Safety assessment of new antithrombotic agents: lessons from the EXTEND study on ximelagatran
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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Safety assessment of new antithrombotic agents: lessons from the EXTEND study on ximelagatran. / Agnelli, G; Eriksson, B I; Cohen, A T; Bergqvist, D; Dahl, O E; Lassen, M R; Mouret, P; Rosencher, N; Andersson, M; Bylock, A; Jensen, E; Boberg, B; EXTEND Study Group.
I: Thrombosis Research, Bind 123, Nr. 3, 2009, s. 488-97.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Safety assessment of new antithrombotic agents: lessons from the EXTEND study on ximelagatran
AU - Agnelli, G
AU - Eriksson, B I
AU - Cohen, A T
AU - Bergqvist, D
AU - Dahl, O E
AU - Lassen, M R
AU - Mouret, P
AU - Rosencher, N
AU - Andersson, M
AU - Bylock, A
AU - Jensen, E
AU - Boberg, B
AU - EXTEND Study Group
N1 - Keywords: Adult; Aged; Aged, 80 and over; Alanine Transaminase; Anticoagulants; Arthroplasty, Replacement, Hip; Azetidines; Benzylamines; Double-Blind Method; Enoxaparin; Female; Hip Fractures; Humans; Liver; Male; Middle Aged; Postoperative Complications; Time Factors; Venous Thromboembolism
PY - 2009
Y1 - 2009
N2 - BACKGROUND: Ximelagatran, the first oral direct thrombin inhibitor, was shown to be an effective antithrombotic agent but was associated with potential liver toxicity after prolonged administration. OBJECTIVES AND METHODS: The aim of the EXTEND study was to assess safety and efficacy of extended administration (35 days) of ximelagatran or enoxaparin for the prevention of venous thromboembolism after elective hip replacement and hip fracture surgery. A follow-up period, including assessment of liver enzymes (in particular alanine aminotransferase; ALAT), until post-operative day 180 was planned, with visits at days 56 and 180. RESULTS: Randomization and administration of study drugs were stopped following a report of serious liver injury occurring 3 weeks after completion of ximelagatran treatment. At the time of study termination, 1158 patients had been randomized and 641 had completed the 35-day treatment; with 303 ximelagatran and 265 enoxaparin patients remaining in the study through to the day 56 follow-up visit. Overall, 58 patients showed an ALAT increase to >2x upper limit of normal: 31 treated with enoxaparin, 27 with ximelagatran. Three ximelagatran patients also showed symptoms potentially related to liver toxicity. Eleven ximelagatran patients showed an ALAT increase after study treatment ended. The clinical development of ximelagatran was terminated and the drug withdrawn from the market. Evaluation of the relative efficacy of the two treatments as specified in the protocol was impossible due to the premature termination of the study. CONCLUSIONS: Prolonged administration of ximelagatran was associated with an increased risk of liver toxicity. In a substantial proportion of patients, ALAT increase occurred after treatment withdrawal. The findings seen with ximelagatran should be considered when designing studies with new antithrombotic agents.
AB - BACKGROUND: Ximelagatran, the first oral direct thrombin inhibitor, was shown to be an effective antithrombotic agent but was associated with potential liver toxicity after prolonged administration. OBJECTIVES AND METHODS: The aim of the EXTEND study was to assess safety and efficacy of extended administration (35 days) of ximelagatran or enoxaparin for the prevention of venous thromboembolism after elective hip replacement and hip fracture surgery. A follow-up period, including assessment of liver enzymes (in particular alanine aminotransferase; ALAT), until post-operative day 180 was planned, with visits at days 56 and 180. RESULTS: Randomization and administration of study drugs were stopped following a report of serious liver injury occurring 3 weeks after completion of ximelagatran treatment. At the time of study termination, 1158 patients had been randomized and 641 had completed the 35-day treatment; with 303 ximelagatran and 265 enoxaparin patients remaining in the study through to the day 56 follow-up visit. Overall, 58 patients showed an ALAT increase to >2x upper limit of normal: 31 treated with enoxaparin, 27 with ximelagatran. Three ximelagatran patients also showed symptoms potentially related to liver toxicity. Eleven ximelagatran patients showed an ALAT increase after study treatment ended. The clinical development of ximelagatran was terminated and the drug withdrawn from the market. Evaluation of the relative efficacy of the two treatments as specified in the protocol was impossible due to the premature termination of the study. CONCLUSIONS: Prolonged administration of ximelagatran was associated with an increased risk of liver toxicity. In a substantial proportion of patients, ALAT increase occurred after treatment withdrawal. The findings seen with ximelagatran should be considered when designing studies with new antithrombotic agents.
U2 - 10.1016/j.thromres.2008.02.017
DO - 10.1016/j.thromres.2008.02.017
M3 - Journal article
C2 - 18485453
VL - 123
SP - 488
EP - 497
JO - Thrombosis Research
JF - Thrombosis Research
SN - 0049-3848
IS - 3
ER -
ID: 21335593