The Middle Child in Heart Failure: Heart Failure with Mid-Range Ejection Fraction (40–50%)

The ‘middle child’, classically the second in a family of three siblings, often feels neglected. While lavish attention is generally paid to the first born and the baby, the middle child is typically squeezed between these two and has trouble finding his/her ‘niche’ in the family. In short, the older child gets all the awards, the younger gets all the love, and the middle gets nothing The analogy within the heart failure (HF) family is striking: The big brother—HF with reduced ejection fraction (HFrEF)—was the first born in HF clinical trials, with the vast majority of early HF trials being restricted to patients with LVEF 50%. Among patients with stable chronic HF, a graded relationship between lower EF and higher risk of events has been demonstrated, with increased risk beginning at an EF 30% (up to 42%).23 However a large gap in evidence still exists for the EF 40–50% group. The MIRACLE EF (ClinicalTrials.gov Identifier: NCT01735916) and MADIT-ASIA (ClinicalTrials.gov Identifier: NCT01872234) trials were designed to address patients with HFmEF (EF 35–50%), but both trials have been halted due to difficulties with enrolment. We have a few options for approaching HFpEF in future trials: we could (i) study HFmEF as a separate population; (ii) include HFmEF in HFpEF trials by lowering the EF criteria; (iii) include HFmEF in HFrEF trials by raising the EF criteria; or (iv) forget about EF cut-offs in umbrella programmes that cover the entire range of EF in HF, and look for heterogeneity in response by EF thereafter. The first approach, while most scientifically desirable for its specific focus on HFmEF, may not be feasible given that the population of HFmEF is less prevalent than that of HFrEF or HFpEF and recruiting adequate numbers of patients will therefore be challenging, as evidenced by the recent termination of the MIRACLE EF and MADIT-ASIA trials which specifically included HF patients in the mid-range of EF. Since current evidence-based therapy for HF includes all patients with LVEF 40%. We might thus argue that future trials in the higher EF ranges should be more inclusive, i.e. to include all patients with LVEF >40% in this broad category as an alternative to planning separate trials in the ‘middle’ range. However, given the imprecision of LVEF measurements, this strategy may result in the inclusion of patients with LVEF closer to 30–35%. The current trend of using a cut-off of 45% stems from efforts to avoid an ‘LVEF gap’ in trials studying both HFpEF and HFrEF (i.e. efforts to avoid excluding any patient with HF in broad HF trial programmes). Considering that patients with HFmEF may have distinct clinical, echocardiographic, and prognostic characteristics, this may not be an ideal approach either. In the fourth approach, an EF-agnostic approach risks being underpowered in particular subgroups that are highly pertinent to clinical practice. Furthermore, this approach will only apply to therapies aimed at common mechanisms underlying both HFpEF and HFrEF. The middle child of HF deserves attention: available data suggest that it constitutes a sizeable proportion (10–20%) of the HF population, has a unique clinical, echocardiographic, haemodynamic, and biomarker profile compared with HFrEF and HFpEF, and carries a poor prognosis. Large gaps in evidence regarding its treatment warrant further study. C.S.P.L. is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore. Conflict of interest: C.S.P.L. has received research support from Boston Scientific, Medtronic, and Vifor Pharma, and has consulted for Bayer and Novartis. S.D.S. has received research support from Novartis and has consulted for Novartis and Bayer.