noninferior to enoxaparin based on a prespecified margin for the primary efficacy outcome in which the upper limit of the two sided 95% CI is 1.25 for relative risk and 5.6% for the absolute NVP-AUY922 risk difference. If both criteria were met, superiority was tested. The primary efficacy endpoint occurred in 15.1% of the apixaban group and 24.4% of the enoxaparin group. Two patients receiving apixaban died from PE and one patient receiving enoxaparin died from bleeding. Major or clinically relevant nonmajor bleeding occurred in 3.5% of the apixaban group and 4.8% of the enoxaparin group. In summary, the findings of these studies suggest that apixaban is significantly more effective than the 40 mg once daily enoxaparin regimen at reducing the composite of DVT, PE and death by any cause, with no increased risk of major bleeding.
In ADVANCE 1, apixaban did not meet the prespecified statistical criteria for noninferiority of efficacy compared with enoxaparin 30 mg twice daily. 2.3.2. Dabigatran Etexilate. Dabigatran is an oral, oncedaily, direct PLX-4720 thrombin inhibitor that can be given in a fixed oral dose without dose adjustment for age, body weight or gender. It has a rapid onset of action and provides predictable anticoagulation without the need for routine coagulation monitoring. The main elimination pathway is renal excretion, accounting for more than 80% of the systemically available dose of dabigatran. Therapeutic doses of dabigatran are unlikely to interact with drugs that are metabolized by the CYP450 system.
It has been shown that food delays the time to peak plasma Thrombosis 5 concentration by 2 hours, but does not have a relevant effect on the extent of dabigatran absorption. Dose ranging studies in patients undergoing THA suggested that the therapeutic window was 12.5 300 mg twice daily and in patients undergoing THA and TKA the optimal total daily dose was 100 300 mg. Two phase III, randomized trials in patients undergoing TKA have been conducted, one with most of its participating centres in the EU and one in North America, comparing dabigatran with enoxaparin. In the European study, once daily dabigatran was as effective as once daily enoxaparin for preventing VTE and all cause mortality in patients undergoing TKA, with similar bleeding rates.
However, in the RE MOBILIZE study , which used the usual North American enoxaparin regimen of 30 mg twice daily, dabigatran 150 mg and 220 mg showed inferior efficacy to enoxaparin for the primary outcome of total VTE and death, although bleeding rates were similar between all three groups. The secondary outcome of major VTE occurred in 3.0% of the dabigatran 150 mg group, 3.4% of the dabigatran 220 mg group and 2.2% of the enoxaparin group. The RE NOVATE study compared once daily dabigatran 220 mg or 150 mg with once daily enoxaparin 40 mg after THA. Both doses of dabigatran were noninferior to enoxaparin for the composite of total VTE and death. Rates of major bleeding did not differ significantly between the groups. There were no significant differences in cardiac events or liver enzyme elevations in any of the three groups.Whereas RE MODEL and RE NOVATE showed the tested doses of dabigatran were noninferior to the 40 mg enoxaparin regimen for VTE prophylaxis, RE MOBILIZE found dabigatran to be inferior to the 30 mg twice daily enoxaparin regimen. Possible reasons for this finding are the higher daily dosage of enoxaparin and longer treatment duration in the RE MOBILIZE study compared with the