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.

The oral direct thrombin inhibitor dabigatran etexilate (Pradaxa^®) was recently approved in Europe for the prevention of venous thromboembolism (VTE) in patients undergoing elective total knee or total hip replacement surgery. In the Phase III RE-MODEL (Eriksson BI et al. J Thromb Haemost2007; 5: 2178–2185) and RENOVATE (Eriksson BI et al. Lancet2007; 370: 949–956) clinical trials the safety and efficacy of 220 mg and 150 mg dabigatran etexilate once daily were studied. In both trials these doses were compared with 40 mg subcutaneous enoxaparin. A post hoc pooled analysis was performed in patients with moderate renal impairment (glomerular filtration rate ≥ 30 and < 50 ml/min) who participated in these two trials. The primary efficacy endpoint in both studies and the post hoc analysis was total VTE and all cause mortality; the key pre-specified secondary efficacy endpoint was major VTE and VTE-related mortality. Bleeding events (the primary safety endpoint) were blindly adjudicated and categorised as major bleeding events (MBE), which includes surgical site bleedings. A total of 1825 patients were treated with 220 mg dabigatran etexilate, 1866 with 150 mg dabigatran etexilate and 1848 with 40 mg enoxaparin. Of these, 337 patients had moderate renal impairment. 68% of these patients could be evaluated for the primary efficacy endpoint, 72% for the secondary efficacy endpoint, and all patients were included in the safety and bleeding analyses. The incidence of total VTE and all cause mortality was 17.7% (14/79), 23.5% (16/68) and 27.8% (25/90) in the 220 mg dabigatran etexilate, 150 mg dabigatran etexilate and enoxaparin groups, respectively. When the secondary efficacy endpoint was analysed a similar trend was seen, with a descriptive statistical significance for a lower event rate in the 220 mg group: 1.2% (1/83; p=0.04 vs enoxaparin using Fisher’s exact test), 4.3% (3/70) with 150 mg dabigatran etexilate; and 9.0% (8/89) in the enoxaparin group. MBE occurred in 6/113 patients (5.3%) in the 220 mg dabigatran etexilate-treated group, in none of the patients in the 150 mg dabigatran etexilate-treated group (0/96; p=0.04 vs enoxaparin using Fisher’s exact test), and in 6/128 patients (4.7%) receiving enoxaparin. Of note, 3/6 MBE in the 220 mg group started before oral dabigatran etexilate treatment was initiated. In conclusion, oral 150 mg dabigatran etexilate showed similar efficacy compared with subcutaneous enoxaparin in patients with moderate renal impairment undergoing hip or knee replacement surgery, with an apparently lower rate of major bleeding. As bleeding is a major concern, especially in this population, the 150 mg once daily dose of dabigatran etexilate is currently recommended by EMEA for this group.

Dabigatran etexilate (Pradaxa^®) is an oral direct thrombin inhibitor that was recently approved in Europe and Canada for the prevention of venous thromboembolism (VTE) in patients undergoing elective total knee replacement or total hip replacement surgery. Two pivotal clinical trials, RE-MODEL (Eriksson BI et al. J Thromb Haemost2007; 5: 2178–2185) and RENOVATE (Eriksson BI et al. Lancet2007; 370: 949–956), studied the efficacy and safety of 220 mg and 150 mg dabigatran etexilate once daily compared with 40 mg subcutaneous enoxaparin. A post hoc pooled analysis was performed in elderly patients (> 75 years) since renal function gradually declines with age. The primary efficacy endpoint was total VTE and all cause mortality and the secondary efficacy endpoint was major VTE and VTE-related mortality. The primary safety endpoint was major bleeding events (MBE), including those occurring at the surgical site. All bleeding events were blindly adjudicated. Of the patients treated with 220 mg dabigatran etexilate (n=1825), 150 mg dabigatran etexilate (n=1866) and enoxaparin (n=1848), 883 patients (16%) were over 75 years. 73% of these elderly patients were evaluable for the primary efficacy endpoint and 75% were evaluable for the secondary efficacy endpoint. All patients > 75 years were evaluable for safety outcomes, including bleeding. The incidence of total VTE and all cause mortality was 20.8% (44/212), 22.6% (49/217), and 27.2% (58/213), respectively, in the three groups. A similar trend was observed for major VTE and VTE-related mortality: 220 mg dabigatran etexilate, 1.9% (4/216, p=0.045 vs enoxaparin using Fisher’s exact test); 150 mg dabigatran etexilate, 4.5% (10/221); enoxaparin, 6.0% (13/218). MBE occurred in 11 of the 295 elderly patients receiving 220 mg dabigatran etexilate (3.7%), 4 of the 282 elderly patients receiving 150 mg dabigatran etexilate (1.4%) and in 9 of the 306 elderly patients taking enoxaparin (2.9%). Notably, 6/11 MBE in the dabigatran 220 mg group and 2/4 MBE in the 150 mg group started before the first dose of treatment. We conclude that in elderly patients (> 75 years) undergoing hip or knee replacement surgery, oral 150 mg dabigatran etexilate exhibited a numerically favourable bleeding profile with no difference in efficacy compared with 40 mg enoxaparin. Because safety, particularly bleeding, is of paramount importance in the elderly, the 150 mg once daily dose of dabigatran etexilate is currently recommended by EMEA for this group.

