Ximelagatran as a New Oral Anticoagulant for Thrombosis

The articles in this issue describe the development, pharmacology, and clinical trials of the oral direct thrombin inhibitor ximelagatran. As described by Dr. Gustafsson, ximelagatran represents the first new oral anticoagulant since the vitamin K antagonist (VKA) warfarin. His article considers the evolution of the drug development process in the more than 60 years between the introduction of each of the agents and its clinical use. In particular, although ximelagatran was developed through a program of targeted drug design, the origins of warfarin lie in studies of a bleeding disease in cattle, and its clinical use followed its use as a rodenticide. Drs. Mattsson, Sarich, and Carlsson consider why thrombin was selected as a logical target in developing a new anticoagulant for use in the treatment and prevention of arterial and venous thromboembolic disorders and describe the mechanism of action of melagatran, the active moiety of ximelagatran.

VKAs are ineffective for the initial treatment of acute deep vein thrombosis and pulmonary embolism. Although VKAs have proven efficacy in the prevention of venous thromboembolism (VTE), their narrow therapeutic window demands close management to balance effective thromboprophylaxis against the risk of serious bleeding. In practice, the realities of routine clinical use, such as the need for regular coagulation monitoring, restrict the use of the VKAs. Consequently, many patients are left at increased risk of thromboembolic events. The unpredictable anticoagulant effects of the VKAs reflect highly variable pharmacokinetics and pharmacodynamics with numerous food and drug-drug interactions. Ximelagatran, in contrast, has a predictable and reproducible pharmacokinetic/pharmacodynamic profile with few clinically relevant drug interactions, as described in the articles by Drs. Wolzt, Sarich, and Eriksson. The article by Drs. Carlsson and Schulman discusses that, due to its predictable characteristics, coagulation monitoring is not required with ximelagatran. Effects of ximelagatran on a range of coagulation assays are described as guidance to what results can be expected in circumstances where an indication of anticoagulant effect may assist with clinical decision making.

Ximelagatran was approved in the European Union in May 2004 for the short-term primary prevention of VTE events in patients undergoing elective hip or knee replacement surgery. Drs. Colwell and Mouret describe the results from the METHRO, EXPRESS, and EXULT studies demonstrating that ximelagatran compares favorably with low-molecular-weight heparin (LMWH) in this orthopedic surgery indication. Ximelagatran has also been evaluated as initial treatment for acute VTE and long-term secondary prevention of VTE (Drs. Huisman and Bounameaux), prevention of stroke in atrial fibrillation (Drs. Olsson and Halperin), and, in a phase II study, prevention of cardiovascular events following recent myocardial infarction (Dr. Wallentin).

Regulatory review of the clinical trial program by the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee took place in September 2004. The Committee reviewed applications for the approval of ximelagatran for short-term use in the prevention of VTE in patients undergoing elective total knee replacement, secondary VTE prevention after 6 months of standard therapy for an acute episode of VTE, and prevention of stroke and systemic embolic events in patients with atrial fibrillation. In each of the indications, the Committee was of the opinion that the benefits of ximelagatran did not outweigh the risks and advised against approval. Specifically, there were concerns about the increased incidence of elevated liver enzyme levels in patients treated with ximelagatran and their potential clinical significance and an apparent increase in the risk of myocardial infarction in the follow-up to one of the four studies (EXULT A) of ximelagatran in the prevention of VTE following total knee replacement.

The chairman of the FDA Committee, Dr. Jeffrey Borer, noted the difficulties in discussing the safety of ximelagatran considering its benefits in comparison with the VKAs such as warfarin. The clinical use of warfarin is undoubtedly associated with several troublesome and potentially serious issues. Surveys demonstrate that warfarin is among the leading causes of emergency hospitalization for adverse drug events, which in some cases prove fatal.[1] [2] [3] In a survey of adverse drug events in Australia, 0.2% of patients receiving warfarin suffered a fatal adverse event,[3] consistent with other studies indicating a median annual rate of fatal bleeding in the range of 0.07-0.7%.[4] Comparative studies have found the risk of bleeding to be lower with ximelagatran than with warfarin. In the SPORTIF V study of stroke prevention in atrial fibrillation, the rate of major bleeding was 2.4% with ximelagatran compared with 3.1% with warfarin. Furthermore, in the THRIVE III study of secondary prevention of VTE, the incidence of major bleeding with ximelagatran was comparable with placebo. This is an important consideration when assessing the balance of benefit to risk of ximelagatran compared with warfarin. It is also pertinent to consider that the standard of warfarin management in the long-term comparative studies with ximelagatran was substantially better (80% of INR values within the range 1.8-3.2)[5] [6] than is typically seen in daily clinical practice. The results of these studies are therefore potentially likely to overemphasize the benefits and underestimate the risks of warfarin in the real-life setting.

