Cinaciguat, a soluble guanylate cyclase activator: results from the randomized, controlled, phase IIb COMPOSE programme in acute heart failure syndromes.
OBJECTIVE
Cinaciguat (BAY 58-2667) is a soluble guanylate cyclase (sGC) activator that, in a previous study among patients with acute heart failure syndromes (AHFS), improved pulmonary capillary wedge pressure (PCWP) at the expense of significant hypotension at doses ≥200 µg/h. The aim of the COMPOSE programme was to investigate the safety and efficacy of fixed, low doses of intravenous cinaciguat (<200 µg/h for 24-48 h) as add-on to standard therapy in adults hospitalized with AHFS.


RESULTS
COMPOSE comprised three randomized, double-blind, placebo-controlled studies in patients with [COMPOSE 1 and 2 (NCT01065077 and NCT01067859)] or without [COMPOSE EARLY (NCT01064037)] a requirement for invasive haemodynamic monitoring. COMPOSE 1 and COMPOSE EARLY assessed the effects of cinaciguat (50, 100, and 150 µg/h) on haemodynamics and dyspnoea, respectively. COMPOSE 2 assessed the haemodynamic effects of 10 and 25 µg/h cinaciguat. COMPOSE was terminated early due to an excess of non-fatal hypotension and recruitment difficulties. In COMPOSE 1 (n = 12), cinaciguat reduced PCWP at 8 h compared with placebo, but there was no relevant change in cardiac index. In COMPOSE EARLY (n = 62), no meaningful difference in dyspnoea was shown between cinaciguat and placebo.


CONCLUSIONS
In this limited database, short-term use of intravenous cinaciguat decreased blood pressure without improving dyspnoea or cardiac index. Given the lack of effect on dyspnoea and cardiac index and the hypotensive effect seen even with low doses, it is doubtful that further studies with intravenous cinaciguat would prove beneficial in this patient population.
Centre for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, 645 North Michigan Ave., Suite 1006, Chicago, IL 60611, USA. m-gheorghiade@northwestern.edu
Mihai
M
Gheorghiade
Stephen J
SJ
Greene
Gerasimos
G
Filippatos
Erland
E
Erdmann
Roberto
R
Ferrari
Phillip D
PD
Levy
Aldo
A
Maggioni
Christina
C
Nowack
Alexandre
A
Mebazaa
D000208:Acute Disease; D000277:Adjuvants, Pharmaceutic / Q000008:administration & dosage / Q000009:adverse effects; D000368:Aged; D000369:Aged, 80 and over; D001565:Benzoates / Q000008:administration & dosage* / Q000009:adverse effects; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D004417:Dyspnea / Q000188:drug therapy; D004789:Enzyme Activation; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism*; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D013577:Syndrome
D000277:Adjuvants, Pharmaceutic; D001565:Benzoates; C480588:BAY 58-2667; D006162:Guanylate Cyclase