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- Evans, H.C., Perry, C.M. & Faulas, D. CNS Drugs (2004) 64: 649. doi:10.2165/00003495-200464060-00010
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Ximelagatran (Exanta™), the first available oral direct thrombin inhibitor, and its active form, melagatran, have been evaluated in the prevention of venous thromboembolism (VTE) in patients undergoing hip or knee replacement.
After oral administration ximelagatran is rapidly bioconverted to melagatran. Melagatran inactivates both circulating and clot-bound thrombin by binding to the thrombin active site, thus, inhibiting platelet activation and/or aggregation and reducing fibrinolysis time.
The efficacy of subcutaneous melagatran followed by oral ximelagatran has been investigated in four European trials and the efficacy of an all oral ximelagatran regimen has been investigated in five US trials.
In a dose-ranging European study, preoperatively initiated subcutaneous melagatran 3mg twice daily followed by oral ximelagatran 24mg twice daily was significantly more effective than subcutaneous dalteparin sodium 5000IU once daily in preventing the occurrence of VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients undergoing hip or knee replacement. In one study, there were no significant differences in VTE prevention between subcutaneous melagatran 3mg administered after surgery followed by ximelagatran 24mg twice daily and enoxaparin sodium (enoxaparin) 40mg once daily. Compared with enoxaparin, significantly lower rates of proximal DVT and/or PE (major VTE) and total VTE were observed when melagatran was initiated preoperatively (2mg) then postoperatively (3mg) and followed by ximelagatran 24mg twice daily.
In the US, four studies showed that postoperatively initiated ximelagatran 24mg twice daily was of similar efficacy to enoxaparin or warfarin in the prevention of VTE in patients undergoing hip or knee replacement. However, ximelagatran 36mg twice daily was superior to warfarin (target international normalised ratio of 2.5) at preventing the incidence of VTE in patients undergoing total knee replacement in two studies.
Ximelagatran alone or after melagatran was generally well tolerated. Overall, the incidence of bleeding events and transfusion rates were not markedly different from those documented for comparator anticoagulants. In a post-hoc analysis of one study, transfusion rates were lower in ximelagatran than enoxaparin recipients.
Conclusions: Oral ximelagatran alone or in conjunction with subcutaneous melagatran has shown good efficacy and was generally well tolerated in the prevention of VTE in patients undergoing orthopaedic surgery. Furthermore, patients receiving ximelagatran/melagatran do not require anticoagulant monitoring. The drug has a low potential for drug interactions and can be administered either by subcutaneous injection or orally. Thus, on the basis of available evidence, ximelagatran/melagatran appears poised to play an important role in the prophylaxis of VTE in patients undergoing orthopaedic surgery.
Melagatran is the active form of the oral direct thrombin inhibitor, ximelagatran. Melagatran is a small-molecule direct thrombin inhibitor which demonstrates high selectivity for the active site of α-thrombin. Melagatran, which can be administered subcutaneously, exerts an antithrombotic effect by inhibiting free and clot-bound thrombin, inhibiting platelet activation and/or aggregation and reducing fibrinolysis time.
Orally administered ximelagatran is rapidly absorbed, and bioconverted via two intermediary compounds to melagatran. Following a single dose of ximelagatran 24 or 36mg in volunteers, the maximum melagatran concentrations are reached within approximately 2.0 hours and are within the predicted therapeutic range. The bioavailability of melagatran following ximelagatran administration is approximately 20%. Following ximelagatran 24mg, melagatran has a large volume of distribution (185L), a relatively high apparent total clearance (48.3 L/h) [both values not corrected for bioavailability] and renal clearance (approximately 6.0 L/h), and a short elimination half-life (approximately 3 hours). Pharmacokinetic properties are not markedly affected by ethnicity or age beyond that attributable to differences in renal clearance. Similarly, coadministration with food has no clinically relevant effects on the pharmacokinetic properties of melagatran following ximelagatran administration.