The mechanisms underlying the liver enzyme elevations with ximelagatran are unclear and are the subject of ongoing investigations. The potential clinical significance of the liver enzyme elevations and how they should be managed is also under debate. Elevations in alanine aminotransferase (ALAT) levels to greater than three times the upper limit of normal (ULN) occurred in 7.9% of patients receiving long-term treatment (>35 days) with ximelagatran.[7] It should be noted that the clinical trial program for ximelagatran excluded patients with known hepatic disease, and initially no limits were defined for discontinuing ximelagatran in the event of ALAT elevations. Increased ALAT levels occurred 1-6 months after initiation of treatment, and, where data were available, recovery to an ALAT level of less than two times the ULN was confirmed in 96% of patients, whether or not they continued to receive ximelagatran. The ALAT elevations were mainly asymptomatic but rare symptomatic cases have been observed.[7] The European license for the prevention of VTE events in patients undergoing elective hip or knee replacement surgery indicates that ALAT levels should be determined before surgery and that melagatran/ximelagatran is contraindicated in patients with hepatic impairment and/or with ALAT levels greater than two times the ULN before administration of treatment.

To provide some context, elevated liver enzyme levels have also been seen associated with LMWH and dextran therapy,[8] [9] but the incidence and potential clinical significance of these elevations have received little attention compared with potential thrombocytopenia during LMWH administration. In the METHRO II study of VTE prevention after total hip or knee replacement surgery, ALAT elevations greater than three times the ULN were more common with the LMWH dalteparin than with ximelagatran (10.8 vs 3.8%, respectively).[10] There are, to our knowledge, no published data on the incidence of liver enzyme elevations during long-term LMWH therapy despite the fact that LMWHs have been in widespread use for more than 20 years. No pharmacological agent is totally free of side effects and many are associated with potentially serious toxicities. In practice, physicians have developed effective ways to manage these risks by watching for clinical symptoms and monitoring for biochemical abnormalities. Continued investigation of the mechanisms of ALAT elevation with ximelagatran and practical strategies for clinical management are to be welcomed.

The increase in myocardial infarction in the ximelagatran group during the follow-up period of the EXULT-A study also needs to be considered in context. Increased thrombin activity in parallel with an increase in thrombotic events has been previously reported when LMWH prophylaxis was stopped approximately 1 week after hip replacement surgery.[11] [12] [13] Because thrombin activity is a systemic phenomenon, an increased risk of arterial thrombotic events might also be expected in predisposed, orthopedic surgery patients when thromboprophylaxis is stopped while thrombin generation is ongoing. Transient increases in thrombin activity and arterial thrombotic events have been observed following discontinuation of anticoagulant therapy with unfractionated heparin,[14] [15] VKAs,[16] and the direct thrombin inhibitors inogatran[17] and argatroban[18] in patients with acute coronary syndromes. It seems possible that the observed increase in myocardial infarction in the follow-up to EXULT-A could reflect a similar phenomenon. In any case, it is important to note that, in the SPORTIF III and V trials, which were large studies of longer duration than EXULT-A, there were no significant differences in the incidence of myocardial infarction between warfarin and ximelagatran.[5] [6] Furthermore, in the ESTEEM trial of secondary prophylaxis after myocardial infarction, ximelagatran specifically lowered the risk of recurrent myocardial infarction compared with placebo, with all patients also receiving acetylsalicyclic acid.[19]

These are certainly interesting times for all of us involved in the management of thromboembolic disorders. Ximelagatran, the first new oral anticoagulant in nearly 60 years, has been introduced in orthopedic surgery in several European countries and South America. The challenge now is to clarify the significance of the observed liver enzyme elevations and how these balance with the efficacy in a range of arterial and venous thromboembolic events, as described in the articles in this issue. It will also be intriguing to see to what extent the various other oral direct thrombin inhibitors and other classes of new anticoagulants currently in development share the profile established for ximelagatran.

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