Correspondence
Bivalirudin in Acute Coronary Syndromes
N Engl J Med 2007; 356:1069-1071March 8, 2007
- Article
To the Editor:
The main message of the study of bivalirudin in patients with acute coronary syndromes, reported by Stone et al. (Nov. 23 issue)1 is that, as compared with heparin or enoxaparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin alone offers a similar degree of protection against ischemic events and a significant reduction in bleeding complications. Most of the benefit of bivalirudin alone was associated with the lower rate of catheterization-related hemorrhage (0.8% with bivalirudin alone vs. 2.5% in the other two groups). Given the importance of bleeding complications for the interpretation of the results, it is surprising that no details on the arterial access used during the trial were provided, although the numbers reported suggest a predominant use of the transfemoral approach. If this is true, considering that severe local arterial complications are rare when the radial artery is used for diagnostic or interventional procedures,2,3 probably little or no benefit should be expected from bivalirudin in the setting of transradial catheterization. We still need better antithrombotic strategies for high-risk acute coronary syndromes, but the reduction of vascular complications is best accomplished by a wider application of the transradial technique.
3 ReferencesMarcelo Sanmartin, M.D.
Hospital Meixoeiro, 36200 Vigo, Spain
marcelo.sanmartin. fernandez@sergas. es 1
Stone GW ,McLaurin BT ,Cox DA , et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203-2216
Full Text | Web of Science | Medline2
Agostoni P ,Biondi-Zoccai GG ,de Benedictis ML , et al. Radial versus femoral approach for percutaneous coronary diagnostic and interventional procedures: systematic overview and meta-analysis of randomized trials. J Am Coll Cardiol 2004;44:349-356
CrossRef | Web of Science | Medline3
Sanmartin M ,Cuevas D ,Goicolea J ,Ruiz-Salmeron R ,Gomez M ,Argibay V . Vascular complications associated with radial artery access for cardiac catheterization. Rev Esp Cardiol 2004;57:581-584
CrossRef | Web of Science | Medline
To the Editor:
Stone et al. suggest that bivalirudin alone, as compared with unfractionated heparin or enoxaparin plus a glycoprotein IIb/IIIa inhibitor or bivalirudin plus a glycoprotein IIb/IIIa inhibitor, is associated with similar rates of ischemia and a lower rate of bleeding in patients with acute coronary syndromes who are undergoing invasive procedures. Bivalirudin is a small synthetic peptide modeled after hirudin, a protein that is 65 amino acids in length and of nonhuman origin. Antihirudin antibody formation in patients treated with recombinant hirudins has been shown in several studies.1-3 In particular, lepirudin has been linked to at least nine cases of severe anaphylaxis,4 four of them with a fatal outcome. In contrast, no clinically relevant antibivalirudin antibody formation has been reported to date. However, since bivalirudin and lepirudin have some identical amino acid sequences, the possible formation of such antibodies or cross-reactivity due to previous exposure to lepirudin is plausible. Thus, before bivalirudin can be widely used as a standard anticoagulant during coronary interventions, more data concerning its safety, especially in the setting of reexposure, are warranted.
4 ReferencesRobert F. Bonvini, M.D.
Vitali Verin, M.D.
Marc Righini, M.D.
University Hospital of Geneva, 1211 Geneva, Switzerland
robert.bonvini@hcuge. ch 1
Eichler P ,Friesen HJ ,Lubenow N ,Jaeger B ,Greinacher A . Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance. Blood 2000;96:2373-2378
Web of Science | Medline2
Eichler P ,Lubenow N ,Strobel U ,Greinacher A . Antibodies against lepirudin are polyspecific and recognize epitopes on bivalirudin. Blood 2004;103:613-616
CrossRef | Web of Science | Medline3
Song XH ,Huhle G ,Wang LC ,Hoffmann U ,Harenberg J . Generation of anti-hirudin antibodies in heparin-induced thrombocytopenic patients treated with r-hirudin. Circulation 1999;100:1528-1532
Web of Science | Medline4
Greinacher A ,Lubenow N ,Eichler P . Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation 2003;108:2062-2065
CrossRef | Web of Science | Medline
Author/Editor Response
Sanmartin questions whether the choice of a vascular access site affected the findings of the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial, noting that hemorrhagic complications are less frequent with radial arterial puncture than with femoral arterial puncture. Of the 13,819 patients from 17 countries enrolled in the ACUITY trial, radial-artery access was used in only 798 patients (5.8%), reflecting the well-recognized infrequency with which this vessel is selected for angiography and coronary intervention. Overall bleeding rates were lower with radial than with femoral access. Given the small number of patients in whom radial access was used, firm conclusions regarding the relative rates of bleeding among the three groups that underwent randomization cannot be reached, although intuitively, the efficacy of bivalirudin monotherapy in reducing bleeding unrelated to the access site is independent of vascular access.
Bonvini and colleagues raise important issues regarding bivalirudin immunogenicity and potential cross-reactivity with recombinant hirudin. Recombinant hirudin is a protein of 65 amino acids derived from yeast cells with a defined tertiary and quaternary structure containing three disulfide cross-links. In contrast, bivalirudin is a smaller, synthetic peptide (20 amino acids) that lacks disulfide bonds, with a resultant minimal secondary structure. As such, bivalirudin would be expected to be less immunogenic than hirudin. Bivalirudin is also typically administered for less than the 2 to 3 days necessary for a B-cell response.1 Among 494 patients in clinical trials who received bivalirudin and who were tested for antibodies, treatment-emergent antibivalirudin antibodies developed in only 2 patients (0.4%), and neither patient had an allergic reaction.2 Regarding readministration, 13 patients received repeat courses of bivalirudin 3 months apart and underwent serial antibody testing. Antibivalirudin antibodies did not develop in any of the patients after either initial or repeat administration.2 In 52 patients with heparin-induced thrombocytopenia undergoing angioplasty with bivalirudin on two or more occasions, no allergic reactions or thrombocytopenia developed.3 In post-marketing surveillance of more than 1.3 million patient-exposures to bivalirudin, anaphylaxis or serious allergic reactions have been reported in less than 1 in 30,000 patients.2 Finally, the C-terminal of bivalirudin contains an 11-amino-acid sequence that is common to lepirudin, and cross-reactivity is thus theoretically possible.4 However, no immunologic reactions have been reported in patients with known previous exposure to lepirudin.2
4 ReferencesGregg W. Stone, M.D.
Columbia University Medical Center, New York, NY 10032
gs2184@columbia.edu Martial Hamon, M.D.
University Hospital of Caen, 14033 Caen, FranceHarvey White, M.D.
Auckland City Hospital, Auckland 1001, New Zealand1
Greinacher A ,Lubenow N ,Eichler P . Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation 2003;108:2062-2065
CrossRef | Web of Science | Medline2
Data on file. Parsippany, NJ: The Medicines Company. (Accessed February 15, 2007, at http://www.themedicinescompany.com.)
3
Mahaffey KW ,Lewis BE ,Wildermann NM , et al. The anticoagulant therapy with bivalirudin to assist in the performance of percutaneous coronary intervention in patients with heparin-induced thrombocytopenia (ATBAT) study: main results. J Invasive Cardiol 2003;15:611-616
Medline4
Eichler P ,Lubenow N ,Strobel U ,Greinacher A . Antibodies against lepirudin are polyspecific and recognize epitopes on bivalirudin. Blood 2004;103:613-616
CrossRef | Web of Science | Medline
