Catheterization and Cardiovascular Interventions 00:00–00 (2015)
Original Studies Bivalirudin Versus Heparin in Patients With Acute Myocardial Infarction: A Meta-Analysis of Randomized Trials Giuseppe Ferrante,1* MD, PhD, Marco Valgimigli,2 MD, PhD, Paolo Pagnotta,1 MD, and Patrizia Presbitero,1 MD Background: The aim of this study was to assess the impact of bivalirudin, as compared to unfractionated heparin, on clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI). Methods: A meta-analysis of randomized trials comparing bivalirudin versus heparin in patients with STEMI undergoing primary percutaneous coronary intervention was performed. Three randomised trials enrolling 7,612 patients were included. Analysis was by intention to treat. Results: At 30 days, bivalirudin, as compared to heparin, was associated with a similar risk of all-cause mortality (3.03% vs. 3.38%, odds ratio (OR) 0.90, 95% confidence intervals (CI) [0.63 to 1.29], P 5 0.57). Bivalirudin significantly increased the risk of definite (2.39% vs. 1.06%, OR 2.49, 95% CI [1.30 to 4.76], P 5 0.006); definite or probable (2.55% vs. 1.35%, OR 2.26, 95% CI [1.07 to 4.79], P 5 0.03), and acute stent thrombosis (1.69% vs. 0.39%, OR 4.34, 95% CI [2.30 to 8.16], P < 0.001); leading to nonsignificantly higher reinfarction rates (2.0% vs. 1.31%, OR 1.72, 95% CI [0.89 to 3.35], P 5 0.11), and to a significantly increased risk of ischemia driven revascularization (2.50% vs. 1.52%, OR 1.80, 95% CI [1.02 to 3.18], P 5 0.04) at 30 days. No firm evidence for a reduction in major bleeding associated with bivalirudin use was found (3.93% vs. 6.39%, OR 0.63, 95% CI [0.39 to 1.04], P 5 0.07). Conclusions: In patients with STEMI, bivalirudin, as compared to heparin, increases the risk of stent thrombosis and ischemia driven repeat revascularization at 30 days. There is no strong evidence that bivalirudin significantly reduces major bleeding at 30 days. Bivalirudin does not have an effect on all-cause mortality at 30 days. VC 2015 Wiley Periodicals, Inc. Key words: bivalirudin; acute myocardial infarction; primary PCI 1
INTRODUCTION
Bivalirudin (Angiomax, Angiox, the Medicines Company), as compared with unfractionated heparin and routine use of glycoprotein IIb/IIIa inhibitors, has been shown to reduce rates of major bleeding and death at 30 days, with a survival benefit that extended to 3 years, in patients with ST-segment elevation myocardial infarction (STEMI) in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) randomized trial [1]. In the European Ambulance Acute Coronary Syndrome Angiography (EUROMAX) randomized trial, bivalirudin, initiated during transport for primary percutaneous coronary intervention (PCI) in patients with STEMI, as compared to heparins with optional use of glycoprotein IIb/ C 2015 Wiley Periodicals, Inc. V
Department of Interventional Cardiology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy 2 Department of Interventional Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands Additional Supporting Information may be found in the online version of this article. Conflicts of interest: Dr. Valgimigli has received lecture fees and has been advisor board member for the Medicine Company. *Correspondence to: Giuseppe Ferrante, MD, PhD, Department of Interventional Cardiology, Istituto Clinico Humanitas IRCCS, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089, Rozzano, Milan, Italy. E-mail [email protected] Received 29 October 2014; Revision accepted 15 March 2015 DOI: 10.1002/ccd.25955 Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com)
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IIIa inhibitors, reduced the primary composite outcome of death or major bleeding at 30 days [2]. In both trials, however, bivalirudin increased the risk of acute stent thrombosis [1,2]. Recently, findings from the How Effective Are Antithrombotic Therapies in Primary PCI (HEAT-PPCI) randomized trial [3] showed that in patients undergoing primary PCI, the use of bivalirudin, as compared to unfractionated heparin with bailout use of glycoprotein IIb/IIIa inhibitors, was associated with a significant increase of the composite outcome of allcause mortality, reinfarction, unplanned target lesion revascularization or stroke at 28 days, that was mainly driven by an increase in reinfarction and stent thrombosis. Of note, there was no effect of bivalirudin on major bleeding reduction. Therefore, whether bivalirudin is superior