Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia.
BACKGROUND
Lepirudin (Refludan) is a hirudin derivative. It is a direct thrombin inhibitor obtained by recombinant technology from the medicinal leech and is approved for treatment of heparin-induced thrombocytopenia complicated by thrombosis. Because 3 cases of fatal anaphylaxis possibly associated with use of lepirudin have been reported, we initiated an investigation of putative lepirudin-associated anaphylaxis.


RESULTS
Aided by the manufacturer (Schering AG, Berlin, Germany), we used the lepirudin study databases to identify all patients in whom possible anaphylaxis/severe allergy was recorded from 1994 to September 2002. The 26 possible cases identified were reviewed independently by 2 investigators. After excluding patients with mild skin reactions, reactions likely caused by concomitant medications, poorly documented cases, and reactions that did not correspond temporally with lepirudin use, there remained 9 patients judged to have had severe anaphylaxis in close temporal association with lepirudin. All reactions occurred within minutes of intravenous lepirudin administration, with 4 fatal outcomes (3 acute cardiorespiratory arrests, 1 hypotension-induced myocardial infarction). In these 4 cases, a previous uneventful treatment course with lepirudin was identified (1 to 12 weeks earlier). We recorded high-titer IgG-anti-lepirudin antibodies in an additional patient with anaphylaxis. Because lepirudin has been used in approximately 35 000 patients, the risk of anaphylaxis is approximately 0.015% (5 of 32 500) on first exposure and 0.16% (4 of 2500) in reexposed patients (7.5% estimated reexposures).


CONCLUSIONS
Lepirudin can cause fatal anaphylaxis, particularly in patients who are treated within 3 months of a previous exposure. The overall risk/benefit assessment of lepirudin as a treatment for heparin-induced thrombocytopenia remains favorable.
Institut für Immunologie und Transfusionsmedizin, Ernst-Moritz-Arndt Universität, Klinikum/Sauerbruchstrasse, 17489 Greifswald, Germany. greinach@uni-greifswald.de
A
A
Greinacher
N
N
Lubenow
P
P
Eichler
D000368:Aged; D000369:Aged, 80 and over; D000707:Anaphylaxis / Q000139:chemically induced* / Q000401:mortality; D000925:Anticoagulants / Q000009:adverse effects; D002318:Cardiovascular Diseases / Q000150:complications; D016208:Databases, Factual; D005260:Female; D005343:Fibrinolytic Agents / Q000009:adverse effects; D006493:Heparin / Q000009:adverse effects; D006629:Hirudins / Q000009:adverse effects* / Q000031:analogs & derivatives*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011358:Product Surveillance, Postmarketing / Q000706:statistics & numerical data*; D011994:Recombinant Proteins / Q000009:adverse effects* / Q000627:therapeutic use; D018570:Risk Assessment; D013921:Thrombocytopenia / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D013923:Thromboembolism / Q000209:etiology / Q000517:prevention & control*
D000925:Anticoagulants; D005343:Fibrinolytic Agents; D006629:Hirudins; D011994:Recombinant Proteins; D006493:Heparin; C083544:lepirudin