Society of Cardiovascular Anesthesiologists

Lepirudin (Recombinant Hirudin) for Parenteral Anticoagulation in Patients With Heparin-Induced Thrombocytopenia.

Greinacher A., Janssens U., Berg G., et al. Circulation 1999; 100:587-593.

Reviewer: Sergio Gregoretti, MD
Department of Anesthesiology
University of Alabama at Birmingham
Birmingham, AL

Introduction. Heparin-induced thrombocytopenia (HIT) is a well-recognized complication of heparin therapy. In the majority of patients thrombocytopenia is modest and resolves without sequelae. In contrast, in a small subset of patients thrombocytopenia is severe with platelet counts often below 50,000/µL, and may be associated with thromboembolic events, such as limb ischemia, stroke, mesenteric and myocardial infarction. This life-threatening form of heparin-induced thrombocytopenia with thromboembolic complications (HITT) is caused by antibodies that activate platelets in the presence of heparin, with release of large amounts of procoagulant factors and massive thrombin generation, eventually leading to diffuse thromboembolic events. When HITT is suspected, immediate cessation of heparin administration is mandatory. However, many patients require further anticoagulation, either for the underlying disease that required heparin treatment to begin with, or HITT-related vessel occlusions. Lepirudin is a recombinant version of hirudin, an anticoagulant present in the saliva of the medicinal leech. Lepirudin, like its natural counterpart, is a potent thrombin inhibitor, which does not require plasma cofactors to exert its effects. Lepirudin binds directly to thrombin, blocking the binding site for fibrinogen on the thrombin molecule. Since thrombin cannot bind fibrinogen, the conversion of fibrinogen to fibrin does not occur and coagulation is prevented. This specific anti-thrombin activity of lepirudin makes it particularly useful for the treatment of HITT. The objective of this study was to assess the efficacy and safety of lepirudin for anticoagulation in patients with HITT.

Methods. This prospective, multicenter study (with 46 participating hospitals!) was performed in patients with severe thrombocytopenia and/or thromboembolic complications, and with a diagnosis of HIT confirmed by a positive heparin-induced platelet activation test. Patients with known thromboembolic complications when therapy was started received intravenously lepirudin 0.4 mg/kg bolus followed by 0.15 mg/kg/h infusion (group A, treatment); patients without thromboembolic complications received only an infusion of 0.1 mg/kg/h (group B, prophylaxis). Infusion rates were adjusted to maintain the activated partial thromboplastin time (aPTT) between 1.5 and 2.5 times normal values. The infusions were maintained as long as clinically indicated. Efficacy was assessed using laboratory and clinical outcomes, namely an increase in platelet count %gt;100,000/µL by day 10 of lepirudin treatment, limb amputation, death, and new thromboembolic events. Safety outcomes included major bleeding and any other adverse event attributable to lepirudin. The outcomes of lepirudin-treated patients were compared with those of historical controls who had been treated for HIT according to the practice before lepirudin was available.

Results. Of the 112 patients enrolled, 93 (59 assigned to group A, and 34 to group B) completed the study according to protocol. The median duration of treatment was 11 days in group A and 8 days in group B. Treatment was continued for %gt;10 days in about 60% of the patients. The outcomes of the two groups were combined and reported as outcomes of the lepirudin-treated patients as a whole. A positive laboratory outcome was obtained in about 90% of patients, i.e. platelet counts above 100,000/µL by day 10 of treatment. Eleven patients (10%) died, but none of the deaths were considered causally related to lepirudin. Ten patients (9%) underwent limb amputation and 20 (18%) experienced a new thromboembolic event. Major bleeding was the most common adverse event with an incidence of 17%. However, no patients suffered intracranial or fatal hemorrhages. Comparison with the historical control group revealed that lepirudin-treated patients had a statistically significant lower incidence of death (10% vs. 22%) and a lower incidence of new thrombotic complications (18% vs. 32%), but there was no difference in the incidence of limb amputations (9% vs. 8%). When all the clinical outcomes were combined (death, limb amputation, and thrombotic events), the incidence was lower in the lepirudin group than in the historical control group. Bleeding events were twice as common in the lepirudin group, but there was no difference between groups in bleeding events requiring transfusion.

Conclusions. The authors concluded that lepirudin was effective for preventing death, limb amputation, and new thrombotic complications in patients with HIT, while having an acceptable safety profile.

Comments. While the data confirm that lepirudin is an effective anticoagulant (target aPTT values were easily maintained), caution seems appropriate before embracing the authors' conclusions. In fact, the retrospective nature of patient selection in the control group makes quite problematic any claim of improved outcome in the lepirudin-treated patients. It was also unfortunate that the outcome results of the two groups of patients, i.e. those with and those without thombotic complications at the beginning of lepirudin treatment, have not been reported separately. It would have certainly been interesting to know whether lepirudin was more effective as a therapeutic or a prophylactic agent. Reporting the outcome results of the two groups separately would have also allowed some comparisons to be made with outcome data in other published series of patients with HIT or HITT, perhaps strengthening the authors' conclusions. More studies are needed to determine the place of lepirudin in the treatment of patients with HIT or HITT.

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