Transcript
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.
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.
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.
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