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............................................................................................................................................................................ 7.2 Clinical characteristics of patients with heart failure with mildly reduced ejection fraction There is a substantial overlap of clinical characteristics, risk factors, patterns of cardiac remodelling, and outcomes among the LVEF categories in HF. Patients with HFmrEF have, on average, features that are more similar to HFrEF than HFpEF, in that they are more commonly men, younger, and are more likely to have CAD (5060%),38,42,43 and less likely to have AF and non-cardiac comorbidities (Supplementary Table 10). However, ambulatory patients with HFmrEF have a lower mortality than those with HFrEF, more akin to those with HFpEF.

Patients with HFmrEF may include patients whose LVEF has improved from <_40% or declined from >_50%.50

7.3 Treatments for patients with heart

failure with mildly reduced ejection fraction As in other forms of HF, diuretics should be used to control congestion. No substantial prospective RCT has been performed exclusively in patients with HFmrEF (Supplementary Table 11). Some data can be gleaned from subgroup analysis of trials in HFpEF, none of which have met their primary endpoint. Although strong recommendations cannot be made about specific therapies at this point in time, we have included a Table of Recommendations to help guide the management of patients in this category. 7.3.1 Angiotensin-converting enzyme inhibitors There are no specific trials of ACE-I in patients with HFmrEF. Although, the PEP-CHF trial was conducted in patients with HFpEF and included patients with an LVEF >40%, it did not report outcomes according to LVEF.11

However, in patients with HFmrEF, many will also have CAD, hypertension, or post-MI LV systolic dysfunction and will, therefore, already be treated with ACE-I.

Therefore, ACE-I use may be considered in patients with HFmrEF.

7.3.2 Angiotensin receptor II type 1 receptor blockers There are no specific trials of ARBs in HFmrEF. The CHARM- Preserved trial missed its primary endpoint of CV death or HF hospitalizations.245 However, a retrospective analysis showed that candesartan reduced the number of patients hospitalized for HF among those with HFmrEF (with similar trends for CV and all-cause mortality).8 Moreover, a recurrent-event analysis suggested a reduction in hospitalizations for HF among the entire CHARM-Preserved cohort, including those with HFmrEF.248 As for ACE-I, many with HFmrEF will already be on an ARB for other CV indications. Therefore, treatment with ARBs may be considered in patients with HFmrEF.

7.3.3 Beta-blockers There is no specific trial of beta-blockade in HFmrEF. An IPD metaanalysis of landmark trials of beta-blockers suggested similar reductions in CV and all-cause mortality (of 50%) for patients in SR with HFrEF and HFmrEF.12 This IPD meta-analysis included the SENIORS trial where nebivolol reduced the composite primary endpoint of allcause mortality or CV hospital admissions in the overall population. No interaction between LVEF (35% of patients had an LVEF of 3550%) and the effect of nebivolol on the primary outcome was observed.119,249 Many patients with HFmrEF may have another CV indication, such as AF or angina, for a beta-blocker. Therefore, treatment with beta-blockers may be considered in patients with HFmrEF.

7.3.4 Mineralocorticoid receptor antagonists There is no specific trial of MRAs in HFmrEF. In a retrospective analysis of the TOPCAT trial in patients with an LVEF >_45%,9 spironolactone reduced hospitalizations for HF in those with an LVEF <55%. There was a similar trend for CV but not all-cause mortality. Treatment with an MRA may be considered in patients with HFmrEF.

7.3.5 Angiotensin receptor-neprilysin inhibitor There is no specific trial of ARNI in HFmrEF. In the PARAGON-HF trial, which included patients with EF >_45%, although the trial missed its primary endpoint overall, a significant EF-by-treatment interaction was observed. Sacubitril/valsartan, compared with valsartan, reduced the likelihood of the primary composite outcome of CV death and total HF hospitalizations by 22% in those with an EF below or equal to the median of 57%.13 Further data are available from a combined analysis of the PARADIGM-HF and PARAGON-HF trials showing that sacubitril/valsartan, compared to other forms of RAAS blockade, has a beneficial effect, especially on hospitalizations for HF in those with HFmrEF.247

Pharmacological treatments to be considered in patients with (NYHA class II–IV) heart failure with mildly reduced ejection fraction

Recommendations Classa Levelb

Diuretics are recommended in patients with congestion and HFmrEF in order to alleviate symptoms and signs.137 I C An ACE-I may be considered for patients with HFmrEF to reduce the risk of HF hospitalization and death.11 IIb C An ARB may be considered for patients with HFmrEF to reduce the risk of HF hospitalization and death.245 IIb C A beta-blocker may be considered for patients with HFmrEF to reduce the risk of HF hospitalization and death.12,119 IIb C An MRA may be considered for patients with HFmrEF to reduce the risk of HF hospitalization and death.246 IIb C Sacubitril/valsartan may be considered for patients with HFmrEF to reduce the risk of HF hospitalization and death.13,247 IIb C

ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; HF = heart failure; HFmrEF = heart failure with mildly reduced ejection fraction; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association. aClass of recommendation. bLevel of evidence. ESC 2021 Downloaded from academic.oup.com/eurheartj/article/42/36/3599/6358045 by guest on 07 October 2026