Physical Disorders May Lessen Effectiveness of Combination Therapy for HFrEF

April 16, 2021
Maggie L. Shaw

This recent study out of Japan compared the use of renin-angiotensin system inhibitors and β-blockers among patients with heart failure, both those who had physical limitations and those who did not.

Individuals with heart failure with reduced ejection fraction (HFrEF) who did not have a physical disorder fared better in a recent study out of Japan that compared the effects on combination therapy (CT) for these patients vs those who had physical disorders. The treatment comprised renin-angiotensin system (RAS) inhibitors and β-blockers.

Findings were published in Circulation Reports.

“Although reduced activities of daily living (ADL) are strongly associated with worse outcomes in patients with acute HF (AHF), it is unknown whether the effects of CT will be the same across different physical activity levels in HF patients,” the authors wrote.

With a composite end point of all-cause mortality and HF-related hospitalization, data were gathered from the Kitakawachi Clinical Background and Outcome of Heart Failure (KICKOFF) Registry for patients with HF hospitalized between April 2015 and August 2017. Patients (N = 1018) were first stratified into 1 of 3 ejection fraction categories: HFrEF (n = 308), HF with midrange ejection fraction (HFmEF; n = 125%), and HF with preserved ejection fraction (HFpEF; n = 585). They then were subdivided into those with the ability to walk independently (no physical disorder) and who could not (have a physical disorder).

After a 1-year follow-up period, the results showed that when the CT was prescribed, those with HFrEF were younger patients with a history of hypertension but not stroke, whereas those with HFpEF typically also had coronary artery disease and/or diabetes.

In addition, for the patients who received the CT, those with HFpEF had fewer prescriptions for oral inotropic agents and digitalis, while those with HFpEF had more prescriptions for diuretics and digitalis.

Also, more patients who received the CT could walk independently outdoors vs the individuals who did not receive the CT for those with HFrEF or HFpEF, and the most prescriptions for CT were given to those with that walking ability, “with the rate of CT prescriptions decreasing with declining ADL,” the authors noted. In contrast, more patients with HFmEF who could walk independently indoors received CT prescriptions.

The mean (SD) ages of the patients were 74.2 (12.6), 76.2 (10.7), and 79.7 (10.5) years, respectively, for the HFrEF, HFmEF, and HFpEF groups; the median (interquartile range) estimated glomerular filtration rates were 47.6 (35.9-61.9), 48.9 (35.0-62.6), and 48.5 (35.3-64.5) mL/min/1.73 m2; and the most common comorbidity was hypertension.

Overall, by the end of the 1-year follow-up, rates of the composite end point were similar across the 3 ejection fraction classifications, at 33.8%, 37.6%, and 34.7% for those with HFrEF, HFmrEF, and HFpEF, respectively. It was only among those with HFrEF that a significant difference in the composite outcome was seen, with the rate being much lower among those who received CT compared with those who did not, particularly for those who could walk by themselves outdoors and who were younger than 80 years (P < .001 for both).

“The main finding of this study is that CT had an effect on outcome in HFrEF patients without a physical disorder, but not in HFrEF patients with a physical disorder. Lower physical activity primarily depresses the metabolism and changes drug pharmacodynamics, drug absorption, distribution, and elimination,” the authors stated. “We conclude that one of the most fundamental therapies for patients with AHF without physical disorders is the use of RAS inhibitors and β-blockers.”


Takabayashi K, Kitaguchi S, Yamamoto T, et al. Association between physical status and the effects of combination therapy with renin-angiotensin system inhibitors and β-blockers in patients with acute heart failure. Cir Rep. 2021;3(4):217-226. doi:10.1253/circrep.CR-20-0123