drug discontinuation. In a secondary analysis, number of life-years gained was estimated in the BIOSTAT-CHF and ASIAN-HF populations (1-3).
- ARNI, BB, MRA, and SGLT2i was the most effective combination of treatments in reducing all-cause death compared to placebo (HR 0.39; 95% CI 0.31-0.49), followed by ARNI, BB, MRA, and vericiguat (HR 0.41, 95% CI 0.32-0.53) and ARNI, BB, MRA, and omecamtiv-mecarbil (HR 0.44, 95% CI 0.36-0.55). There was no significant difference in the reduction of all-cause death between these three different combinations.
- The combination of ARNI, BB, MRA, and SGLT2i was significantly more effective in reducing all-cause death compared to the combination of ARNI, BB, and MRA (HR 0.88, 95% CI 0.78-0.99, P=0.037).
Composite of CV death and hospitalization for HF
- The combination of ARNI, BB, MRA, and SGLT2i was also the most effective in reducing the composite outcome of CV death and HF hospitalization compared to ACEi alone (HR 0.36, 95% CI 0.29-0.46), followed by ARNI, BB, MRA, and vericiguat (HR 0.43, 95% CI 0.34-0.55) and ARNI, BB, MRA, and omecamtiv-mecarbil (HR 0.44, 95% CI 0.35-0.56).
- Similar to the other outcomes, ARNI, BB, MRA, and SGLT2i was the most effective combination of treatments in reducing CV death compared to placebo (HR 0.33, 95% CI 0.26-0.43), followed by ARNI, BB, MRA, and vericiguat (HR 0.35, 95% CI 0.26-0.47) and ARNI, BB, MRA, and omecamtiv-mecarbil (HR 0.38, 95% CI 0.27-0.46).
- The likelihood of drug discontinuation due to any reason was lower with ACEi (OR 0.89, 95% CI 0.82-0.96) and ARNI (OR 0.77, 95% CI 0.67-0.93), but higher with ARB (OR 1.2, 95% CI 1.07-1.36) compared to placebo. There were no significant differences between the other drug classes and placebo.
Estimated life-years gained
- The estimated life years gained with ARNI, BB, MRA and SGLT2i compared to placebo (no treatment) was 7.9 (4.7-11.2) years for a 50-year-old person and 5.0 (2.5-7.5) years for a 70-year old person.
This meta-analysis showed that ARNI, BB, MRA, and SGLT2i was the most effective treatment combination in reducing all-cause death, the composite outcome of CV death and HF hospitalization, and CV death alone in patients with HFrEF.
The authors of the article wrote: “The substantial combined survival benefit of comprehensive therapy for HFrEF compared to single pharmacological agents, advocates for early initiation of comprehensive treatment over sequencing of single agents with titration to target dosages.”