Thromb Haemost 2020; 120(02): 348-362
DOI: 10.1055/s-0039-1700872
Trial Protocol Design Paper
Georg Thieme Verlag KG Stuttgart · New York

Individual Patient Data Pooled Analysis of Randomized Trials of Bivalirudin versus Heparin in Acute Myocardial Infarction: Rationale and Methodology

Behnood Bikdeli
1   Division of Cardiology, Department of Medicine, NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, New York, United States
2   Center for Outcomes Research & Evaluation, Yale School of Medicine, Yale University, New Haven, Connecticut, United States
3   Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, United States
,
Thomas McAndrew
3   Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, United States
,
Aaron Crowley
3   Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, United States
,
Shmuel Chen
1   Division of Cardiology, Department of Medicine, NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, New York, United States
3   Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, United States
,
Ghazaleh Mehdipoor
3   Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, United States
,
Björn Redfors
1   Division of Cardiology, Department of Medicine, NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, New York, United States
3   Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, United States
4   Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden
,
Yangbo Liu
3   Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, United States
,
Zixuan Zhang
3   Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, United States
,
Mengdan Liu
3   Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, United States
,
Yiran Zhang
3   Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, United States
,
Dominic P. Francese
3   Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, United States
,
David Erlinge
5   Department of Cardiology, Lund University, Lund, Sweden
,
Stefan K. James
6   Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden
,
Yaling Han
7   Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, China
,
Yi Li
7   Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, China
,
Adnan Kastrati
8   Department of Cardiology, Deutsches Herzzentrum München, Technische Universität, Munich, Germany
,
Stefanie Schüpke
8   Department of Cardiology, Deutsches Herzzentrum München, Technische Universität, Munich, Germany
,
Rod H. Stables
9   Liverpool Heart and Chest Hospital, Liverpool, United Kingdom
10   University of Liverpool, Liverpool, United Kingdom
,
Adeel Shahzad
9   Liverpool Heart and Chest Hospital, Liverpool, United Kingdom
,
Philippe Gabriel Steg
11   Hôpital Bichat, Paris, France
12   Imperial College, Royal Brompton Hospital, London, United Kingdom
,
Patrick Goldstein
13   Lille University Hospital, Lille, France
,
Enrico Frigoli
14   Department of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland
,
Roxana Mehran
3   Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, United States
15   The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States
,
Marco Valgimigli
14   Department of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland
,
Gregg W. Stone
3   Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, United States
15   The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States
› Author Affiliations
Funding This project was partially supported by a research grant from The Medicines Company (Parsippany, New Jersey, United States) to the Cardiovascular Research Foundation (New York, New York, United States) and by the Cardiovascular Research Foundation.
Further Information

Publication History

29 June 2019

12 September 2019

Publication Date:
09 December 2019 (online)

Abstract

Background Individual randomized controlled trials (RCTs) of periprocedural anticoagulation with bivalirudin versus heparin during percutaneous coronary intervention (PCI) have reported conflicting results. Study-level meta-analyses lack granularity to adjust for confounders, explore heterogeneity, or identify subgroups that may particularly benefit or be harmed.

Objective To overcome these limitations, we sought to develop an individual patient-data pooled database of RCTs comparing bivalirudin versus heparin.

Methods We conducted a systematic review to identify RCTs in which ≥1,000 patients with acute myocardial infarction (AMI) undergoing PCI were randomized to bivalirudin versus heparin.

Results From 738 identified studies, 8 RCTs met the prespecified criteria. The principal investigators of each study agreed to provide patient-level data. The data were pooled and checked for accuracy against trial publications, with discrepancies addressed by consulting with the trialists. Consensus-based definitions were created to resolve differing antithrombotic, procedural, and outcome definitions. The project required 3.5 years to complete, and the final database includes 27,409 patients (13,346 randomized to bivalirudin and 14,063 randomized to heparin).

Conclusion We have created a large individual patient database of bivalirudin versus heparin RCTs in patients with AMI undergoing PCI. This endeavor may help identify the optimal periprocedural anticoagulation regimen for patient groups with different relative risks of adverse ischemic versus bleeding events, including those with ST-segment and non-ST-segment elevation MI, radial versus femoral access, use of a prolonged bivalirudin infusion or glycoprotein inhibitors, and others. Adherence to standardized techniques and rigorous validation processes should increase confidence in the accuracy and robustness of the results.

