Bivalirudin as compared to unfractionated heparin among patients undergoing coronary angioplasty

Summary

It has been shown that bleeding complications are associated with higher mortality rates among patients undergoing coronary angioplasty. Due to its properties, bivalirudin may provide benefits in terms of bleeding and thrombotic complications as compared to unfractionated heparin (UFH).The aim of the current study was to perform a meta-analysis of randomised trials to evaluate whether bivalirudin might offer benefits in terms of mortality as compared to UFH.

We obtained results from all randomised trials evaluating the benefits of adjunctive bivalirudin as compared to UFH with or without Gp IIb-IIIa inhibitors among patients undergoing coronary angioplasty. The literature was scanned by formal searches of electronic databases (MEDLINE and CENTRAL) from January 1990 to October 2008.The following keywords were used: randomised trial, coronary angioplasty, stent, reperfusion, primary angioplasty, bivalirudin, direct thrombin inhibitors, hirulog. Primary endpoint was mortality. Secondary endpoint was infarction. Safety endpoint was the risk of major bleeding complications. No language restriction was applied.

A total of nine randomised trials were included in the metaanalysis, with 15655 patients randomised to bivalirudin and 13104 patients randomised to UFH. We did not observe any difference in mortality between bivalirudin and UFH (1.73% vs 1.67%, p = 0.15) without any relationship between the baseline risk of mortality (r = 0.17, p = 0.71) or the reduction in major bleeding complications (r = –0.29, p = 0.53) and the benefits in mortality with bivalirudin. A trend in higher risk of myocardial infarction was observed with bivalirudin (6.9% vs 5.9%, p = 0.07, p het = 0.65). Bivalirudin was associated with a significant reduction in major bleeding complications (1.7% vs 3.4%, p < 0.0001), as compared to UFH.

This meta-analysis shows that among patients undergoing coronary angioplasty, bivalirudin is associated with significant reduction in major bleeding complications. However, these benefits did not translate into benefits in mortality, with even a trend in higher risk of myocardial infarction.

Keywords

Antithrombin - clinical trials - direct antithrombin agents - acute myocardial infarction - coronary angioplasty - bivalirudin

