Heart failure

Heart failure with mid-range ejection fraction: still a grey area?

Thursday, 5 Mar 2020

The increase in publications on Heart Failure with mid-range Ejection Fraction (HFmrEF; LVEF 40–49%) since its introduction into the 2016 European Society of Cardiology (ESC) Heart Failure Guidelines1 reflects the greater attention given to a previously under-studied group of patients.2 Although little is still known about the pathophysiology of HFmrEF, it seems to be a transitional state between Heart Failure with reduced Ejection Fraction (HFrEF; LVEF ≤40%) and Heart Failure with preserved Ejection Fraction (HFpEF; LVEF ≥50%).3 It’s also becoming clearer that recommended therapies for patients with HFrEF are also the best option for those with HFmrEF.4

The ESC created the HFmrEF category to stimulate research

The ESC introduced the concept of HFmrEF into its 2016 Guidelines for the diagnosis and treatment of acute and chronic heart failure with the goal of stimulating research into the underlying pathophysiology and treatment of patients who don’t fit neatly into the classic HFpEF and HFrEF definitions.1 While therapies for patients with heart failure with an ejection fraction ≤40% have been widely studied and researchers have looked into the characteristics, pathophysiology and prognosis of HFpEF, patients with an ejection fraction from 40–49% have largely been excluded from heart failure trials.2

It appears that the ESC’s strategy has been successful, with an increase in research over the past few years into the prevalence, prognosis, and response to treatment of HFmrEF.2

Research focuses on whether HFmrEF is a separate entity to other HF categories

According to the ESC differentiating patients with heart failure based on LVEF is important because HFrEF and HFpEF have different aetiologies, demographics, co-morbidities and response to therapies.1 “It is only in patients with HFrEF that therapies have been shown to reduce both morbidity and mortality,” their guidelines explain.

Whether patients with an intermediate ejection fraction show similar characteristics to patients with HFrEF or are more like patients with HFpEF – or a completely different phenotype – could determine prognosis and response to treatment. For this reason, research is focused on determining whether HFmrEF is a separate entity or whether it’s actually a transitional state between HFpEF and HFrEF.2

Current research suggests that HFmrEF is a transitional state

Results of current studies suggest that HFmrEF is a transitional state between HFpEF and HFrEF, but that it seems to most often resemble HFrEF in response to treatment.2

This finding may be unsurprising, given that ECHO results can vary over time and a small change in ejection fraction could tip a patient from one category into another, and possibly back again. Speaking to the limbic, Assoc. Professor John Amerena, Director of Cardiology Research at Barwon Health, said: “ECHO is not as precise a science as we would like. We expect a 5% variance in ejection fraction between tests, depending on other parameters, such as heart rate and loading conditions. It’s not a reproducible measure on a day-to-day basis.”

In fact, The National Heart Foundation of Australia and Cardiac Society of Australian and New Zealand (CSANZ) explain that the variation in ECHO is one of the reasons why they did not include a separate midrange category in their guidelines for the prevention, detection, and management of heart failure in Australia 2018.4 “Although variability in LVEF measurement by echocardiography is improving, the EF range of only 10% is too narrow to confidently ascribe a new and separate group with current diagnostic test accuracy,” the writing group explains.4

CSANZ decided against introducing a midrange category into HF guidelines

The CSANZ chose a cut-off of 50% to distinguish between HFpEF and HFrEF and avoided introducing a new midrange category since it’s unclear how a new category would inform clinical management. “Indeed, post hoc analyses of the small number of patients with heart failure associated with a ‘mid-range’ EF evaluated in RCTs suggest they may receive similar benefits from blockade of the renin-angiotensin system, beta blockers, and mineralocorticosteroid receptor antagonists (MRAs) to patients with heart failure associated with an LVEF of less than 40%,” they say.4

Assoc. Professor Amerena summarises the current thinking in Australia: “There is good evidence-based treatment for HFrEF, but the evidence base for improving outcomes in  HFpEF is poor. Studies suggest that patients with HFmrEF respond to treatment similar to those with HFrEF. Therefore, therapy recommendations for patients with HFmrEF are the same as those with HFrEF.”

Investigating treatment strategies for HFmrEF

The ESC guidelines recommend therapy for HFmrEF based on the evidence for HFpEF, since patients with HFmrEF have generally been included in trials investigating treatment of HFpEF.1 Even so, data supporting a therapeutic benefit of any therapy in patients with HFpEF is limited, although the guidelines note, “For patients in sinus rhythm, there is some evidence that nebivolol (Nebilet), digoxin, spironolactone and candesartan might reduce HF hospitalizations.”1

The writing group notes that data from the SENIORS study5 also suggests a possible mortality benefit for the nonselective beta-blocker, nebivolol, regardless of baseline EF. “In older patients with HFrEF, HFpEF or HFmrEF, nebivolol reduced the combined endpoint of death or cardiovascular hospitalization, with no significant interaction between treatment effect and baseline LVEF,” they say.1

Since the ESC guidelines were published, new evidence of the benefit of beta-blockers on HFmrEF includes an individual patient data meta-analysis of 11 major trials, 6 where data was stratified by baseline LVEF and heart rhythm. The analysis found that beta-blockers improved prognosis for patients with heart failure in sinus rhythm with a reduced LVEF and also in the small subgroup of patients with LVEF 40–49%. In contrast, there was no improvement in prognosis for patients in atrial fibrillation at baseline, or in patients with HFpEF.6

HFmrEF responds to treatment similarly to HFrEF

In clinical practice, most patients with heart failure tend to receive guideline recommended heart failure therapies regardless of ejection fraction.1

As noted by Assoc. Professor Amerena, patients with HFmrEF have been found to respond to therapy in a similar way to those with HFrEF.2,7,8

A pragmatic approach to mid-range EF recommended

While researchers continue to look into the pathophysiology and optimal treatment of patients with HFmrEF, the advice in Australia is to consider it as being on the milder spectrum of HFrEF, rather than as a separate entity. Assoc. Professor Amerena says that this approach makes it straightforward to determine the best treatment options, and points out, “In clinical practice, most clinicians would treat patients with HFmrEF as if they had HFrEF.”



  1. Ponikowski P et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016;37:2129–2200.https://academic.oup.com/eurheartj/article/37/27/2129/1748921
  2. Lopatin Y. Heart failure with mid-range ejection fraction and how to treat it. Cardiac Failure Review 2018;4(1):9–13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971675/
  3. Tsuji K et al. Characterization of heart failure patients with mid-range left ventricular ejection fraction – a report from the CHART-2 study. Eur J Heart Fail 2017; 19(10):1258–1269. https://onlinelibrary.wiley.com/doi/full/10.1002/ejhf.807
  4. Atherton J et al. National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Guidelines for the prevention, detection, and management of heart failure in Australia 2018. Heart, Lung and Circulation 2018;27:1123–1208. https://www.heartlungcirc.org/article/S1443-9506(18)31777-3/fulltext
  5. van Veldhuisen DJ et al. Heart failure patients with impaired and preserved left ventricular ejection fraction: Data from SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure). 2009; 53(23):2150–2158. https://www.sciencedirect.com/science/article/pii/S0735109709009875
  6. Cleland J et al. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Eur Heart J 2018;39:26–35. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837435/
  7. Solomon SD et al. Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction. Eur Heart J 2016;37:455–462. https://www.ncbi.nlm.nih.gov/pubmed/26374849
  8. Lund LH Heart failure with mid-range ejection fraction: Lessons from CHARM. Cardiac Failure Review 2-18;4(2):70–72. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125705/

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