Oral Anticoagulants recurrent risk reduction.6 For this indication, the recommended dose of dabigatran is 150 mg twice daily in patients with a creatinine clearance (CrCl) >30 mL/ min, which should only be initiated following 5 to 10 days of parenteral anticoagulation. For use in atrial fibrillation, 150 mg twice daily is also recommended, however there is no requirement for parenteral anticoagulation prior to initiating dabigatran in this instance. A dosage reduction to 75 mg twice daily is recommended for use in atrial fibrillation with a CrCl of 15-30 mL/min. However, this dose has not been studied through clinical trials, but rather represents a recommendation based on pharmacokinetic extrapolation. Additionally, the use of dabigatran in patients with a CrCl <15 mL/min should be avoided. Because dabigatran is subject to drug interactions with p-glycoprotein inhibitors and inducers, in those with a CrCl 30-50 mL/min who are using concomitant p-glycoprotein inhibitors such as dronedarone or oral ketoconazole, a reduction in dabigatran dosing to 75 mg twice daily is recommended. Anyone with a CrCl <30 mL/min who is taking a concomitant p-glycoprotein inhibitor should avoid the use of dabigatran altogether. Regarding the indication of VTE treatment and recurrent risk reduction, dabigatran use in anyone with a CrCl <30 mL/min should be avoided as clinical trials have excluded this population.7 Approval for stroke and systemic embolism prevention in those with non-valvular atrial fibrillation was granted based on the results of the phase III noninferiority study, The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. This trial compared the use of 2 different doses of dabigatran versus warfarin in patients with atrial fibrillation having at least 1 risk factor for stroke. For the primary efficacy endpoint of stroke or systemic embolism, dabigatran dosed at 110 mg twice daily, was noninferior to warfarin (1.53% vs. 1.69% of patients annually, hazard ratio 0.91 (0.74-1.11); P<0.001 for noninferiority). Dabigatran dosed at 150 mg twice daily was superior to warfarin (1.11% vs. 1.69% of patients annually, hazard ratio 0.66 (0.53-0.82); P<0.001 for superiority). The rate of major bleeding was significantly lower with dabigatran 110 mg twice daily compared to warfarin, whereas major bleeding rates were similar between dabigatran 150 mg twice daily and warfarin. Of note, for dabigatran 150 mg twice daily, the rate of gastrointestinal (GI) bleeding was higher in comparison to warfarin (1.51% vs. 1.02% CONTINUING EDUCATION of patients annually, relative risk 1.50 (1.19-1.89); P<0.001), and the incidence of intracranial bleeding was lower (0.30% vs. 0.75% of patients annually, relative risk 0.40 (0.27-0.60); P<0.001).8 Several trials were instrumental in supporting the approval of dabigatran for use in the treatment and recurrent risk reduction of VTE. In RE-COVER, a randomized, double-blind, noninferiority trial, following an initial median treatment period of 9 days with parenteral anticoagulation, patients with acute VTE received either dabigatran 150 mg twice daily or dose-adjusted warfarin for a period of 6 months. Dabigatran was found to be noninferior to warfarin for the primary efficacy endpoint of recurrent VTE and related deaths (2.4% vs. 2.1% of patients, CI -0.8-1.5; P<0.001 for noninferiority). The risk of major bleeding was similar between groups.9 In a repeat trial, RE-COVER II, the results of the RE-COVER trial were confirmed and dabigatran was again found noninferior to warfarin for the primary efficacy endpoint of recurrent VTE and related deaths (2.3% vs. 2.2% of patients, hazard ratio 1.08 (0.64-1.8); P<0.001 for noninferiority). Major bleeding episodes between groups were also found to be similar (1.2% vs. 1.7% of patients, hazard ratio 0.69 (0.36-1.32); P<0.001).10 Extended treatment with dabigatran for 6-36 months in patients with acute VTE who had already received a minimum of 3 months of anticoagulation was investigated through the RE-MEDY and RESONATE trials. RE-MEDY served as the active-control study by comparing dabigatran 150 mg twice daily to dose adjusted warfarin, whereas RE-SONATE was designed as its placebo-control counterpart, comparing dabigatran 150 mg twice daily to placebo. RE-MEDY found dabigatran to be noninferior to warfarin in the prevention of recurrent VTE or related deaths (1.8% vs. 1.3% of patients, hazard ratio 1.44 (0.78-2.64); P=0.01 for noninferiority). No significant difference in the rate of major bleeding was found between groups (0.9% vs. 1.8% of patients, hazard ratio 0.52 (0.27-1.02); P=0.06). In RE-SONATE, dabigatran was found to be superior in significantly decreasing the incidence of recurrent VTE and related deaths compared to placebo (0.4% vs. 5.6% of patients, hazard ratio 0.08 (0.02-0.25); P<0.001). No significant difference between groups in the rate of major bleeding was found.11 Although several trials have shown no significant difference in major bleeding risk between dabigatran

AJP Fall 2015