For a clinical trial, it was determined that there were no effective treatments for heart failure with preserved ejection fraction (HFpEF). Preclinical investigations show that neladenoson bialanate, a first-in-class partial adenosine A1 receptor agonist, had the potential to ameliorate a variety of heart failure-related cardiac and noncardiac problems, although it has not yet been tested to treat HFpEF. Researchers wanted to see if neladenoson can help patients with HFpEF improve their exercise capacity, physical activity, cardiac biomarkers, and quality of life, as well as to find the best dose. A randomized phase 2b clinical trial was undertaken in 76 locations across the United States, Europe, and Japan. Between May 10, 2017, and December 7, 2017, patients with New York Heart Association class II or III HFpEF and increased natriuretic peptide levels (N=305) were enrolled (date of final follow-up: June 20, 2018). For 20 weeks, participants were randomised (1:2:2:2:2) to receive neladenoson (n=27 [5 mg], n=50 [10 mg], n=51 [20 mg], n=50 [30 mg], and n=51 [40 mg]) or a matching placebo (n=76). The major outcome measure was the difference in the 6-minute walk test distance between the baseline and 20 weeks (minimal clinically important difference, 40 m). Bradyarrhythmias and adverse events were two important safety measures. A multiple comparison process using 5 modeling techniques (linear, Emax, 2 versions of sigmoidal Emax, and quadratic) was utilized to analyze distinct dose-response profiles to evaluate the effects of varying dosages of neladenoson. Nearly 261 (86%) of the 305 patients (mean age, 74 years; 160 [53%] women; mean 6-minute walk test distance, 321.5 m) completed the trial and were included in the primary analysis. The mean absolute changes in 6-minute walk test distance from baseline for the placebo group were 0.2 m (95% CI, 12.1 to 12.4 m); 19.4 m (95% CI, 10.8 to 49.7 m) for the 5 mg of neladenoson group; 29.4 m (95% CI, 3.0 to 55.8 m) for the 10 mg of neladenoson group; 13.8 m (95% CI, 2.3 to 29.8 m) for 20 mg of neladenoson group; 16.3 m (95% CI, −1.1 to 33.6 m) for 30 mg of neladenoson group; and 13.0 m (95% CI, −5.9 to 31.9 m) for 40 mg of neladenoson group. There was no optimal dose of neladenoson found since none of the neladenoson groups increased their 6-minute walk test distance by 40 meters from baseline. There was no significant dose-response connection for the change in 6-minute walk test distance among the 5 dose-response models (P=.05 for Emax, P=.18 for quadratic, P=.21 for sigmoidal Emax 1, P=.39 for linear, and P=.52 for sigmoidal Emax 2). The neladenoson groups (61/229 [26.6%]) and the placebo group (21/76 [27.6%]) had similar serious adverse events. There was no significant dose-response association for neladenoson in patients with HFpEF in terms of change in exercise capacity from baseline to 20 weeks. If neladenoson is to be developed further for the treatment of patients with HFpEF, fresh approaches will be required in light of the findings by the researchers.
Link:jamanetwork.com/journals/jama/fullarticle/2735073?resultClick=1
