Efficacy and Safety Profile of Dabigatran Etexilate for the Prevention of Venous Thromboembolism in Moderately Renally Impaired Patients after Total Knee or Hip Replacement Surgery.

Dabigatran etexilate (Pradaxa®), an oral direct thrombin inhibitor, was recently approved in Europe for the prevention of venous thromboembolism (VTE) in patients undergoing elective total knee replacement or total hip replacement surgery. In phase III clinical trials two doses were studied: 220 mg once daily and 150 mg once daily. A post hoc pooled analysis was performed in patients with moderate renal impairment (GFR ≥30 and < 50 mL/min). The efficacy and safety of 220 mg and 150 mg dabigatran etexilate were compared with 40 mg subcutaneous enoxaparin. The analysis included data from the RE-MODEL (Eriksson BI et al. J Thromb Haemost2007; 5: 2178–2185) and the RE-NOVATE (Eriksson BI et al. Lancet2007; 370: 949–956) pivotal trials. The primary efficacy endpoint in both studies and this analysis was total VTE and all cause mortality, similarly, the key pre-specified secondary efficacy endpoint was major VTE and VTE-related mortality. Bleeding events (primary safety endpoint) were blindly adjudicated and categorized as major bleeding events (MBE) including surgical site bleeds. Of the patients treated with 220 mg dabigatran etexilate (1825), 150 mg dabigatran etexilate (1866) and 40 mg enoxaparin (1848), 337 patients had moderate renal impairment. 68% of these patients were evaluable for the primary efficacy endpoint, 242 were evaluable for the secondary efficacy endpoint, and all patients were available for safety and bleeding. The incidence of total VTE and all cause mortality was 17.7%, 23.5% and 27.8% in the 220 mg, 150 mg dabigatran etexilate and enoxaparin groups respectively. When the secondary endpoint was analyzed a similar trend, with a descriptive statistical significance for a lower event rate in the 220 mg group, was seen (see table). MBEs occurred in 6 of 113 patients in the 220 mg dabigatran treated group (5.3%), in none of the patients in the 150 mg dabigatran etexilate treated group (0.0%), and in 6 of 128 patients receiving 40 mg enoxaparin (4.7%). Notably, 3 of the 6 major bleeding events in the 220mg group started before any oral dabigatran etexilate treatment. In conclusion, in patients with moderate renal impairment undergoing hip or knee replacement surgery, oral 150 mg dabigatran etexilate showed similar efficacy compared with subcutaneous 40 mg enoxaparin, with apparently lower rates of major bleeding. Because of the potential negative impact of major bleeding especially in this population the 150 mg once daily dabigatran etexilate dose is currently recommended for this group. Table 1: Efficacy and bleeding endpoints in patients with moderate renal impairment (p-value from Fisher’s exact test compared to Enoxaparin) Event Dabigatran etexilate 220 mg qd Dabigatran etexilate 150 mg qd Enoxaparin 40 mg qd Total VTE and all cause mortality 17.7% (14/79) (CI 10.0%–27.9%) p=0.14 23.5% (16/68) (CI 14.1%–35.4%) p=0.59 27.8% (25/90) (CI 18.9%–38.2%) Major VTE and VTE related mortality 1.2% (1/83) (CI 0.0%–6.5%) p=0.04 4.3% (3/70) (CI 0.9%–12.0%) p=0.35 9.0% (8/89) (CI 4.0%–16.9%) MBE 5.3% (6/113) (CI 2.0%–11.2%) p=0.82 0.0% (0/96) (CI 0.0–3.8%) p=0.04 4.7% (6/128) (CI 1.7%–9.9%)