PMID- 35299288 OWN - NLM STAT- MEDLINE DCOM- 20220517 LR - 20220716 IS - 1752-8062 (Electronic) IS - 1752-8054 (Print) IS - 1752-8054 (Linking) VI - 15 IP - 5 DP - 2022 May TI - Vericiguat in combination with isosorbide mononitrate in patients with chronic coronary syndromes: The randomized, phase Ib, VISOR study. PG - 1204-1214 LID - 10.1111/cts.13238 [doi] AB - 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. CI - (c) 2022 Bayer AG. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. FAU - Boettcher, Michael AU - Boettcher M AUID- ORCID: 0000-0001-8931-4564 AD - Clinical Pharmacology, Bayer AG, Wuppertal, Germany. AD - Graduate Physicist and Physician and Lecturer at the University of Applied Science at the RFH-Cologne, Cologne, Germany. FAU - Mikus, Gerd AU - Mikus G AD - Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Heidelberg, Germany. FAU - Trenk, Dietmar AU - Trenk D AD - Department of Cardiology and Angiology II, Section Clinical Pharmacology, Heart Center, University of Freiburg, Bad Krozingen, Germany. FAU - Dungen, Hans-Dirk AU - Dungen HD AD - Department of Internal Medicine, Cardiology, Charite - Universitatsmedizin Berlin, Berlin, Germany. FAU - Donath, Frank AU - Donath F AD - SocraTec R&D GmbH, Erfurt, Germany. FAU - Werner, Nikos AU - Werner N AD - Heart Center Trier, Krankenhaus der Barmherzigen Bruder, Nordallee, Trier, Germany. FAU - Karakas, Mahir AU - Karakas M AD - Department of Intensive Care Medicine, University Medical Center, Hamburg Eppendorf, Hamburg, Germany. FAU - Besche, Nina AU - Besche N AD - Chrestos Concept GmbH & Co. KG, Essen, Germany. FAU - Schulz-Burck, Dominik AU - Schulz-Burck D AD - Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany. FAU - Gerrits, Mireille AU - Gerrits M AD - Merck Sharp & Dohme Corp, a Subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, USA. FAU - Hung, James AU - Hung J AD - Clinical Operations, Study Medical Experts, Bayer SA, Sao Paulo, Brazil. FAU - Becker, Corina AU - Becker C AUID- ORCID: 0000-0003-4715-6726 AD - Clinical Pharmacology, Bayer AG, Wuppertal, Germany. LA - eng SI - ClinicalTrials.gov/NCT03255512 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20220317 PL - United States TA - Clin Transl Sci JT - Clinical and translational science JID - 101474067 RN - 0 (Heterocyclic Compounds, 2-Ring) RN - 0 (Pyrimidines) RN - IA7306519N (Isosorbide Dinitrate) RN - LV66ADM269 (vericiguat) RN - LX1OH63030 (isosorbide-5-mononitrate) SB - IM MH - Adult MH - Double-Blind Method MH - *Heart Failure/drug therapy MH - *Heterocyclic Compounds, 2-Ring/adverse effects MH - Humans MH - Isosorbide Dinitrate/adverse effects/analogs & derivatives MH - Pyrimidines MH - Syndrome PMC - PMC9099120 COIS- 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. EDAT- 2022/03/18 06:00 MHDA- 2022/05/18 06:00 PMCR- 2022/05/01 CRDT- 2022/03/17 20:18 PHST- 2022/01/14 00:00 [revised] PHST- 2021/10/18 00:00 [received] PHST- 2022/01/21 00:00 [accepted] PHST- 2022/03/18 06:00 [pubmed] PHST- 2022/05/18 06:00 [medline] PHST- 2022/03/17 20:18 [entrez] PHST- 2022/05/01 00:00 [pmc-release] AID - CTS13238 [pii] AID - 10.1111/cts.13238 [doi] PST - ppublish SO - Clin Transl Sci. 2022 May;15(5):1204-1214. doi: 10.1111/cts.13238. Epub 2022 Mar 17.