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The Efficacy and Safety Study of Oral Direct Thrombin Inhibitor Ximelagatran Compared with Dose-Adjusted Warfarin in the Prevention of Stroke and Systemic Embolic Events in Patients with Atrial Fibrillation (SPORTIF V) was presented by Dr. Jonathan Halperin. Ximelagatran has already been shown to be as effective as warfarin in the prevention of deep-venous thrombosis, and it offers the advantages of no blood monitoring, no dose adjustments, and little interaction with drugs and food. Warfarin has been shown to reduce strokes by 62% in nonvalvular atrial fibrillation, but due to the disadvantages of this agent only one-third of candidate patients were on it in a recent family practice survey. Thus, this study of the efficacy of ximelagatran in nonvalvular atrial fibrillation has been eagerly awaited. SPORTIF V enrolled 3922 patients in the United States and Canada with atrial fibrillation and at leastone risk factor for stroke and randomized them to either adjusted-dose warfarin (INR 2-3) or ximelagatran 36 mg b.i.d. It was a blinded study with sham INR testing and sham dose adjustments in the ximelagatran group. The primary end point was an intention-to-treat analysis of all strokes and systemic embolic events over 12 months. Secondary end points included the primary end point plus all-cause mortality, adverse events, and an on-treatment analysis of the end points. Also, they pooled data from SPORTIF III (an open-label study) to assess low-frequency adverse events. Since a placebo-controlled trial was deemed unethical, the data analysis was for noninferiority of ximelagatran vs warfarin. Patient characteristics were similar to older trials, with a history of stroke in 25%, age older than 75 in 40%, and hypertension in 80%. INR averaged 2.4 in the warfarin group, with 68% at target throughout the study and 83% at the expanded range of 1.8-3.2.
After 20 months of follow-up, the stroke/embolus rate was 1.2% in the warfarin group and 1.6% in the ximelagatran group, which was not statistically different. Similar results were seen for the secondary end points and subgroups. Cerebral hemorrhage rates were low and not different, 2.4% vs 3.1%, as were major bleeding events, 3.1% vs 2.4%. Major and minor bleeding events were more common with warfarin, 47 events vs 37 events (P < .0001). Liver function test abnormalities were observed more frequently with ximelagatran, 6% vs 0.8% on warfarin; peak incidence was at 3 months, and the abnormalities tended to resolve by 6 months even with continued therapy. If major bleeding and death are pooled from SPORTIF III and V, there is a significant advantage to ximelagatran. The investigators concluded that ximelagatran is as effective as warfarin in preventing stoke/emboli in nonvalvular atrial fibrillation patients with risk factors for stroke and produces less bleeding but raises liver function tests transiently in 6%. Thus, it is a promising option for such patients.
Comment by Michael H. Crawford, MD
SPORTIF is the largest trial to date of nonvalvular atrial fibrillation, with more than 7000 total patients enrolled. Thus, the safety and end point data are quite robust, especially when data are pooled between the substudies for less-frequently occurring events. The overall stroke rate in SPORTIF is 1.6%, which is low considering that these are higher-risk patients because most had more than one risk factor for stroke in addition to atrial fibrillation. The control rate based upon older placebo-controlled studies in such patients would be 6-7%, so the risk of stroke is reduced by at least two-thirds. The trend toward less bleeding with this fixed-dose agent is encouraging. It is remarkable that the investigators got the dose right in this large study. Since there was no difference between the efficacy of ximelagatran and warfarin, the attractive features of ximelagatran will create a clamoring for FDA approval of this new agent. However, there are some issues with this drug. The liver function test abnormalities in 6% are of concern, but there was a trend for them to resolve over 6 months. The drug is excreted by the kidneys so renal insufficiency will require dosage adjustment. Finally, b.i.d. dosing is not ideal. If patients miss doses because of this, the benefits seen in this study may not be realized. At this point, ximelagatran appears very promising, but more clinical experience in patients not carefully selected for a trial needs to be obtained.
Dr. Crawford, Professor of Medicine and Associate Chief of Cardiology for Clinical Programs at the University of California, San Francisco, is Editor of Clinical Cardiology Alert.