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Lepirudin is a recombinant hirudin derived from transfected yeast cells. The hirudins are direct thrombin inhibitors which render the thrombin molecule incapable of promoting fibrin formation and catalysing other haemostatic reactions.

In initial studies, parenteral lepirudin has shown promising efficacy as an antithrombotic agent. Lepirudin increased or maintained platelet counts at normal baseline values while maintaining adequate anticoagulation in patients with heparin-induced thrombocytopenia (HIT), and has not been associated with the development of immune-mediated thrombocytopenia,

Preliminary studies in patients with deep vein thrombosis (DVT) suggest that lepirudin may be more effective than unfractionated heparin (UFH) at preventing pulmonary perfusion defects. In patients with unstable angina pectoris, preliminary data also showed lepirudin to be significantly more effective than UFH according to the combined incidence of cardiovascular mortality, new acute myocardial infarction (AMI) or refractory angina, However, additional studies involving larger patient numbers are necessary before firm conclusions can be made regarding the relative efficacy of lepirudin in these indications. Similarly, promising but limited data on the use of lepirudin during haemodialysis or heart surgery and in patients with disseminated intravascular coagulation (DIC) require further confirmation.

Bleeding complications and the possible induction of allergic or anaphylactic reactions are the most serious adverse events associated with lepirudin therapy. Major bleeding complication rates appear to be similar with lepirudin and UFH monotherapy; however, lepirudin may be associated with an increased incidence of minor bleeding including bruising.

Initial encouraging results showing an improvement in coronary artery patency with high-dose lepirudin versus UFH as an adjunct to thrombolytic therapy in patients with AMI were subsequently overshadowed by reports of a high incidence of major bleeding events including cerebral haemorrhage among lepirudin recipients. Moreover, at lower doses which did not produce an unacceptably high incidence of haemorrhagic complications, lepirudin appeared to have only a small efficacy advantage over UFH.

Positive lepirudin antibody titres developed in 38 of 82 patients (46.3%) with heparin-induced thrombocytopenia (HIT) after greater than or equal to 6 days’ treatment with lepirudin and resulted in a prolongation of aPTT values to >100 seconds in 3 patients. Limited data are available on re-exposure of patients to lepirudin; however, 4 patients with antilepirudin antibodies treated with a second course of lepirudin did not develop allergic reactions.

In patients with DVT, pulmonary perfusion defects were statistically significantly less frequent during 5 days’ treatment with subcutaneous lepirudin (0.75, 1.25 or 2 mg/kg twice daily; n = 91) than during 5 days of intravenous UFH (5000IU bolus plus 1250 IU/h infusion; n = 30) [3 to 9 vs 27%]. However, too few clinical embolic events in this study precluded any firm conclusions regarding the efficacy of lepirudin relative to that of UFH. Moreover, assessment of existing thromboemboli by phlebography revealed no significant difference be tween lepirudin and UFH, with the majority of thrombi showing no change. Data on the efficacy of lepirudin in the prophylaxis of DVT are currently limited to the results of 1 small study in patients undergoing hip replacement surgery which reported no cases of DVT, pulmonary embolism or bleeding during lepirudin therapy.

Although not conclusive, data are accumulating on the use of lepirudin in the treatment of patients with unstable angina. According to the results of the OASIS I study, the combined incidence of cardiovascular mortality, new AMI or refractory angina was statistically significantly lower with medium-dose intravenous lepirudin (0.4 mg/kg bolus plus 0.15 mg/kg/h; n = 267) than with intravenous UFH (5000IU bolus plus 1000 or 1200 IU/h; n = 371) [3 vs 6.5%]. Despite an increase in ischaemic events approximately 8 days after the cessation of lepirudin therapy, differences in the combined incidence of various ischaemic events in favour of lepirudin did persist during long term follow-up(180 days); however, these differences were statistically significant only for the combined incidence of cardiovascular death, new AMI and refractory or severe angina without revascularisation (19.7 vs 27.3%).

A limited number of patients (n = 40) with unstable angina have also received lepirudin as a periprocedural antithrombotic therapy during coronary angioplasty. In these patients, high-dose intravenous lepirudin (0.5 mg/kg bolus plus 0.04 to 0.24 mg/kg/h for 48 hours) was as effective as UFH (150 IU/kg plus 7 to 20 IU/kg/h for 48 hours) in the prevention of early restenosis and was associated with a lower incidence of cardiac events (death, AMI, acute occlusion or emergency intervention).

Lepirudin appears to have a narrow therapeutic window when used as an adjunct to thrombolytic therapy in patients with AMI. In the HIT-SK study, high-dose intravenous lepirudin (0.4 mg/kg bolus plus 0.15 mg/kg/h for 48 to 72 hours) as an adjunct to streptokinase produced a statistically significantly higher early, complete and sustained patency rate than UFH (76.9 vs 42.0%) but was associated with a high incidence of major bleeding events (26.7%). Although treatment with lower doses of lepirudin was associated with a positive risk/benefit ratio and a lower rate of major bleeding events, the improvement in early, complete and sustained coronary artery patency was somewhat lower (50 to 61.4%). In the HIT-III study, patient recruitment was stopped prematurely because of an unexpectedly high incidence of intracranial haemorrhage with high-dose lepirudin therapy as an adjunct to alteplase (3.4 vs 0% in the UFH group) and the study results also revealed a higher overall 30-day mortality rate with lepirudin (9.5 vs 5.2%).

Promising results from 3 small studies (total n = 36) also suggest that lepirudin is able to prevent clotting within extracorporeal circuits. In patients undergoing haemodialysis, lepirudin was at least as effective as UFH at preventing coagulation and was also associated with a lower incidence of platelet deposition on the inlet of the artificial kidney. Similarly successful anticoagulation has been reported with lepirudin during CPB.

Lepirudin is contraindicated in pregnant or lactating women and in patients with a known sensitivity to hirudins. Lepirudin should also be used with caution in patients who are receiving concomitant treatment with thrombolytics or coumarin derivatives because of a potential increased risk of bleeding. A careful risk-benefit assessment should be made before administering lepirudin to patients with a possible bleeding tendency. Because of a possible enhanced anticoagulant effect of lepirudin, strict monitoring of aPTT is essential in patients who develop anti-lepirudin antibodies.

No specific antidote is available at present for the treatment of bleeding associated with lepirudin overdosage. In case of overdosage, blood transfusion may be necessary and current guidelines for shock therapy should be followed.