Cinaciguat, a soluble guanylate cyclase activator: results from the randomized, controlled, phase IIb COMPOSE programme in acute heart failure syndromes

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 epsilon 200 g/h. The aim of the COMPOSE programme was to investigate the safety and efficacy of fixed, low doses of intravenous cinaciguat (200 g/h for 2448 h) as add-on to standard therapy in adults hospitalized with AHFS. 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 g/h) on haemodynamics and dyspnoea, respectively. COMPOSE 2 assessed the haemodynamic effects of 10 and 25 g/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. 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.