title: Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  Regado Biosciences Inc.
authors.affiliation: Cleveland Clinic Coordinating Center for Clinical Research (C5Research), Cleveland, OH, USA. Electronic address: lincofa@ccf.org.
authors.forename: A Michael
authors.initials: AM
authors.lastname: Lincoff
authors.affiliation: Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Roxana
authors.initials: R
authors.lastname: Mehran
authors.affiliation: Duke Clinical Research Institute, Duke Medicine, Durham, NC, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Povsic
authors.affiliation: Regado Biosciences, Basking Ridge, NJ, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Zelenkofske
authors.affiliation: Duke Clinical Research Institute, Duke Medicine, Durham, NC, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Canadian VIGOUR Centre, University of Alberta, Edmonton, AB, Canada.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Armstrong
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: P Gabriel
authors.initials: PG
authors.lastname: Steg
authors.affiliation: University of Freiburg, Freiburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.affiliation: University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Mauricio G
authors.initials: MG
authors.lastname: Cohen
authors.affiliation: St Michael's Hospital, Toronto, ON, Canada.
authors.forename: Christopher
authors.initials: C
authors.lastname: Buller
authors.affiliation: North Estonia Medical Centre, Tallinn, Estonia.
authors.forename: Peep
authors.initials: P
authors.lastname: Laanmets
authors.affiliation: University Hospital of Ferrara, Institute of Cardiology, Ferrara, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Valgimigli
authors.affiliation: North Estonia Medical Centre, Tallinn, Estonia.
authors.forename: Toomas
authors.initials: T
authors.lastname: Marandi
authors.affiliation: National Institute of Cardiovascular Diseases, Bratislava, Slovakia.
authors.forename: Viliam
authors.initials: V
authors.lastname: Fridrich
authors.affiliation: Southlake Regional Health Centre, Newmarket, ON, Canada.
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Cantor
authors.affiliation: Semmelweis University Heart and Vascular Center, Budapest, Hungary.
authors.forename: Bela
authors.initials: B
authors.lastname: Merkely
authors.affiliation: Hospital Universitario La Paz, IdiPaz, Madrid, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Lopez-Sendon
authors.affiliation: Medical Center Alkmaar, Alkmaar, Netherlands.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Cornel
authors.affiliation: Medical University of Lodz, Bieganski Hospital, Lodz, Poland.
authors.forename: Jaroslaw D
authors.initials: JD
authors.lastname: Kasprzak
authors.affiliation: General University Hospital, Prague, Czech Republic.
authors.forename: Michael
authors.initials: M
authors.lastname: Aschermann
authors.affiliation: Heart Institute Sheba Medical Center, Tel Aviv University, Tel Hashomer, Israel.
authors.forename: Victor
authors.initials: V
authors.lastname: Guetta
authors.affiliation: Santo Andre's Hospital, Leiria, Portugal.
authors.forename: Joao
authors.initials: J
authors.lastname: Morais
authors.affiliation: University Hospitals Leuven Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Sinnaeve
authors.affiliation: Wilhelminen Hospital, Vienna, Austria.
authors.forename: Kurt
authors.initials: K
authors.lastname: Huber
authors.affiliation: Liverpool Heart & Chest Hospital, Liverpool, UK.
authors.forename: Rod
authors.initials: R
authors.lastname: Stables
authors.affiliation: Duke Clinical Research Institute, Duke Medicine, Durham, NC, USA.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Sellers
authors.affiliation: Cleveland Clinic Coordinating Center for Clinical Research (C5Research), Cleveland, OH, USA.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Borgman
authors.affiliation: Regado Biosciences, Basking Ridge, NJ, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Glenn
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Arnold I
authors.initials: AI
authors.lastname: Levinson
authors.affiliation: Duke Clinical Research Institute, Duke Medicine, Durham, NC, USA.
authors.forename: Renato D
authors.initials: RD
authors.lastname: Lopes
authors.affiliation: Duke Clinical Research Institute, Duke Medicine, Durham, NC, USA.
authors.forename: Vic
authors.initials: V
authors.lastname: Hasselblad
authors.affiliation: University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Becker
authors.affiliation: Duke Clinical Research Institute, Duke Medicine, Durham, NC, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Alexander
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000627:therapeutic use*; D052157:Aptamers, Nucleotide / Q000627:therapeutic use*; D003029:Coagulants / Q000008:administration & dosage; D004342:Drug Hypersensitivity / Q000453:epidemiology; D057239:Early Termination of Clinical Trials; D005060:Europe / Q000453:epidemiology; D015949:Factor IXa / Q000037:antagonists & inhibitors*; D005260:Female; D006470:Hemorrhage / Q000453:epidemiology; D006629:Hirudins; D006801:Humans; D008297:Male; D008875:Middle Aged; D009656:North America / Q000453:epidemiology; D009841:Oligonucleotides / Q000008:administration & dosage; D010446:Peptide Fragments / Q000627:therapeutic use*; D062645:Percutaneous Coronary Intervention; D011994:Recombinant Proteins / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D052157:Aptamers, Nucleotide; D003029:Coagulants; D006629:Hirudins; D009841:Oligonucleotides; D010446:Peptide Fragments; C515724:RB 006; C515725:RB 007; D011994:Recombinant Proteins; D015949:Factor IXa; C074619:bivalirudin