to heparin in the setting of STEMI remains controversial, in particular with respect to individual outcomes owing to reduced statistical power of single randomised trials, due to sample size limitations, in assessing the existence of significant treatment differences. We thus performed a meta-analysis of randomized trials to assess if bivalirudin is superior to heparin with respect to clinical outcomes in patients with STEMI. METHODS Data Sources and Search Strategy A meta-analysis of randomized trials using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2009 guidelines was performed to assess clinical outcomes in studies comparing bivalirudin versus heparin in patients with STEMI [4]. Two reviewers (G.F., M.V.) independently identified eligible randomized trials by an electronic search of MEDLINE, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov databases (from database inception up to June 6, 2014) using the terms “bivalirudin,” “heparin,” “acute myocardial infarction.” A sensitive filter for randomized controlled trials was used. No language, publication date, or publication status restrictions were imposed. Conference proceedings (from 2006 to 2014) of the American Heart Association, the American College of Cardiology, the Transcatheter Cardiovascular Therapeutics, The European Society of Cardiology were hand-searched. All suitable nonpublished completed registered studies were considered for inclusion. We checked reference lists of identified articles, recent editorials, and related reviews. Study Selection Eligible trials included all randomized controlled trials comparing bivalirudin versus heparin with routine
or optional use of glycoprotein IIb/IIIa inhibitors in patients with STEMI. Studies were included if they met the following inclusion criteria: (1) randomization between bivalirudin and heparin; (2) study population of patients with STEMI; (3) a minimum length of follow-up of 28 days from time of randomization. Exclusion criteria were (a) lack of randomized design, (b) a clinical setting different from STEMI; (c) duration of follow-up restricted to in-hospital stay. Data Extraction
Two reviewers (G.F., M.V.) independently assessed trial eligibility based on titles, abstracts, full-text reports. The presence of sources of bias was systematically assessed following the approach recommended by the Cochrane Collaboration that identifies selection, performance, attrition, detection, reporting bias, other sources of bias for each study, and classifies each of these as low, unclear, high by analysing the following seven domains: random sequence generation, allocation concealment, blinding of participants and of outcome assessment, incomplete outcome data, selective outcome reporting and “other issues” [5]. A risk of bias summary reporting each risk of bias item for each included study was provided. Disagreements were resolved via the consensus of the two reviewers. Endpoints
The primary outcome was all-cause death. Secondary outcomes were reinfarction, stent thrombosis [as defined by the Academic Research Consortium [6], i.e. definite stent thrombosis, definite or probable stent thrombosis, acute (24 hr from the index procedure) stent thrombosis, subacute stent thrombosis (>24 hr to 30 days from the index procedure)], ischemia driven target vessel or lesion revascularization according to the definition used in each trial, stroke, major adverse cardiovascular events (MACE) (i.e., all-cause death, reinfarction, ischemia driven target vessel or lesion revascularization, or stroke). The key safety endpoint was the incidence of major bleeding. In the main analysis, major bleeding was defined using the protocol definition adopted in two out the included studies [1,2], i.e. bleeding not related to coronary-artery bypass grafting (CABG) that included intracranial, retroperitoneal or intraocular bleeding; bleeding at the access site, with a hematoma that was 5 cm or larger or that required intervention; a decrease in the hemoglobin level of 4 g per deciliter or more without an overt bleeding source or 3 g per deciliter or more with an overt bleeding source; reoperation for bleeding; or blood transfusion; or as grade 3 to 5 bleeding according to the Bleeding Academic Research
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd. Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
Bivalirudin in Acute Myocardial Infarction
