Critical Appraisal of Bivalirudin versus Heparin for Percutaneous Coronary Intervention: A Meta-Analysis of Randomized Trials

May Critical Appraisal of Bivalirudin versus Heparin for Percutaneous Coronary Intervention: A Meta-Analysis of Randomized Trials Anthony A. Bavry 0 1 Islam Y. Elgendy 0 1 Ahmed Mahmoud 0 1 Manoj P. Jadhav 0 1 Tianyao Huo 0 1 0 1 North Florida/South Georgia Veterans Health System, Gainesville, Florida, United States of America, 2 Department of Medicine, University of Florida , Gainesville, Florida , United States of America 1 Academic Editor: Kevin J. Croce, Harvard Medical School , UNITED STATES Percutaneous coronary intervention with bivalirudin plus bail-out glycoprotein IIb/IIIa inhibitors has been shown to be as effective as unfractionated heparin plus routine glycoprotein IIb/IIIa inhibitors in preventing cardiac ischemic events, but with a lower bleeding risk. It is unknown whether bivalirudin would have the same beneficial effects if compared with heparin when the use of glycoprotein IIb/IIIa inhibitors was similar between treatment arms. We searched the MEDLINE, Web of Science, and Cochrane databases from inception until March 2015 for randomized trials that compared bivalirudin to heparin in patients undergoing percutaneous coronary intervention. We required that the intended use of glycoprotein IIb/IIIa inhibitors was similar between the study groups. Summary estimates were principally constructed by the Peto method. Fifteen trials met our inclusion criteria, which yielded 25,824 patients. Bivalirudin versus heparin was associated with an increased hazard of stent thrombosis (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.15-1.92, P = .002, I2 = 16.9%), with a similar hazard of myocardial infarction (OR 1.09, 95% CI 0.98-1.22, P = .11, I2 = 35.8%), all-cause mortality (OR 0.88, 95% CI 0.72-1.08, P = .21, I2 = 31.5%) and major adverse cardiac events (OR 1.04, 95% CI 0.94-1.14, P = .46, I2 = 53.9%). Bivalirudin was associated with a reduced hazard of major bleeding (OR 0.80, 95% CI 0.70-0.92, P = .001, I2 = 63.5%). The dose of heparin in the control arm modified this association; when the dose of unfractionated heparin in the control arm was 100 units/kg, bivalirudin was associated with a reduction in major bleeding (OR 0.55, 95% CI 0.45-0.68, P < .0001), but when the dose of unfractionated heparin was 75 units/kg, bivalirudin was not associated with reduction in bleeding (OR 1.09, 95% CI 0.91-1.31, P = .36). Among patients undergoing PCI, bivalirudin was associated with an increased hazard of stent thrombosis. Bivalirudin may be associated with a reduced hazard of major bleeding; however, this benefit was no longer apparent when compared with a dose of unfractionated heparin 75 units/kg. - Competing Interests: The authors have declared that no competing interests exist. Unfractionated heparin has been widely used for anticoagulation during percutaneous coronary intervention (PCI). The addition of glycoprotein IIb/IIIa inhibitors to unfractionated heparin has been shown to reduce peri-procedural ischemic events compared with heparin alone; however, this approach can increase bleeding risk [1]. The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial demonstrated that bivalirudin, a direct thrombin inhibitor, was non-inferior to unfractionated heparin combined with a routine glycoprotein IIb/IIIa inhibitor in preventing major adverse cardiac events (MACE), but with a lower risk of bleeding [2]. Both unfractionated heparin and bivalirudin are approved by the European Medicines Agency and United States Food and Drug Administration and endorsed by the European Society of Cardiology and American College of Cardiology/American Heart Association as acceptable anticoagulants during PCI [3,4]. A recent meta-analysis compared a bivalirudin-based regimen with a heparin-based regimen during PCI [5]. The study concluded that bivalirudin increased the risk of MACE, myocardial infarction, and stent thrombosis. There was significant heterogeneity in major bleeding and bivalirudin was only associated with a reduction in major bleeding when compared with heparin plus a routine glycoprotein IIb/IIIa inhibitor. This is not a novel finding since the reduction in major bleeding with bivalirudin has been consistently observed in analyses in which the control arm routinely used glycoprotein IIb/IIIa inhibitors in addition to heparin [6]. As the routine use of glycoprotein IIb/IIIa inhibitors during PCI is no longer contemporary, and may confound any associations between bivalirudin and ischemic/bleeding events, we aimed to conduct a comprehensive meta-analysis to compare the efficacy and safety of bivalirudin versus heparin during PCI, while controlling for the use of glycoprotein IIb/IIIa inhibitors. We performed a computerized literature search of the MEDLINE database without language restriction from inception until March 2015 using the search strategy shown in Fig 1 [2,743]. We also searched both the Web of Science and Cochrane databases using the keywords bivalirudin and heparin, which did not identify additional studies beyond MEDLINE. Additionally, we searched for abstracts of scientific sessions reported in European Heart Journal, Circulation, and Journal of the American College of Cardiology from 2012 onwards using the same keywords. To ensure that no potentially important studies were missed, the reference lists from the retrieved articles and prior meta-analyses were also checked. We selected studies that reported clinical outcomes at 30 days (or during hospitalization if 30-day outcomes were not available) in which patients were randomized to receive either bivalirudin or heparin during PCI. We required that patients were randomized to 1) bivalirudin plus a bail-out glycoprotein IIb/IIIa inhibitor versus heparin plus a bail-out glycoprotein IIb/ IIIa inhibitor or 2) bivalirudin plus a routine glycoprotein IIb/IIIa inhibitor versus heparin plus a routine glycoprotein IIb/IIIa inhibitor. Bivalirudin was given as a bolus (0.75 mg/kg), followed by infusion (1.75 mg/kg/hour for the duration of the procedure). Heparin could be administered as either unfractionated or low-molecular-weight heparin. The dose of unfractionated heparin ranged from 60 to 140 units/kg. We excluded studies that randomized patients to bivalirudin plus a bail-out glycoprotein IIb/IIIa inhibitor versus heparin plus a Fig 1. Study selection flow diagram. Summary of how the systematic search was conducted and eligible studies were identified. ACC = American College of Cardiology; ADP = adenosine diphosphate; AHA = American Heart Association; ESC = European Society of Cardiology; GP IIb/IIIa = glycoprotein IIb/IIIa; MeSH = Medical Subject Headings; TCT = Transcatheter Cardiovascular Therapeutics. routine glycoprotein IIb/IIIa inhibitor, and studies that used different adenosine diphosphate (ADP) receptor antagonists between treatment arms. Additionally, in order to focus on contemporary practice, we excluded trials that did not routinely use stents. Two aut (...truncated)