Evaluation of the acute coronary syndrome safety profile of dabigatran etexilate in patients undergoing major orthopedic surgery: findings from four Phase 3 trials.
BACKGROUND
Several anticoagulants have been associated with a 'rebound effect' that potentially increases the risk of thrombosis and cardiovascular events following discontinuation. Four Phase 3 trials of dabigatran etexilate in major orthopedic surgery incorporated measures to assess the risk of acute coronary syndrome (ACS) events during and after treatment.


METHODS
Patients in RE-MOBILIZE®, RE-MODEL™, RE-NOVATE®, and RENOVATE® II were randomized to dabigatran etexilate (150 mg or 220mg once daily) or enoxaparin for 6-35 days, and followed for up to 90 days. ACS data were tabulated from investigator-reported serious adverse events using ACS-specific Medical Dictionary for Regulatory Authorities (MedDRA) lower-level terms. To ensure that all ACS events were identified in the initial three studies, RE-MOBILIZE®, RE-MODEL™, and RE-NOVATE®, a broader list of MedDRA terms was prespecified that would trigger treatment-blinded adjudication.


RESULTS
When pooling the four trials, patients receiving dabigatran etexilate 220 mg had the fewest treatment-emergent, investigator-reported ACS events (6 [0.16%] vs 14 [0.51%] for dabigatran 150 mg and 13 [0.35%] for enoxaparin). Corresponding post-treatment rates were 2 (0.06%), 1 (0.04%), and 4 (0.11%). Similarly, treatment-emergent centrally adjudicated definite or likely ACS events in the first three trials were fewer in patients on dabigatran 220 mg (16 [0.60%]) than dabigatran 150 mg (26 [0.95%]) and enoxaparin (20 [0.74%]). The corresponding numbers post treatment were 2, 2, and 7. None of these between-group differences were statistically significant.


CONCLUSIONS
No increased ACS signal was detected with dabigatran etexilate compared with enoxaparin during or after treatment.
University Hospital Sahlgrenska, Gothenburg, Sweden. b.eriksson@orthop.gu.se
Bengt I
BI
Eriksson
John J
JJ
Smith
Joseph
J
Caprini
Stefan
S
Hantel
Andreas
A
Clemens
Martin
M
Feuring
Janet
J
Schnee
Gregory W
GW
Barsness
D054058:Acute Coronary Syndrome / Q000401:mortality*; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000627:therapeutic use; D001562:Benzimidazoles / Q000627:therapeutic use*; D000069604:Dabigatran; D064420:Drug-Related Side Effects and Adverse Reactions / Q000401:mortality; D006801:Humans; D015994:Incidence; D038622:Internationality; D008297:Male; D008875:Middle Aged; D009985:Orthopedics / Q000706:statistics & numerical data*; D011183:Postoperative Complications / Q000401:mortality* / Q000517:prevention & control*; D011725:Pyridines / Q000627:therapeutic use*; D018570:Risk Assessment; D012307:Risk Factors; D016019:Survival Analysis; D015996:Survival Rate; D013927:Thrombosis / Q000401:mortality* / Q000517:prevention & control*; D016896:Treatment Outcome
D000925:Anticoagulants; D001562:Benzimidazoles; D011725:Pyridines; D000069604:Dabigatran