The direct thrombin inhibitor melagatran followed by oral ximelagatran compared with enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement: the EXPRESS study.
BACKGROUND
Ximelagatran and its subcutaneous (s.c.) form melagatran are novel direct thrombin inhibitors for the prevention and treatment of thromboembolic disease.


METHODS
In a double-blind study, 2835 consecutive patients undergoing total hip or knee replacement were randomized to either melagatran/ximelagatran or enoxaparin. Melagatran 2 mg was started immediately before surgery; 3 mg was then administered postoperatively, followed by 24 mg of oral ximelagatran b.i.d. beginning the next day. Enoxaparin 40 mg, administered subcutaneously o.d., was started 12 h before surgery. Both treatments were continued for 8-11 days. The main efficacy outcome measures were major venous thromboembolism (VTE); [proximal deep vein thrombosis (DVT), non-fatal and/or fatal pulmonary embolism (PE), death where PE could not be ruled out], and total VTE (proximal and distal DVT; PE; death from all causes). DVT was detected by mandatory bilateral ascending venography at the end of the treatment period or earlier if clinically suspected. The main safety outcome was bleeding.


RESULTS
The rates of major and total VTE were significantly lower in the melagatran/ximelagatran group compared with the enoxaparin group (2.3% vs. 6.3%, P = 0.0000018; and 20.3% vs. 26.6%, P < 0.0004, respectively). Fatal bleeding, critical site bleeding and bleeding requiring reoperation did not differ between the two groups. 'Excessive bleeding as judged by the investigator' was more frequent with melagatran/ximelagatran than with enoxaparin.


CONCLUSIONS
In patients undergoing total hip or knee replacement, preoperatively initiated s.c. melagatran followed by oral ximelagatran was significantly more effective in preventing VTE than preoperatively initiated s.c. enoxaparin.
Eriksson
B I
BI
Department of Orthopedics, Sahlgrenska University Hospital/Ostra, Göteborg, Sweden. b.eriksson@orthop.gu.se
Agnelli
G
G
Cohen
A T
AT
Dahl
O E
OE
Lassen
M R
MR
Mouret
P
P
Rosencher
N
N
Kälebo
P
P
Panfilov
S
S
Eskilson
C
C
Andersson
M
M
Freij
A
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage*; D019644:Arthroplasty, Replacement, Hip / Q000009:adverse effects* / Q000401:mortality; D019645:Arthroplasty, Replacement, Knee / Q000009:adverse effects* / Q000401:mortality; D001384:Azetidines / Q000008:administration & dosage; D001596:Benzylamines; D004311:Double-Blind Method; D017984:Enoxaparin / Q000008:administration & dosage; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D011300:Preoperative Care; D013810:Therapeutic Equivalency; D013917:Thrombin / Q000037:antagonists & inhibitors; D013923:Thromboembolism / Q000188:drug therapy / Q000401:mortality / Q000517:prevention & control*; D020246:Venous Thrombosis / Q000188:drug therapy / Q000401:mortality / Q000517:prevention & control*
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D017984:Enoxaparin; C109573:melagatran; C426686:ximelagatran; D013917:Thrombin; D005998:Glycine