Subcutaneous melagatran is rapidly absorbed with maximum concentrations occurring after approximately 0.5 hours in healthy volunteers. The volume of distribution of melagatran is approximately 20L following intravenous melagatran and only a small proportion of the drug is bound to plasma proteins. Melagatran has an elimination half-life of approximately 2 hours following subcutaneous administration. Renal clearance of subcutaneous melagatran 3mg was approximately 5 L/h and total clearance of subcutaneous melagatran 2–3mg was approximately 8.0 L/h, in volunteers. Melagatran is predominantly eliminated in the urine within the first 12 hours postadministration of either oral ximelagatran or subcutaneous melagatran.
The pharmacokinetic profile of melagatran is not significantly affected by obesity (body mass index [BMI] 32–39 kg/m2) or mild-to-moderate liver failure (Child-Pugh A or B); however, the pharmacokinetics of the drug in patients with severe renal impairment (glomerular filtration rate 0.3–1.44 L/h) are markedly different from those in individuals with normal renal function. Melagatran has no known food interactions and no clinically relevant drug interactions involving cytochrome P450 enzymes. Concomitant administration of aspirin and melagatran may have additive effects on capillary bleeding time.
Ximelagatran/melagatran (henceforth referred to as ximelagatran) has been compared with other antithrombotic agents for the prevention of total venous thromboembolism (VTE) and major VTE. In Europe, VTE prophylaxis is traditionally initiated prior to surgery and in the US prophylaxis is initiated following surgery. In Europe, four randomised, controlled studies have investigated the efficacy of subcutaneous melagatran followed by oral ximelagatran and each have altered the initiation of the prophylaxis to optimise efficacy and tolerability. In the US, the efficacy of an all oral regimen of ximelagatran initiated postoperatively has been investigated in five randomised, controlled studies.
European Trials: The MElagatran for THRombin inhibition in Orthopaedic surgery (METHRO) studies have investigated the efficacy of melagatran administered pre- or postoperatively followed by twice-daily oral ximelagatran. In METHRO II, the efficacy of preoperatively administered melagatran was dose-dependent (p < 0.0001), and the efficacy of the highest dosage (melagatran 3mg twice daily followed by ximelagatran 24mg twice daily) was superior to that of subcutaneous dalteparin sodium (dalteparin) 5000IU once daily in patients undergoing either total hip or total knee replacement for both total VTE (15.1 versus 28.2% of patients; p < 0.0001) and major VTE (2.5 versus 6.5%; p < 0.05). Postoperative administration of subcutaneous melagatran 3mg followed by ximelagatran 24mg twice daily was at least as effective as preoperatively initiated enoxaparin sodium (enoxaparin) 40mg once daily overall (31.0 and 27.3%, of patients) and in patients undergoing total knee replacement (44.1 and 46.0%), but was significantly less effective in patients undergoing hip replacement (25.4 and 19.4%; p = 0.004), for the prevention of total VTE in METHRO III. There were no significant differences between ximelagatran and enoxaparin recipients for the prevention of major VTE. In the EXpanded PRophylaxis Evaluation Surgery Study (EXPRESS), patients undergoing total knee or hip replacement received either subcutaneous melagatran 2mg preoperatively and 3mg postoperatively followed by oral ximelagatran 24mg twice daily or subcutaneous enoxaparin 40mg once daily initiated the evening before surgery. For total VTE there was a 23.7% reduction in relative risk favouring ximelagatran (20.3 versus 26.6% of patients; p < 0.001) and for major VTE, there was a 63.2% reduction in relative risk favouring ximelagatran (2.3 versus 6.3%; p < 0.0001).
