Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement - A phase 2 dose-finding study

被引:146
作者
Heit, JA
Colwell, CW
Francis, CW
Ginsberg, JS
Berkowitz, SD
Whipple, J
Peters, G
机构
[1] Mayo Clin & Mayo Fdn, Div Cardiovasc Dis, Rochester, MN 55905 USA
[2] Scripps Clin, Dept Orthoped Surg, La Jolla, CA USA
[3] Univ Rochester, Med Ctr, Dept Med, Rochester, NY 14642 USA
[4] McMaster Univ, Div Hematol, Hamilton, ON L8S 4L8, Canada
[5] AstraZeneca LP, Wayne, PA USA
关键词
D O I
10.1001/archinte.161.18.2215
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: Up to one third of patients who undergo total knee replacement develop deep vein thrombosis after surgery despite receiving low-molecular-weight heparin prophylaxis. Ximelagatran is a novel direct inhibitor of free and clot-bound thrombin. Methods: We performed a randomized, parallel, dose-finding study of 600 adults undergoing elective total knee replacement at 68 North American hospitals to determine the optimum dose of ximelagatran to use as prophylaxis against venous thromboembolism after total knee replacement. Patients received either ximelagatran twice daily by mouth in blinded fixed doses of 8, 12, 18, or 24 mg or open-label enoxaparin sodium, 30 mg, subcutaneously twice daily, starting 12 to 24 hours after surgery and continuing for 6 to 12 days. We measured the 6- to 12-day cumulative incidence of symptomatic or venographic deep vein thrombosis, symptomatic pulmonary embolism, and bleeding. Results: A total of 594 patients received at least I dose of the study drug; 443 patients were evaluable for efficacy. Rates of overall venous thromboembolism (and proximal deep vein thrombosis or pulmonary embolism) for the 8-, 12-, 18-, and 24-mg doses of ximelagatran were 27% (6.6%), 19.8% (2.0%), 28.7% (5.8%), and 15.8% (3.2%), respectively. Rates of overall venous thromboembolism (22.7%) and proximal deep vein thrombosis or pulmonary embolism (3.1%) for enoxaparin did not differ significantly compared with 24-mg ximelagatran (overall difference, -6.9%; 95% confidence interval, -18.0% to 4.2%; P=.3). There was no major bleeding with administration of 24 mg of ximelagatran twice daily. Conclusion: Fixed-dose, unmonitored ximelagatran, 24 mg twice daily, given after surgery appears to be safe and effective oral prophylaxis against venous thromboembolism after total knee replacement.
引用
收藏
页码:2215 / 2221
页数:7
相关论文
共 16 条
[1]  
Eriksson B. I., 2000, Haemostasis, V30, P20
[2]   Prevention of thromboembolism with use of recombinant hirudin - Results of a double-blind, multicenter trial comparing the efficacy of desirudin (Revasc) with that of unfractionated heparin in patients having a total hip replacement [J].
Eriksson, BI ;
Ekman, S ;
Lindbratt, S ;
Baur, M ;
Bach, D ;
Torholm, C ;
Kalebo, P ;
Close, P .
JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME, 1997, 79A (03) :326-333
[3]   A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement [J].
Eriksson, BI ;
WilleJorgensen, P ;
Kalebo, P ;
Mouret, P ;
Rosencher, N ;
Bosch, P ;
Baur, M ;
Ekman, S ;
Bach, D ;
Lindbratt, S ;
Close, P .
NEW ENGLAND JOURNAL OF MEDICINE, 1997, 337 (19) :1329-1335
[4]   Prevention of deep-vein thrombosis after total hip replacement: Direct thrombin inhibition with recombinant hirudin, CGP 39393 [J].
Eriksson, BI ;
Ekman, S ;
Kalebo, P ;
Zachrisson, B ;
Bach, D ;
Close, P .
LANCET, 1996, 347 (9002) :635-639
[5]  
FRIEDMAN RJ, 1994, J BONE JOINT SURG AM, V76A, P1174
[6]   Prevention of venous thromboembolism [J].
Geerts, WH ;
Heit, JA ;
Clagett, GP ;
Pineo, GF ;
Colwell, CW ;
Anderson, FA ;
Wheeler, HB .
CHEST, 2001, 119 (01) :132S-175S
[7]   USE OF HIRULOG IN THE PREVENTION OF VENOUS THROMBOSIS AFTER MAJOR HIP OR KNEE SURGERY [J].
GINSBERG, JS ;
NURMOHAMED, MT ;
GENT, M ;
MACKINNON, B ;
SICURELLA, J ;
BRILLEDWARDS, P ;
LEVINE, MN ;
PANJU, AA ;
POWERS, P ;
STEVENS, P ;
TURPIE, AGG ;
WEITZ, J ;
BULLER, HR ;
TENCATE, JW ;
NEEMEH, J ;
ADELMAN, B ;
FOX, I ;
MARAGANORE, J ;
HIRSH, J .
CIRCULATION, 1994, 90 (05) :2385-2389
[8]  
Heit JA, 1997, THROMB HAEMOSTASIS, V77, P32
[9]   Low molecular weight heparin: Biochemistry, pharmacology, perioperative prophylaxis regimens, and guidelines for regional anesthetic management [J].
Horlocker, TT ;
Heit, JA .
ANESTHESIA AND ANALGESIA, 1997, 85 (04) :874-885
[10]   PULMONARY ANGIOGRAPHY, VENTILATION LUNG-SCANNING, AND VENOGRAPHY FOR CLINICALLY SUSPECTED PULMONARY-EMBOLISM WITH ABNORMAL PERFUSION LUNG-SCAN [J].
HULL, RD ;
HIRSH, J ;
CARTER, CJ ;
JAY, RM ;
DODD, PE ;
OCKELFORD, PA ;
COATES, G ;
GILL, GJ ;
TURPIE, AG ;
DOYLE, DJ ;
BULLER, HR ;
RASKOB, GE .
ANNALS OF INTERNAL MEDICINE, 1983, 98 (06) :891-899