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Erschienen in:
01.09.2000 | Adis Drug Evaluation
Desirudin
A Review of its Use in the Management of Thrombotic Disorders
Erschienen in: Drugs | Ausgabe 3/2000
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Abstract
Desirudin, a recombinant hirudin used in the prevention and management of thromboembolic disease, is a thrombin inhibitor which binds directly and with high affinity to clot-bound and fluid phase thrombin. As a prophylaxis in patients undergoing hip replacement surgery, desirudin was significantly more effective in reducing the incidence of deep vein thrombosis (DVT) than either unfractionated or low molecular weight heparin. However, results in patients with acute coronary syndromes are less conclusive. A significant reduction with desirudin compared with heparin in the incidence of death or non-fatal (re)infarction at 24 hours in patients with acute myocardial infarction (MI) was reported in the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) IIb trial but not in the TIMI (Thrombolysis and Thrombin Inhibition in Myocardial Infarction) 9B trial. Despite the early reduction shown in GUSTO IIb, desirudin was not associated with an improved long term clinical benefit at 30 days compared with heparin.
Similar results were seen in patients with unstable angina/non-Q-wave MI enrolled in the GUSTO IIb trial. In addition, desirudin and heparin showed similar efficacy in preventing restenosis 30 weeks after coronary angioplasty for unstable angina, despite desirudin being associated with a significant reduction in the rate of cardiac events within the first 96 hours.
Desirudin is as well tolerated as heparin with a similar incidence of moderate and severe bleeding, intracranial haemorrhage or stroke reported when trialled in the prevention of DVT associated with hip replacement surgery or the treatment of acute coronary syndromes. However, in the GUSTO IIb trial a significantly higher incidence of transfusions was observed in patients with unstable angina/non-Q-wave MI.
Conclusions: Desirudin is clearly more effective than heparin in the prevention of DVT in patients undergoing elective hip replacement, although cost factors may influence its ultimate place in therapy. In the treatment of acute coronary syndromes the role of desirudin is less certain; however, it may be useful for patients in whom heparin therapy is not a viable option.
Pharmacodynamic Profile
Desirudin is a synthetic analogue of hirudin manufactured by recombinant DNA technology. It is a direct and potent inhibitor of fluid phase and clot-bound thrombin. Desirudin forms a stable stoichiometric complex with thrombin, inhibiting fibrinogen clotting and other thrombin-catalysed haemostatic reactions such as the activation of the clotting factors V, VIII and XIII and thrombin-induced platelet activation.
Thrombin inhibition by desirudin results in a dose-dependent prolongation of activated partial thromboplastin time (aPTT) in patients with unstable angina, those undergoing hip replacement surgery and healthy volunteers. Collectively, all doses of desirudin maintained the aPTT within a40-second range significantly more frequently than heparin, and significantly fewer patients given desirudin required a dosage adjustment. Thrombin times were also prolonged in a dose-dependent manner after single subcutaneous injections of desirudin in healthy volunteers.
Desirudin (1 mg/kg bolus dose) does not interfere with platelet aggregation induced by ADP, collagen, adrenaline, thrombofax or ristocetin. Platelet numbers generally remained within normal limits in healthy volunteers. Effects of desirudin on bleeding time are equivocal; a 1.0 mg/kg intravenous bolus dose prolonged bleeding times in a small group of healthy volunteers. In contrast, peak levels of subcutaneously administered desirudin (0.3 to 0.5 mg/kg, 8-hourly for 3 days) were not associated with a clear increase in bleeding time.
Moderate and severe renal impairment increased the anticoagulant effect of desirudin by 2- and 6-fold, respectively. Participants with severe renal impairment had aPTTs above baseline 60 hours after a 30-minute infusion of 0.125 mg/kg of desirudin, despite a 4-fold dose reduction compared with healthy volunteers and participants with mild renal impairment.
Pharmacokinetic Profile
The pharmacokinetic profile of intravenously administered desirudin is best described by an open 2-compartment model with first order elimination kinetics. After subcutaneous administration, the pharmacokinetics of recombinant hirudins best fit a 1-compartment model; however, this has not been quantified with desirudin. Desirudin is distributed in the extracellular space with a volume of distribution at steady state of 0.25 and 0.27 L/kg after subcutaneous and intravenous administration, respectively. Maximum plasma concentration is dose proportional irrespective of the route of administration; 154 to 1691 nmol/L after single intravenous bolus injections of 0.1 to 1.0 mg/kg and 21.1 to 107 nmol/L after single subcutaneous doses of 0.1 to 0.75 mg/kg.
Desirudin is primarily metabolised and eliminated by the kidney and has a terminal elimination half-life (t12) of 2 to 3 hours after intravenous administration. Total plasma clearance (CLt) is within the range of 0.12 to 0.13 L/h/kg after subcutaneous and intravenous administration. Approximately 50% of the administered dose is excreted unchanged in urine and 2 metabolites are detected in trace amounts only [desirudin minus 1 (G1u65) and 2 (Leu64-Glu65) C-terminal amino acids], suggesting little or no hepatic metabolism. There is no evidence of a saturable elimination mechanism.
