Emerging Drug List CANADIAN COORDINATING OFFICE FOR HEALTH XIMELAGATRAN FOR THE PROPHYLAXIS OF VARIOUS TECHNOLOGY ASSESSMENT COMPLICATIONS DUE TO THROMBOSIS NO. 47 JUNE 2003 Generic (Trade Name): Ximelagatran (Exanta™) Manufacturer: AstraZeneca Indication: Ximelagatran is currently being investigated for use in the treatment of venous throm- boembolism (VTE), the prophylaxis of VTE in orthopedic surgery, the prophylaxis of stroke in patients with atrial fibrillation and secondary prophylaxis in patients post- myocardial infarction (MI).1,2 Current Regulatory Ximelagatran is not currently marketed in Canada. In July 2002, a marketing application Status: was made to the European Commission to use ximelagatran to reduce the incidence of VTE in orthopedic surgery; a similar application is expected in the US in the fourth quarter of 2003. Furthermore, a marketing application for the treatment of VTE is expected to be submitted to the European Commission toward the end of 2003.1 Description: Ximelagatran is an orally administered prodrug of the direct thrombin inhibitor melaga- tran. After administration, the prodrug is rapidly converted to the active form, with maxi- mum concentrations achieved between 1.5 to 2 hours. Melagatran is primarily removed renally, exhibiting a half-life ranging from 2.5 to 3.5 hours.3 Unlike warfarin, the anticoagu- lant effect of ximelagatran is not monitored by a target international normalized ratio (INR). Current Treatment: The choice of antithrombotic or anticoagulant agents depends on the particular indication, along with individual patient characteristics. For the treatment or prophylaxis of VTE, vitamin K antagonists [warfarin sodium (Coumadin® - Bristol Myers Squibb), nicoumalone (Sintrom® - Novartis)], heparin, or low molecular weight heparins [dalteparin (Fragmin® - Pharmacia), enoxaparin (Lovenox® - Aventis Pharma), nadroparin (Fraxiparine™ - Sanofi- Synthelabo), tinzaparin (Innohep® - Leo)], can be used. Agents commercially available in Canada that, like ximelagatran, directly inhibit thrombin include lepirudin (Refludan™ - Aventis Pharma) and argatroban (Argatroban® - Calea). These are usually employed in patients where heparin-induced thrombocytopenia is a concern, similar to the heparinoid danaparoid (Orgaran® - Organon).4,5 Cost: No cost information was available at the time of this review. Evidence: Several clinical trials have been undertaken to investigate the efficacy of ximelagatran in a variety of clinical situations. These include prophylaxis in orthopedic surgery (including EXPRESS, EXULT and METHRO trials2), prophylaxis of stroke in patients with atrial fibrillation (SPORTIF trials), DVT treatment and secondary prophylaxis (the THRIVE trials), and secondary prophylaxis in post-MI (the ESTEEM trials). Few phase II and phase III trial results can be found in the published literature; however several presenta- tions regarding the results of ximelagatran trials have been made available at annual meetings and through company press releases.6-15 The Canadian Coordinating Office for Health Technology Assessment (CCOHTA) is a non-profit organization funded by the federal, provincial and territorial governments. (www.ccohta.ca) Emerging Drug List CANADIAN COORDINATING OFFICE FOR HEALTH XIMELAGATRAN FOR THE PROPHYLAXIS OF VARIOUS TECHNOLOGY ASSESSMENT COMPLICATIONS DUE TO THROMBOSIS Prophylaxis in Orthopedic Surgery Ximelagatran versus enoxaparin: The EXPRESS trial randomized 2,800 patients undergoing total hip or total knee replacement surgery to either enoxaparin [40 mg subcutaneously (sc) od] or two sc doses of melagatran on the day of surgery, followed by a fixed oral dose of 24 mg ximelagatran. Combined outcomes in this trial were VTE (defined as either a proximal or distal DVT or pulmonary embolism (PE) detected by mandatory phlebography), and major VTE (defined as a proximal DVT or PE detected by mandatory phlebography). The results of this trial, not yet available in published form, were a 3.7% reduction (1.8% vs. 5.5%) in the incidence of major VTE after total hip replacement and a 4.9% reduction (3.3% vs. 8.2%) in the incidence of major VTE after total knee replacement.7 Ximelagatran versus warfarin: At the Meeting of the American Society of Hematology (ASH), the results of the EXULT A trial were reported. This trial involved 1,851 patients undergoing total knee replacement randomized to either warfarin initated the evening of the day of surgery or ximelagatran (24 or 36 mg) initated the morning after surgery. The investigators reported that the patients who received ximelagatran 36 mg had a lower rate of a combined outcome (proximal or distal DVT or PE or all-cause mortality, 20.3 vs. 27.6%; p=0.03).1 A published trial of ximelagatran compared to warfarin for the prophylaxis of VTE in patients (n=680) who had undergone total knee arthroplasty is available.8 Francis et al. randomized patients to receive either 24 mg of ximelagatran twice daily starting the day after surgery or warfarin titrated to a desired INR of 2.5 starting the evening of surgery, which was continued for 7 to 