Consortium (BARC) classification [7], which was used in the HEAT-PPCI trial [3]. Sensitivity analyses in which major bleeding was defined according to different bleeding scales were performed, thus including major bleeding events assessed on the basis of the Thrombolysis in Myocardial Infarction (TIMI) [8], or the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) scales [9], which were available in two out of three included studies [1,2]. The composite of major or minor bleeding was assessed also, using the TIMI bleeding scale which was available in two out of three included studies [1,2], and the BARC definition of two to five bleeding which was used in the HEAT-PPCI trial [3]. Statistical Analysis
Data synthesis and data analysis. The odds ratios (ORs) with 95% confidence interval (95% CI) for the endpoints were calculated from the available data. The number of patients needed to treat for an additional beneficial outcome (NNTB), and the number needed to treat for an additional harmful outcome (NNTH), were calculated from meta-analytical estimates of pooled ORs, using the macro “metannt”, as 1/(projected control group event rate projected treatment group event rate). The corresponding 95% CI was calculated by using 95% CI of the effect size applied to the control group event rate. The presence of heterogeneity among studies was evaluated with the Cochran Q chi[2] test with P 0.10 considered to be statistically significant, estimating the between-studies variance tau[2], and using I2 test to evaluate the inconsistency [10]. The I2 statistic is derived from the Q statistic ([Qdf/Q] 100) and I2 describes the percentage of total variation across studies that is due to heterogeneity: values of 25, 50, and 75% correspond to low, moderate, high I2. Trial-specific ORs were combined with the DerSimonian and Laird random-effects model [11] owing to the detection of heterogeneity for most endpoints. For those endpoints where I2 was equal to 0, also the Mantel Haenszel fixed-effects model was used. The use of any test, such as Peters’ test or Eggers’ test, for the quantitative assessment of small study effects was not performed, being the number of included studies 25%, which largely depends on differences across trials with respect to arterial access route, duration of bivalirudin infusion, timing of bivalirudin administration, the percentage of novel P2YR antagonists and of glycoprotein IIb/IIIa inhibitors use. The impact of these variables on the comparison between bivalirudin and heparin could not be adequately assessed because this is not an individual patient data meta-analysis, and outcome data according to these variables are not homogeneously reported across the included trials. The present analysis is restricted to time of observation of event until 28–30 days after the time of randomization, and therefore a longer followup is needed to confirm these findings.
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CONCLUSIONS
This meta-analysis of randomized trials provides evidence for a disadvantage of bivalirudin over unfractionated heparin in terms of stent thrombosis and of ischemia driven revascularization at 30 days and for lack of effect of bivalirudin on all-cause mortality. There is no strong evidence for an advantage of bivalirudin, as compared to heparin, on major bleeding.
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Huber K, Deliargyris EN, Bernstein D, Schuette D, Prats J, Clayton T, Pocock S, Hamon M, Goldstein P, EUROMAX Investigators. Bivalirudin started during emergency transport for primary PCI. N Engl J Med 2013;369:2207–2217. Shahzad A, Kemp I, Mars C, Wilson K, Roome C, Cooper R, Andron M, Appleby C, Fisher M, Khand A, Kunadian B, Mills JD, Morris JL, Morrison WL, Munir S, Palmer ND, Raphael A, Perry RA, Ramsdale DR, Velavan P, Stables RH. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): An open-label, single centre, randomised controlled trial. Lancet 2014;384:1849–1858. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: Explanation and elaboration. Br Med J 2009;339:b2700. Higgins JP, Altman DG, Sterne JAC, Green S, editors. Assessing Risk of Bias in Included Studies. The Cochrane Handbook for Systematic Reviews, Version 5.1.0 (updated March 2011). The Cochrane Collaboration, Chapter 8; 2011. Available at: http://www.cochrane-handbook.org. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel MA, Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW, Serruys PW. Clinical end points in coronary stent trials: A case for standardized definitions. Circulation 2007;115:2344–2351. Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. Standardized bleeding definitions for cardiovascular clinical trials: A consensus report from the bleeding academic research consortium. Circulation 2011;123:2736–2747. Bovill EG, Terrin ML, Stump DC, Berke AD, Frederick M, Collen D, Feit F, Gore JM, Hillis LD, Lambrew CT. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI), phase II trial. Ann Intern Med 1991;115:256–265. GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO investigators. N Engl J Med 1993;329:673– 682. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. Br Med J 2003;327:557–560. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 7:177–188. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Comparison of two methods to detect publication bias in meta-analysis. JAMA 2006;295:676–680. Higgins JP, Altman DG, Sterne JAC, editors. Chapter 10.4.3.1: Recommendations on testing for funnel plot asymmetry. The Cochrane Handbook for Systematic Reviews, Version 5.1.0 (updated March 2011). The Cochrane Collaboration. 2011. Available at: http://www.cochrane-handbook.org Schulz S, Richardt G, Laugwitz KL, Morath T, Neudecker J, Hoppmann P, Mehran R, Gershlick AH, T€olg R, Anette Fiedler K, Abdel-Wahab M, Kufner S, Schneider S, Schunkert H, Ibrahim T, Mehilli J, Kastrati A and for the Bavarian Reperfusion Alternatives Evaluation (BRAVE) 4 Investigators. Prasugrel plus bivalirudin vs. clopidogrel plus heparin in patients with STsegment elevation myocardial infarction. Eur Heart J 2014;35: 2285–2294.
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd. Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
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15. Zeymer U, van ’t Hof A, Adgey J, Nibbe L, Clemmensen P, Cavallini C, Ten Berg J, Coste P, Huber K, Deliargyris EN, Day J, Bernstein D, Goldstein P, Hamm C, Steg PG. Bivalirudin is superior to heparins alone with bailout GP IIb/IIIa inhibitors in patients with ST-segment elevation myocardial infarction transported emergently for primary percutaneous coronary intervention: A pre-specified analysis from the EUROMAX trial. Eur Heart J 2014;35:2460–2467. 16. Gurbel PA, Bliden KP, Zaman KA, Yoho JA, Hayes KM, Tantry US. Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: Results of the clopidogrel loading with eptifibatide to arrest the reactivity of platelets (Clear Platelets) study. Circulation 2005;111:1153–1159. 17. Valgimigli M, Tebaldi M, Campo G, Gambetti S, Bristot L, Monti M, Parrinello G, Ferrari R FABOLUS PRO, Investigators. Prasugrel versus tirofiban bolus with or without short post-bolus infusion with or without concomitant prasugrel administration in patients with myocardial infarction undergoing coronary stenting: The FABOLUS PRO (facilitation through aggrastat by drOpping or shortening infusion line in patients with STsegment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse) trial. JACC Cardiovasc Interv 2012;5:268–277. 18. Steg PG, Bhatt DL, Hamm CW, Stone GW, Gibson CM, Mahaffey KW, Leonardi S, LiuT Skerjanec S, Day JR, Iwaoka RS, Stuckey TD, Gogia HS, Gruberg L, French WJ, White HD, Harrington RA, CHAMPION Investigators. Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: A pooled analysis of patient-level data. Lancet 2013;382: 1981–1992. 19. Genereux P, Mehran R, Palmerini T, Caixeta A, Kirtane AJ, Lansky AJ, Brodie BR, Witzenbichler B, Mockel M, Guagliumi G, Peruga JZ, Dudek D, Fahy MP, Dangas G, Stone GW, HORIZONS-AMI Trial Investigators. Radial access in patients
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with ST-segment elevation myocardial infarction undergoing primary angioplasty in acute myocardial infarction: The HORIZONS-AMI trial. EuroIntervention 2011;7:905–916. Vorobcsuk A, Konyi A, Aradi D, Horvath IG, Ungi I, Louvard Y, Komocsi A. Transradial versus transfemoral percutaneous coronary intervention in acute myocardial infarction systematic overview and meta-analysis. Am Heart J 2009;158:814–821. Komocsi A, Aradi D, Kehl D, Ungi I, Thury A, Pinter T, Nicolantonio D, Tornyos JJ, Vorobcsuk AA. Meta-analysis of randomized trials on access site selection for percutaneous coronary intervention in ST-segment elevation myocardial infarction. Arch Med Sci 2014;10:203–212. Mamas MA, Ratib K, Routledge H, Neyses L, Fraser DG, de Belder M, Ludman PF, Nolan J, British Cardiovascular Intervention Society and the National Institute for Cardiovascular Outcomes Research. Influence of arterial access site selection on outcomes in primary percutaneous coronary intervention: Are the results of randomized trials achievable in clinical practice? JACC Cardiovasc Interv 2013;6:698–706. Jolly SS, Yusuf S, Cairns J, Niemel€a K, Xavier D, Widimsky P, Budaj A, Niemel€a M, Valentin V, Lewis BS, Avezum A, Steg PG, Rao SV, Gao P, Afzal R, Joyner CD, Chrolavicius S, Mehta SR, RIVAL Trial Group. Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): A randomised, parallel group, multicentre trial. Lancet 2011;377:1409–1420. Valgimigli M, Calabro P, Cortese B, Frigoli E, Garducci S, Rubartelli P, Ando G, Santarelli A, Galli M, Garbo R, Repetto A, Ierna S, Briguori C, Limbruno U, Violini R, Gagnor A, MATRIX Investigators. Scientific foundation and possible implications for practice of the minimizing adverse haemorrhagic events by transradial access site andSystemic implementation of AngioX (MATRIX) trial. J Cardiovasc Transl Res 2014;7:101– 111.
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd. Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
Original Studies Bivalirudin Versus Heparin in Patients With Acute Myocardial Infarction: A Meta-Analysis of Randomized Trials Giuseppe Ferrante,1* MD, PhD, Marco Valgimigli,2 MD, PhD, Paolo Pagnotta,1 MD, and Patrizia Presbitero,1 MD Background: The aim of this study was to assess the impact of bivalirudin, as compared to unfractionated heparin, on clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI). Methods: A meta-analysis of randomized trials comparing bivalirudin versus heparin in patients with STEMI undergoing primary percutaneous coronary intervention was performed. Three randomised trials enrolling 7,612 patients were included. Analysis was by intention to treat. Results: At 30 days, bivalirudin, as compared to heparin, was associated with a similar risk of all-cause mortality (3.03% vs. 3.38%, odds ratio (OR) 0.90, 95% confidence intervals (CI) [0.63 to 1.29], P 5 0.57). Bivalirudin significantly increased the risk of definite (2.39% vs. 1.06%, OR 2.49, 95% CI [1.30 to 4.76], P 5 0.006); definite or probable (2.55% vs. 1.35%, OR 2.26, 95% CI [1.07 to 4.79], P 5 0.03), and acute stent thrombosis (1.69% vs. 0.39%, OR 4.34, 95% CI [2.30 to 8.16], P < 0.001); leading to nonsignificantly higher reinfarction rates (2.0% vs. 1.31%, OR 1.72, 95% CI [0.89 to 3.35], P 5 0.11), and to a significantly increased risk of ischemia driven revascularization (2.50% vs. 1.52%, OR 1.80, 95% CI [1.02 to 3.18], P 5 0.04) at 30 days. No firm evidence for a reduction in major bleeding associated with bivalirudin use was found (3.93% vs. 6.39%, OR 0.63, 95% CI [0.39 to 1.04], P 5 0.07). Conclusions: In patients with STEMI, bivalirudin, as compared to heparin, increases the risk of stent thrombosis and ischemia driven repeat revascularization at 30 days. There is no strong evidence that bivalirudin significantly reduces major bleeding at 30 days. Bivalirudin does not have an effect on all-cause mortality at 30 days. VC 2015 Wiley Periodicals, Inc. Key words: bivalirudin; acute myocardial infarction; primary PCI 1
INTRODUCTION
Bivalirudin (Angiomax, Angiox, the Medicines Company), as compared with unfractionated heparin and routine use of glycoprotein IIb/IIIa inhibitors, has been shown to reduce rates of major bleeding and death at 30 days, with a survival benefit that extended to 3 years, in patients with ST-segment elevation myocardial infarction (STEMI) in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) randomized trial [1]. In the European Ambulance Acute Coronary Syndrome Angiography (EUROMAX) randomized trial, bivalirudin, initiated during transport for primary percutaneous coronary intervention (PCI) in patients with STEMI, as compared to heparins with optional use of glycoprotein IIb/ C 2015 Wiley Periodicals, Inc. V
Department of Interventional Cardiology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy 2 Department of Interventional Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands Additional Supporting Information may be found in the online version of this article. Conflicts of interest: Dr. Valgimigli has received lecture fees and has been advisor board member for the Medicine Company. *Correspondence to: Giuseppe Ferrante, MD, PhD, Department of Interventional Cardiology, Istituto Clinico Humanitas IRCCS, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089, Rozzano, Milan, Italy. E-mail [email protected] Received 29 October 2014; Revision accepted 15 March 2015 DOI: 10.1002/ccd.25955 Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com)
