Phenotype HF with midrange EF resembles HFrEF, albeit with better outcomes


News - Apr. 30, 2017

Paris, France | Heart failure with mid ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire EF spectrum

Presented at ESC Heart Failure 2017 by Lars LUND (Stockholm, Sweden)

The 2012 ESC Guidelines on heart failure (HF) already mentioned that the range of ejection fraction (EF) between 35% and 50% represents a ‘grey’ area of patients who most probably have primarily mild systolic dysfunction. After some more papers discussing this EF range had been published, the 2016 ESC HF guidelines acknowledged patients with LVEF between 40% and 49% as a separate category, called HFmrEF for ‘mid-range’ or ‘moderately reduced’. The aim of separately identifying HFmrEF patients is to stimulate research, as little is known to date about this group of patients.

The CHARM study that evaluates the effect of candesartan in HF provides a unique opportunity to study the entire EF spectrum. In the overall analysis of CHARM, candesartan treatment was associated with a reduced risk of CV death or hospital admission for chronic HF (HR: 0.84, 95%CI: 0.77-0.91, P<0.0001), while CHARM-Preserved did not show an effect of candesartan as compared with placebo (HR: 0.89, 95%CI: 0.77-1.03, P=0.118).

The current analysis aimed to assess time to CV death or first HF hospitalisation as a primary outcome across the EF spectrum. Associations between EF and outcomes were assessed irrespective of treatment, while other analyses focussed on the effect of candesartan according to EF. EF was analysed as separate categories, as well as on a continuous spectrum by means of spline analysis.

Main results

  • Baseline characteristics in HFmrEF were quite similar to HFrEF with regard to age, sex, SBP, ischaemic cause and AF status, while BMI was somewhat higher in HFmrEF, and the percentage of patients with DM was the same.
  • In spline analysis, a higher EF was associated with a lower risk of the primary outcome, up to EF of ~40-50%, seen by a steep decline of the event rate, after which the curve flattens.
  • Similar spline curves were observed for the secondary outcomes of HF hospitalisation, CV death, all cause hospitalisation, all cause death and recurrent HF hospitalisation.
  • Candesartan reduced CV death and time to first HF hospitalisation in HFrEF (HR: 0.82, 95%CI: 0.75-0.91, P<0.001), HFmrEF (HR: 0.76, 95%CI: 0.61-0.96, P=0.02), but not HFpEF (HR: 0.95, 95%CI: 0.79-1.14).
  • A spline curve for the treatment effect showed that candesartan reduced the primary outcome in the HFrEF and HFmrEF range, up to EF >50%.
  • Spline curves for the secondary outcomes roughly mirrored the picture of the primary outcome, with a reduction of events with candesartan up to EF ~35-50%. Recurrent HF hospitalisations were reduced irrespective of EF.
  • Spline analyses showed diverging curves of the 95% CI at the extremes of the EF spectrum.


These data suggest that HFmrEF resembles HFrEF with respect to most characteristics, but the clinical outcomes are better. With increasing EF, up to 50%, improvements in outcomes are seen. A significant treatment effect of candesartan as compared with placebo was seen in HFmrEF and HFrEF, but not HFpEF.

Limitations of the study include the limited statistical power at the extremes of the EF spectrum and multiple outcomes testing. Also, the common variability in EF measurements applies.

During the discussion, dr. Massimo Francesco PIEPOLI (Piacenza, IT) concluded that indeed the HFmrEF category has an intermediate character, which has prognostic value. When EF moves towards reduced EF, things are getting worse. A novelty of this study is the finding that candesartan also works at midrange EF. Dr. Piepoli did note that the patients were enrolled about 15 years ago, which may mean that their background therapy differs from today’s standard treatment.


Our coverage of ESC HF 2017 is based on the information provided during the congress.

Facebook Comments


We’re glad to see you’re enjoying PACE-CME…
but how about a more personalized experience?

Register for free