12 days. Evaluations done centrally indicated the combined outcomes of major VTE (proximal DVT or PE) or total VTE were not statistically differ- ent between the two groups. Major VTE occurred in 3.3% and 5.0% (p>0.2) of ximelaga- tran and warfarin recipients. Total VTE occurred in 19.2% and 25.7% (p=0.07) of xime- lagatran and warfarin recipients.8 Ximelagatran versus dalteparin: In a dose-ranging pilot trial (METHRO I), 136 patients undergoing orthopedic surgery were randomized to receive melagatran/ximelagatran or dalteparin. The results demonstrated that the melagatran/ximelagatran combination was efficacious in this setting.9 Subsequently, a larger trial was conducted to evaluate the efficacy, including identifying dose-response relationships from these agents. In the METHRO II trial, patients (n=1,876) undergoing total hip or knee replacement received dalteparin 5,000 IU once daily or varied doses of melagatran before surgery followed by ximelagatran orally twice daily afterwards (i.e. 8, 12, 18, 24 mg) for 7 to 10 days. In those patients receiving the highest dose of ximelagatran with evaluable venograms, the combined outcome major VTE (proximal DVT or PE) was lower than in the dalteparin group (2.5% vs. 6.5%; odds ratio 0.36 [95% CI: 0.15, 0.87], p=0.03).10 The Canadian Coordinating Office for Health Technology Assessment (CCOHTA) is a non-profit organization funded by the federal, provincial and territorial governments. (www.ccohta.ca) Emerging Drug List CANADIAN COORDINATING OFFICE FOR HEALTH XIMELAGATRAN FOR THE PROPHYLAXIS OF VARIOUS TECHNOLOGY ASSESSMENT COMPLICATIONS DUE TO THROMBOSIS Prophylaxis of Stroke Ximelagatran versus warfarin: In SPORTIF III, an open-label, parallel group, trial using a blinded assessor, 3,410 patients with atrial fibrillation and one other stroke risk factor were randomized to either ximelagatran or dose-adjusted warfarin (target INR between 2.0 and 3.0) to assess the impact of therapy on subsequent incidence of stroke and systemic embolic events. The incidence of strokes and systemic events was not signifi- cantly different [1.6% in the ximelagatran recipients vs. 2.3% (p>0.05) in the warfarin (INR 2.5) group].11 SPORTIF V is an ongoing trial of similar design, with more extensive blinding measures. Follow-up is expected to conclude by the end of 2003. DVT Treatment and Secondary Prophylaxis Ximelagatran versus placebo: The results of the THRIVE III trial were presented at the December 2002 meeting of the ASH. This trial examined the merits of extended therapy with fixed dose ximelagatran (24 mg twice daily for 18 months) versus placebo in 1,233 patients who had experienced a DVT or PE, which was previously treated with six months of standard anticoagulation therapy. The investigators reported that the estimated cumulative risk of a recurring VTE event (DVT or PE) during 18 months of treatment was 2.8% for ximelagatran vs. 12.5% for placebo recipients (p<0.001 compared to place- bo), without a significantly increased risk of bleeding (total bleeding events 23.9 vs. 21% with placebo; p=0.1703).1 Secondary Prophylaxis Post-MI ESTEEM phase III studies are not yet underway but results will likely emerge in 2004/2005. Adverse Effects: In the EXPRESS trial, excessive bleeding at the operative site, as judged by the investi- gator, was more common in the group receiving ximelagatran than the group receiving enoxaparin (3% vs. 1.2%). In the EXULT A trial, the incidence of major bleeding was more common in the ximelagatran 24 mg trial arm (1.3%), than the ximelagatran 36 mg (0.8%) and warfarin (0.7%) recipients. The incidence of any observed bleeding was 4.8% and 5.3% for ximelagatran 24 mg and 36 mg respectively, and 4.5% or warfarin. In the published trial, major bleeding occurred in 1.7% (6/345) of ximelagatran recipients vs. 0.9% (3/330) of those receiving warfarin. Major and minor bleeding together were more common in ximelagatran recipients, occuring in 9.6% (33/345) compared with 7.3% (24/330) of warfarin recipients. In the THRIVE III trial (n=1,233), six ximelagatran recipients experienced major bleeding events compared with five on placebo during the 18-month period. With long-term use during the THRIVE III study, alanine aminotransferase levels were increased as com- pared to placebo (estimated cumulative risk of 6.4% vs. 1.2%), however these levels did decrease with or without drug cessation. The Canadian Coordinating Office for Health Technology Assessment (CCOHTA) is a non-profit organization funded by the federal, provincial and territorial governments. (www.ccohta.ca) Emerging Drug List CANADIAN COORDINATING OFFICE FOR HEALTH XIMELAGATRAN FOR THE PROPHYLAXIS OF VARIOUS TECHNOLOGY ASSESSMENT COMPLICATIONS DUE TO THROMBOSIS Commentary: Ximelagatran is the first oral direct thrombin inhibitor to proceed to late stage clinical development; very little progress has been made in recent history in regards to oral anti- coagulation. Other oral direct thrombin inhibitors may soon follow. The advent of these medications is very attractive to those practising in several therapeutic areas (e.g.