2. Academic Validation
  3. Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial

Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial

  • Lancet. 2016 Jan 23;387(10016):349-356. doi: 10.1016/S0140-6736(15)00515-2.
A Michael Lincoff 1,  Roxana Mehran 2,  Thomas J Povsic 3,  Steven L Zelenkofske 4,  Zhen Huang 3,  Paul W Armstrong 5,  P Gabriel Steg 6,  Christoph Bode 7,  Mauricio G Cohen 8,  Christopher Buller 9,  Peep Laanmets 10,  Marco Valgimigli 11,  Toomas Marandi 10,  Viliam Fridrich 12,  Warren J Cantor 13,  Bela Merkely 14,  Jose Lopez-Sendon 15,  Jan H Cornel 16,  Jaroslaw D Kasprzak 17,  Michael Aschermann 18,  Victor Guetta 19,  Joao Morais 20,  Peter R Sinnaeve 21,  Kurt Huber 22,  Rod Stables 23,  Mary Ann Sellers 3,  Marilyn Borgman 24,  Lauren Glenn 4,  Arnold I Levinson 25,  Renato D Lopes 3,  Vic Hasselblad 3,  Richard C Becker 26,  John H Alexander 3,  REGULATE-PCI Investigators
Affiliations

Affiliations

  • 1 Cleveland Clinic Coordinating Center for Clinical Research (C5Research), Cleveland, OH, USA. Electronic address: [email protected].
  • 2 Mount Sinai School of Medicine, New York, NY, USA.
  • 3 Duke Clinical Research Institute, Duke Medicine, Durham, NC, USA.
  • 4 Regado Biosciences, Basking Ridge, NJ, USA.
  • 5 Canadian VIGOUR Centre, University of Alberta, Edmonton, AB, Canada.
  • 6 Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
  • 7 University of Freiburg, Freiburg, Germany.
  • 8 University of Miami Miller School of Medicine, Miami, FL, USA.
  • 9 St Michael's Hospital, Toronto, ON, Canada.
  • 10 North Estonia Medical Centre, Tallinn, Estonia.
  • 11 University Hospital of Ferrara, Institute of Cardiology, Ferrara, Italy.
  • 12 National Institute of Cardiovascular Diseases, Bratislava, Slovakia.
  • 13 Southlake Regional Health Centre, Newmarket, ON, Canada.
  • 14 Semmelweis University Heart and Vascular Center, Budapest, Hungary.
  • 15 Hospital Universitario La Paz, IdiPaz, Madrid, Spain.
  • 16 Medical Center Alkmaar, Alkmaar, Netherlands.
  • 17 Medical University of Lodz, Bieganski Hospital, Lodz, Poland.
  • 18 General University Hospital, Prague, Czech Republic.
  • 19 Heart Institute Sheba Medical Center, Tel Aviv University, Tel Hashomer, Israel.
  • 20 Santo Andre's Hospital, Leiria, Portugal.
  • 21 University Hospitals Leuven Campus Gasthuisberg, Leuven, Belgium.
  • 22 Wilhelminen Hospital, Vienna, Austria.
  • 23 Liverpool Heart & Chest Hospital, Liverpool, UK.
  • 24 Cleveland Clinic Coordinating Center for Clinical Research (C5Research), Cleveland, OH, USA.
  • 25 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 26 University of Cincinnati College of Medicine, Cincinnati, OH, USA.
PMID: 26547100 DOI: 10.1016/S0140-6736(15)00515-2
Abstract

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.

Figures
Products