Physicians' Academy for Cardiovascular Education

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

HF hospitalization

CV death


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.


Show references

Find this article online at ESC Heart Fail.

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