Dabigatran etexilate (Pradaxa^®) is an oral direct thrombin inhibitor that was recently approved in Europe and Canada for the prevention of venous thromboembolism (VTE) in patients undergoing total knee arthroplasty (TKA) or total hip arthroplasty (THA) surgery. In the phase III studies, concomitant administration of selective nonsteroidal anti-inflammatory drugs (NSAIDs with t½≤12 hours) and acetylsalicylic acid (ASA; < 160 mg/day) was allowed during treatment with dabigatran etexilate or enoxaparin. Due to the potential additional anticoagulant activity of these concomitant therapies a separate post hoc analysis was conducted to investigate the bleeding risk in these patients. We analysed the pooled study population (8,135 patients) from the three phase III trials in THA and TKA surgery (RE-MOBILIZE, RE-MODEL and RE-NOVATE) for major bleeding events (MBE). All MBE, which included surgical site bleeds, were assessed by an independent, expert adjudication committee. We report the rates of MBE and odds ratios (with 95% confidence intervals [CI]) for comparison of the subgroup concomitantly treated with NSAID (or ASA) versus the subgroup of patients without concomitant antithrombotically active medication. The overall rate of MBE (with and without NSAIDs and ASA) was 1.4% [CI 1.0–1.9], 1.1% [0.7–1.5] and 1.4% [1.0–2.0] with dabigatran etexilate 220 mg, 150 mg, and enoxaparin, respectively. Of the total population, 57.4% of patients received concomitant antithrombotic treatment: 54.1% received NSAID and 4.7% received ASA. The MBE rate in patients receiving dabigatran etexilate or enoxaparin plus NSAIDs was similar to the rate in patients taking only dabigatran etexilate or enoxaparin; 1.5% vs. 1.4% [OR 1.05; 0.55–2.01] for dabigatran etexilate 220 mg, 1.1% vs. 1.0% [OR 1.19; 0.55–2.55] for dabigatran etexilate 150 mg, and 1.6% vs. 1.2% [OR 1.32; 0.67–2.57] for enoxaparin. A similar pattern was seen in patients concomitantly receiving ASA; in this small group only a few patients with MBE were observed: 2 (1.6%) in the dabigatran etexilate 220 mg group, 2 (1.6%) in the 150 mg group, and 4 (3.0%) in the enoxaparin group. No relevant differences in risk for MBE were detected between treatments by co-medication subgroup or within treatment groups when comparing patients receiving dabigatran etexilate or enoxaparin only versus those concomitantly receiving NSAIDs or ASA. In conclusion, patients concomitantly receiving dabigatran etexilate and NSAIDs (with t½ ≤12 hours) or ASA (< 160 mg/day) have a similar risk of MBE to patients taking only dabigatran etexilate. These data support the use of dabigatran etexilate for the prevention of VTE in patients after THA or TKA, when concomitant use of NSAIDs or ASA (< 160 mg/day) is required.

BACKGROUND: Oral DVT prophylaxis not requiring monitoring is an advantage in orthopaedic patients. Dabigatran etexilate is an oral direct thrombin inhibitor undergoing evaluation for the prevention of venous thromboembolic events (VTE) following orthopaedic surgery.

METHODS: In a phase III, multicenter, non-inferiority, double-blind study, patients undergoing total knee replacement were randomized to 3 treatments. The patients received 8±2 days of oral dabigatran etexilate, 150 or 220 mg once daily starting with a half dose (i.e.75 or 110 mg) 1–4 hours after surgery, or subcutaneous enoxaparin 40 mg once daily starting 12 hours prior to surgery. The primary efficacy outcome was the composite of total VTE and all causes of mortality during the treatment period. All efficacy and safety outcome events were adjudicated by blinded independent committees.

RESULTS: Efficacy could be evaluated for 1541 (75%) treated and operated patients. Total VTE and death occurred in 40.5%, 36.4% and 37.7% of patients assigned to dabigatran etexilate 150 or 220mg once daily or enoxaparin, respectively. Proximal DVT and/ or PE occurred in 3.8%, 2.6% and 3.5% of patients receiving dabigatran 150 or 220mg or enoxaparin, respectively. Three deaths occurred during the treatment period, one in each of the treatment groups. Safety was evaluated for all 2076 patients receiving study treatment. The rate of major bleeding was 1.3%, 1.5% and 1.3% of patients receiving dabigatran 150 or 220mg or enoxaparin. Elevated LFTs (ALT > 3xULN) occurred in 3.7%, 2.8% and 4.0% of the patients treated with 150 and 220 mg dabigatran or enoxaparin during the study. A temporary rise in LFTs was observed during the follow-up period in 0.5% of the patients who had received dabigatran and in 0.4% of the patients who had received enoxaparin.

CONCLUSIONS: Non-inferiority for the primary efficacy endpoint was met for both doses of dabigatran etexilate compared to enoxaparin. There was no difference in bleeding rates between the treatment groups. Oral administration of dabigatran etexilate once daily, given early in the postoperative period, was effective and safe for the prevention of total VTE in patients undergoing total knee replacement surgery.