US Trials: In all of the US trials, oral ximelagatran was initiated postoperatively. The incidence of major VTE was similar in recipients of twice-daily ximelagatran 24mg to that in patients receiving enoxaparin 30mg following total knee replacement in a dose-ranging study (both 3% of patients), but significantly less than that in enoxaparin recipients after total hip replacement (3.6 versus 1.2%; p-values not stated). In patients undergoing total knee replacement, oral ximelagatran 24mg twice daily was at least as effective as warfarin (target international normalised ratio of 2.5) in preventing total VTE (incidence 19.2 and 25.7%, respectively) or major VTE (incidence 3.3 and 5.0%, respectively). Ximelagatran 36mg twice daily was more effective than warfarin in preventing total VTE in both EXanta Used to Lessen Thrombosis (EXULT) A (20.3% versus 27.6% of patients; p < 0.01) and B (22.5 versus 31.9%; p < 0.001) studies. There was no significant advantage of ximelagatran 36mg over warfarin in the prevention of major VTE in either EXULT A (2.7 versus 4.1% of patients) or EXULT B (3.9 versus 4.1%).
Ximelagatran was generally well tolerated by patients undergoing orthopaedic surgery. Events related to bleeding were those most frequently reported in trials conducted in Europe and the US.
European Trials: In European trials, bleeding events did not markedly differ between ximelagatran, enoxaparin or dalteparin recipients. Ximelagatran recipients showed dose-dependent increases in the incidence of severe bleeding amongst all patients (p = 0.002) and in blood transfusion volume amongst patients undergoing hip replacement (p = 0.0013) in METHRO II. Overall, the incidence of severe bleeding for ximelagatran 24mg twice daily recipients was 5.0% in METHRO II, 1.4% in METHRO III and 3.3% in EXPRESS. Severe bleeding occurred in 2.4% of dalteparin recipients (METHRO II) and in 1.7% (METHRO III) and 1.2% (EXPRESS) of enoxaparin recipients. In METHRO III, ximelagatran recipients had significantly lower transfusion rates than enoxaparin recipients (61.8 versus 66.2% of patients; p < 0.05). The incidence of blood transfusion was numerically higher in ximelagatran 24mg than dalteparin recipients (77 and 72% of patients, respectively) in METHRO II, and in ximelagatran than enoxaparin recipients in EXPRESS (66.8 and 61.7%).
US Trials: No significant tolerability differences were detected between clinically relevant dosages of ximelagatran and either enoxaparin or warfarin in the US trials. The incidence of major bleeding events was similar in both ximelagatran 24mg and enoxaparin 30mg treatment groups undergoing either knee (0% and 1% of patients) or hip (0.8 and 0.9%) replacement. In patients undergoing knee replacement, the incidence of major bleeding was low between ximelagatran 24mg, 36mg and warfarin recipients in EXULT A (0.8, 0.8 and 0.7% of patients, respectively) and between ximelagatran 36mg and warfarin recipients in EXULT B (1.0 and 0.4%). In ximelagatran 24mg and enoxaparin 30mg recipients, respectively, transfusions occurred in 35 and 37% of patients undergoing knee replacement and 48 and 48% of patients undergoing hip replacement. Transfusion rates were also similar between ximelagatran 24mg and warfarin recipients (38 and 34% of patients, respectively).
Dosage and Administration
In clinical trials, the drug regimen for VTE thromboprophylaxis differed between Europe and the US, with anticoagulants generally initiated prior to surgery in European trials and after surgery in US trials. The most effective regimen in European trials was melagatran 2mg administered preoperatively followed by melagatran 3mg in the evening after surgery and ximelagatran 24mg twice daily initiated the day after surgery (EXPRESS). Melagatran 3mg administered 4–12 hours after surgery followed by twice-daily ximelagatran 24mg initiated the day after surgery was at least as effective as enoxaparin 40mg at preventing VTE in patients undergoing hip or knee replacement (METHRO III). In the US, twice-daily ximelagatran 36mg initiated the morning after surgery was the most effective treatment regimen.
Clinical trials indicate that dosage adjustment is not necessary in elderly patients, patients with obesity (BMI 32–39 kg/m2), patients of different ethnicities, or patients with hepatic impairment (Child-Pugh A or B). However, ximelagatran/melagatran is contraindicated in patients with severe renal impairment (creatinine clearance rate <1.8 L/h).