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.
Methods and 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 ≈35 000 patients, the risk of anaphylaxis is ≈0.015% (5 of 32 500) on first exposure and 0.16% (4 of 2500) in reexposed patients (7.5% estimated reexposures).
Conclusion— 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.
Received February 3, 2003; de novo received July 18, 2003; revision received September 2, 2003; accepted September 4, 2003.
Heparin-induced thrombocytopenia (HIT) is a prothrombotic syndrome that can be associated with thromboembolic complications.1 Affected patients require alternative anticoagulation. The first approved anticoagulant not crossreacting with HIT antibodies was the recombinant hirudin, lepirudin (Schering AG, Berlin, Germany).2
Although hirudin is a nonhuman protein, there are few reports on immune reactions toward it.3 In the major clinical studies of acute coronary syndromes, patients were usually treated with hirudin for 2 to 3 days only, a period too short for a B-cell response to develop. However, in patients receiving lepirudin for HIT, we and others have found a high incidence of anti-hirudin antibodies (44%).4–6 However, until now, only 2 patients with allergic reactions to hirudins have been reported.7,8
In 2002, 3 patients with potential anaphylactic reactions associated with lepirudin treatment were identified by the manufacturer’s (Schering AG) pharmacosurveillance system. We therefore reassessed the risk of allergic and anaphylactic reactions potentially caused by lepirudin.
As part of the ongoing lepirudin pharmacosurveillance program, a review of the safety database, including clinical investigations and postmarketing reports, was initiated. The reporting period ranged from March 1994 until September 2002.
All cases reported to the manufacturer or the marketing authorization holder as anaphylactic or severe allergic reaction in conjunction with lepirudin treatment were identified, as were all cases in which such reactions were noted in the case narrative.
In addition, the adverse event database was screened for 289 terms potentially related to allergic, anaphylactic, or shock reactions (eg, hypotension, tachycardia). This initial screen retrieved 345 reports, which were reviewed by medical experts for cases representing or mentioning possible anaphylactic or anaphylactoid reactions irrespective of causality. The resulting case records were then independently assessed by 2 different medical experts aiming to identify cases with a reasonable probability of representing severe allergic reactions to lepirudin.
One additional patient was identified in December 2002 in whom anti-hirudin antibodies were tested as described.4
Twenty-six cases were reported as likely being the result of severe allergic or anaphylactic reactions in conjunction with lepirudin treatment. Of the 26 reports, 17 were excluded for the following reasons: insufficient information (n=4); lack of temporal association with lepirudin use (1 resolved when lepirudin was continued, 2 occurred 10 hours and 4 days after discontinuation of lepirudin); mild or moderate allergic reactions (2 skin reactions, 1 skin reaction, facial and pharyngeal edema with tachycardia but no drop in blood pressure); probable reaction to other drugs (3 streptokinase, 3 contrast medium); and unclear clinical presentation and negative test for anti-hirudin antibodies (1 patient).
The remaining 9 patients were considered to have experienced severe anaphylactic reactions (Table). All occurred within minutes of treatment initiation (time of onset unknown in 1 patient).
The 4 patients who experienced the event during reexposure to lepirudin suffered from severe cardiac disease and died shortly after the onset of the anaphylactic event (3 acute cardiorespiratory arrests, 1 secondary myocardial infarction).
The time interval to the preceding treatment course with lepirudin ranged from 1 to 12 weeks. Allergic symptoms were not reported for the preceding treatment courses in any of these patients. Only the additional patient (identified in December 2002) was tested for anti-hirudin antibodies. She showed high-titer anti-lepirudin antibodies of the IgG (1:5000) but not of the IgE or IgM class and had a positive rechallenge test.
Despite increasing use of lepirudin, the number of reports on anaphylaxis per year did not increase since 1994. All fatal cases occurred during the last 18 months.
This study shows that Refludan, containing lepirudin as an active ingredient, has been associated with severe anaphylactic reactions, and recent preexposure seems to be related to reactions with fatal outcome. The patients who died were suffering from severe cardiac disease, which could have contributed to the fatalities. Because we had serum from 1 patient only to prove the anti-lepirudin antibodies, this study highly implicates but does not conclusively prove that all anaphylactic reactions observed were immune mediated.