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IIIa inhibitors, reduced the primary composite outcome of death or major bleeding at 30 days [2]. In both trials, however, bivalirudin increased the risk of acute stent thrombosis [1,2]. Recently, findings from the How Effective Are Antithrombotic Therapies in Primary PCI (HEAT-PPCI) randomized trial [3] showed that in patients undergoing primary PCI, the use of bivalirudin, as compared to unfractionated heparin with bailout use of glycoprotein IIb/IIIa inhibitors, was associated with a significant increase of the composite outcome of allcause mortality, reinfarction, unplanned target lesion revascularization or stroke at 28 days, that was mainly driven by an increase in reinfarction and stent thrombosis. Of note, there was no effect of bivalirudin on major bleeding reduction. Therefore, whether bivalirudin is superior to heparin in the setting of STEMI remains controversial, in particular with respect to individual outcomes owing to reduced statistical power of single randomised trials, due to sample size limitations, in assessing the existence of significant treatment differences. We thus performed a meta-analysis of randomized trials to assess if bivalirudin is superior to heparin with respect to clinical outcomes in patients with STEMI. METHODS Data Sources and Search Strategy A meta-analysis of randomized trials using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2009 guidelines was performed to assess clinical outcomes in studies comparing bivalirudin versus heparin in patients with STEMI [4]. Two reviewers (G.F., M.V.) independently identified eligible randomized trials by an electronic search of MEDLINE, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov databases (from database inception up to June 6, 2014) using the terms “bivalirudin,” “heparin,” “acute myocardial infarction.” A sensitive filter for randomized controlled trials was used. No language, publication date, or publication status restrictions were imposed. Conference proceedings (from 2006 to 2014) of the American Heart Association, the American College of Cardiology, the Transcatheter Cardiovascular Therapeutics, The European Society of Cardiology were hand-searched. All suitable nonpublished completed registered studies were considered for inclusion. We checked reference lists of identified articles, recent editorials, and related reviews. Study Selection Eligible trials included all randomized controlled trials comparing bivalirudin versus heparin with routine
or optional use of glycoprotein IIb/IIIa inhibitors in patients with STEMI. Studies were included if they met the following inclusion criteria: (1) randomization between bivalirudin and heparin; (2) study population of patients with STEMI; (3) a minimum length of follow-up of 28 days from time of randomization. Exclusion criteria were (a) lack of randomized design, (b) a clinical setting different from STEMI; (c) duration of follow-up restricted to in-hospital stay. Data Extraction
Two reviewers (G.F., M.V.) independently assessed trial eligibility based on titles, abstracts, full-text reports. The presence of sources of bias was systematically assessed following the approach recommended by the Cochrane Collaboration that identifies selection, performance, attrition, detection, reporting bias, other sources of bias for each study, and classifies each of these as low, unclear, high by analysing the following seven domains: random sequence generation, allocation concealment, blinding of participants and of outcome assessment, incomplete outcome data, selective outcome reporting and “other issues” [5]. A risk of bias summary reporting each risk of bias item for each included study was provided. Disagreements were resolved via the consensus of the two reviewers. Endpoints
