1. In this randomized controlled trial, heart failure with preserved ejection fraction (HFpEF) patients did not have improved exercise capacity with neladenoson versus placebo.
2. There were no changes in activity intensity, NT-proBNP level, high-sensitivity troponin T level, or quality of life with neladenoson.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Heart failure with preserved ejection fraction (HFpEF) has high mortality and morbidity, including low exercise capacity. Neladenoson bialanate is a partial adenosine A1 receptor agonist that improves mitochondrial function and reverses ventricular remodeling, but it is unclear if it is beneficial for HFpEF. In this randomized clinical trial, neladenoson did not improve exercise capacity in patients with HFpEF over a 20 week period compared with placebo. In addition, neladenoson did not improve activity intensity, NT-proBNP level, high-sensitivity troponin T level, or quality of life. Serious adverse effects were similar among groups.
Though the study suggests neladenoson does not benefit HFpEF patients, some limitations should be noted. First, it is possible that longer treatment periods were needed to see an effect. Second, the lack of preclinical HFpEF models and mechanistic studies of neladenoson in humans obscures whether improvements in mitochondrial respiration were achieved in the clinical setting.
Relevant Reading: Rationale and design of the phase 2b clinical trials to study the effects of the partial adenosine A1-receptor agonist neladenoson bialanate in patients with chronic heart failure with reduced (PANTHEON) and preserved (PANACHE) ejection fraction.
In-Depth [randomized controlled trial]: This was a phase 2b, randomized, parallel-group, dose-finding, double-blind, multi-center clinical trial. 305 patients were recruited at 76 centers in the United States, Europe, and Japan. Key inclusion criteria were age of 45 years or older, New York Heart Association functional class II, III, or IV HFpEF, and LVEF of 45% or greater. There were also key criteria to ensure adequate guideline-based therapy and baseline lab values prior to enrollment. The primary efficacy endpoint was the absolute change from baseline in 6-minute walk test distance after 20 weeks of treatment. Secondary efficacy end points included change from baseline to 20 weeks for each of the following: (1) activity intensity, (2) NT-proBNP level, (3) high-sensitivity troponin T level, and (4) the KCCQ (quality of life) overall summary score.
After 20 weeks of treatment, the mean absolute change from baseline in 6-minute walk test distance was 0.2m (CI95−12.1 to 12.4 m) for the placebo group; 19.4 m (CI95 −10.8 to 49.7 m) for the 5 mg of neladenoson group; 29.4 m (CI95 3.0 to 55.8 m) for the 10mg of neladenoson group; 13.8m (CI95 −2.3 to 29.8 m) for the 20mg of neladenoson group; 16.3m (CI95 −1.1 to 33.6 m) for the 30 mg of neladenoson group; and 13.0 m (CI95 −5.9 to 31.9 m) for the 40mg of neladenoson group. There was no statistically significant dose-response relationship for the change in 6-minute walk test distance among the 5 different dose-response models (p > 0.05). There was also no evidence of a dose-response relationship for any of the secondary efficacy end points, including in activity intensity, NT-proBNP level, high-sensitivity troponin T level, and quality of life (p > 0.05).
©2019 2 Minute Medicine, Inc. All rights reserved. No works may be reproduced without expressed written consent from 2 Minute Medicine, Inc. Inquire about licensing here. No article should be construed as medical advice and is not intended as such by the authors or by 2 Minute Medicine, Inc.