Dabigatran approved for treatment of venous thromboembolism

In April 2014 FDA approved dabigatran (Pradaxa) for the treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for five to 10 days, as well as for the reduction of recurrence risk for deep vein thrombosis and pulmonary embolism in those previously treated.

Dabigatran was originally approved in 2010 for stroke prevention in patients with non-valvular atrial fibrillation. As an oral direct thrombin inhibitor, dabigatran inhibits both clot-bound and free thrombin, as well as thrombin-induced platelet aggregation. Dabigatran is contraindicated in patients with active bleeding, history of hypersensitivity to dabigatran, or mechanical heart valves.  

Efficacy

The efficacy of dabigatran for treatment of DVT and PE is based on four randomized controlled trials (RCTs). RE-COVER and RE-COVER II evaluated dabigatran 150 mg by mouth twice daily vs. warfarin adjusted to an INR of 2.0 to 3.0 for six months as initial VTE treatment, each after initial parenteral anticoagulation. Over 4,000 patients with DVT, PE, or both were included in total. Both RCTs found dabigatran noninferior to warfarin, based on the outcome of symptomatic, recurrent, objective VTE and related deaths. The pooled hazard ratio (HR) in comparison to warfarin was 1.09 (0.76 to 1.57).

The RE-MEDY and RE-SONATE trials evaluated extended duration of treatment with dabigatran 150 mg by mouth twice daily vs. warfarin adjusted to an INR of 2.0 to 3.0 (RE-MEDY) or vs. placebo (RE-SONATE), for at least an additional six months of treatment, in patients who completed an initial VTE treatment course of at least three months. The RE-MEDY trial evaluated more than 2,000 patients and found dabigatran to be noninferior to warfarin for the primary outcome of recurrent or fatal VTE [HR 1.44 (0.78 to 2.64)]. The RE-SONATE trial evaluated more than 1,200 patients and found that dabigatran significantly reduced the risk of recurrent VTE in comparison to placebo [HR 0.08 (0.02 to 0.25)].

See also: FDA study shows dabigatran lowers stroke risk

Safety

The risk of major bleeding for dabigatran vs. warfarin was not significantly different in either RECOVER or RECOVER II [HR 0.82 (0.45-1.48) and HR 0.69 (0.36 to 1.32), respectively]. The composite outcome of major bleeding or clinically relevant nonmajor bleeding (CRNMB) was significantly reduced with dabigatran vs. warfarin in both trials [HR 0.63 (0.47 to 0.84) and HR 0.67 (0.56 to 0.81), respectively].

In the extended duration studies, the risk of major bleeding with dabigatran was not significantly different from that of warfarin [HR 0.52 (0.27 to 1.02)] or placebo (0% in placebo, 0.3% in dabigatran). Although the risk of the composite bleeding outcome of major bleeding or CRNMB was significantly lower with extended treatment of dabigatran vs. warfarin [HR 0.54 (0.41 to 0.71], the risk was significantly higher with dabigatran in comparison to placebo [HR 2.92 (1.52 to 5.60)].

Across the active intervention trials, the incidence of gastrointestinal events in the dabigatran and warfarin groups was similar (24.7% on dabigatran vs. 22.7% on warfarin). The incidence of dyspepsia and gastritis-like symptoms in patients taking dabigatran was 7.5% and 3.0% compared to 5.5% and 1.7% in patients taking warfarin. 

See also: Report: Dabigatran moves from mother to fetus

Dosing

In patients with a creatinine clearance (CrCl) of 30 ml/min or greater, the dabigatran dose for VTE treatment is 150 mg by mouth twice daily after five to 10 days of parenteral anticoagulation. The drug should not be used in patients with a CrCl less than 30 mL/min or in patients on hemodialysis for this indication. In addition, in patients with a CrCl less than 50 mL/min who are taking a pg-p inhibitor or in any patient taking a pg-p inducer, the use of dabigatran for VTE treatment should be avoided.

The capsule should be swallowed whole and not chewed, crushed, or opened. The package insert provides detailed recommendations for switching patients to or from dabigatran and another anticoagulant or for discontinuation suggestions before surgery and other procedures.