Approximately 35 000 patients have been treated with lepirudin so far. If one extrapolates the reexposure rate of ≈7.5% observed in 2 prospective trials assessing lepirudin in HIT,9,10 then ≈2500 patients will have been reexposed. Thus, the risk for severe anaphylactic reactions during lepirudin treatment is ≈0.015% (5 of 32 500) on first treatment with lepirudin and 0.16% (4 of 2500) in reexposed patients.
In the known reexposure cases, the time period between last treatment with lepirudin and reexposure ranged between 1 and 12 weeks, and the anaphylactic reactions manifested within minutes of initiation of lepirudin therapy. This strongly suggests that in these patients, circulating anti-hirudin antibodies were already present at the start of lepirudin treatment. This was most likely the case in the dialysis patient in whom immunization was triggered by previous treatment with lepirudin, although contact with leeches, hirudins in ointments, or naturally occurring antibodies have not been formally excluded as causes.
It is known that not only IgE antibodies but also IgG antibodies can cause allergic reactions to drugs such as protamine,11 thiamine,12 and dextrans.13 This could also be the case for hirudin, because we could demonstrate high-titer anti-hirudin antibodies of the IgG class but no IgE antibodies in 1 of the patients. This is in line with a report by Bircher et al7 on a volunteer who received several uneventful intravenous injections of the r-hirudin desirudin. Five years later, this patient again received 15 mg desirudin subcutaneously twice within 1 week and developed a prickling cutaneous sensation, generalized urticaria, and slight respiratory depression controlled by steroids. No specific IgE antibodies to hirudin or candida or S cerevisia were detected, although high-titer (1:1600) anti-hirudin IgG antibodies were present directly before the injection, which were boosted after the injection (titer 1:12 800 at 2.5 weeks) and then declined.
Recombinant hirudins are produced in yeast, and small amounts of yeast proteins are found in the commercial preparations (<0.001%). Yeast proteins or other compounds such as mannitol could have been responsible for some of the anaphylactic reactions, because in 5 of the 10 patients with anaphylaxis, no evidence for previous hirudin treatment was found.
Anti-hirudin antibodies can also be induced by other hirudins and low-dose subcutaneous injection, eg, by 15 mg desirudin subcutaneously twice a day.14 Currently, besides lepirudin, the recombinant hirudin desirudin (Aventis, Frankfurt, Germany) and bivalirudin (The Medicines Co, Parsippany, NJ), which shares the thrombin-exosite-binding amino acid sequence with hirudin, are approved or under trial in various countries for thrombosis prophylaxis after orthopedic surgery or for cardiac intervention.
To put the risk of anaphylaxis caused by lepirudin into perspective, it should be emphasized that the death rate of >20% in patients with HIT before lepirudin became available has been reduced to <10% in lepirudin-treated patients.2
In conclusion, lepirudin could be associated with anaphylaxis, and patients who have been preexposed to the drug, especially within recent months, could be at an increased risk for severe anaphylactic reactions. Omission of the bolus might reduce the severity of anaphylaxis. Alternative treatment options should be considered before reexposure to lepirudin. Treatment with lepirudin should only be started in an environment where treatment for anaphylactic reaction is readily available. The overall risk/benefit assessment of lepirudin as a treatment for HIT remains favorable.
This study was only feasible by major contributions of the pharmacovigilance group atSchering AG, namely Dr R. Dorow, Dr A. Kluczka, and Dr R. Graf. Preparation of the manuscript was supported by DFG Gr 1096/2-4 and by the German Federal Ministry for Education and Research (NBL3 program, reference-01-ZZ0103).
Guest Editor for this article was Douglas L. Mann, MD, Baylor College of Medicine, Houston, Tex.
Drs Greinacher and Lubenow work as consultants for Berlex, Inc, and Pharmion, which hold the marketing rights for lepirudin (Refeludan) in the United States and Europe, respectively. Dr Greinacher was also the medical expert involved in the adverse drug reaction report and the resulting activities at the European Medicines Evaluation Agency. The authors do not believe that these activities constitute a conflict of interest with the content of this article.
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