Lepirudin

Summary

Abstract

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.

Conclusions: Lepirudin has shown promising activity as an antithrombotic agent and may be a suitable substitute anticoagulant for heparin in patients with HIT. The narrow therapeutic window of lepirudin makes it difficult to assess the role of this agent when used as an adjunct to thrombolytic therapy in patients with AMI. However, initial data suggest that lepirudin may be a potentially useful agent in the management of patients with unstable angina, DVT or DIC and in preventing thrombus formation in extracorporeal circuits. Further studies should more fully elucidate the efficacy of lepirudin in these indications.

Pharmacodynamic Properties

Lepirudin is a recombinant hirudin derived from transfected yeast cells, which directly inhibits thrombin. In contrast to that of heparin, the antithrombotic mechanism of action of the hirudins is independent of the presence of antithrombin and instead involves the formation of a stable noncovalent complex between the hirudin and thrombin molecules. This renders the thrombin molecule incapable of promoting fibrin formation and catalysing other haemostatic reactions such as activation of clotting factors V, VIII and XIII and thrombin-induced platelet aggregation. Importantly, the hirudins appear to inhibit not only free but also clot-bound thrombin which continues to have prothrombotic activity. However, they appear to have a limited inhibitory effect on the generation of thrombin from prothrombin.

Lepirudin has demonstrated antithrombotic activity in several animal models of thrombosis and was more effective than unfractionated heparin (UFH) at inhibiting thrombin formation in the hamster femoral vein model of mural thrombosis and in a baboon model of cardiopulmonary bypass (CPB). Lepirudin also prevented disseminated clotting in animal models of disseminated intravascular coagulation (DIC) and reduced elevated plasma levels of fibrin/fibrinogen degradation products, D-dimer, thrombin-antithrombin complex and plasmin α₂-antiplasmin complex in patients with DIC.

Thrombin-induced platelet activation was inhibited by lepirudin in blood taken from healthy volunteers during bleeding; however, platelet aggregation induced by endogenously generated thrombin after intrinsic activation of platelet-rich plasma was inhibited less efficiently.

Inhibition of thrombin by lepirudin results in a dose-dependent prolongation of the activated partial thromboplastin time (aPTT); this coagulation parameter is currently used to monitor the anticoagulant activity of lepirudin. However, problems of standardisation and reports of wide interindividual variability of aPTT ratios among lepirudin-treated patients suggest that aPTT may not be the optimal marker.

Positive lepirudin antibody titres developed in 38 of 82 patients (46.3%) with heparin-induced thrombocytopenia (HIT) after ≥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.

Pharmacokinetic Profile

Lepirudin is rapidly distributed throughout the extracellular compartment after intravenous administration; its plasma pharmacokinetics are best described by a 2-compartment model. In contrast, the pharmacokinetic profile of lepirudin after subcutaneous administration best fits a 1-compartment model with an absorption phase. There was no evidence of drug accumulation following repeated subcutaneous (0.5 or 1.0 mg/kg/day) or intravenous administration of lepirudin (0.1 or 0.2 mg/kg/day) to healthy young volunteers. Similarly, significant drug accumulation was not evident after subcutaneous administration of lepirudin 0.75 mg/kg twice daily for 5 days to patients with deep vein thrombosis (DVT).

Volume of distribution determinations at steady state ranged from 13.3 to 22.4L, suggesting that lepirudin is primarily confined to the extracellular space.

Lepirudin is excreted predominantly by the kidney and undergoes minimal, if any, hepatic metabolism. The terminal elimination half-life (t1/2β) of lepirudin after subcutaneous administration (1.6 to 2.6 hours) is longer than that after intravenous administration (0.8 to 2 hours). This difference has been ascribed to a slower absorption rate of lepirudin from subcutaneous tissue. Renal clearance accounted for approximately 40 to 45% of the systemic clearance of an intravenously administered dose of lepirudin.

In patients with renal impairment, the renal clearance of lepirudin is reduced. Dosage adjustments are recommended in these patients. Alterations in the pharmacokinetics of lepirudin (t1/2β 3.5 hours; renal clearance 3.4 L/h) after subcutaneous administration to healthy elderly volunteers was also attributed to reduced renal function and/or delayed absorption of the drug from subcutaneous tissue. Renal clearance of lepirudin was also slightly reduced in the elderly after intravenous administration of the drug (3.7 L/h).

