By Michael H. Crawford, MD, Editor

Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco

Dr. Crawford reports no financial relationships relevant to this field of study.

SYNOPSIS: A meta-analysis of 11 trials of beta-blockers for heart failure showed that beta-blockers increased left ventricular ejection fraction and reduced cardiovascular mortality in patients in sinus rhythm with baseline ejection fractions < 50%, including those in the 40-49% range.

SOURCES: Cleland JGF, Bunting KV, Flather MD, 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.

Wilcox JE, Mann DL. Beta-blockers for the treatment of heart failure with a mid-range ejection fraction: Deja-vu all over again? Eur Heart J 2018;39:36-38.

Randomized, controlled trials of beta-blockers in patients with heart failure associated with reduced left ventricular ejection fraction (HFrEF) have shown improvement in EF and reductions in morbidity and mortality. More recently, heart failure with preserved EF (HFpEF) has received considerable attention, but no therapy to date has improved mortality in these patients. HFpEF has been defined as EFs > 40%, > 45%, or > 50%. Thus, uncertainty exists as to the EF above which beta-blocker therapy is futile. Also, beta-blocker therapy has not reduced mortality in HF patients with atrial fibrillation (AF), but the relation of this observation to EF is unclear.

Investigators from the Beta-blockers in Heart Failure Collaborative Group studied the effect of beta-blockers on EF and outcomes stratified by baseline EF and rhythm. They selected 11 randomized, controlled trials of beta-blockers in HF and obtained original patient data to perform a meta-analysis. The primary outcomes selected were all-cause mortality and cardiovascular death. EF was analyzed as a continuous variable and categorized into groups based on EF ranges. Statistical analysis was based on the intention-to-treat principle. Individual data from the 11 trials were obtained on more than 18,000 patients. Those with missing data, rhythm other than sinus, or AF were excluded, leaving 14,262 with sinus rhythm and 3,050 with AF who were followed for a mean of 1.5 years. The median age was 65 years, 24% were women, and 66% exhibited ischemic heart disease. Median EF was 27%, and 721 patients registered an EF between 40-49%, while 317 demonstrated an EF > 50%. Patient characteristics between those randomized to beta-blockers vs. placebo were well matched. As expected, baseline EF was inversely associated with mortality. This association was stronger for those in sinus rhythm. Mortality was predominantly cardiovascular (CV), with sudden death and worsening HF the most common. Beta-blockers reduced mortality compared to placebo in those with sinus rhythm that was consistent across all EF groups, except for the small group with EF > 50%. For those in the 40-49% group, CV mortality in the beta-blocker group compared to placebo was 4.5% vs. 9.2% (hazard ratio, 0.48; 95% confidence interval, 0.24-0.97). Also, EF increased on beta-blockers in all with sinus rhythm except for those with EF > 50%. In those with AF, beta-blockers increased LVEF in those in whom it was < 50% at baseline, but did not improve outcomes. The authors concluded that beta-blockers increase EF and reduce CV mortality in patients with HF in sinus rhythm with baseline EF < 50%.

COMMENTARY

This study addressed an important issue that is confusing if one looks at the various HF guidelines; namely, those with an EF of 40-49%. Studies of HFpEF have used cutoffs of > 40% and > 45%, recognizing up to a 10% error in EF measurements and the desire to increase enrollment. However, patients in the 40-49% range often represent patients with HFrEF in whom EF has improved.

This distinction is critical because beta-blockers would be indicated in this group. Some have called this group “HF improved” or “recovered EF.” The European Society of Cardiology has labelled it “HF with mid-range EF,” and suggested it be treated as HFpEF, which would contraindicate beta-blockers. Thus, this analysis of 11 randomized, controlled beta-blocker trials is important because it suggests that this group should be treated with beta-blockers.

To be fair, these 11 trials were designed to treat HF due to reduced EF, but, for several reasons, some patients with EFs > 50% were included. However, this provided the opportunity to study the effect of beta-blockers in those with EFs near 50%.

An explanation for the results of this analysis was suggested in the editorial accompanying the paper. Those editorialists noted that most of the patients in the 40-49% EF group registered EFs < 43%. Accordingly, they emphasized that the 40-49% group is heterogeneous; some may be those with initial EFs < 40% in whom EF recovered somewhat, and some may be HFpEF patients in whom EF deteriorated somewhat. They recommended that in this group, EF must be examined in the overall context of the patient and their course up to that point to classify these patients properly. Of course, this is not always possible, so treatment with beta-blockers in this group should be attempted since this meta-analysis did not show any harm in doing this.

The authors also noted that both the TOPCAT study (spironolactone) and the CHARM study (candesartan) in HFpEF patients showed a trend toward mortality reduction in the 40-49% EF subgroups, but not those with higher EFs, which would lend further support to this recommendation.