Cinaciguat, a soluble guanylate cyclase activator, unloads the heart but also causes hypotension in acute decompensated heart failure

• Published in: European heart journal Vol. 34; no. 1; pp. 57 - 67
• Main Authors: Erdmann, Erland, Semigran, Marc J, Nieminen, Markku S, Gheorghiade, Mihai, Agrawal, Rahul, Mitrovic, Veselin, Mebazaa, Alexandre
• Format: Journal Article
• Language: English
• Published: England 01.01.2013
• Subjects: Acute Disease; Benzoates - administration & dosage; Benzoates - adverse effects; Dose-Response Relationship, Drug; Double-Blind Method; Early Termination of Clinical Trials; Female; Glomerular Filtration Rate - drug effects; Guanylate Cyclase-Activating Proteins - administration & dosage; Guanylate Cyclase-Activating Proteins - adverse effects; Heart Failure - drug therapy; Heart Failure - physiopathology; Hemodynamics - drug effects; Humans; Hypotension - chemically induced; Hypotension - physiopathology; Infusions, Intravenous; Male; Middle Aged; Tachycardia, Ventricular - chemically induced; Treatment Outcome
• ISSN: 0195-668X; 1522-9645
• DOI: 10.1093/eurheartj/ehs196

Cinaciguat (BAY 58-2667) is a novel soluble guanylate cyclase activator. This study evaluated the haemodynamic effect and safety of cinaciguat added to standard therapy in patients with acute decompensated heart failure (ADHF). In this placebo-controlled, phase IIb study (NCT00559650), 139 patients admitted with ADHF, pulmonary capillary wedge pressure (PCWP) ≥18 mmHg, left ventricular ejection fraction <40%, and a pre-existing need for invasive haemodynamic monitoring were randomized 2:1 to cinaciguat:placebo (continuous i.v. infusion). The dose was titrated for 8 h and maintained for 16-40 h (starting dose: 100 μg/h). At 8 h, mean PCWP changed from 25.7 ± 5.0 mmHg by -7.7 mmHg with cinaciguat and from 25.0 ± 5.3 mmHg by -3.7 mmHg with placebo (P < 0.0001). The mean right atrial pressure changed from 12.4 ± 5.3 mmHg by -2.7 mmHg with cinaciguat and from 11.8 ± 4.9 mmHg by -0.6 mmHg with placebo (P= 0.0019). Cinaciguat also decreased the pulmonary and systemic vascular resistance and the mean arterial pressure, and increased the cardiac index (all P < 0.0001 vs. placebo). Systolic blood pressure changed by -21.6 ± 17.0 mmHg with cinaciguat and -5.0 ± 14.5 mmHg with placebo. Adverse events were experienced by 71 and 45% of patients receiving cinaciguat and placebo, respectively. No adverse effects on the 30-day mortality were seen; however, the trial was stopped prematurely due to an increased occurrence of hypotension at cinaciguat doses ≥200 µg/h. Cinaciguat unloaded the heart in patients with ADHF. However, high doses were associated with hypotension.