Chondroitin was slightly reduced.41 Renal excretion is the major elimination route. Almost 80% of circulating active and small amounts of conjugated dabigatran is excreted in the urine. Based on the rate of metabolism and excretion, the mean terminal half life of dabigatran after oral ingestion is approximately 8 hours after a single dose and ranges from 12 to 14 hours after multiple doses. The half life is increased to more than 24 hours in patients with a creatinine clearance of less than 30 mL/min.44 Thus, close monitoring of the renal function every 6 to 12 months is recommended during the long term therapy of dabigatran in patients at risk of developing renal impairment. Clinical Development Prevention of VTE. The phase II Boehringer Ingelheim Study in Thrombosis trials demonstrated that dabigatran etexilate was effective in the chemical screening prevention of VTE following total hip replacement.45 This phase II trial is a multicenter, openlabel, dose escalating study involving 314 patients. The primary safety outcome was major bleeding. The study concluded that dabigatran has a satisfactory antithrombotic potential with acceptable safety profile.
Two doses of dabigatran etexilate were further rhein evaluated in phase III trials for VTE prophylaxis after hip or knee replacement. The RE MODEL trial46 was a randomized, double blind study involving 2076 patients undergoing total knee arthroplasty who received dabigatran etexilate, 150 mg or 220 mg once daily or enoxaparin 40 mg daily sc, within 6 to 10 days postoperatively. The primary efficacy outcomes were similar in all 3 treatment arms. The incidence of major bleeding did not differ significantly between the 3 groups. The investigators concluded that both the doses of dabigatran etexilate were noninferior to enoxaparin based on the prespecified noninferiority criteria and have similar safety profile as enoxaparin. Meanwhile, dabigatran etexilate was compared with enoxaparin in VTE prophylaxis following total hip arthroplasty.47,48 These 2 studies compared dabigatran with enoxaparin administered using the European ZD6474 approval dose of 40 mg once daily, starting the evening before surgery. The dabigatran etexilate versus Enoxaparin in Prevention of VTE Post Total Knee Replacement trial49 compared dabigatran with enoxaparin administered using the North American approved dose of 30 mg twice daily, starting 12 to 24 hours after surgery.
The primary outcome of these 3 trials was total occurrence of VTE, nonfatal PE, and death from all causes during treatment. The RE NOVATE I trial randomly assigned 3494 patients to oral dabigatran once daily or enoxaparin for 28 to 35 days. The efficacy of dabigatran etexilate was similar to that of enoxaparin. The incidence of major bleeding did not differ significantly among terms the 3 groups, with P ?.44 for 220 mg and P ?.60 for 150 mg, compared with enoxaparin. The RE NOVATE II trial involved 2055 patients who were relegated to receive oral dabigatran 220 mg once daily or enoxaparin. The primary efficacy outcome occurred in 7.7% of the dabigatran group versus 8.8% of the enoxaparin group, risk difference being 1.1%, P.0001 for the prespecified noninferiority margin. Major bleeding occurred in 1.4% of the dabigatran group and 0.9% of the enoxaparin group. The last study in the series.