BACKGROUND: REG1 is a novel anticoagulation system consisting of pegnivacogin, an RNA aptamer inhibitor of coagulation factor IXa, and anivamersen, a complementary sequence reversal oligonucleotide. We tested the hypothesis that near complete inhibition of factor IXa with pegnivacogin during percutaneous coronary intervention, followed by partial reversal with anivamersen, would reduce ischaemic events compared with bivalirudin, without increasing bleeding. METHODS: We did a randomised, open-label, active-controlled, multicentre, superiority trial to compare REG1 with bivalirudin at 225 hospitals in North America and Europe. We planned to randomly allocate 13,200 patients undergoing percutaneous coronary intervention in a 1:1 ratio to either REG1 (pegnivacogin 1 mg/kg bolus [>99% factor IXa inhibition] followed by 80% reversal with anivamersen after percutaneous coronary intervention) or bivalirudin. Exclusion criteria included ST segment elevation myocardial infarction within 48 h. The primary efficacy endpoint was the composite of all-cause death, myocardial infarction, stroke, and unplanned target lesion revascularisation by day 3 after randomisation. The principal safety endpoint was major bleeding. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, identifier NCT01848106. The trial was terminated early after enrolment of 3232 patients due to severe allergic reactions. FINDINGS: 1616 patients were allocated REG1 and 1616 were assigned bivalirudin, of whom 1605 and 1601 patients, respectively, received the assigned treatment. Severe allergic reactions were reported in ten (1%) of 1605 patients receiving REG1 versus one (<1%) of 1601 patients treated with bivalirudin. The composite primary endpoint did not differ between groups, with 108 (7%) of 1616 patients assigned REG1 and 103 (6%) of 1616 allocated bivalirudin reporting a primary endpoint event (odds ratio [OR] 1·05, 95% CI 0·80-1·39; p=0·72). Major bleeding was similar between treatment groups (seven [<1%] of 1605 receiving REG1 vs two [<1%] of 1601 treated with bivalirudin; OR 3·49, 95% CI 0·73-16·82; p=0·10), but major or minor bleeding was increased with REG1 (104 [6%] vs 65 [4%]; 1·64, 1·19-2·25; p=0·002). INTERPRETATION: The reversible factor IXa inhibitor REG1, as currently formulated, is associated with severe allergic reactions. Although statistical power was limited because of early termination, there was no evidence that REG1 reduced ischaemic events or bleeding compared with bivalirudin. FUNDING: Regado Biosciences Inc.

Canadian VIGOUR Centre University of Alberta Edmonton AB Canada

Cleveland Clinic Coordinating Center for Clinical Research Cleveland OH USA

Duke Clinical Research Institute Duke Medicine Durham NC USA

General University Hospital Prague Czech Republic

Heart Institute Sheba Medical Center Tel Aviv University Tel Hashomer Israel

Hospital Universitario La Paz IdiPaz Madrid Spain

Liverpool Heart and Chest Hospital Liverpool UK

Medical Center Alkmaar Alkmaar Netherlands

Medical University of Lodz Bieganski Hospital Lodz Poland

Mount Sinai School of Medicine New York NY USA

National Institute of Cardiovascular Diseases Bratislava Slovakia

North Estonia Medical Centre Tallinn Estonia

Perelman School of Medicine University of Pennsylvania Philadelphia PA USA

Regado Biosciences Basking Ridge NJ USA

Santo Andre's Hospital Leiria Portugal

Semmelweis University Heart and Vascular Center Budapest Hungary

Southlake Regional Health Centre Newmarket ON Canada

St Michael's Hospital Toronto ON Canada

Université Paris Diderot Sorbonne Paris Cité Paris France

University Hospital of Ferrara Institute of Cardiology Ferrara Italy

University Hospitals Leuven Campus Gasthuisberg Leuven Belgium

University of Cincinnati College of Medicine Cincinnati OH USA

University of Freiburg Freiburg Germany

University of Miami Miller School of Medicine Miami FL USA

Wilhelminen Hospital Vienna Austria

Lancet. 2016 Jan 23;387(10016):314-315. doi: 10.1016/S0140-6736(15)00727-8. PubMed

Lancet. 2016 Mar 19;387(10024):1162. doi: 10.1016/S0140-6736(16)00712-1. PubMed   Boudoulas, Dean [corrected to Boudoulas, Konstantinos D.]

Lancet. 2016 Apr 9;387(10027):1510-1511. doi: 10.1016/S0140-6736(16)00694-2. PubMed

Lancet. 2016 Apr 9;387(10027):1510. doi: 10.1016/S0140-6736(16)30128-3. PubMed

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ClinicalTrials.gov
NCT01848106