• References

• 1 Stettler C, Wandel S, Allemann S. et al. Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis. Lancet 2007; 370: 937-948.
• 2 De Luca G, Suryapranata H, Stone GW. et al. Coronary stenting versus balloon angioplasty for acute myocardial infarction: A meta-regression analysis of randomized trials. Int J Cardiol 2008; 126: 37-44.
• 3 De Luca G, Dudek D, Sardella G. et al. Adjunctive manual thrombectomy improves myocardial perfusion and mortality in patients undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction: a meta-analysis of randomized trials. Eur Heart J 2008; 28: 3002-3010.
• 4 De Luca G, Suryapranata H, Stone GW. et al. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: a metaanalysis of randomized trials. JAMA 2005; 293: 1759-1765.
• 5 Mehta SR, Granger CB, Eikelboom JW. et al. Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: results from the OASIS-5 trial. J Am Coll Cardiol 2007; 50: 1742-1751.
• 6 De Luca G, Marino P. Adjunctive benefits from low-molecular-weight heparins as compared to unfractionated heparin among patients with ST-segment elevation myocardial infarction treated with thrombolysis. A meta-analysis of the randomized trials. Am Heart J 2007; 154: 1085.e1-1086.e1.
• 7 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: 2218-2230.
• 8 Chong BH, Isaacs A. Heparin-induced thrombocytopenia: what clinicians need to know. Thromb Haemost 2009; 101: 279-283.
• 9 De Luca G, Marino P. Advances in antithrombotic therapy as adjunct to reperfusion therapies for ST-segment elevation myocardial infarction. Thromb Haemost 2008; 100: 184-195.
• 10 Eikelboom J, White H, Yusuf S. The evolving role of direct thrombin inhibitors in acute coronary syndromes. J Am Coll Cardiol 2003; 41 (4 Suppl S): 70S-78S.
• 11 Verstraete M. Direct thrombin inhibitors: appraisal of the antithrombotic/hemorrhagic balance. Thromb Haemost 1997; 78: 357-363.
• 12 Warkentin TE, Greinacher A, Koster A. Bivalirudin. Thromb Haemost 2008; 99: 830-839.
• 13 Heras M, Chesebro JH, Penny WS. et al. Effects of thrombin inhibition on development of acute plateletthrombus deposition during angioplasty in pigs. Circulation 1989; 79: 657-665.
• 14 Badimon L, Badimon J, Lassila R. et al. Thrombin regulation of platelet interaction with damaged vessel wall and isolated collagen type I at arterial flow conditions in a porcine model: effects of hirudins, heparin, and calcium chelation. Blood 1991; 78: 423-434.
• 15 Busch G, Steppich B, Sibbing D. et al. Bivalirudin reduces platelet and monocyte activation after elective percutaneous coronary intervention. Thromb Haemost 2009; 101: 340-344.
• 16 Bittl JA, Chaitman BR, Feit F. et al. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: Final report reanalysis of the Bivalirudin Angioplasty Study. Am Heart J 2001; 142: 952-959.
• 17 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: 847-853.
• 18 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: 1092-1096.
• 19 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: 853-863.
• 20 Stone GW, White HD, Ohman EM. et al. Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial investigators. Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial. Lancet 2007; 369: 907-919.
• 21 Kastrati A, Neumann FJ, Mehilli J. et al. ISARREACT 3 Trial Investigators. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med 2008; 359: 688-696.
• 22 Sibbing D, Busch G, Braun S. et al. Impact of bivalirudin or unfractionated heparin on platelet aggregation in patients pretreated with 600 mg clopidogrel undergoing elective percutaneous coronary intervention. Eur Heart J 2008; 29: 1504-1509.
• 23 Briguori C. Randomised Comparison of Bivalirudin Monotherapy versus Unfractionated Heparin plus Tirofiban in Diabetic Patients Undergoing Elective Coronary Stenting (NAPLES Study). http://www.clinicaltrialresults.org/ (accessed on October 16, 2008).
• 24 Antoniucci D. A Randomized Trial Comparing Bivalirudin With Unfractionated Heparin In Patients Undergoing Elective PCI (ARNO Trial). http://www.clinicaltrialresults.org (accessed on October 16, 2008).
• 25 Manoukian SV, Feit F, Mehran R. et al. Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndromes: an analysis from the ACUITY Trial. J Am Coll Cardiol 2007; 49: 1362-1368.
• 26 Kinnaird TD, Stabile E, Mintz GS. et al. Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions. Am J Cardiol 2003; 92: 930-935.
• 27 Rao SV, O’Grady K, Pieper KS. et al. Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes. Am J Cardiol 2005; 96: 1200-1206.
• 28 Agema WR, Jukema JW, Zwinderman AH. et al. A meta-analysis of the angiotensin-converting enzyme gene polymorphism and restenosis after percutaneous transluminal coronary revascularization: evidence for publication bias. Am Heart J 2002; 144: 760-768.
• 29 De Luca G, Suryapranata H, Stone GW. et al. Relationship between patient’s risk profile and benefits in mortality from adjunctive abciximab to mechanical revascularization for ST-segment elevation myocardial infarction: a meta-regression analysis of randomized trials. J Am Coll Cardiol 2006; 47: 685-686.
• 30 Moher D, Cook DJ, Eastwood S. et al. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet 1999; 354: 1896-1900.
• 31 Jani SM, Smith DE, Share D. et al. Blood transfusion and in-hospital outcomes in anemic patients with myocardial infarction undergoing percutaneous coronary intervention. Clin Cardiol 2007; 30 (10 Suppl 2): II49-56.
• 32 Kim P, Dixon S, Eisenbrey AB. et al. Impact of acute blood loss anemia and red blood cell transfusion on mortality after percutaneous coronary intervention. Clin Cardiol 2007; 30 (10 Suppl 2): II35-43.
• 33 Yatskar L, Selzer F, Feit F. et al. Access site hematoma requiring blood transfusion predicts mortality in patients undergoing percutaneous coronary intervention: data from the National Heart, Lung, and Blood Institute Dynamic Registry. Catheter Cardiovasc Interv 2007; 69: 961-966.
• 34 Wang TY, Xiao L, Alexander KP. et al. Antiplatelet therapy use after discharge among acute myocardial infarction patients with in-hospital bleeding. Circulation 2008; 118: 2139-2145.
• 35 Chase AJ, Fretz EB, Warburton WP. et al. Association of the arterial access site at angioplasty with transfusion and mortality: the M.O.R.T.A.L study (Mortality benefit Of Reduced Transfusion after percutaneous coronary intervention via the Arm or Leg). Heart 2008; 94: 1019-1025.
• 36 Brasselet C, Tassan S, Nazeyrollas P. et al. Randomised comparison of femoral versus radial approach for percutaneous coronary intervention using abciximab in acute myocardial infarction: results of the FARMI trial. Heart 2007; 93: 1556-1561 Epub 2007 Jul 16.
• 37 Cantor WJ, Mahaffey KW, Huang Z. et al. Bleeding complications in patients with acute coronary syndrome undergoing early invasive management can be reduced with radial access, smaller sheath sizes, and timely sheath removal. Catheter Cardiovasc Interv 2007; 69: 73-83.
• 38 Büchler JR, Ribeiro EE, Falcão JL. et al. A randomized trial of 5 versus 7 French guiding catheters for transfemoral percutaneous coronary stent implantation. J Interv Cardiol 2008; 21: 50-55.
• 39 Ducas J, Chan MC, Miller A. et al. Immediate protamine administration and sheath removal following percutaneous coronary intervention: a prospective study of 429 patients. Catheter Cardiovasc Interv 2002; 56: 196-199.