Download PDF
Thromb Haemost 2009; 102(03): 428-436
DOI: 10.1160/TH09-05-0287
Review Article
Schattauer GmbH

Bivalirudin as compared to unfractionated heparin among patients undergoing coronary angioplasty

A meta-analyis of randomised trials
Giuseppe De Luca
1   Division of Cardiology, Maggiore della Carità Hospital, Eastern Piedmont University A. Avogadro, Novara, Italy
,
Ettore Cassetti
1   Division of Cardiology, Maggiore della Carità Hospital, Eastern Piedmont University A. Avogadro, Novara, Italy
,
Monica Verdoia
1   Division of Cardiology, Maggiore della Carità Hospital, Eastern Piedmont University A. Avogadro, Novara, Italy
,
Paolo Marino
1   Division of Cardiology, Maggiore della Carità Hospital, Eastern Piedmont University A. Avogadro, Novara, Italy
› Author Affiliations
Further Information

Publication History

Received: 09 June 2009

Accepted after major revision: 13 June 2009

Publication Date:
22 November 2017 (online)

Also available at
    Permissions and Reprints

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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    PubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    PubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 8 Chong BH, Isaacs A. Heparin-induced thrombocytopenia: what clinicians need to know. Thromb Haemost 2009; 101: 279-283.
    Thieme ConnectPubMedSearch in Google Scholar
  • 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.
    Thieme ConnectPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 11 Verstraete M. Direct thrombin inhibitors: appraisal of the antithrombotic/hemorrhagic balance. Thromb Haemost 1997; 78: 357-363.
    Thieme ConnectPubMedSearch in Google Scholar
  • 12 Warkentin TE, Greinacher A, Koster A. Bivalirudin. Thromb Haemost 2008; 99: 830-839.
    Thieme ConnectPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    PubMedSearch in Google Scholar
  • 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.
    Thieme ConnectPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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).
    PubMed
  • 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).
    PubMed
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    PubMedSearch in Google Scholar
  • 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.
    PubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    PubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar