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Bivalirudin (Angiox™, Angiomax®) is a synthetic 20-amino acid peptide analogue of hirudin. It is a direct thrombin inhibitor that binds specifically and reversibly to both fibrin-bound and unbound thrombin. Intravenous bivalirudin is approved in Europe for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI). In the US, bivalirudin is approved in patients with unstable angina pectoris undergoing percutaneous transluminal coronary angioplasty (PTCA) and has recently been approved for use with provisional glycoprotein (GP) IIb/IIIa inhibition in patients undergoing PCI.
Bivalirudin plus provisional GP IIb/IIIa inhibition is effective in patients undergoing PCI. The large, well controlled REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events) study showed that bivalirudin plus provisional GP IIb/IIIa inhibition was noninferior to heparin plus planned GP IIb/IIIa inhibition and that bivalirudin was associated with a reduced risk of bleeding complications. In patients with heparin-induced thrombocytopenia (HIT), bivalirudin was effective against ischaemic events and there was a low incidence of bleeding complications. Bivalirudin should be considered as an alternative to heparin plus planned GP IIb/IIIa inhibition in any patient undergoing urgent or elective PCI, especially in any patient with a high risk of bleeding complications.
Bivalirudin directly inhibits thrombin by binding to the active site and exosite 1 of thrombin. This binding is specific, noncompetitive and initially irreversible. The inhibition is reversed as bivalirudin is slowly cleaved by thrombin, freeing the active site and allowing thrombin to regain its activity.
Intravenous administration of bivalirudin results in a dose-dependent increase in anticoagulation parameters. Bivalirudin inhibits thrombin generation and activity, as well as thrombin-mediated platelet activation.
Bivalirudin does not bind to plasma proteins other than thrombin and has a small volume of distribution. It is cleared from plasma by a combination of proteolytic cleavage and renal mechanisms; bivalirudin plasma clearance is affected by impaired renal function. In patients with normal renal function, bivalirudin is rapidly cleared from plasma and has a terminal half-life of 25 minutes.
The REPLACE-2 trial in patients undergoing PCI found that bivalirudin plus provisional GP IIb/IIIa inhibition was noninferior to heparin plus planned GP IIb/IIIa inhibition for the composite primary endpoint of death, myocardial infarction (MI), repeat revascularisation or major bleeding at 30 days, or for the secondary endpoint of death, MI or repeat revascularisation. There was no between-group difference in the incidence of all-cause mortality after 1 year.
Similar outcomes were observed in REPLACE-2 substudies of special patient groups, including patients with impaired renal function, diabetes mellitus or acute coronary syndromes, and in other studies in patients undergoing brachytherapy or patients with HIT.
Bivalirudin has been associated with a lower incidence of bleeding complications than heparin. In the REPLACE-2 trial, there was a significant 41% relative reduction in the incidence of major bleeding in the bivalirudin plus provisional GP IIb/IIIa inhibitor group compared with the heparin plus planned GP IIb/IIIa inhibitor group (2.4% vs 4.1%; p < 0.001).
The incidence of major bleeding was lower in bivalirudin recipients than heparin recipients across most analysed subgroups of patients including those with impaired renal function or anaemia and female patients. The incidence of bleeding events was also low in a noncomparative trial of bivalirudin in patients with HIT.
Bivalirudin was generally well tolerated. In REPLACE-2, the most frequent adverse events in bivalirudin recipients were back pain, angina pectoris, pain, hypotension and nausea.
Total 30-day costs were lower for bivalirudin plus provisional GP IIb/IIIa inhibitor recipients than for heparin plus planned GP IIb/IIIa inhibitor recipients ($US10 868 vs $US11 242; year of costing 2002) in REPLACE-2. Approximately 80% of the cost reduction was due to a difference in anticoagulation cost (between bivalirudin and GP IIb/IIIa inhibitors) and 20% was due to differences in the incidences of ischaemic and haemorrhagic complications.
