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A new oral direct thrombin inhibitor—ximelagatran (Exanata; Astra-Zeneca)—steals the stage at this year’s American College of Cardiology 52nd Scientific Session in Chicago. Data from the SPORTIF III (Stroke Prevention Prophylaxis Using an Oral Thrombin Inhibitor in Atrial Fibrillation) trial was presented at a Late Breakers session April 9, 2003. The SPORTIF III trial was an open-label trial conducted at 259 centers worldwide, enrolling 3407 patients with nonvalvular atrial fibrillation and at least 1 other additional stroke risk factor. Patients were randomized to receive either warfarin at a dose adjusted to maintain the INR between 2.0 and 3.0 or ximelagatran in a fixed dose of 36 mg twice per day. In the noninferiority, intention-to-treat analysis, the primary end point compared the rates of all strokes (ischemic and hemorrhagic) and systemic thromboembolic events. The mean follow-up time was 17 months. There were 56 events or 2.3% events per year in the warfarin-treated group compared to 40 events or 1.6% events per year in the ximelagatran-treated arm. Though powered to only show "noninferiority," the observed risk reduction of 30% was not statistically significant but trended in favor of ximelagatran. Importantly, major and minor bleeding episodes were statistically fewer in the ximelagatran arm as well (25.5% vs 29.5%; P = .007). Liver enzyme elevations (3 times normal) were notable: 6.5% ximelagatran vs 0.7% warfarin. Though 1.2% of subjects were discontinued from the trial as protocol withdrawals due to these elevated LFTs, there was complete resolution of liver functions within 2-6 months in the remaining patients.
Ximelagatran represents a potentially major therapeutic advance. Since it is still in development (phase III/pre-NDA), we do not have a lot of pharmacokinetic and pharmacodynamic details. However, what we do know is compelling. It would represent the first new oral anticoagulant in 50 years. It is a direct thrombin inhibitor that is given in a fixed dose requiring no titration and no anticoagulation monitoring. It was a prompt onset and offset. At this point, no serious drug-drug interactions have been reported. It is estimated that 45% of afib patients at significant risk for stroke do not use anticoagulants, namely warfarin, for reasons of safety and noncompliance. If the liver enzyme elevations prove to be transient and the bleeding safety and efficacy profile remains as seen in the current SPORTIF III trial, ximelagatran will be a great addition to the neurologist/cardiologist drug armamentarium. Stayed tuned for the result of SPORTIF V, scheduled to be presented at the American Heart Association meetings in the fall of 2003.
COX-IIs for Migraine
NSAIDS represent a standard for mild-to-moderate migraine treatment. Given the overuse potential of these drugs in chronic migraine patients and the safety advantages of COX-II selective inhibitors, the use of these new drugs for migraine has been inevitable but heretofore without controlled data. At the AAN meetings this year, Silberstein presented the results of a double-blind, placebo-controlled, parallel group study comparing Vioxx 25 mg (n = 183) , 50 mg (n = 192), and placebo (n = 192) in patients with moderate-to-severe migraine (Abstract S42.003). On the primary end point of migraine pain relief at 2 hours, 54% (25 mg) and 57% (50 mg) experienced symptom reduction compared to 34.3% (placebo) in the placebo-treated group (P < .001). The Vioxx treated groups also achieved better 24-hour sustained pain-free response (33.5 and 37.4% vs 17.1%; P = .001).
At the Cornell Headache Service, the standard acute migraine abortive regimen includes a potent oral triptan, a COX-II inhibitor and antiemetic. While admittedly there are no head-to-head data comparing generic NSAIDS and COX-IIs and the cost deferential is significant, I believe the better safety profile and the convenience of once-daily dosing makes the COX-IIs a compelling first-line choice. — Jeffrey Reich
Dr. Reich is Assistant Professor of Neurology, New York Presbyterian Hospital - Cornell Campus.