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Neladenoson not beneficial in HFpEF
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Patients with HF with preserved ejection fraction experienced no significant increase in exercise capacity in 20 weeks with neladenoson, a partial adenosine A1 receptor agonist, according to findings published in JAMA.
Sanjiv J. Shah, MD, and colleagues sought to determine whether neladenoson improved exercise capacity, physical activity, cardiac biomarkers and quality of life in patients with HFpEF, and to find an optimal neladenoson dosage leading to significant improvement.
Previously, Cardiology Today reported on data presented at the American College of Cardiology Scientific Sessions how neladenoson was unsuccessful in improving walking distance in patients with HFpEF at 20 weeks.
“HFpEF is common, is increasing in prevalence, is associated with high morbidity and mortality and lacks effective therapies,” Shah, a professor of medicine and the director of the T1 Center for Cardiovascular Therapeutics at Northwestern University Feinberg School of Medicine, and colleagues wrote. “Patients with HFpEF commonly have markedly reduced reserve capacity, whereby cardiac, vascular and skeletal muscle dysfunction become apparent during exertion.”
Diversity in dose response
The researchers examined data between May and December 2017 of 305 patients (mean age, 74 years; 53% women; mean 6-minute walk test distance, 321.5 m) enrolled in the PANACHE trial with HFpEF, NYHA class II or III with elevated natriuretic peptide levels.
The patients were stratified into dosage groups of 5 mg (n = 27), 10 mg (n = 50), 20 mg (n = 51), 30 mg (n = 50), 40 mg (n = 51) and placebo (n = 76), Shah and colleagues wrote.
The primary outcome was change in 6-minute walk test distance from baseline to 20 weeks with a minimal clinically important difference of 40 m. A multiple comparison procedure using five modeling techniques (linear, Emax, two variations of sigmoidal Emax and quadratic) were used to evaluate diverse dose-response profiles, the researchers wrote.
Shah and colleagues found the greatest mean absolute changes from baseline were in the 5-mg (19.4 m; 95% CI, –10.8 to 49.7) and 10-mg (29.4 m; 95% CI, 3-55.8) neladenoson groups. The 20-mg (13.8 m; 95%, –2.3 to 29.8) and 30-mg (16.3 m; 95% CI, –1.1 to 33.6) neladenoson groups were the next highest.
The 40-mg neladenoson (13 m; 95% CI, –5.9 to 31.9) and placebo (0.2 m; 95% CI, –12.1 to 12.4) groups had the lowest change in distance from baseline, the researchers wrote.
Shah and colleagues discerned there was no significant dose-response relationship in 6-minute walk test distance in the five 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).
There were similar serious adverse event rates among the neladenoson and placebo groups (26.6% vs. 27.6%), the researchers wrote.
Novel approaches needed
“In light of these findings, novel approaches will be needed if further development of neladenoson for the treatment of patients with HFpEF is pursued,” Shah and colleagues wrote. – by Earl Holland Jr.
Disclosures: Shah reports he receives personal fees from Amgen, Bayer, Boehringer Ingelheim, Cardiora, Eisai, Ionis, Ironwood, MyoKardia, Merck, Sanofi and United Therapeutics, and grants and personal fees from Actelion, AstraZeneca and Novartis. Please see the study for all other authors’ relevant financial disclosures.
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