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Novel nitroxyl donor may improve cardiac function in advanced HF
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Patients with advanced HF who were treated with a novel nitroxyl donor had improved cardiac performance, according to a study published in the European Journal of Heart Failure.
In this randomized, double blind, multicenter, phase 2a study, 46 patients who were hospitalized for advanced HF with reduced ejection fraction, including some with acute decompensation, were assigned a novel second-generation nitroxyl donor (n = 34; BMS-986231, Bristol-Myers Squibb) or placebo (n = 12). The nitroxyl donor was administered to patients intravenously for 6 hours.
Patients were enrolled into four cohorts of ascending doses of BMS-986231: 3 µg/kg per minute (n = 6; mean age, 64 years; 67% men), 5 µg/kg per minute (n = 9; mean age, 61 years; 89% men), 7 µg/kg per minute (n = 12; mean age, 62 years; 100% men) and 12 µg/kg per minute (n = 7; mean age, 48 years; 71% men).
Primary pharmacodynamic endpoints were changes during infusion from baseline in pulmonary arterial diastolic pressure, pulmonary capillary wedge pressure and Fick-estimated cardiac index, which was measured by a pulmonary artery catheter. Secondary endpoints were defined as changes in pulmonary arterial systolic pressure, right atrial pressure, peripheral arterial diastolic BP, peripheral arterial systolic BP, heart rate and calculated mean arterial pressure.
Two hours after the start of infusion, BMS-986231 decreased pulmonary capillary wedge pressure by 4.7 mm Hg in all dose groups vs. an increase of 0.2 mm Hg in the placebo group. The reduction was sustained throughout the duration of the infusion.
Reductions in pulmonary arterial diastolic pressure and pulmonary arterial systolic pressure were seen in all groups assigned BMS-986231. Right atrial pressure was reduced in patients assigned the highest dose.
Stroke volume index increased by 84% in patients assigned 12 µg/kg per minute of BMS-986231 vs. 4% in those assigned placebo. Cardiac index increased as total peripheral vascular resistance decreased in all doses of the nitroxyl donor. Cardiac power index increased significantly in patients who received the highest dose.
Drug-related arrhythmia, increased heart rate or symptomatic hypotension did not occur in patients assigned BMS-986231.
Throughout the 30-day follow-up, no toxicities related to the nitroxyl donor were identified, although mild to moderate headaches during infusion occurred in 8.8% of patients. No treatment-related serious adverse events occurred in both groups.
“Although positive inotropy and/or lusitropy cannot be extrapolated from these findings alone, the hemodynamic findings are consistent with the drug’s purported mechanisms of action derived from preclinical studies and are highly applicable therapeutic findings in this patient population,” Cristina Tita, MD, a cardiologist at Henry Ford Hospital in Detroit, and colleagues wrote. “The clinical significance of these findings is currently unknown, however, and further studies to assess the safety and efficacy of BMS-986231 in patients with HF are needed.” – by Darlene Dobkowski
Disclosures: The study was supported by Bristol-Myers Squibb and Cardioxyl Pharmaceuticals. Tita reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
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