A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial.
BACKGROUND
Dabigatran etexilate is an oral direct thrombin inhibitor undergoing evaluation for the prevention of venous thromboembolism (VTE) following orthopedic surgery.


METHODS
In a multicenter, parallel-group, double-blind study, 1973 patients undergoing total hip or knee replacement were randomized to 6-10 days of oral dabigatran etexilate (50, 150 mg twice daily, 300 mg once daily, 225 mg twice daily), starting 1-4 h after surgery, or subcutaneous enoxaparin (40 mg once daily) starting 12 h prior to surgery. The primary efficacy outcome was the incidence of VTE (detected by bilateral venography or symptomatic events) during treatment.


RESULTS
Of the 1949 treated patients, 1464 (75%) patients were evaluable for the efficacy analysis. VTE occurred in 28.5%, 17.4%, 16.6%, 13.1% and 24% of patients assigned to dabigatran etexilate 50, 150 mg twice daily, 300 mg once daily, 225 mg twice daily and enoxaparin, respectively. A significant dose-dependent decrease in VTE occurred with increasing doses of dabigatran etexilate (P < 0.0001). Compared with enoxaparin, VTE was significantly lower in patients receiving 150 mg twice daily [odds ratio (OR) 0.65, P = 0.04], 300 mg once daily (OR 0.61, P = 0.02) and 225 mg twice daily (OR 0.47, P = 0.0007). Compared with enoxaparin, major bleeding was significantly lower with 50 mg twice daily (0.3% vs. 2.0%, P = 0.047) but elevated with higher doses, nearly reaching statistical significance with the 300 mg once-daily dose (4.7%, P = 0.051).


CONCLUSIONS
Oral administration of dabigatran etexilate, commenced early in the postoperative period, was effective and safe across a range of doses. Further optimization of the efficacy/safety balance will be addressed in future studies.
Eriksson
B I
BI
Sahlgrenska University Hospital/Ostra, Göteborg, Sweden. b.eriksson@orthop.gu.se
Dahl
O E
OE
Büller
H R
HR
Hettiarachchi
R
R
Rosencher
N
N
Bravo
M-L
ML
Ahnfelt
L
L
Piovella
F
F
Stangier
J
J
Kälebo
P
P
Reilly
P
P
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000494:pharmacology*; D019644:Arthroplasty, Replacement, Hip / Q000009:adverse effects*; D019645:Arthroplasty, Replacement, Knee / Q000009:adverse effects*; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D000069604:Dabigatran; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D017984:Enoxaparin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011183:Postoperative Complications; D011184:Postoperative Period; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D012044:Regression Analysis; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013923:Thromboembolism / Q000517:prevention & control*
D000925:Anticoagulants; D001562:Benzimidazoles; D017984:Enoxaparin; D011725:Pyridines; D013917:Thrombin; D000069604:Dabigatran