Bistro i

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.

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 Etexilatein Patients Undergoing Total Hip Replacement:

BISTRO I

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

Objective:• To determine the safe therapeutic range of

dabigatran etexilate following total hip replacement

Dose Escalating Safety Study of Dabigatran Etexilatein Patients Undergoing Total Hip Replacement:

BISTRO I

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

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 Etexilatein Patients Undergoing Total Hip Replacement:

BISTRO I

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

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

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 Etexilatein Patients Undergoing Total Hip Replacement:

BISTRO I

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

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 Etexilatein Patients Undergoing Total Hip Replacement:

BISTRO I

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

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 Etexilatein Patients Undergoing Total Hip Replacement:

BISTRO I

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

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 Etexilatein Patients Undergoing Total Hip Replacement:

BISTRO I

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

Safety Results

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

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 Etexilatein Patients Undergoing Total Hip Replacement:

BISTRO I

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

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 Etexilatein Patients Undergoing Total Hip Replacement:

BISTRO I

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

Efficacy Results

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

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 Etexilatein Patients Undergoing Total Hip Replacement:

BISTRO I

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