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Abstract & Commentary
Source: Olsson SB; Executive Steering Committee on behalf of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): Randomized controlled trial. Lancet. 2003; 362:1691-1698.
Warfarin, a compound initially introduced in 1948 as rat poison, has been the mainstay of anticoagulation for more than 50 years. Patients with atrial fibrillation (AF) require warfarin for stroke prophylaxis, but many shy away from the perceived stigma of this medication and the demanding blood monitoring program it requires. New alternative anticoagulants now exist that may be equally efficacious as warfarin and allow a more convenient fixed dosing schedule with a superior safety profile.
Taking its cue from the medicinal leech, Hirudo medicinalis, the compound ximelagatran (trade name Exanta) acts as a direct thrombin inhibitor. It has been studied in a series of multicenter trials known as SPORTIF (Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation). SPORTIF III was published in Lancet in November 2003. In this study, 3410 patients with AF and 1 or more stroke risk factors were studied over a period of 1 year or more, randomized to either ximelagatran or open-label warfarin (at an INR range of 2-3). The primary event rate defined as all stroke (ischemic or hemorrhagic) occurred at a rate of 2.3% per year on warfarin compared to 1.6% per year on ximelagatran. This represented a relative risk reduction of 29% (which did not reach statistical significance). The risk of major and minor hemorrhages was significantly lower with ximelagatran (25.8% per year) than with warfarin (29.8% per year). This was primarily minor bleeding with major bleeding limited to approximately 1.5% in both groups. Abnormalities in liver function tests (elevations in alanine aminotransferase [ALT] greater than 3 times normal) occurred in 6% of ximelagatran-treated patients compared to 1% on warfarin (P < .0001).
The results of SPORTIF V were also recently released at the November 2003 meeting of the American Heart Association. This study differed slightly from SPORTIF III in that a double blind was maintained, with either real or "sham" dose adjustments made for patients on warfarin, as well as those on fixed-dose ximelagatran. SPORTIF V included 3922 patients with AF, with an event rate of 1.6% per year on ximelagatran compared to 1.2% per year on warfarin, a nonsignificant difference. The incidence of bleeding (combined major and minor events) was significantly lower with ximelagatran (37% compared to 47% on warfarin [P < .0001]). As in SPORTIF III, there was a transient increase in liver enzymes, which resolved over 2-6 months, regardless of whether ximelagatran therapy was maintained or discontinued.
When taken together, pooled analysis of SPORTIF III and V in the total group of 7329 patients shows an overall event rate of 1.6% for both drugs. The SPORTIF investigators have successfully demonstrated clinical equivalence between ximelagatran and warfarin. Indeed, ximelagatran may be safer from a bleeding perspective; however, the observed incidence of liver function abnormalities may be unacceptable. While no clinically significant liver disease has been documented, patients who take ximelagatran would require years of therapy, and long-term safety data are lacking. Neither should the issue of cost be ignored, as it is likely that this agent will be many-fold more expensive than generic warfarin. Perhaps this cost will be offset by avoiding years of laboratory fees for INR measurements. Should ximelagatran meet with FDA approval in the coming months, it may fall on the shoulders of clinicians to be the final arbiter of this complex risk-benefit calculus. — Alan Z. Zegal, Assistant Professor, Department of Neurology, Weill-Cornell Medical College, Attending Neurologist, New York Presbyterian Hospital; Assistant Editor, Neurology Alert.