 
  • References

  • 1 Levine GN, Bates ER, Blankenship JC. , et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation 2011; 124 (23) e574-e651
  • 2 Capodanno D, De Caterina R. Bivalirudin for acute coronary syndromes: premises, promises and doubts. Thromb Haemost 2015; 113 (04) 698-707
  • 3 Stone GW, Witzenbichler B, Guagliumi G. , et al; HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358 (21) 2218-2230
  • 4 Kianoush S, Bikdeli B, Desai MM, Eikelboom JW. Risk of stent thrombosis and major bleeding with bivalirudin compared with active control: a systematic review and meta-analysis of randomized trials. Thromb Res 2015; 136 (06) 1087-1098
  • 5 Appleton DL, Cooke RH, Rao SV, Jovin IS. Anticoagulation in transradial percutaneous coronary intervention. Catheter Cardiovasc Interv 2014; 83 (02) 237-242
  • 6 Shahzad A, Kemp I, Mars C. , et al; HEAT-PPCI trial investigators. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 2014; 384 (9957): 1849-1858
  • 7 Steg PG, van 't Hof A, Hamm CW. , et al; EUROMAX Investigators. Bivalirudin started during emergency transport for primary PCI. N Engl J Med 2013; 369 (23) 2207-2217
  • 8 Schulz S, Richardt G, Laugwitz KL. , et al; Bavarian Reperfusion Alternatives Evaluation (BRAVE) 4 Investigators. Prasugrel plus bivalirudin vs. clopidogrel plus heparin in patients with ST-segment elevation myocardial infarction. Eur Heart J 2014; 35 (34) 2285-2294
  • 9 Fahrni G, Wolfrum M, De Maria GL, Banning AP, Benedetto U, Kharbanda RK. Prolonged high-dose bivalirudin infusion reduces major bleeding without increasing stent thrombosis in patients undergoing primary percutaneous coronary intervention: novel insights from an updated meta-analysis. J Am Heart Assoc 2016; 5 (07) e003515
  • 10 Valgimigli M, Frigoli E, Leonardi S. , et al; MATRIX Investigators. Bivalirudin or unfractionated heparin in acute coronary syndromes. N Engl J Med 2015; 373 (11) 997-1009
  • 11 Garcia-Garcia HM, Picchi A, Sardella G. , et al. Comparison of intra-procedural vs. post-stenting prolonged bivalirudin infusion for residual thrombus burden in patients with ST-segment elevation myocardial infarction undergoing: the MATRIX (Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and angioX) OCT study. Eur Heart J Cardiovasc Imaging 2019; jez040
  • 12 Cavender MA, Sabatine MS. Bivalirudin versus heparin in patients planned for percutaneous coronary intervention: a meta-analysis of randomised controlled trials. Lancet 2014; 384 (9943): 599-606
  • 13 Grajek S, Michalak M, Gwizdała A. , et al. Patients treated with bivalirudin are still at higher risk of stent thrombosis: a comprehensive meta-analysis of randomised clinical trials of bivalirudin and heparin for percutaneous coronary interventions. Kardiol Pol 2018; 76 (04) 740-749
  • 14 De Luca G, Cassetti E, Verdoia M, Marino P. Bivalirudin as compared to unfractionated heparin among patients undergoing coronary angioplasty: a meta-analysis of randomised trials. Thromb Haemost 2009; 102 (03) 428-436
  • 15 Riley RD, Lambert PC, Abo-Zaid G. Meta-analysis of individual participant data: rationale, conduct, and reporting. BMJ 2010; 340: c221
  • 16 Bikdeli B, Stone GW. Bivalirudin bewilderment. Kardiol Pol 2018; 76 (04) 711-712
  • 17 Stewart LA, Clarke M, Rovers M. , et al; PRISMA-IPD Development Group. Preferred Reporting Items for Systematic Review and Meta-Analyses of Individual Participant Data: the PRISMA-IPD statement. JAMA 2015; 313 (16) 1657-1665
  • 18 Yusuf S, Flather M. Magnesium in acute myocardial infarction. BMJ 1995; 310 (6982): 751-752
  • 19 Cutlip DE, Windecker S, Mehran R. , et al; Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007; 115 (17) 2344-2351
  • 20 Mehran R, Rao SV, Bhatt DL. , et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011; 123 (23) 2736-2747
  • 21 Vranckx P, Leonardi S, Tebaldi M. , et al. Prospective validation of the Bleeding Academic Research Consortium classification in the all-comer PRODIGY trial. Eur Heart J 2014; 35 (37) 2524-2529
  • 22 McAndrew T, Redfors B, Crowley A. , et al. How Cox models react to a study-specific confounder in a patient-level pooled dataset: random effects better cope with an imbalanced covariate across trials unless baseline hazards differ. J Appl Stat 2019; 1903-1916
  • 23 Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 1994; 81 (03) 515-526
  • 24 Little RJA, Rubin DB. Statistical Analysis with Missing Data. 2nd ed. New York: John Wiley & Sons; 2002
  • 25 Stone GW, McLaurin BT, Cox DA. , et al; ACUITY Investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355 (21) 2203-2216
  • 26 Kastrati A, Neumann FJ, Schulz S. , et al; ISAR-REACT 4 Trial Investigators. Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction. N Engl J Med 2011; 365 (21) 1980-1989
  • 27 Han Y, Guo J, Zheng Y. , et al; BRIGHT Investigators. Bivalirudin vs heparin with or without tirofiban during primary percutaneous coronary intervention in acute myocardial infarction: the BRIGHT randomized clinical trial. JAMA 2015; 313 (13) 1336-1346
  • 28 Erlinge D, Omerovic E, Fröbert O. , et al. Bivalirudin versus heparin monotherapy in myocardial infarction. N Engl J Med 2017; 377 (12) 1132-1142
  • 29 Bittl JA, Strony J, Brinker JA. , et al; Hirulog Angioplasty Study Investigators. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. N Engl J Med 1995; 333 (12) 764-769
  • 30 White HD, Aylward PE, Frey MJ. , et al; Hirulog Early Reperfusion/Occlusion (HERO) Trial Investigators. Randomized, double-blind comparison of hirulog versus heparin in patients receiving streptokinase and aspirin for acute myocardial infarction (HERO). Circulation 1997; 96 (07) 2155-2161
  • 31 Lincoff AM, Kleiman NS, Kottke-Marchant K. , et al. Bivalirudin with planned or provisional abciximab versus low-dose heparin and abciximab during percutaneous coronary revascularization: results of the Comparison of Abciximab Complications with Hirulog for Ischemic Events Trial (CACHET). Am Heart J 2002; 143 (05) 847-853
  • 32 Antman EM, McCabe CH, Braunwald E. Bivalirudin as a replacement for unfractionated heparin in unstable angina/non-ST-elevation myocardial infarction: observations from the TIMI 8 trial. The Thrombolysis in Myocardial Infarction. Am Heart J 2002; 143 (02) 229-234
  • 33 Lincoff AM, Bittl JA, Harrington RA. , et al; REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003; 289 (07) 853-863
  • 34 Lincoff AM, Bittl JA, Kleiman NS. , et al; REPLACE-1 Investigators. Comparison of bivalirudin versus heparin during percutaneous coronary intervention (the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events [REPLACE]-1 trial). Am J Cardiol 2004; 93 (09) 1092-1096
  • 35 Kuchulakanti P, Wolfram R, Torguson R. , et al. Bivalirudin compared with IIb/IIIa inhibitors in patients with in-stent restenosis undergoing intracoronary brachytherapy. Cardiovasc Revasc Med 2005; 6 (04) 154-159
  • 36 Gibson CM, Morrow DA, Murphy SA. , et al; TIMI Study Group. A randomized trial to evaluate the relative protection against post-percutaneous coronary intervention microvascular dysfunction, ischemia, and inflammation among antiplatelet and antithrombotic agents: the PROTECT-TIMI-30 trial. J Am Coll Cardiol 2006; 47 (12) 2364-2373
  • 37 Kastrati A, Neumann FJ, Mehilli J. , et al; ISAR-REACT 3 Trial Investigators. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med 2008; 359 (07) 688-696
