Vericiguat in combination with isosorbide mononitrate in patients with chronic coronary syndromes: The randomized, phase Ib, VISOR study

Abstract

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.

Trial registration: ClinicalTrials.gov NCT03255512.

Conflict of interest statement

M.B., C.B., and D.S.‐B. are employees of Bayer and may own stock in the company. J.H. is an employee of Bayer. G.M. and D.T. received speakers’ fees and honoraria for advisory boards from Bayer. N.W. received travel grants from Bayer. N.B. is an employee of Chrestos Concept GmbH & Co. KG, which received funding for this analysis from Bayer AG. M.G. is a former contractor for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. H.‐D.D. has received institutional payment as an investigator and personal honoraria for advisory boards from Bayer. M.K. is supported by a Clinician Scientist Professorship Grant from the Else Kroener‐Fresenius‐Foundation and reports both, personal fees and grant support, from Daiichi‐Sankyo, Adrenomed, Sphingotec, and Vifor Pharma, all outside the submitted work. All other authors declared no competing interests for this work.

© 2022 Bayer AG. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

FIGURE 1

VISOR study design. aIn‐house phases; b30 min before breakfast; cAfter breakfast. Visits 5, 7, and 9 were ambulatory visits at day 7, day 21, and day 35 ± 2 days, respectively. ER, extended release; ISMN, isosorbide mononitrate; OD, once daily

FIGURE 2

Hemodynamic profile time points. Axis is time in minutes. Black arrows represent time points at which hemodynamic measurements were taken. ISMN, isosorbide mononitrate

FIGURE 3

Patient disposition. ISMN, isosorbide mononitrate

FIGURE 4

Results of the ANCOVA. Least squares mean difference (±90% CI) in hemodynamic parameter between vericiguat + ISMN and placebo + ISMN: (a) SBP, (b) DBP, and (c) HR. Circles indicate first dose; squares indicate steady‐state. ANCOVA, analysis of covariance; CI, confidence interval; DBP, diastolic blood pressure; HR, heart rate; ISMN, isosorbide mononitrate; SBP, systolic blood pressure