Will direct thrombin inhibitors replace warfarin for preventing embolic events in atrial fibrillation?
OBJECTIVE
Atrial fibrillation is the most frequently encountered tachyarrhythmia requiring therapy. Treatment issues include therapy for any reversible cause; the identification and treatment of any underlying structural disorder; control of the ventricular rate, both for symptom reduction and prevention of tachycardic-induced cardiomyopathy; restoration and maintenance of sinus rhythm when symptoms persist despite rhythm control; and anticoagulation in patients with high-risk markers for systemic embolization: age over 65 years, hypertension, diabetes, ventricular failure, rheumatic valvular disease, and prior stroke or other embolic event. In such patients, anticoagulation with warfarin is currently recommended. Warfarin therapy carries significant risks (especially bleeding), inconveniences (the cost of prothrombin time monitoring, the need for rigid dietary stability, the concerns of drug and herbal interactions), and other concerns (the issue of generic formulation substitution).


RESULTS
Under development are oral thrombin inhibitors. The first to reach clinical approval will likely be ximelagatran. In clinical trials to date, ximelagatran has proven to be equal to or superior to warfarin in the prevention and treatment of thrombophlebitis. In atrial fibrillation patients, the Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) trials completed so far appear to show a similar or better efficacy for ximelagatran versus warfarin as regards both prevention of embolic events and lower risks of major bleeding, with no serious adverse effects except for apparently reversible alterations in liver function tests in approximately 6% of subjects, all occurring early in therapy to date. If the remaining SPORTIF trial (SPORTIF V) is confirmatory (results to be available in late 2003), it is expected that this exciting new product will be submitted this winter to the Food and Drug Administration for approval. Recent findings also include the observations in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) and Rate Control Versus Electrical Cardioversion (RACE) trials that anticoagulation should not be discontinued despite the restoration and maintenance of sinus rhythm.


CONCLUSIONS
Oral direct thrombin inhibitors, such as ximelagatran, appear likely to replace the use of warfarin in most patients in the near future, because of a better risk-benefit profile.
Reiffel
James A
JA
Department of Clinical Medicine, Columbia University, New York, New York, USA. jar2@columbia.edu
D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000150:complications / Q000188:drug therapy*; D001384:Azetidines / Q000008:administration & dosage / Q000627:therapeutic use*; D001596:Benzylamines; D002986:Clinical Trials as Topic; D004617:Embolism / Q000209:etiology / Q000517:prevention & control*; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D011517:Prothrombin Time / Q000191:economics; D016032:Randomized Controlled Trials as Topic; D020521:Stroke / Q000209:etiology / Q000517:prevention & control; D020246:Venous Thrombosis / Q000209:etiology / Q000517:prevention & control; D014859:Warfarin / Q000008:administration & dosage / Q000627:therapeutic use*
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D005343:Fibrinolytic Agents; C426686:ximelagatran; D014859:Warfarin