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


RESULTS
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.


CONCLUSIONS
Cinaciguat unloaded the heart in patients with ADHF. However, high doses were associated with hypotension.
Herzzentrum der Universität zu Köln, Cologne, Germany. erland.erdmann@uni-koeln.de
Erland
E
Erdmann
Marc J
MJ
Semigran
Markku S
MS
Nieminen
Mihai
M
Gheorghiade
Rahul
R
Agrawal
Veselin
V
Mitrovic
Alexandre
A
Mebazaa
D000208:Acute Disease; D001565:Benzoates / Q000008:administration & dosage* / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D057239:Early Termination of Clinical Trials; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D051604:Guanylate Cyclase-Activating Proteins / Q000008:administration & dosage* / Q000009:adverse effects*; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007022:Hypotension / Q000139:chemically induced* / Q000503:physiopathology; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D017180:Tachycardia, Ventricular / Q000139:chemically induced; D016896:Treatment Outcome
D001565:Benzoates; D051604:Guanylate Cyclase-Activating Proteins; C480588:BAY 58-2667