To the Editor: In his Editorial about ximelagatran,1 Dr Gurewich discusses the significant limitations of vitamin K antagonists for anticoagulation and the need for a therapeutic alternative, particularly for long-term anticoagulation, and we acknowledge these limitations. Studies of ximelagatran for short-term (7-12 days) thromboprophylaxis in knee replacement surgery patients,2 long-term (18 months) secondary prevention of recurrent venous thromboembolism (VTE) following treatment of VTE,3 and long-term (average 1.4 years) stroke prevention in patients with atrial fibrillation4 - 5 were conducted, and the commercial marketing application for ximelagatran for these uses was discussed at the US Food and Drug Administration’s Cardiovascular and Renal Drugs Advisory Committee meeting on September 10, 2004.6 We were concerned about the liver and cardiovascular risk findings. Major bleeding rates were not shown to be different between ximelagatran and warfarin. Efficacy for long-term use compared with warfarin, studied solely in the atrial fibrillation trials, showed conflicting results.
In the long-term studies,7 37 (approximately 1 in 200) patients treated with ximelagatran had concurrent elevations of levels of both alanine aminotransferase (ALT) and total bilirubin, connoting severe liver injury,8 including 9 deaths, 3 of them likely related to hepatic dysfunction. The Editorial advances the option that “diligent postmarketing surveillance” could suffice to study risk for delayed hepatotoxicity. However, analysis of data from the population with measurement of long-term end points shows that initial signs of liver injury (ALT levels >3 times the upper limit of normal) were observed during the first month of ximelagatran therapy in 6 of 37 patients who went on to develop severe liver injury (ALT levels >3 times the upper limit of normal and total bilirubin levels >2 times the upper limit of normal).7 The possibility that severe liver injury may occur during the first month of treatment cannot be excluded. We believe that postmarketing surveillance (eg, MedWatch reporting) is most appropriate for identification of new and unexpected events associated with drug therapy, not for formal quantification of a robust and clinically significant risk identified in preapproval studies. Monitoring patients in randomized, controlled studies is the best method for clarifying and quantifying the risk of ximelagatran-associated liver toxicity.
An increased rate of myocardial infarction/coronary artery disease events in patients randomized to ximelagatran was observed by Fiessinger et al in the THRIVE long-term deep vein thrombosis treatment trial9 and in the short-term knee replacement surgery studies, indicating possible cardiovascular toxicity. Randomized, controlled studies would also be needed to study this risk.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
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