Is Ejection Fraction in Heart Failure a Limitation or an Opportunity?

The quantity ‘ejection fraction’ (EF) is among the most ingrained and commonly used quantities in clinical medicine. EF is used in heart failure (HF) for diagnosis, characterization, prognosis, patient triage, and treatment selection,1 and continues to be a fundamental entry criterion for HF and post-myocardial infarction clinical trials. HF with reduced EF (HFrEF; EF <40%) is well characterized and treatable; HF with preserved EF (HFpEF; EF ≥50%) is a common and complex syndrome so far without evidence-based therapy; and HF with mid-range EF (HFmrEF; EF 40–49%) was recently introduced to distinguish the grey zone where EF is not normal but there is no evidence-based therapy.1 However, concurrent with improved understanding of different EF phenotypes,2 an increasing criticism of EF as a measurement and concept has emerged, and in this issue of the Journal, Mele et al. offer a critical appraisal of the EF quantity.3 Are these concerns reasonable? What are the unmet needs in HF? They are: (i) improved resources and logistics for increasing HF care needs; (ii) improved utilization of existing evidence-based therapies in HFrEF; and (iii) evidence for existing and novel interventions in HFpEF (and HFmrEF) as well as in acute HF. Heart failure affects more than 2% of the population,4 is the most common cause of hospitalization,5 and is among the most common causes of death, with mortality at 1 year in population-wide registries ranging between 10% and 35%.6, 7 Moreover, health care-related costs associated with an increasing HF prevalence are projected to increase three-fold between 2010 and 2030.8 This means that every clinician encounters HF, and important patient conversations and treatment decisions occur in emergency departments, internal medicine, cardiology and geriatrics wards, intensive care and peri-operative settings, palliative, hospice, and home care, and outpatient care in the specialist, generalist, and primary care settings. HF care is sub-optimal in non-specialist settings.7, 9 How could clinicians understand HF and make adequate treatment decisions in these diverse settings if not with the help of EF? In this context, EF is not a limitation but a tool. In HFrEF, we are excited about novel interventions and positive trials, but as clinician-scientists, we would make perhaps a greater difference if we developed tools to optimize utilization of existing interventions. While angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy and beta-blockers are generally well used (∼80–90% of HFrEF patients, although often with sub-optimal dosing), use of mineralocorticoid receptor antagonists (about one-third), cardiac resynchronization therapy, and implantable cardioverter defibrillators (highly variable geographically but overall much less than half of all patients who would benefit) is much worse.10 The introduction of sacubitril/valsartan has likewise been highly variable, and durable left ventricular assist devices remain reserved for those who by luck are referred in the right context and at the right time.11 What better way to standardize care and implement quality assurance and utilization measures than by using EF? Again, EF is a not a limitation but a tool. In ongoing and planned HF trials, EF remains a fundamental entry criterion. Trialists and sponsors appear to believe that HFrEF and HFpEF are different syndromes, and are beginning to learn where in the HF phenotype spectrum HFmrEF may fit.2 If many patients with HFrEF and HFmrEF have an ischaemic event as primary underlying cause,12, 13 whereas a patient with HFpEF has hypertension and co-morbidities contributing to a progressive syndrome,14 then EF is a useful categorizer, which suggests that treatment targets may be different and that trial approaches should consequently be different in these settings. Many might concede that EF is the best measure to categorize HF currently available but argue that for future classification, trials, and eventually treatment decisions, there are better classifiers or phenotyping tools. Certainly this should and is being explored. On a broad scale, drug and device development programmes may take several forms as follows:15 (i) testing existing HFrEF drugs in HFmrEF and HFpEF.16 There is potential certainly in HFmrEF and if generic drugs prove effective in HFrEF and possibly HFpEF then many patients can be helped at low costs to society; here EF and particularly HFmrEF represent an opportunity; (ii) testing novel interventions in HF using EF criteria but with additional entry criteria for optimal enrichment and potential treatment response, such as in the ongoing PARAGON-HF trial requiring evidence of structural heart disease; (iii) novel interventions and novel targets, such as co-morbidity-driven inflammation and microvascular endothelial dysfunction in HFpEF.14 Until novel classifiers and targets are reproducible and treatable, we are obliged to use what we have: EF and the various evidence-based and guideline-recommended treatments indicated according to EF.1Conflict of interest: none declared.