  • 38 Tavano D, Visconti G, D'Andrea D. , et al. Comparison of bivalirudin monotherapy versus unfractionated heparin plus tirofiban in patients with diabetes mellitus undergoing elective percutaneous coronary intervention. Am J Cardiol 2009; 104 (09) 1222-1228
  • 39 Parodi G, Migliorini A, Valenti R. , et al. Comparison of bivalirudin and unfractionated heparin plus protamine in patients with coronary heart disease undergoing percutaneous coronary intervention (from the Antithrombotic Regimens aNd Outcome [ARNO] trial). Am J Cardiol 2010; 105 (08) 1053-1059
  • 40 Cortese B, Limbruno U, Severi S, De Matteis S, Diehl L, Pitì A. Effect of prolonged bivalirudin infusion on ST-segment resolution following primary percutaneous coronary intervention (from the PROBI VIRI 2 study). Am J Cardiol 2011; 108 (09) 1220-1224
  • 41 Moliterno DJ. ; TENACITY Steering Committee and Investigators. A randomized two-by-two comparison of high-dose bolus tirofiban versus abciximab and unfractionated heparin versus bivalirudin during percutaneous coronary revascularization and stent placement: the tirofiban evaluation of novel dosing versus abciximab with clopidogrel and inhibition of thrombin (TENACITY) study trial. Catheter Cardiovasc Interv 2011; 77 (07) 1001-1009
  • 42 Patti G, Pasceri V, D'Antonio L. , et al. Comparison of safety and efficacy of bivalirudin versus unfractionated heparin in high-risk patients undergoing percutaneous coronary intervention (from the Anti-Thrombotic Strategy for Reduction of Myocardial Damage During Angioplasty-Bivalirudin vs Heparin study). Am J Cardiol 2012; 110 (04) 478-484
  • 43 Deshpande NV, Pratiti R, Admane P, Mukherjee D, Mardikar HM. Safety and efficacy of bivalirudin with glycoprotein IIb/IIIa for high-risk percutaneous coronary intervention. Indian Heart J 2012; 64 (05) 444-448
  • 44 Waksman R, Bertrand O, Driesman M. , et al. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndrome initially treated with fondaparinux: results from an international, multicenter, randomized pilot study (SWITCH III). J Interv Cardiol 2013; 26 (02) 107-113
  • 45 Xiang DC, Gu XL, Song YM. , et al. Evaluation on the efficacy and safety of domestic bivalirudin during percutaneous coronary intervention. Chin Med J (Engl) 2013; 126 (16) 3064-3068
  • 46 Feldman A, Suleiman K, Bushari L. , et al. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention in patients at high risk for bleeding. Int J Angiol. 2014; 23 (04) 227-232
  • 47 Briguori C, Visconti G, Focaccio A. , et al. Novel approaches for preventing or limiting events (Naples) III trial: randomized comparison of bivalirudin versus unfractionated heparin in patients at increased risk of bleeding undergoing transfemoral elective coronary stenting. JACC Cardiovasc Interv 2015; 8 (03) 414-423
  • 48 He P, Wei H, Wulasihan M. , et al. Comparisons of effectiveness and safety between bivalirudin and heparin with tirofiban in ST-segment elevation myocardial infarction treated with percutaneous coronary intervention. Int J Clin Exp Med 2016; 9 (12) 23472-23481
  • 49 Mehrzad M, Tuktamyshov R, Mehrzad R. Safety, efficiency and cost effectiveness of Bivalirudin: a systematic review. World J Cardiol 2017; 9 (09) 761-772
  • 50 Flather MD, Farkouh ME, Pogue JM, Yusuf S. Strengths and limitations of meta-analysis: larger studies may be more reliable. Control Clin Trials 1997; 18 (06) 568-579 , discussion 661–666
  • 51 Pereira TV, Ioannidis JP. Statistically significant meta-analyses of clinical trials have modest credibility and inflated effects. J Clin Epidemiol 2011; 64 (10) 1060-1069
  • 52 LeLorier J, Grégoire G, Benhaddad A, Lapierre J, Derderian F. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med 1997; 337 (08) 536-542