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Effects of a Novel Nitroxyl Donor in Acute Heart Failure: The STAND-UP AHF Study
G Michael Felker1, John J V McMurray2, John G Cleland3
1Duke University School of Medicine and the Duke Clinical Research Institute, Durham, North Carolina, USA.
Insights
Cimlanod, a nitroxyl donor, showed reasonable safety at 6 μg/kg/min in acute heart failure patients. While it reduced congestion markers, these effects were temporary, indicating limited sustained efficacy.
Area of Science:
- Cardiology
- Pharmacology
Background:
- Nitroxyl (HNO) donors possess vasodilator, inotropic, and lusitropic properties.
- Cimlanod (Bristol-Myers Squibb-986231) is an investigational HNO donor for acute heart failure (AHF).
Purpose of the Study:
- To determine well-tolerated doses of cimlanod in AHF patients.
- To assess potential efficacy signals, including biomarkers, symptoms, and clinical events.
Main Methods:
- A Phase IIb, double-blind, randomized, placebo-controlled trial involving 48-hour cimlanod infusions in hospitalized AHF patients with ejection fraction ≤40%.
- Part I: Escalating doses of cimlanod vs. placebo (1:1 randomization). Part II: Two highest tolerated doses from Part I vs. placebo (1:1:1 randomization).
- Primary endpoint: Rate of clinically relevant hypotension (systolic blood pressure <90 mm Hg or symptomatic).
Main Results:
- Part I: Hypotension occurred in 20% with cimlanod vs. 8% with placebo.
- Part II: Hypotension incidence was 21% for cimlanod 6 μg/kg/min and 35% for 12 μg/kg/min, versus 18% for placebo.
- N-terminal pro-B-type natriuretic peptide and bilirubin decreased during cimlanod infusion but did not persist post-treatment.
Conclusions:
- Cimlanod at 6 μg/kg/min was reasonably well-tolerated compared to placebo in AHF patients.
- Cimlanod demonstrated a temporary reduction in congestion markers, but these effects were not sustained beyond the treatment period.
Objectives:
The primary objective was to identify well-tolerated doses of cimlanod in patients with acute heart failure (AHF). Secondary objectives were to identify signals of efficacy, including biomarkers, symptoms, and clinical events.
Background:
Nitroxyl (HNO) donors have vasodilator, inotropic and lusitropic effects. Bristol-Myers Squibb-986231 (cimlanod) is an HNO donor being developed for acute heart failure (AHF).
Methods:
This was a phase IIb, double-blind, randomized, placebo-controlled trial of 48-h treatment with cimlanod compared with placebo in patients with left ventricular ejection fraction ≤40% hospitalized for AHF. In part I, patients were randomized in a 1:1 ratio to escalating doses of cimlanod or matching placebo. In part II, patients were randomized in a 1:1:1 ratio to either of the 2 highest tolerated doses of cimlanod from part I or placebo. The primary endpoint was the rate of clinically relevant hypotension (systolic blood pressure <90 mm Hg or patients became symptomatic).
Results:
In part I (n = 100), clinically relevant hypotension was more common with cimlanod than placebo (20% vs. 8%; relative risk [RR]: 2.45; 95% confidence interval [CI]: 0.83 to 14.53). In part II (n = 222), the incidence of clinically relevant hypotension was 18% for placebo, 21% for cimlanod 6 μg/kg/min (RR: 1.15; 95% CI: 0.58 to 2.43), and 35% for cimlanod 12 μg/kg/min (RR: 1.9; 95% CI: 1.04 to 3.59). N-terminal pro-B-type natriuretic peptide and bilirubin decreased during infusion of cimlanod treatment compared with placebo, but these differences did not persist after treatment discontinuation.
Conclusions:
Cimlanod at a dose of 6 μg/kg/min was reasonably well-tolerated compared with placebo. Cimlanod reduced markers of congestion, but this did not persist beyond the treatment period. (Evaluate the Safety and Efficacy of 48-Hour Infusions of HNO (Nitroxyl) Donor in Hospitalized Patients With Heart Failure [STANDUP AHF]; NCT03016325).
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