NO DIFFERENCE DETECTED IN EFFICACY OF DABIGATRAN ETEXILATE WHEN INITIAL DOSING WAS DELAYED: A POST HOC ANALYSIS OF POOLED DATA FROM THE EUROPEAN PIVOTAL PHASE III TRIALS

Abstract

Dabigatran etexilate (Pradaxa^®) is an oral anticoagulant licensed in multiple countries, Europe and Canada, for the prevention of venous thromboembolic events (VTE) in patients undergoing total hip replacement surgery (THR) or total knee replacement surgery (TKR). The label recommendation for therapy initiation of dabigatran etexilate is a half dose given 1–4 hours after surgery. If this is not possible, then dabigatran etexilate should be started the day following surgery with the full dose. In the European pivotal Phase III clinical trials, this initial dosing was delayed until the day after surgery in 14% of the cases. This prompted a post hoc study to analyze if these patients received adequate thromboprophylaxis. Pooled efficacy data of major VTE events (composite of proximal DVT, symptomatic DVT, pulmonary embolism and VTE-related death) from the two European pivotal trials (RE-MODEL; Eriksson BI et al. J Thromb Haemost2007;5:2178–2185, and RENOVATE; Eriksson BI et al. Lancet2007;370:949–956) where analyzed. The group with delayed dosing was compared to the group that received therapy initiation on the day of surgery to determine if there was any significant effect on clinical outcome. The final decision on the timing of the administration of the first dose required sometimes clinical judgment, and in particular good haemostasis had to be present. Therefore, the bleeding rate and the timing of the first dose are confounded and an analysis of bleeding events was not performed. The major VTE rate in the group with delayed treatment initiation compared with the 1–4 hour post surgery treatment initiation group were 2.2% (95% CI: 0.1–4.4) vs. 3.0% (95% CI: 2.0–3.9) for 220 mg dabigatran etexilate, 8.3% (95% CI: 4.3–12.4) vs. 3.5% (95% CI 2.5–4.5) for 150 mg dabigatran etexilate, and 4.3% (95% CI 1.2–7.4) vs. 3.7% (95% CI 2.7–4.8) for 40 mg enoxaparin. As the confidence intervals overlap markedly, no statistically significant differences where found. In conclusion, no difference in the rates of major VTE and VTE related mortality was seen when the doses of dabigatran etexilate were postponed to the first postoperative day. These data need to be interpreted carefully due to the low number of patients in the delayed treatment group. As recommended in the current labelling of dabigatran etexilate, treatment should be initiated 1–4 hours post-surgery.