Ximelagatran Versus Warfarin in the Prevention of Atrial Fibrillation–Related Stroke: Both Sides of the Story
To the Editor:
We have carefully read the interesting article by Akins et al1 focusing on a pivotal issue in the prevention of atrial fibrillation-related stroke. The authors pooled the data from high-risk (previous stroke/TIA) versus nonhigh-risk (no previous stroke/TIA) patients included in SPORTIF III2 and SPORTIF V3 trials in which the direct thrombin inhibitor ximelagatran was compared with warfarin in the primary and secondary prevention of thromboembolic stroke. The authors concluded stating that ximelagatran was at least as effective as warfarin.
In our opinion, some points deserve attention and a deeper examination. Our group recently published nonfunded/nonbiased meta-analytic data about the comparison of ximelagatran versus conventional anticoagulant therapy in different clinical settings (ie, prophylaxis of deep vein thrombosis after total knee or hip replacement; treatment of deep vein thrombosis, and primary prevention of thromboembolic stroke in patients with nonvalvular atrial fibrillation) showing that ximelagatran/melagatran was comparable to conventional anticoagulant therapy in terms of risk of major adverse events. The overall risk of major bleeds was also comparable between the 2 treatment modes, although in the management of deep vein thrombosis and in the prevention of atrial fibrillation-related stroke, prolonged ximelagatran/melagatran was associated with a significantly lower risk of bleeds (in absolute terms, the risk was reduced from 3.3% to 2.2%, with a number needed to harm by causing one major bleed in the conventional anticoagulant arm of 100).4–6 However, the risk of hepatic toxicity, measured as the rate of alanine aminotransferase elevation ≥3 above the upper normal limit was prohibitive with ximelagatran. In particular, for treatments of ≥3 months the odds of hepatotoxicity was 6.73 (5.01 to 9.05; P<0.001). In absolute terms, for prolonged treatments, the incidence of hepatotoxicity increased from 1.1% to 7.1%, with a number needed to harm of 17.
This point is crucial because, although ximelagatran was promising for some attractive features and was associated with a lower risk of hemorrhages, in the era of evidence-based medicine one of the duties of the research is the completeness and, in our opinion, 2 points in the discussion could be misleading. The first is the statement that the results in the group of high-risk patient (ie, a 0.5 increase in the percentage of patients free of stroke per year for the ximelagatran group) are “quite encouraging,” and the second is that the manufacturer “voluntarily” decided to withdraw the product from the European market. Serious liver injury and related mortality have persuaded the Food and Drug Administration to deny approval of ximelagatran/melagatran in the United States7 and the European Agency for the Evaluation of Medicinal Products to approve only short-term administration,8 but a further fatality related to liver injury in a postmarketing study “has led” the manufacturer, AstraZeneca, to withdraw the drug.9 Ximelagatran failed to fulfill its promises and it is adequate to report both the sides of the story.
In conclusion, we agree with the authors about the potential of this new class of drugs and wait for the results of ongoing trials evaluating dabigatran etexilate.10
Akins PT, Feldman HA, Zoble RG, Newman D, Spitzer SG, Diener HC, Albers GW. Secondary stroke prevention with Ximelagatran versus warfarin in patients with atrial fibrillation: pooled analysis of SPORTIF III and SPORTIF V clinical trials. Stroke. 2007; 38: 874–880.
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): randomised controlled trial. Lancet. 2003; 362: 1691–1698.
Albers GW, Diener HC, Frison L, Grind M, Nevinson M, Partridge S, Halperin JL, Horrow J, Olsson SB, Petersen P, Vahanian A. SPORTIF Executive Steering Committee for the SPORTIF V Investigators. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA. 2005; 293: 690–698.
Testa L, Andreotti F, Biondi Zoccai GGL, Burzotta F, Bellocci F, Crea F. Ximelagatran/melagatran against conventional anticoagulation: a meta-analysis based on 22639 patients. Int J Cardiol. 2007 (in press).
Testa L, Biondi-Zoccai GGL, Porto I, Andreotti F, Crea F. The direct thrombin inhibitor Ximelagatran/melagatran: a systematic review on clinical applications and an evidence based assessment of risk benefit profile. Exp Opin Drug Metab Toxicol. 2007 (in press).
Testa L, Andreotti F, Trotta G, Biondi Zoccai GGL, Burzotta F, Bellocci F, Crea F. Ximelagatran/melagatran versus conventional anticoagulant therapy: meta-analysis of 13 randomised controlled trials enrolling 22639 patients. Oral Presentation for the Young Investigator Award in Thrombosis. European Society of Cardiology/World congress of Cardiology 2007.
AstraZeneca receives action letter from FDA for Exanta™ (ximelagatran). Available at http://fdaadvisorycommittee.com.
Successful outcome of the mutual recognition procedure for Exanta™ (ximelagatran) in Europe. Press release from European Agency for the Evaluation of Medicinal Products (EMEA). Available at http://www.emea.eu.int.
AstraZeneca Decides to Withdraw Exanta™ (ximelagatran). Press release from AstraZeneca international, February 14, 2006. Accessed February 15, 2006, at http://www.astrazeneca.com/pressrelease.
Registered ongoing clinical trials for Dabigatran Etexilate. Available at http://www.clinicaltrials.gov.