Universität zu Köln

Tita, Cristina, Gilbert, Edward M., Van Bakel, Adrian B., Grzybowski, Jacek, Haas, Garrie J., Jarrah, Mohammad, Dunlap, Stephanie H., Gottlieb, Stephen S., Klapholz, Marc, Patel, Parag C., Pfister, Roman, Seidler, Tim ORCID: 0000-0002-6158-5087, Shah, Keyur B., Zielinski, Tomasz, Venuti, Robert P., Cowart, Douglas, Foo, Shi Yin, Vishnevsky, Alexander and Mitrovic, Veselin (2017). A Phase 2a dose-escalation study of the safety, tolerability, pharmacokinetics and haemodynamic effects of BMS-986231 in hospitalized patients with heart failure with reduced ejection fraction. Eur. J. Heart Fail., 19 (10). S. 1321 - 1333. HOBOKEN: WILEY. ISSN 1879-0844

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Abstract

Aims This study was designed to evaluate the safety, tolerability and haemodynamic effects of BMS-986231, a novel second-generation nitroxyl donor with potential inotropic, lusitropic and vasodilatory effects in patients hospitalized with decompensated heart failure and reduced ejection fraction (HFrEF). Methods and results Forty-six patients hospitalized with decompensated HFrEF were enrolled into four sequential dose-escalation cohorts in this double-blind, randomized, placebo-controlled Phase 2a study. Patients with baseline pulmonary capillary wedge pressure (PCWP) of 20 mmHg and a cardiac index of 2.5 L/min/m(2) received one 6-h i.v. infusion of BMS-986231 (at 3, 5, 7 or 12 mu g/kg/min) or placebo. BMS-986231 produced rapid and sustained reductions in PCWP, as well as consistent reductions in time-averaged pulmonary arterial systolic pressure, pulmonary arterial diastolic pressure and right atrial pressure. BMS-986231 increased non-invasively measured time-averaged stroke volume index, cardiac index and cardiac power index values, and decreased total peripheral vascular resistance. There was no evidence of increased heart rate, drug-related arrhythmia or symptomatic hypotension with BMS-986231. Analyses of adverse events throughout the 30-day follow-up did not identify any toxicities specific to BMS-986231, with the potential exception of infrequent mild-to-moderate headaches during infusion. There were no treatment-related serious adverse events. Conclusions BMS-986231 demonstrated a favourable safety and haemodynamic profile in patients hospitalized with advanced heart failure. Based on preclinical data and these study's findings, it is possible that the haemodynamic benefits may be mediated by inotropic and/or lusitropic as well as vasodilatory effects. The therapeutic potential of BMS-986231 should be further assessed in patients with heart failure.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Tita, Cristina UNSPECIFIED UNSPECIFIED UNSPECIFIED Gilbert, Edward M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Van Bakel, Adrian B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Grzybowski, Jacek UNSPECIFIED UNSPECIFIED UNSPECIFIED Haas, Garrie J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jarrah, Mohammad UNSPECIFIED UNSPECIFIED UNSPECIFIED Dunlap, Stephanie H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gottlieb, Stephen S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Klapholz, Marc UNSPECIFIED UNSPECIFIED UNSPECIFIED Patel, Parag C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pfister, Roman UNSPECIFIED UNSPECIFIED UNSPECIFIED Seidler, Tim UNSPECIFIED orcid.org/0000-0002-6158-5087 UNSPECIFIED Shah, Keyur B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zielinski, Tomasz UNSPECIFIED UNSPECIFIED UNSPECIFIED Venuti, Robert P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cowart, Douglas UNSPECIFIED UNSPECIFIED UNSPECIFIED Foo, Shi Yin UNSPECIFIED UNSPECIFIED UNSPECIFIED Vishnevsky, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Mitrovic, Veselin UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-216454
DOI:	10.1002/ejhf.897
Journal or Publication Title:	Eur. J. Heart Fail.
Volume:	19
Number:	10
Page Range:	S. 1321 - 1333
Date:	2017
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1879-0844
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NITROXYL DONOR BMS-986231; OXYGEN-CONSUMPTION; CARDIAC-OUTPUT; HNO; CYCLASE; FORCE; DOGS Multiple languages Cardiac & Cardiovascular Systems Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21645