Efficacy and Safety of Revacept, a Novel Lesion-Directed Competitive Antagonist to Platelet Glycoprotein VI, in Patients Undergoing Elective Percutaneous Coronary Intervention for Stable Ischemic Heart Disease: The Randomized, Double-blind, Placebo-Controlled ISAR-PLASTER Phase 2 Trial

Abstract

Importance: The assessment of new antithrombotic agents with a favorable safety profile is clinically relevant.

Objective: To test the efficacy and safety of revacept, a novel, lesion-directed antithrombotic drug, acting as a competitive antagonist to platelet glycoprotein VI.

Design, setting, and participants: A phase 2 randomized clinical trial; patients were enrolled from 9 centers in Germany from November 20, 2017, to February 27, 2020; follow-up ended on March 27, 2020. The study included patients with stable ischemic heart disease (SIHD) undergoing elective percutaneous coronary intervention (PCI).

Interventions: Single intravenous infusion of revacept, 160 mg, revacept, 80 mg, or placebo prior to the start of PCI on top of standard antithrombotic therapy.

Main outcomes and measures: The primary end point was the composite of death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin to at least 5 times the upper limit of normal within 48 hours from randomization. The safety end point was bleeding type 2 to 5 according to the Bleeding Academic Research Consortium criteria at 30 days.

Results: Of 334 participants (median age, 67.4 years; interquartile range, 60-75.1 years; 253 men [75.7%]; and 330 White participants [98.8%]), 120 were allocated to receive the 160-mg dose of revacept, 121 were allocated to receive the 80-mg dose, and 93 received placebo. The primary end point showed no significant differences between the revacept and placebo groups: 24.4%, 25.0%, and 23.3% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .98). The high dose of revacept was associated with a small but significant reduction of high-concentration collagen-induced platelet aggregation, with a median 26.5 AU × min (interquartile range, 0.5-62.2 AU × min) in the revacept, 160 mg, group; 43.5 AU × min (interquartile range, 22.8-99.5 AU × min) in the revacept, 80 mg, group; and 41.0 AU × min (interquartile range, 31.2-101.0 AU × min) in the placebo group (P = .02), while adenosine 5'-diphosphate-induced aggregation was not affected. Revacept did not increase Bleeding Academic Research Consortium type 2 or higher bleeding at 30 days compared with placebo: 5.0%, 5.9%, and 8.6% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .36).

Conclusions and relevance: Revacept did not reduce myocardial injury in patients with stable ischemic heart disease undergoing percutaneous coronary intervention. There were few bleeding events and no significant differences between treatment arms.

Trial registration: ClinicalTrials.gov Identifier: NCT03312855.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Hein-Rothweiler reported grants from German Center for Cardiovascular Research, Deutsches Herzzentrum München, the Federal Ministry of Education and Research, and advanceCOR GmbH during the conduct of the study. Dr Schüpke reported grants from Else Kröner-Fresenius-Stiftung (Else Kröner-Memorial grant) during the conduct of the study and DZHK (German Center for Cardiovascular Research) for the Intracoronary Stenting and Antithrombotic Regimen: Lesion Platelet Adhesion as Selective Target of Endovenous Revacept in Patients With Chronic Coronary Syndromes Undergoing Percutaneous Coronary Intervention trial and personal fees from Bayer Vital GmbH, Daiichi Sankyo, and Biopas Laboratoires outside the submitted work. Dr Bernlochner reported personal fees from Sysmex Europe GmbH outside the submitted work. Dr Sibbing reported personal fees from Sanofi, Bayer, Pfizer, Daiichi Sankyo, and AstraZeneca outside the submitted work. Dr Gori reported personal fees from Abbott Vascular and grants from Novasc outside the submitted work. Dr Landmesser reported personal fees from Biotronik, Bayer, Boehringer, Pfizer, Daiichi Sankyo, Novartis, and Abbott outside the submitted work. Dr Pieske reported personal fees from Bayer Healthcare Steering Committee, Merck Steering Committee, Novartis Steering Committee, Servier, AstraZeneca, and Bristol Myers Squibb outside the submitted work. Dr Zeiher reported personal fees from AstraZeneca outside the submitted work. Dr Schunkert reported personal fees from MSD Sharp and Dohme, Amgen, Bayer Vital GmbH, Boehringer Ingelheim, Daiichi Sankyo, Novartis, Servier, Brahms, Bristol Myers Squibb, Medtronic, Sanofi Aventis, Synlab, Pfizer, and Vifor and grants from AstraZeneca outside the submitted work. Dr Gawaz is cofounder of advanceCor, the manufacturer of Revacept. Dr Hapfelmeier receives research funding from the Bavarian Ministry of Economic Affairs, Regional Development and Energy, not related to this study. Dr Holdenrieder has received Research grants from Roche Diagnostics and VolitionRx, as well as consultancy and advisory fees from VolitionRx. Dr Leistner receives research funding from the DZHK (German Center for Cardiovascular Research) and the Berlin Institute of Health, both not related to this study. Furthermore, he reports speaker or advisory board/steering committee member honoraria from Bayer Healthare, Novartis, AstraZeneca, Biotronik, BMS, Abbott Vascular, B.Braun, Boehringer Ingelheim, and Vifor. No other disclosures were reported.

Figures

Figure 1.. Screening, Randomization, Treatment, and Follow-up

Patients were evaluated from randomization until death, withdrawal of consent, or the last contact date. CAD indicates coronary artery disease; hs, high-sensitivity; OAC, oral anticoagulation.

Figure 2.. Primary End Point in the 3 Treatment Groups

The primary end point was a composite of death or myocardial injury, defined as increase in high-sensitivity cardiac troponin T to at least 5 times the upper limit of normal within 48 hours from randomization. There was only 1 death in the trial; thus, the end point largely reflects myocardial injury.

Figure 3.. Inhibition of Collagen-Induced Platelet Aggregation (A) and ADP-Induced Platelet Aggregation (B)

Horizontal bars indicate the median values, boxes indicate the 25th and 75th percentiles, and vertical lines indicate the 5th and 95th percentiles. The results are shown for collagen concentration of 253 μg/mL. ADP indicates adenosine 5′-diphosphate; AU, aggregation unit.