1. Dose Escalating Safety Study of a
New Oral Direct Thrombin Inhibitor,
Dabigatran Etexilate, in Patients
Undergoing Total Hip Replacement:
BISTRO I
Eriksson BI, Dahl OE, Ahnfelt L, Kalebo P, Stangier J, Nehmiz G,
Hermansson K, Kohlbrenner V.
J Thromb Haemost. 2004;2(9):1573-80.

2. Background:
• Dabigatran etexilate (BIBR 1048) is an oral
direct thrombin inhibitor undergoing evaluation
for the prevention of venous thromboembolism
(VTE) following total hip replacement
• Following oral administration, dabigatran
etexilate is rapidly converted to its active form
dabigatran (BIBR 953 ZW)
Dose Escalating Safety Study of Dabigatran Etexilate
in Patients Undergoing Total Hip Replacement:
BISTRO I
Eriksson B.I., et al. J Thromb Haemost. 2004;2(9):1573-80.

3. Objective:
• To determine the safe therapeutic range of
dabigatran etexilate following total hip
replacement
Dose Escalating Safety Study of Dabigatran Etexilate
in Patients Undergoing Total Hip Replacement:
BISTRO I
Eriksson B.I., et al. J Thromb Haemost. 2004;2(9):1573-80.

4. Methods:
• This was a multicenter, open label, sequential
dose escalating study conducted at
– 11 sites in Sweden
– 7 sites in Norway
Dose Escalating Safety Study of Dabigatran Etexilate
in Patients Undergoing Total Hip Replacement:
BISTRO I
Eriksson B.I., et al. J Thromb Haemost. 2004;2(9):1573-80.

5. Study Design
Dabigatran Etexilate
25mg bid
Dabigatran Etexilate
50mg bid
Dabigatran Etexilate
200mg bid
Dabigatran Etexilate
100mg bid
Dabigatran Etexilate
150mg bid
Dabigatran Etexilate
300mg bid
Dabigatran Etexilate
150mg qd
Dabigatran Etexilate
300mg qd
Dabigatran Etexilate
12.5mg bid
Total Hip
replacement
Surgery
Dabigatran Etexilate
12.5mg bid
Dabigatran Etexilate
150mg qd
Dabigatran Etexilate
300mg bid
Dabigatran Etexilate
200mg bid
Dabigatran Etexilate
150mg bid
Dabigatran Etexilate
100mg bid
Dabigatran Etexilate
50mg bid
Dabigatran Etexilate
25mg bid
Dabigatran Etexilate
12.5mg bid
4-8h post-op dose One day post-op dose
Dosing interval:
10-12h
Treatment
continued for
6-10 days

6. Methods:
• Primary safety outcome:
– Rate of major bleeding events during the treatment
phase
• Major bleeding was defined according to
recommended guidelines and included clinically
overt bleeding associated with ≥20 g/L-1
fall in
hemoglobin, clinically overt bleeding leading to
transfusion of ≥2 units packed cells
Dose Escalating Safety Study of Dabigatran Etexilate
in Patients Undergoing Total Hip Replacement:
BISTRO I
Eriksson B.I., et al. J Thromb Haemost. 2004;2(9):1573-80.

7. Methods:
• Primary efficacy outcome:
– Rate of VTE events in each group
• VTE included:
– DVT detected by venography
– Symptomatic and objectively confirmed DVT
and PE
• Secondary efficacy outcome:
– Objectively confirmed VTE during the follow-up period
Dose Escalating Safety Study of Dabigatran Etexilate
in Patients Undergoing Total Hip Replacement:
BISTRO I
Eriksson B.I., et al. J Thromb Haemost. 2004;2(9):1573-80.

8. Results:
• Of the 314 patients enrolled, 289 received at
least one dose of dabigatran etexilate
• Two hundred and sixty-two patients (90.7%)
completed the study
• Patient demographic and surgical
characteristics were similar for all treatment
groups
• Median treatment duration, defined as days on
which treatment occurred, was 8 days (range 1-
11 days)
Dose Escalating Safety Study of Dabigatran Etexilate
in Patients Undergoing Total Hip Replacement:
BISTRO I
Eriksson B.I., et al. J Thromb Haemost. 2004;2(9):1573-80.

9. Safety Results:
• A total of 289 patients were treated across the
nine dose levels
• Most blood loss occurred during surgery or prior
to administration of dabigatran etexilate
• A weak dose-response relationship was seen
for the incidence of bleeding events requiring
bleed transfusion
• On average, 7% of treated patients had a
bleeding event requiring blood transfusion
Dose Escalating Safety Study of Dabigatran Etexilate
in Patients Undergoing Total Hip Replacement:
BISTRO I
Eriksson B.I., et al. J Thromb Haemost. 2004;2(9):1573-80.

10. Safety Results
Eriksson B.I., et al. J Thromb Haemost. 2004;2(9):1573-80.

11. Efficacy Results:
• The overall DVT rate was 12.4% (28/225
patients)
• Patients receiving the 12.5 mg twice daily dose
showed the highest total and proximal DVT
rates
– 20.8% and 12.5%, respectively
Dose Escalating Safety Study of Dabigatran Etexilate
in Patients Undergoing Total Hip Replacement:
BISTRO I
Eriksson B.I., et al. J Thromb Haemost. 2004;2(9):1573-80.

12. Efficacy Results:
• The lowest total DVT rates occurred at the
higher 300 mg once and twice daily doses
– 6.1 and 0%
• No consistent dose-response relationship was
observed
• No PE events or deaths occurred during the
treatment or follow-up period
Dose Escalating Safety Study of Dabigatran Etexilate
in Patients Undergoing Total Hip Replacement:
BISTRO I
Eriksson B.I., et al. J Thromb Haemost. 2004;2(9):1573-80.

13. Efficacy Results
Eriksson B.I., et al. J Thromb Haemost. 2004;2(9):1573-80.

14. Conclusion:
• This dose finding study shows that
– Dabigatran etexilate demonstrates an
acceptable safety profile across a wide range
of doses
– The therapeutic window appears to be above
12.5 mg and below 300 mg twice daily
Dose Escalating Safety Study of Dabigatran Etexilate
in Patients Undergoing Total Hip Replacement:
BISTRO I
Eriksson B.I., et al. J Thromb Haemost. 2004;2(9):1573-80.