KeywordsPercutaneous Coronary Intervention Major Bleeding Abciximab Bivalirudin Activate Clotting Time
- 2.Simonton C. Direct thrombin inhibitors. J Invasive Cardiol 2004 Jul; 16 (7 Suppl.): 17S–23SGoogle Scholar
- 22.Angiox: European public assessment report and product information [online]. Available from URL: http://www.emea.eu.int/humandocs/Humans/EPAR/angiox/angioxM.htm [Accessed 2005 Mar 29]
- 24.The Medicines Company. Angiomax (bivalirudin): prescribing information. Parsippany (NJ): The Medicines Company, 2005 Jun 14Google Scholar
- 25.Bittl JA, Strony J, Brinker JA, et al. Treatment with bivalirudin (hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. Hirulog Angioplasty Study Investigators. N Engl J Med 1995 Sep 21; 333(12): 764–9Google Scholar
- 27.Lincoff AM, Kleiman NS, Kottke-Marchant K, et al. Bivalirudin with planned or provisional abciximab versus lowdose 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 May; 143(5): 847–53PubMedCrossRefGoogle Scholar
- 28.Lincoff AM, Kleiman NS, Kereiakes DJ, et al. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein Ilb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA 2004 Aug 11; 292(6): 696–703PubMedCrossRefGoogle Scholar
- 29.Saw J, Lincoff AM, DeSmet W, et al. Lack of clopidogrel pretreatment effect on the relative efficacy of bivalirudin with provisional glycoprotein IIb/IIIa blockade compared to heparin with routine glycoprotein IIb/IIIa blockade: a REPLACE-2 substudy. J Am Coll Cardiol 2004 Sep 15; 44(6): 1194–9PubMedGoogle Scholar
- 33.Awar M, Kabous N, Patel T, et al. Safety of bivalirudin during brachytherapy with beta radiation [abstract no. A30]. 26th Annual Scientific Sessions of the Society for Cardiac Angiography and Interventions (SCAI); May 7–10 2003; Boston (MA)Google Scholar
- 34.Wolfram R, Kuchulakanti PK, Rha SW, et al. Safety of bivalirudin as a single antithrombotic agent in patients undergoing percutaneous coronary intervention and vascular brachytherapy with gamma and beta emitters [abstract no. 1063-62]. J Am Coll Cardiol 2004 Mar 3; 43 (5 Suppl. A): 52ACrossRefGoogle Scholar
- 35.Gurm HS, Sarembock IJ, Kereiakes DJ, et al. Use of bivalirudin during percutaneous coronary intervention in patients with diabetes mellitus: an analysis from the randomized evaluation in percutaneous coronary intervention linking angiomax to reduced clinical events (REPLACE)-2 trial. J Am Coll Cardiol 2005 Jun 21; 45(12): 1932–8PubMedCrossRefGoogle Scholar
- 36.Rajagopal V, Lincoff AM, Cohen DJ, et al. Outcomes of patients with acute coronary syndromes who are treated with bivalirudin during PCI: an analysis from the REPLACE-2 trial [abstract no. 1624]. Circulation 2004 Oct 26; 110 (17 Suppl.): III–340Google Scholar
- 39.Dangas G, Lasic Z, Mehran R, et al. Effectiveness of the concomitant use of bivalirudin and drug-eluting stents (from the prospective, multicenter BivAlirudin and Drug-Eluting STents [ADEST] study). Am J Cardiol. In PressGoogle Scholar
- 41.Barman N, Gurm H, Bhatt D, et al. Clinical outcomes associated with the use of bivalirudin for patients with acute coronary syndrome undergoing early percutaneous coronary intervention [abstract no. TCT-408]. Am J Cardiol 2004 Sep 30; 94 (6 Suppl.): 191EGoogle Scholar
- 42.Mehran R, Aymong E, Moses J, et al. Early clinical benefit with bivalirudin compared to unfractionated heparin during percutaneous coronary intervention [abstract no. TCT-309]. Am J Cardiol 2003; 92 (6 Suppl.): 134LGoogle Scholar
- 44.Jennings HR, Poe KL, Carrico JM, et al. Percutaneous coronary intervention outcomes and the impact of pharmacologic selection: glycoprotein IIbIIIa inhibitors versus bivalirudin [abstract no. 1039-29]. J Am Coll Cardiol 2005 Feb 1; 45 Suppl. A: 37AGoogle Scholar
- 45.Ebrahimi R, Lincoff AM, Shah AP, et al. Bivalirudin versus heparin in percutaneous coronary interventions: a meta-analysis [abstract no. 1039-25]. J Am Coll Cardiol 2005 Feb 1; 45 Suppl. A: 36AGoogle Scholar
- 46.Rao AK, Pratt C, Berke A, et al. Thrombolysis in myocardial infarction (TIMI) trial-phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988 Jan; 11(1): 1–11PubMedCrossRefGoogle Scholar
- 48.Tsuchiya Y, Lansky A, Costa RA, et al. Gender and outcomes after percutaneous coronary intervention in patients treated with bivalirudin and provisional glycoprotein IIb/IIIa blockade versus heparin and planned glycoprotein IIb/IIIa blockade: results from the REPLACE-2 trial [abstract no. TCT-231]. Am J Cardiol 2004 Sep 30; 94 (6 Suppl.): 106E–7EGoogle Scholar
- 49.Voeltz MD, Attubato MJ, Feit F, et al. Anemia is associated with increased major bleeding complications and early mortality in patients undergoing percutaneous coronary intervention: implications for choices in antithrombotic therapy [abstract no. 1037-13]. J Am Coll Cardiol 2005 Feb 1; 45 (3 Suppl. A): 31AGoogle Scholar
- 53.Cohen DJ, Lincoff AM, Lavelle TA, et al. Economic evaluation of bivalirudin with provisional glycoprotein IIb/IIIa inhibition versus heparin with routine glycoprotein IIb/IIIa inhibition for percutaneous coronary intervention: results from the REPLACE-2 trial. J Am Coll Cardiol 2004 Nov 2; 44(9): 1792–800PubMedGoogle Scholar
- 56.Minutello RM, Wong SC, Chou ET, et al. Angiomax facilitates early sheath removal after coronary angioplasty: the AFRICA study [abstract no. TCT-340]. Am J Cardiol 2003; 92 (6 Suppl.): 146LGoogle Scholar
- 59.Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction-2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). Circulation 2002 Oct 1; 106(14): 1893–900PubMedCrossRefGoogle Scholar
- 63.Benefits and controversies: the REPLACE-2 trial [interview with REPLACE-2 investigator Michael Attubato, MD]. Cath Lab Digest 2003; 11 (4)Google Scholar
- 69.Bivalirudin in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention (BIAMI trial) [online]. Available from URL: http://www.clinicaltrials.gov/ct/show/NCT00093184?order=3 [Accessed 2005 May 20]
- 70.HORIZONS trial [online]. Available from URL: http://www.lebauercvresearch.org/ [Accessed 2005 Jul 26]