For nearly 50 years, the mainstay of oral antithrombotic therapy has been the coumarin compound warfarin. Oral anticoagulants are effective for primary and secondary prevention of venous thromboembolism, for prevention of systemic embolism in patients with prosthetic heart valves or atrial fibrillation (AF), for prevention of acute myocardial infarction (AMI) in patients with peripheral arterial disease and for prevention of stroke, recurrent infarction, or death in patients with AMI.

For most of these indications, a moderate anticoagulant intensity (INR 2.0 to 3.0) is appropriate. As effective as these anticoagulants are, they have drawbacks. Warfarin acts indirectly, and its effect takes several days, until previously synthesized vitamin K­dependent plasma clotting factors have been catabolized. Thus, in most situations, warfarin must be initiated in conjunction with a rapidly acting anticoagulant, such as heparin. In addition, warfarin interacts with many other drugs, often making anticoagulant control difficult to achieve. Finally, use of either drug requires careful laboratory monitoring, an inconvenience to both patient and doctor.

Hope for Complications from Anticoagulant Use 

The main complication of oral anticoagulant therapy is bleeding, and risk is related to the intensity of anticoagulation. Contributing factors are the underlying medical illness and concomitant administration of aspirin, nonsteroidal anti-inflammatory drugs, or other drugs that impair platelet function or produce gastric erosions. The risk of major bleeding is also related to age >65 years, a history of stroke or gastrointestinal bleeding, and co-morbid conditions such as renal insufficiency or anemia. The elderly are more prone to bleeding even after controlling for anticoagulation intensity.

A new oral anticoagulant has been developed based on a compound, Hirudin, produced by the medicinal leech, hirudo medicinalis. Hirudin, a direct thrombin inhibitor, acts independently of antithrombin and other plasma proteins. As the result of intensive investigations, the interaction of hirudin with thrombin is now understood in great detail and has led to the discovery of other direct thrombin inhibitors. Ximelagatran, is the first of the oral direct thrombin inhibitors to be tested. Ximelagatran is metabolized to melagatran and does not require laboratory monitoring. Both drugs are in the process of being tested in largescale clinical studies.

A Potential Alternative to Warfarin Therapy 

Ximelagatran has predictable pharmacokinetics and no known food or pharmacokinetic drug interactions. Ximelagatran is under investigation as an alternative to warfarin for prevention of thromboembolism in patients with nonvalvular AF, as well as for use in other conditions requiring longterm anticoagulation with warfarin. Two long-term studies (SPORTIF III and SPORTIF V) in patients with AF and at least one additional risk factor for stroke compared the safety and efficacy of fixed-dose ximelagatran 36 mg BID, without coagulation monitoring, with dose-adjusted warfarin. The objective was to establish the non-inferiority of ximelagatran relative to warfarin for use in non-valvular AF.

In SPORTIF III, 3410 patients with AF and one or more risk factors were randomized to open label warfarin or ximelegatran. The primary event rate of stroke or systemic embolism was 2.3% in the warfarin group compared to 1.6% in the ximelagatran group. This corresponded to a relative risk reduction of 29%. The rates of major bleeding, fatal stroke and mortality were similar between the groups, but ximelegatran was associated with a lower rate of minor and major hemorrhage. The conclusion of the study was that in high-risk patients with AF, fixed-dose ximelegatran was at least as effective as well controlled warfarin for prevention of stroke and systemic embolism.

SPORTIF V Results Presented 

OAt the recent American Heart Association meeting in November 2003, results of the SPORTIF V trial were presented. Similar to SPORTIF III, the primary end point was the incidence of stroke and systemic embolization. The results were promising, showing an event rate of 1.2% /year with warfarin compared to 1.6% /year with ximelagatran. Additionally, the composite of CVA/death and bleeding, favored ximelagatran. One of the concerns, however, was the transient increase in the liver enzymes in approximately 6% of patients receiving ximelagatran. Initial reports seem to favor the safety and efficacy of ximelagatran as an antithrombotic alternative to warfarin for high-risk patients with AF. The drug is not yet market-released and we would anticipate about 1-2 years before FDA approval. .

Shapiro
S. S. Treating Thrombosis in the 21st Century.
N Engl J Med 349:1762-1764 (2003)