Evaluation of the Acute Coronary Syndrome Safety Profile of Dabigatran Etexilate in Patients Undergoing Major Orthopaedic Surgery: Findings From Four Phase III Trials

We have previously investigated the incidence of acute coronary syndrome (ACS) events in patients treated with the new oral, reversible, direct thrombin inhibitor, dabigatran etexilate (DE) compared with enoxaparin in the treatment and post-treatment periods in patients undergoing major orthopaedic surgery in three phase III trials (RE-MODEL^™, RE-NOVATE^® and RE-MOBILIZE^®). Whether identified through local investigator reporting or blinded central event adjudication, no significant differences in ACS event rates were detected among orthopaedic surgery patients treated with DE compared with enoxaparin during or after treatment. Overall event rates were low, consistent between investigator and centrally adjudicated assessments, and without evidence for a ‘rebound’ effect for either agent in this post-surgical population. In a pooling with a fourth trial (RE-NOVATE^® II), we have now conducted an analysis of investigator-reported adverse events possibly related to ACS from 10,148 treated patients.

Patients in the RE-MODEL^™, RE-NOVATE^®, RE-NOVATE^® II and RE-MOBILIZE^® trials were randomized to receive oral DE 150 mg (n = 2737) or 220 mg (n = 3692) once daily, or subcutaneous enoxaparin (n = 3719) for 6–35 days, and were followed for 90 days post-surgery. Potential ACS events during treatment were identified based on investigator-reported adverse events classified using pre-specified Standard Medical Dictionary for Regulatory Authorities (MedDRA) Queries (SMQs). This list included terms relating to locally diagnosed ACS as well as broader MedDRA terms that could reflect undiagnosed ACS.

In all four trials, adverse events included in the SMQ ‘ischaemic heart disease’ (sub-terms myocardial infarction [MI], acute MI, angina pectoris, myocardial ischaemia, ACS, unstable angina, coronary artery disease, coronary artery occlusion, cardiac enzymes increased, electrocardiogram ST segment depression, electrocardiogram T wave abnormal, ischaemic cardiomyopathy and troponin increased) were reported by the investigator in 16 (0.4%) and 32 (1.2%) patients in the DE 220 mg and DE 150 mg groups, respectively, compared to 25 (0.7%) in the enoxaparin group during treatment. The incidence of individual adverse event terms possibly related to ACS in the respective treatment groups (DE 220 mg, DE 150 mg and enoxaparin) was as follows: MI 3 (0.1%), 11 (0.4%) and 9 (0.2%); acute MI 1 (0.0%), 3 (0.1%) and 1 (0.0%); ACS 1 (0.0%), 0 (0.0%) and 0 (0.0%); unstable angina 1 (0.0%), 0 (0.0%) and 0 (0.0%).

The analysis of > 10,000 patients showed no significant differences in investigator-reported ACS-related adverse event rates among orthopaedic surgery patients during treatment, comparing DE with enoxaparin. This is in agreement with, and supports previous findings of, investigator-related and centrally adjudicated ACS events from three trials.

Eriksson:Bristol-Myers Squibb: Consultancy; Bayer: Consultancy; Astellas: Consultancy. Smith:Boehringer Ingelheim: Employment. Caprini:ESAI: Consultancy; Pfizer: Consultancy; GSK: Consultancy; Sanofi: Consultancy; Boehringer Ingelheim: Consultancy; Covidien: Consultancy. Hantel:Boehringer Ingelheim: Employment. Clemens:Boehringer Ingelheim: Employment. Feuring:Boehringer Ingelheim: Employment.