TY - JOUR
T1 - Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI)
T2 - A randomised clinical trial
AU - REGULATE-PCI Investigators
AU - Lincoff, A. Michael
AU - Mehran, Roxana
AU - Povsic, Thomas J.
AU - Zelenkofske, Steven L.
AU - Huang, Zhen
AU - Armstrong, Paul W.
AU - Steg, P. Gabriel
AU - Bode, Christoph
AU - Cohen, Mauricio G.
AU - Buller, Christopher
AU - Laanmets, Peep
AU - Valgimigli, Marco
AU - Marandi, Toomas
AU - Fridrich, Viliam
AU - Cantor, Warren J.
AU - Merkely, Bela
AU - Lopez-Sendon, Jose
AU - Cornel, Jan H.
AU - Kasprzak, Jaroslaw D.
AU - Aschermann, Michael
AU - Guetta, Victor
AU - Morais, Joao
AU - Sinnaeve, Peter R.
AU - Huber, Kurt
AU - Stables, Rod
AU - Sellers, Mary Ann
AU - Borgman, Marilyn
AU - Glenn, Lauren
AU - Levinson, Arnold I.
AU - Lopes, Renato D.
AU - Hasselblad, Vic
AU - Becker, Richard C.
AU - Alexander, John H.
N1 - Funding Information:
AML reports institutional research support and travel reimbursement from Regado Biosciences, Roche, Genentech, Eli Lilly, Pfizer, and Takeda; institutional research support from AstraZeneca; institutional research support and consulting fees from CSL; consulting fees from Sermonix; and consulting fees and travel reimbursement from Amgen. RM reports consulting and/or advisory board fees from Regado Biosciences, Abbott Vascular, AstraZeneca, Boston Scientific, Covidien, CSL Behring, Janssen Pharmaceuticals, Maya Medical, Merck, and Sanofi-Aventis; and institutional research support from AstraZeneca, The Medicines Company, Bristol-Myers Squibb, Sanofi-Aventis, Lilly, and Daiichi Sankyo. TJP reports institutional research support from Regado Biosciences. SLZ is an employee of Regado Biosciences. PWA reports research support from Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, and Regado Biosciences; and consulting, advisory board fees, or honoraria from Boehringer Ingelheim, Eli Lilly, Roche, Bayer, AstraZeneca, GlaxoSmithKline, and Regado Biosciences. PGS reports honoraria or consulting fees from Regado Biosciences, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Lilly, MerckSharpeDohme, Novartis, Otsuka, Pfizer, Roche, Medtronic, Sanofi, Servier, Vivus, Janssen, The Medicines Company, and Orexigen; and research support from Sanofi and Servier. CBo reports consulting fees or honoraria from AstraZeneca, Bayer, Daiichi Sankyo, and Merck. MGC reports consulting fees or honoraria from Cleveland Clinic Foundation and The Medicines Company; and research grants from The Medicines Company, AstraZeneca, and Daiichi Sankyo. CBu reports research grants, consulting fees, and honoraria from Regado Biosciences. MV reports research grants from Medtronic, Terumo, and The Medicines Company; and consulting fees or honoraria from Terumo, Abbott Vascular, AstraZeneca, Correvio, and Alvimedica. VF and BM report consulting fees and honoraria from Regado Biosciences. JL-S reports research grants from Servier, Menarini, AstraZeneca, and Boehringer Ingelheim; and consulting fees or honoraria from Servier, Menarini, GlaxoSmithKline, Novartis, Bristol-Myers Squibb, Lilly, AstraZeneca, Pfizer, and Boehringer Ingelheim. JHC reports consulting fees and honoraria from AstraZeneca and Eli Lilly. JDK reports other support from Regado Biosciences. JM reports consulting fees or honoraria from Bayer HealthCare, MSD, AstraZeneca, Lilly, Bristol-Myers Squibb, Pfizer, Jaba Recordati, and Servier. PRS reports other support from PPD (contract research organisation for the REGULATE-PCI trial); research grants from AstraZeneca; consulting fees, honoraria, and non-financial support from AstraZeneca, Bayer, Boehringer Ingelheim, and Daiichi Sankyo; and personal fees from GlaxoSmithKline, Bristol-Myers Squibb, Sanofi, and The Medicines Company. MAS is employed by the Duke Clinical Research Institute (DCRI), which was contracted and paid by Regado Biosciences to provide academic and operational leadership for the REGULATE-PCI trial. AIL reports consulting fees from Regado Biosciences, Stallergenes, Endo Pharmaceuticals, and the US Department of Health and Human Services. RDL reports institutional research support from Regado Biosciences, Bristol-Myers Squibb, and GlaxoSmithKline; and consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer. RCB reports consulting fees and honoraria from Regado Biosciences; and research support from the National Heart, Lung, and Blood Institute. JHA reports institutional research support and consulting fees from Regado Biosciences and Bristol-Myers Squibb; consulting fees from the American College of Cardiology, Portola, and the VA Cooperative Studies Program; institutional research support from Boehringer Ingelheim, CSL Behring, National Institutes of Health, Tenex Therapeutics, and Vivus Pharmaceuticals. ZH, PL, TM, WJC, MA, VG, KH, RS, MB, LG, and VH declare no competing interests. Duke University owns a small amount of equity in Regado Biosciences. The amount and terms of this equity are unknown to anyone involved in this project.
Publisher Copyright:
© 2016 Elsevier Ltd.
PY - 2016/1/23
Y1 - 2016/1/23
N2 - Summary 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 13200 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.
AB - Summary 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 13200 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.
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U2 - 10.1016/S0140-6736(15)00515-2
DO - 10.1016/S0140-6736(15)00515-2
M3 - Article
C2 - 26547100
AN - SCOPUS:84959556076
VL - 387
SP - 349
EP - 356
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 10016
ER -