Ximelagatran for Secondary Prevention of Venous Thromboembolism
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《新英格兰医药杂志》
To the Editor: Schulman et al. (Oct. 30 issue)1 state that their study of ximelagatran for the secondary prevention of venous thromboembolism was performed "in accordance with the Declaration of Helsinki and Good Clinical Practice." However, 97 patients assigned to the placebo group had a history of recurrent venous thromboembolism, accounting for 16 percent of patients in this group. The current accepted international recommendation for patients with recurrent venous thromboembolism is 12 months of primary oral anticoagulant therapy.2 Thus, the assignment of these patients to no therapy is a violation of the Helsinki Declaration. The authors should have studied the effect of ximelagatran as compared with the best current therapeutic approach (i.e., coumadin therapy).
References
Schulman S, W?hlander K, Lundstr?m T, Clason SB, Eriksson H. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003;349:1713-1721.
Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest 2001;119:Suppl:176S-193S.
To the Editor: Schulman et al. report the superiority of ximelagatran over placebo for the secondary prevention of venous thromboembolism for an extended treatment period of 18 months. It is well documented that the risk of recurrent venous thromboembolism after an episode of venous thromboembolism is increased in patients with cancer1 or known recurrent venous thromboembolism2,3 and can be reduced by prolonged anticoagulation. We believe that the inclusion of such high-risk patients in the study could have influenced the results. The authors state that the risk reduction was similar in all subgroups, but it would be important to know exactly how many patients in the placebo group who had recurrent events were high-risk patients. The difference in the number of events between the placebo group and the ximelagatran group (12 events in the ximelagatran group vs. 71 in the placebo group) might be ascribed to high-risk patients in the placebo group (a total of 129 such patients). On the basis of the data as presented, it is not clear whether the described benefit of ximelagatran applies to patients with a first episode of venous thromboembolism, those with recurrent venous thromboembolism, those with cancer, or all these subgroups.
Carsten B?ger, M.D.
Stephan Schroll, M.D.
Stephan Holmer, M.D.
Klinikum der Universit?t Regensburg
93042 Regensburg, Germany
carsten.boeger@klinik.uni-regensburg.de
References
Lee AYY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146-153.
Schulman S, Granqvist S, Holmstr?m M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997;336:393-398.
Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003;348:1425-1434.
The authors reply: In our study, we did not specifically encourage the recruitment of patients with recurrent thromboembolism. Indeed, the first exclusion criterion of the study protocol applied to patients with a need for continuous treatment with anticoagulants, as judged by the investigator. The guidelines referred to by Vaknansky et al., which are American, not international, recommend 12 months or more of anticoagulation after a recurrent thrombotic event, either idiopathic or associated with a thrombophilic defect.1 Furthermore, the grade of the recommendation is only 1C, or intermediate strength, suggesting that the best action may differ, depending on the circumstances or patients' or societal values.2 The same recommendation pertains to patients with venous thromboembolism and cancer.1
Only a single randomized study of the duration of anticoagulation, used exclusively after recurrent venous thromboembolism, has been performed. The prophylactic effect of anticoagulation for four years, as compared with six months, was counterbalanced by a trend toward a higher risk of major hemorrhage in the group treated for four years.3 It is therefore justifiable that the ethics committees in all the participating countries (the United States did not participate) approved the study.
Among the 66 patients in the present study who had active cancer during the previous five years, a recurrent event was diagnosed in only 3 patients, and no conclusion regarding risk reduction can be drawn. There was a substantial and clinically important reduction in the risk of recurrence among patients receiving ximelagatran, regardless of the number of previous thromboembolic events.
Sam Schulman, M.D.
Karolinska Hospital
S-171 76 Stockholm, Sweden
sam.schulman@ks.se
Henry Eriksson, M.D.
Sahlgrenska University Hospital–?stra
S-416 85 G?teborg, Sweden
References
Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest 2001;119:Suppl:176S-193S.
Guyatt G, Schun?mann H, Cook D, Jaeschke R, Pauker S, Bucher H. Grades of recommendation for antithrombotic agents. Chest 2001;119:Suppl:3S-7S.
Schulman S, Granqvist S, Holmstr?m M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997;336:393-398.(Arkady Vaknansky, M.D.)
References
Schulman S, W?hlander K, Lundstr?m T, Clason SB, Eriksson H. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003;349:1713-1721.
Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest 2001;119:Suppl:176S-193S.
To the Editor: Schulman et al. report the superiority of ximelagatran over placebo for the secondary prevention of venous thromboembolism for an extended treatment period of 18 months. It is well documented that the risk of recurrent venous thromboembolism after an episode of venous thromboembolism is increased in patients with cancer1 or known recurrent venous thromboembolism2,3 and can be reduced by prolonged anticoagulation. We believe that the inclusion of such high-risk patients in the study could have influenced the results. The authors state that the risk reduction was similar in all subgroups, but it would be important to know exactly how many patients in the placebo group who had recurrent events were high-risk patients. The difference in the number of events between the placebo group and the ximelagatran group (12 events in the ximelagatran group vs. 71 in the placebo group) might be ascribed to high-risk patients in the placebo group (a total of 129 such patients). On the basis of the data as presented, it is not clear whether the described benefit of ximelagatran applies to patients with a first episode of venous thromboembolism, those with recurrent venous thromboembolism, those with cancer, or all these subgroups.
Carsten B?ger, M.D.
Stephan Schroll, M.D.
Stephan Holmer, M.D.
Klinikum der Universit?t Regensburg
93042 Regensburg, Germany
carsten.boeger@klinik.uni-regensburg.de
References
Lee AYY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146-153.
Schulman S, Granqvist S, Holmstr?m M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997;336:393-398.
Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003;348:1425-1434.
The authors reply: In our study, we did not specifically encourage the recruitment of patients with recurrent thromboembolism. Indeed, the first exclusion criterion of the study protocol applied to patients with a need for continuous treatment with anticoagulants, as judged by the investigator. The guidelines referred to by Vaknansky et al., which are American, not international, recommend 12 months or more of anticoagulation after a recurrent thrombotic event, either idiopathic or associated with a thrombophilic defect.1 Furthermore, the grade of the recommendation is only 1C, or intermediate strength, suggesting that the best action may differ, depending on the circumstances or patients' or societal values.2 The same recommendation pertains to patients with venous thromboembolism and cancer.1
Only a single randomized study of the duration of anticoagulation, used exclusively after recurrent venous thromboembolism, has been performed. The prophylactic effect of anticoagulation for four years, as compared with six months, was counterbalanced by a trend toward a higher risk of major hemorrhage in the group treated for four years.3 It is therefore justifiable that the ethics committees in all the participating countries (the United States did not participate) approved the study.
Among the 66 patients in the present study who had active cancer during the previous five years, a recurrent event was diagnosed in only 3 patients, and no conclusion regarding risk reduction can be drawn. There was a substantial and clinically important reduction in the risk of recurrence among patients receiving ximelagatran, regardless of the number of previous thromboembolic events.
Sam Schulman, M.D.
Karolinska Hospital
S-171 76 Stockholm, Sweden
sam.schulman@ks.se
Henry Eriksson, M.D.
Sahlgrenska University Hospital–?stra
S-416 85 G?teborg, Sweden
References
Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest 2001;119:Suppl:176S-193S.
Guyatt G, Schun?mann H, Cook D, Jaeschke R, Pauker S, Bucher H. Grades of recommendation for antithrombotic agents. Chest 2001;119:Suppl:3S-7S.
Schulman S, Granqvist S, Holmstr?m M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997;336:393-398.(Arkady Vaknansky, M.D.)