An increase in renal impairment from mild to severe was associated with markedly increased estimates of specific area under the plasma concentrationtime curve (from 1370 to 8330 (nmol · h/L)/(mg/kg), t12 (from 2.4 to 12.2 hours) and median residence time (from 2.5 to 10.5 hours). Desirudin remained in the systemic circulation of participants with severe renal impairment for longer than in those with mild impairment or healthy volunteers; in addition, participants with moderate and severe renal impairment had lower rates of renal (1.7 and 0.6 L/h, respectively) and total clearance (3.1 and 1.2 L/h). The total percentage of desirudin excreted unchanged in urine (55 to 60%) was similar in all groups including healthy volunteers.
Therapeutic Efficacy
The efficacy of desirudin has been evaluated in several large multicentre, randomised, double-blind clinical trials in patients with acute myocardial infarction (MI) or unstable angina and as a prophylaxis for deep vein thrombosis (DVT) in patients undergoing hip replacement surgery.
Patients undergoing total hip replacement surgery. Desirudin is significantly more effective as prophylaxis for DVT after total hip replacement than either unfractionated heparin or enoxaparin. Compared with heparin, desirudin is significantly better in preventing thromboembolic events such as DVT, pulmonary embolism, unexplained death or death related to thromboembolism during the treatment period. A significantly lower incidence of proximal and overall DVT was seen in patients given desirudin.
Patients with acute MI. Desirudin showed similar efficacy to heparin in the treatment of patients with acute MI, with no differences between the 2 treatments in the composite end-point of death or (re)infarction at 30 days in either the TIMI (Thrombolysis and Thrombin Inhibition in Myocardial Infarction) 9B or GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) IIb trials. This is despite a reduction in death or (re)infarction within the first 24 hours of treatment in desirudin patients in the larger GUSTO IIb trial. In the smaller TIMI 9B trial there were also no significant differences between desirudin and heparin with regard to the incidence of severe congestive heart failure (CHF) or cardiogenic shock (also defined as 30-day primary clinical end-points).
Patients with unstable angina. The GUSTO IIb clinical trial found similar results in patients with unstable angina/non-Q-wave MI, with a reported lower incidence of death or (re)infarction within the first 24 hours in desirudin compared with heparin-treated patients. However, this initial improvement in clinical outcome was not sustained, with no significant differences observed between desirudin or heparin at 30 days. Similarly, in patients undergoing coronary angioplasty for unstable angina in the multicentre randomised double-blind HELVETICA (Hirudin in a European Trial versus Heparin in the Prevention of Restenosis after Percutaneous Transluminal Coronary Angioplasty) trial, the rate of cardiac events was reduced within the first 96 hours of desirudin compared with heparin treatment, but there were no significant differences in the event-free survival rate between desirudin and heparin at 30 weeks. Combining data from patients with acute MI and unstable angina in the GUSTO IIb study produced a small but significant reduction in the 30-day incidence of acute MI.
Tolerability
There were no significant differences in total blood loss, number of patients receiving transfusions or rates of bleeding-related complications in 2079 patients undergoing hip replacement surgery given either desirudin or enoxaparin as prophylaxis against DVT. Desirudin was as well tolerated as unfractionated heparin in a smaller study (n = 1119) and unlike heparin, caused no thrombocytopenia.
In 2 multicentre randomised double-blind clinical trials, desirudin had a similar tolerability profile to heparin in patients with acute MI, with no significant differences in rates of major haemorrhage in the TIMI 9B trial or in intracranial haemorrhage, moderate to severe bleeding, stroke, or number of patients requiring a transfusion in the GUSTO IIb trial.
Similar tolerability profiles were seen in the GUSTO IIb trial in patients with unstable angina/non-Q-wave MI for desirudin and heparin, except for a significant increase in the rate of transfusion in patients who received desirudin. The incidence of moderate bleeding was higher in diabetic patients given desirudin compared with heparin. Rates of severe or moderate bleeding complications were similar in patients with unstable angina given desirudin or heparin for the prevention of restenosis after coronary angioplasty in the HELVETICA trial.
Desirudin is a weak allergen after repeated exposures, as shown in healthy volunteers, with a 0.5% incidence of an allergic skin reaction reported after 2 to 3 exposures. Based on results from healthy volunteers, the risk that patients with a thrombotic disorder will develop an allergic skin reaction per therapeutic course of desirudin was calculated to be between 0.005 and 1.185%. Desirudin had no effect on total immunoglobulin (Ig) E levels and hirudin-specific IgG antibodies were not detected. No anaphylaxis was reported in the TIMI 9B study.
Dosage and Administration
Desirudin is approved in Europe for use in the prevention of DVT in patients undergoing elective hip and knee replacement surgery, although to date no clinical trials have been published with regard to the latter. It is not currently approved for the treatment of other thrombotic disorders discussed in this review.
The recommended daily dosage for adults and elderly patients is 15mg administered subcutaneously twice daily for 9 to 12 days, with the first injection given 5 to 15 minutes before surgery but after the induction of regional block anaesthesia (if used). Subcutaneous injections should preferably be rotated between at least 4 different abdominal sites. Desirudin should not be given intramuscularly.
Desirudin is contraindicated in patients with severe renal or hepatic impairment, known sensitivity to natural or recombinant hirudins, active bleeding and/or irreversible coagulation disorders, severe uncontrolled hypotension or subacute bacterial endocarditis. Desirudin should be used with caution in patients receiving anticoagulants and/or platelet inhibitors and/or nonsteroidal anti-inflammatory drugs.
The aPTT should be carefully monitored in patients with moderate renal impairment, mild to moderate hepatic impairment or conditions with increased risk of haemorrhage and in patients receiving combined therapy with oral anticoagulants.