vericiguat and Syndrome

Vericiguat is a soluble guanylate cyclase stimulator indicated to reduce the risk of cardiovascular death and heart failure (HF) hospitalization in adults with symptomatic chronic HF and ejection fraction less than 45%. Guidelines recommend short-acting nitrates, such as sublingual nitroglycerin, for the treatment of acute angina pectoris in patients with chronic coronary syndromes (CCSs), common comorbidities in HF. We evaluated safety, tolerability, and the pharmacodynamic interaction between vericiguat and nitroglycerin, coadministered in patients with CCSs. In this phase Ib, double-blind, randomized, multicenter study, 36 patients with CCSs received either vericiguat 2.5 mg (up-titrated every 2 weeks to 5 mg and 10 mg) or placebo. Patients also received nitroglycerin (0.4 mg sublingual). In total, 31 patients completed the study (vericiguat + nitroglycerin, n = 21; placebo + nitroglycerin, n = 10). There was no increase in treatment-emergent adverse events (TEAEs) with vericiguat + nitroglycerin vs. placebo + nitroglycerin; three patients discontinued due to TEAEs (vericiguat + nitroglycerin, n = 1; placebo + nitroglycerin, n = 2). Decreases in mean blood pressure (BP; 6-10 mmHg systolic BP (SBP); 4-6 mmHg diastolic BP (DBP)) were independent of vericiguat exposure and occurred to a similar extent at trough and peak concentrations with all vericiguat doses and placebo. Coadministration of vericiguat with nitroglycerin in patients with CCSs was well tolerated, and the combination is unlikely to cause significant adverse effects beyond those known for nitroglycerin.

Topics: Adult; Double-Blind Method; Heart Failure; Heterocyclic Compounds, 2-Ring; Humans; Nitroglycerin; Pyrimidines; Stroke Volume; Syndrome

Vericiguat was developed for the treatment of symptomatic chronic heart failure (HF) in adult patients with reduced ejection fraction who are stabilized after a recent decompensation event. Guidelines recommend long-acting nitrates, such as isosorbide mononitrate, for angina prophylaxis in chronic coronary syndromes (CCS), common comorbidities in HF. This study evaluated safety, tolerability, and the pharmacodynamic (PD) interaction between co-administered vericiguat and isosorbide mononitrate in patients with CCS. In this phase Ib, double-blind, multicenter study, patients were randomized 2:1 to receive vericiguat plus isosorbide mononitrate (n = 28) or placebo plus isosorbide mononitrate (n = 13). Isosorbide mononitrate was uptitrated to a stable dose of 60 mg once daily, followed by co-administration with vericiguat (uptitrated every 2 weeks from 2.5 mg to 5 mg and 10 mg) or placebo. Thirty-five patients completed treatment (vericiguat, n = 23; placebo, n = 12). Mean baseline- and placebo-adjusted vital signs showed reductions of 1.4-5.1 mmHg (systolic blood pressure) and 0.4-2.9 mmHg (diastolic blood pressure) and increases of 0.0-1.8 beats per minute (heart rate) with vericiguat plus isosorbide mononitrate. No consistent vericiguat dose-dependent PD effects were noted. The incidence of adverse events (AEs) was 92.3% and 66.7% in the vericiguat and placebo groups, respectively, and most were mild in intensity. Blood pressure and heart rate changes observed with vericiguat plus isosorbide mononitrate were not considered clinically relevant. This combination was generally well-tolerated. Concomitant use of vericiguat with isosorbide mononitrate is unlikely to cause significant AEs beyond those known for isosorbide mononitrate.

Topics: Adult; Double-Blind Method; Heart Failure; Heterocyclic Compounds, 2-Ring; Humans; Isosorbide Dinitrate; Pyrimidines; Syndrome