Overview of Ximelagatran in Worldwide Clinical Trials

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Abstract

The pharmacological profile of ximelagatran-including predictable pharmacokinetics, a relatively wide therapeutic window, and low potential for interactions with other drugs, food, or alcohol-supports its administration without coagulation monitoring or dose adjustment. Furthermore, ximelagatran can be administered in fixed doses irrespective of age, body weight, ethnicity, or mild/moderate impairment of renal function. Fixed-dose oral ximelagatran provides a simpler therapeutic option for anticoagulation in orthopedic surgery patients after hospital discharge and in the treatment of acute VTE, compared with parenteral LMWH or adjusted-dose warfarin. This potential for greater convenience is combined with the superior efficacy of ximelagatran 36 mg twice daily compared with warfarin for the prevention of VTE in patients undergoing TKR, without an increase in bleeding (North American regimen). In European studies in THR and TKR, SC melagatran followed by oral ximelagatran 24 mg twice daily proved superior to enoxaparin (with a slight increase in bleeding rate) employing the treatment regimen used in EXPRESS, and was as effective as enoxaparin with a similar bleeding rate with the regimen used in METHRO III. Based on the results of Phase II and III studies, ximelagatran is also as effective as conventional anticoagulant therapy for the treatment of acute DVT and PE. In comparison with current standard anticoagulation for patients with acute VTE, the rapid onset of action of oral ximelagatran avoids the need for parenteral administration of UFH or LMWH during the delayed onset of VKA activity. Ximelagatran also permits rapid discontinuation and restarting of anticoagulation if necessary, without an extended period of underprotection or the complexity of switching between heparin and VKA. Long-term anticoagulation is indicated for patients with VTE, AF, and after an ACS. Therefore, an orally administered agent with predictable anticoagulant effect and no requirement for coagulation monitoring or dose adjustment is clinically advantageous. As long-term VKA treatment incurs a significant risk of bleeding, a further clinical objective is to improve the benefit-to-risk ratio of anticoagulant therapy. For this reason, two recent studies evaluated the use of extended-duration, low-intensity warfarin (mean: approximately 2 years) after a 3- to 6-month period of standard-dose therapy. In one of these studies, the low-intensity regimen (target INR: 1.5-2.0) was found to significantly reduce the incidence of VTE compared with placebo with no significant increase in major bleeding, although minor bleeding was significantly more frequent with warfarin. In the second study, a conventional-intensity warfarin regimen (target INR: 2.0-3.0) was found to be more effective than a low-intensity regimen (target INR: 1.5-1.9) in the prevention of recurrent VTE, while the frequency of overall bleeding did not differ significantly between the two regimens. The authors concluded that long-term conventional-intensity warfarin therapy is more effective than a low-intensity regimen. Hence, the intensity of warfarin therapy should not be reduced after the first 3 months of treatment. The THRIVE III results have now shown that ximelagatran, 24 mg twice daily, was superior to placebo for extended prevention of VTE after an initial 6-month course of heparin followed by VKA, with an incidence of major and minor bleeding similar to that with placebo, and no requirement for coagulation monitoring or dose adjustment. SPORTIF III and SPORTIF V, with a total enrollment of over 7,000 patients with NVAF and at least one additional risk factor for stroke, represent the largest clinical trials of antithrombotic therapy for stroke prevention in AF to date. This total patient population is also larger than that included in a meta-analysis of 6 trials confirming the efficacy of adjusted-dose warfarin. In SPORTIF III, patients with NVAF receiving ximelagatran obtained a clinical benefit at least as great as those receiving well-controlled warfarin for the prevention of stroke and systemic embolic events. This effect was consistent across predefined subpopulations and irrespective of independent risk factors for stroke. Establishment of non-inferiority permits the selection of one drug over another based on such alternative factors as safety, convenience, or cost. Ximelagatran was used without coagulation monitoring or dose adjustment, and was associated with a significantly lower incidence of total bleeding than observed with warfarin. Finally, when ximelagatran was added to aspirin after acute MI in the ESTEEM study, the magnitude of benefit in reducing the composite endpoint of death, non-fatal reinfarction, and severe recurrent ischemia was similar to that observed in other trials adding either warfarin or clopidogrel to aspirin. This promising result should be followed by active-comparator studies. The implications of ALAT elevations associated with ximelagatran are as yet unknown, but may indicate a need to test liver enzymes for a period of time after the initiation of treatment. Further evaluation of this question is ongoing. To date, ALAT elevations have typically occurred between 2 and 6 months after commencing ximelagatran treatment, have resolved whether or not therapy is continued, and have not been associated with any specific clinical symptoms. In addition to the clinical data documenting the favorable efficacy and safety profile of ximelagatran in comparison with standard anticoagulant therapy, the convenience of its oral, fixed-dose administration might help encourage the wider use of appropriate anticoagulation across the population at risk, and thereby lower the overall burden of thromboembolic events.

Original languageEnglish
Pages (from-to)43-68
Number of pages26
JournalToday's Therapeutic Trends
Volume22
Issue number1
StatePublished - Mar 2004

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