Which HF medication is superior in HFmrEF?

The impact of heart failure therapy in patients with mildly reduced ejection fraction: a network meta-analysis

Literature - Leite M, Sampaio F, Saraiva FA, et al. - ESC Heart Fail. 2023 Mar 10 [Online ahead of print]. doi: 10.1002/ehf2.14284

Introduction and methods


According to the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic HF, pharmacological treatment recommended for HFrEF patients may also be considered for patients with HFmrEF [1]. In fact, the 2022 AHA/ACC/HFSA Guideline for the Management of HF recommends SGLT2i therapy for HFmrEF [2]. However, as no RCTs have been conducted exclusively in HFmrEF patients, treatment for this patient group is regarded as a gray zone [3].

Aim of the study

The authors performed a network meta-analysis to compare the effects of different HF pharmacological therapies on CV outcomes in HFmrEF patients.


For this random-effects network-meta-analysis using both direct and indirect comparisons, a literature review of studies evaluating the efficacy of MRA, ARNI, RAASi (ARB/ACEi), SGLT2i, and beta-blocker (BB) in patients with chronic HF and LVEF 40% –49% was conducted. In total, 4 subgroup analyses of 6 RCTs, 1 individual patient-level data analysis of 11 RCTs on BB therapy, and 1 patient-level pooled meta-analysis of 2 RCTs (n=7966) were included.


The primary endpoint was a composite outcome of CV death or HF hospitalization. Other endpoints were the individual components of the primary endpoint (i.e., HF hospitalization and CV death).

Main results

CV death or HF hospitalization

  • Only SGLT2i therapy reduced the risk of the primary endpoint compared with placebo (HR: 0.81, 95%CI: 0.67–0.98), whereas MRA, ARNI, RAASi, and BB did not lead to a statistically significant difference.
  • None of the drug-to-drug comparisons yielded significant results, although there were trends towards superiority of ARNI, MRA, and SGLT2i.

HF hospitalization

  • All medications seemed to reduce the risk of HF hospitalization, with significant results versus placebo observed for ARNI (HR: 0.60; 95%CI: 0.39–0.92), SGLT2i (HR: 0.74; 95%CI: 0.59–0.93), and RAASi (HR: 0.72; 95%CI: 0.53–0.98).
  • ARNI appeared to have a greater risk reduction effect compared with the other pharmacological classes, but none of the drug-to-drug comparisons were significant.

CV death

  • Of the 5 drug classes, only BB reduced CV death risk compared with placebo (HR: 0.48, 95%CI: 0.24–0.95).
  • There were no significant differences in any drug-to-drug comparison.


In this network meta-analysis of HFmrEF patients, SGLT2i treatment significantly reduced the risk of CV death or HF hospitalization by 19% compared with placebo, whereas other HF drugs (MRA, ARNI, RAASi, and BB) showed nonsignificant trends towards risk reduction. Compared with placebo, ARNI, SGLT2i, and RAASi reduced the risk of HF hospitalization, while BB reduced CV death risk. Drug-to-drug comparisons did not show significant superiority of any drug class.


1. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, Burri H, Butler J, Celutkiene J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. European Heart Journal. Oxford University Press. 2021; 42: 3599–3726.

2. Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, Fang JC, Fedson SE, Fonarow GC, Hayek SS, Hernandez AF, Khazanie P, Kittleson MM, Lee CS, Link MS, Milano CA, Nnacheta LC, Sandhu AT, Stevenson LW, Vardeny O, Vest AR, Yancy CW. 2022 AHA/ACC/HFSA guideline for the Management of Heart Failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. Lippincott Williams and Wilkins. 2022; 145: E895–E1032.

3. Zhu K, Ma T, Su Y, Pan X, Huang R, Zhang F, Yan C, Xu D. Heart failure with mid-range ejection fraction: every coin has two sides. Front Cardiovasc Med. 2021; 8: 683418.

Find this article online at ESC Heart Fail.

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