A good correlation between plasma lepirudin concentrations and increases in aPTT values from normal control values has been reported. Maximum aPTT values generally correlate well with peak plasma drug concentrations and were achieved 10 minutes, 3 to 6 hours and 2 to 3 hours, respectively, after administration of lepirudin by intravenous bolus injection, intravenous infusion or subcutaneous injection.

Therapeutic Efficacy

At present, efficacy data on lepirudin as an antithrombotic agent are available from a limited number of studies in patients with HIT, unstable angina, DVT and acute myocardial infarction (AMI) and in patients undergoing haemodialysis or CPB.

Lepirudin may be a suitable substitute anticoagulant for heparin in patients with HIT who require further anticoagulation. Platelet counts increased after 3 to 6 days of lepirudin therapy without the development of thromboembolic or haemorrhagic complications in 1 small study in patients with HIT. In a larger multicentre study (n = 82), platelet counts were increased or maintained at normal baseline values while maintaining adequate anticoagulation in 64.6% of patients with HIT treated with a range of lepirudin dosages. A final evaluation of the results of another study of a similar design is awaited with interest.

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 between 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.

Tolerability

The most important adverse events associated with lepirudin therapy are bleeding complications and possible allergic or anaphylactic reactions. However, further studies are required to more fully characterise the tolerability profile of lepirudin.

In patients with HIT treated with lepirudin (n = 125), the rates of total and major bleeding events were 39 and 11%, respectively. Wound bleeding (9% of patients), haematoma and haematuria (each 7%), puncture site bleeds (6%), epistaxis (4%), rectal bleeding and postoperative haemothorax (each 3%) and vaginal bleeding (2%) were the most frequent bleeding complications among 198 lepirudin-treated patients with HIT. Other bleeding events including gastrointestinal, oesophageal and lung bleeding and haematemesis occurred with an incidence of ≤1%.

Available data from 2 comparative studies suggest that the incidence of major bleeding with lepirudin monotherapy is similar to that reported with UFH alone. However, minor bleeding events such as skin bruising and oozing at puncture sites appear to be more frequent with lepirudin than with UFH therapy.

Notably, the potential for bleeding appears to be greater when lepirudin is used in combination with thrombolytic therapy. Indeed, reports of an unacceptably high rate of intracerebral haemorrhage among patients treated with high-dose lepirudin as an adjunct to alteplase resulted in the premature termination of the HIT-III study.

Allergic reactions have been reported in patients treated with lepirudin and have included cutaneous reactions, anaphylaxis, pruritus, hot flushes, isolated chills, cough, dyspnoea, bronchospasm, stridor, oedema of the face, tongue or larynx and angioedema. Injection site reactions have been reported rarely in patients treated with lepirudin.

Dosage and Abddministration

Lepirudin is indicated for the treatment of adult patients with confirmed HIT and thromboembolic disease requiring parenteral antithrombotic therapy. Dosage recommendations for the use of lepirudin in patients with DVT, unstable angina, AMI and DIC or during CPB or haemodialysis are not available.

In patients with HIT, the dosage regimen for lepirudin consists of an initial intravenous bolus dose of 0.4 mg/kg followed by 0.15 mg/kg/h administered as a continuous intravenous infusion for 2 to 10 days or longer if necessary. For patients weighing >110kg, the dosage of lepirudin should not be increased beyond the 110kg bodyweight dose (44mg intravenous bolus dose followed by 16.5 mg/h continuous intravenous infusion). In patients with renal impairment [creatinine clearance ≤3.6 L/h (≤60 ml/min)] dosage reduction is necessary.

The aPTT value, which should be monitored 4 hours after the start of therapy and at least once daily thereafter, should be used to adjust the lepirudin infusion rate. The therapeutic target range for aPTT is dependent on the test reagent used and varies between 1.5- and 3-fold (for Actin FS® and Neothromtin® reagents) and 1.5- and 2.5-fold prolongation (for all other reagents) of the normal control value. Dosage modification is necessary if an aPTT value is confirmed to be above or below the target range.

Prior reduction of the lepirudin dose to achieve an aPTT ratio of just above 1.5 is necessary if a patient is to receive oral anticoagulation with a coumarin derivative after treatment with lepirudin. Administration of lepirudin should then be stopped when an international normalised ratio (INR) of 2.0 is reached.

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.