LEPIRUDIN - A REVIEW OF ITS POTENTIAL PLACE IN THE MANAGEMENT OF THROMBOTIC DISORDERS

Lepirudin is a recombinant hirudin derived from transfected yeast cell s. The hirudins are direct thrombin inhibitors which render the thromb in molecule incapable of promoting fibrin formation and catalysing oth er haemostatic reactions. In initial studies, parenteral lepirudin has shown promising efficacy as an antithrombotic agent. Lepirudin increa sed or maintained platelet counts at normal baseline values while main taining adequate anticoagulation in patients with heparin-induced thro mbocytopenia (HIT), and has not been associated with the development o f immune-mediated thrombocytopenia, Preliminary studies in patients wi th deep vein thrombosis (DVT) suggest that lepirudin may be more effec tive than unfractionated heparin (UFH) at preventing pulmonary perfusi on defects. In patients with unstable angina pectoris, preliminary dat a also showed lepirudin to be significantly more effective than UFH ac cording to the combined incidence of cardiovascular mortality, new acu te myocardial infarction (AMI) or refractory angina, However, addition al studies involving larger patient numbers are necessary before firm conclusions can be made regarding the relative efficacy of lepirudin i n these indications. Similarly, promising but limited data on the use of lepirudin during haemodialysis or heart surgery and in patients wit h disseminated intravascular coagulation (DIC) require further confirm ation. Bleeding complications and the possible induction of allergic o r anaphylactic reactions are the most serious adverse events associate d 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 corona ry artery patency with high-dose lepirudin versus UFH as an adjunct to thrombolytic therapy in patients with AMI were subsequently overshado wed by reports of a high incidence of major bleeding events including cerebral haemorrhage among lepirudin recipients. Moreover, at lower do ses which did not produce an unacceptably high incidence of haemorrhag ic complications, lepirudin appeared to have only a small efficacy adv antage 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 resulte d in a prolongation of aPTT values to >100 seconds in 3 patients. Limi ted data are available on re-exposure of patients to lepirudin; howeve r, 4 patients with antilepirudin antibodies treated with a second cour se of lepirudin did not develop allergic reactions. In patients with D VT, 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%]. Ho wever, too few clinical embolic events in this study precluded any fir m conclusions regarding the efficacy of lepirudin relative to that of UFH. Moreover, assessment of existing thromboemboli by phlebography re vealed no significant difference be tween lepirudin and UFH, with the majority of thrombi showing no change. Data on the efficacy of lepirud in in the prophylaxis of DVT are currently limited to the results of 1 small study in patients undergoing hip replacement surgery which repo rted 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 cardio vascular mortality, new AMI or refractory angina was statistically sig nificantly lower with medium-dose intravenous lepirudin (0.4 mg/kg bol us 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 e vents in favour of lepirudin did persist during long term follow-up(18 0 days); however, these differences were statistically significant onl y for the combined incidence of cardiovascular death, new AMI and refr actory or severe angina without revascularisation (19.7 vs 27.3%). A l imited number of patients (n = 40) with unstable angina have also rece ived lepirudin as a periprocedural antithrombotic therapy during coron ary 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 effectiv e as UFH (150 IU/kg plus 7 to 20 IU/kg/h for 48 hours) in the preventi on of early restenosis and was associated with a lower incidence of ca rdiac 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 st udy, 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 statis tically significantly higher early, complete and sustained patency rat e 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 low er rate of major bleeding events, the improvement in early, complete a nd sustained coronary artery patency was somewhat lower (50 to 61.4%). In the HIT-III study, patient recruitment was stopped prematurely bec ause of an unexpectedly high incidence of intracranial haemorrhage wit h 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 3 0-day mortality rate with lepirudin (9.5 vs 5.2%). Promising results f rom 3 small studies (total n = 36) also suggest that lepirudin is able to prevent clotting within extracorporeal circuits. In patients under going haemodialysis, lepirudin was at least as effective as UFH at pre venting coagulation and was also associated with a lower incidence of platelet deposition on the inlet of the artificial kidney. Similarly s uccessful anticoagulation has been reported with lepirudin during CPB. Lepirudin is contraindicated in pregnant or lactating women