The primary outcome was all-cause death. Secondary outcomes were reinfarction, stent thrombosis [as defined by the Academic Research Consortium [6], i.e. definite stent thrombosis, definite or probable stent thrombosis, acute (24 hr from the index procedure) stent thrombosis, subacute stent thrombosis (>24 hr to 30 days from the index procedure)], ischemia driven target vessel or lesion revascularization according to the definition used in each trial, stroke, major adverse cardiovascular events (MACE) (i.e., all-cause death, reinfarction, ischemia driven target vessel or lesion revascularization, or stroke). The key safety endpoint was the incidence of major bleeding. In the main analysis, major bleeding was defined using the protocol definition adopted in two out the included studies [1,2], i.e. bleeding not related to coronary-artery bypass grafting (CABG) that included intracranial, retroperitoneal or intraocular bleeding; bleeding at the access site, with a hematoma that was 5 cm or larger or that required intervention; a decrease in the hemoglobin level of 4 g per deciliter or more without an overt bleeding source or 3 g per deciliter or more with an overt bleeding source; reoperation for bleeding; or blood transfusion; or as grade 3 to 5 bleeding according to the Bleeding Academic Research
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd. Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
Bivalirudin in Acute Myocardial Infarction
Consortium (BARC) classification [7], which was used in the HEAT-PPCI trial [3]. Sensitivity analyses in which major bleeding was defined according to different bleeding scales were performed, thus including major bleeding events assessed on the basis of the Thrombolysis in Myocardial Infarction (TIMI) [8], or the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) scales [9], which were available in two out of three included studies [1,2]. The composite of major or minor bleeding was assessed also, using the TIMI bleeding scale which was available in two out of three included studies [1,2], and the BARC definition of two to five bleeding which was used in the HEAT-PPCI trial [3]. Statistical Analysis
Data synthesis and data analysis. The odds ratios (ORs) with 95% confidence interval (95% CI) for the endpoints were calculated from the available data. The number of patients needed to treat for an additional beneficial outcome (NNTB), and the number needed to treat for an additional harmful outcome (NNTH), were calculated from meta-analytical estimates of pooled ORs, using the macro “metannt”, as 1/(projected control group event rate projected treatment group event rate). The corresponding 95% CI was calculated by using 95% CI of the effect size applied to the control group event rate. The presence of heterogeneity among studies was evaluated with the Cochran Q chi[2] test with P 0.10 considered to be statistically significant, estimating the between-studies variance tau[2], and using I2 test to evaluate the inconsistency [10]. The I2 statistic is derived from the Q statistic ([Qdf/Q] 100) and I2 describes the percentage of total variation across studies that is due to heterogeneity: values of 25, 50, and 75% correspond to low, moderate, high I2. Trial-specific ORs were combined with the DerSimonian and Laird random-effects model [11] owing to the detection of heterogeneity for most endpoints. For those endpoints where I2 was equal to 0, also the Mantel Haenszel fixed-effects model was used. The use of any test, such as Peters’ test or Eggers’ test, for the quantitative assessment of small study effects was not performed, being the number of included studies 25%, which largely depends on differences across trials with respect to arterial access route, duration of bivalirudin infusion, timing of bivalirudin administration, the percentage of novel P2YR antagonists and of glycoprotein IIb/IIIa inhibitors use. The impact of these variables on the comparison between bivalirudin and heparin could not be adequately assessed because this is not an individual patient data meta-analysis, and outcome data according to these variables are not homogeneously reported across the included trials. The present analysis is restricted to time of observation of event until 28–30 days after the time of randomization, and therefore a longer followup is needed to confirm these findings.
3.
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7.
8.
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CONCLUSIONS
This meta-analysis of randomized trials provides evidence for a disadvantage of bivalirudin over unfractionated heparin in terms of stent thrombosis and of ischemia driven revascularization at 30 days and for lack of effect of bivalirudin on all-cause mortality. There is no strong evidence for an advantage of bivalirudin, as compared to heparin, on major bleeding.
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