FDA approvalsPerspective

FDA approves Pradaxa to treat DVT, PE

Boehringer Ingelheim announced that the FDA has approved dabigatran to treat deep vein thrombosis and pulmonary embolism.

According to a company press release, the agency approved dabigatran (Pradaxa), an oral anticoagulant, for the treatment of DVT and PE in patients who have been on a parenteral anticoagulant for 5 days to 10 days, and to reduce the risk of recurrent DVT and PE in patients who were previously treated.

Dabigatran was previously approved for prevention of stroke in patients with nonvalvular atrial fibrillation.

The approval was based on the results of four phase 3 clinical trials, according to the release.

The RE-COVER and RE-COVER II trials of patients with DVT and PE who had been treated with a parenteral anticoagulant for 5 days to 10 days found that dabigatran was noninferior to warfarin in reducing recurrent DVT and PE at a median of 174 days of therapy. Researchers also found that dabigatran was associated with lower rates of overall bleeding but a higher rate of any gastrointestinal bleeding compared with warfarin (3.1% vs. 2.4%), according to the release.

The RE-MEDY trial of patients previously treated for acute DVT and PE with 3 months to 12 months of anticoagulant therapy showed noninferiority for dabigatran compared with warfarin in reducing DVT and PE after a median 534 days of therapy. Compared with warfarin, dabigatran was associated with a lower rate of overall bleeding and a higher rate of any gastrointestinal bleeding (3.1% vs. 2.2%), the company stated in the release.

The RE-SONATE trial of patients who had been treated for acute DVT and PE with anticoagulant therapy for 6 months to 18 months found that dabigatran reduced the risk for recurrent DVT and PE by 92% compared with placebo after a median 182 days of treatment (dabigatran group, 0.4%; placebo group, 5.6%; HR=0.08; 95% CI, 0.02-0.25), according to the release. The trial also indicated that compared with placebo, dabigatran was associated with higher rates of any bleeding (dabigatran group, 10.5%; placebo group, 6.1%; HR=1.77; 95% CI, 1.2-2.61), clinically relevant non-major bleeding (dabigatran group, 5%; placebo group, 2%; HR=2.54; 95% CI, 1.34-4.82) and gastrointestinal bleeding (dabigatran group, 0.7%; placebo group, 0.3%).

Boehringer Ingelheim announced that the FDA has approved dabigatran to treat deep vein thrombosis and pulmonary embolism.

According to a company press release, the agency approved dabigatran (Pradaxa), an oral anticoagulant, for the treatment of DVT and PE in patients who have been on a parenteral anticoagulant for 5 days to 10 days, and to reduce the risk of recurrent DVT and PE in patients who were previously treated.

Dabigatran was previously approved for prevention of stroke in patients with nonvalvular atrial fibrillation.

The approval was based on the results of four phase 3 clinical trials, according to the release.

The RE-COVER and RE-COVER II trials of patients with DVT and PE who had been treated with a parenteral anticoagulant for 5 days to 10 days found that dabigatran was noninferior to warfarin in reducing recurrent DVT and PE at a median of 174 days of therapy. Researchers also found that dabigatran was associated with lower rates of overall bleeding but a higher rate of any gastrointestinal bleeding compared with warfarin (3.1% vs. 2.4%), according to the release.

The RE-MEDY trial of patients previously treated for acute DVT and PE with 3 months to 12 months of anticoagulant therapy showed noninferiority for dabigatran compared with warfarin in reducing DVT and PE after a median 534 days of therapy. Compared with warfarin, dabigatran was associated with a lower rate of overall bleeding and a higher rate of any gastrointestinal bleeding (3.1% vs. 2.2%), the company stated in the release.

The RE-SONATE trial of patients who had been treated for acute DVT and PE with anticoagulant therapy for 6 months to 18 months found that dabigatran reduced the risk for recurrent DVT and PE by 92% compared with placebo after a median 182 days of treatment (dabigatran group, 0.4%; placebo group, 5.6%; HR=0.08; 95% CI, 0.02-0.25), according to the release. The trial also indicated that compared with placebo, dabigatran was associated with higher rates of any bleeding (dabigatran group, 10.5%; placebo group, 6.1%; HR=1.77; 95% CI, 1.2-2.61), clinically relevant non-major bleeding (dabigatran group, 5%; placebo group, 2%; HR=2.54; 95% CI, 1.34-4.82) and gastrointestinal bleeding (dabigatran group, 0.7%; placebo group, 0.3%).

    Perspective

    On April 7, the FDA approved dabigatran for the treatment of venous thromboembolism based on the results of the phase 3 RECOVER and RECOVER II trials. The approved dose is 150 mg twice daily for patients with a creatinine clearance >30 mL/min.

    A main caveat is that, for patients with acute VTE, the drug is approved only to be used after 5 to 10 days of initial parenteral anticoagulation based on the phase 3 clinical trial designs. The same caveat will, by the way, apply to edoxaban (Savaysa, Daiichi Sankyo) if/when it becomes FDA approved for the treatment of VTE (see Table). This need for an initial parenteral anticoagulant for the first 5 to 10 days before the oral anticoagulant drug is started is, obviously, a major disadvantage, as it complicates the anticoagulant management: The patient needs to learn how to inject low–molecular-weight heparin (LMWH) and has the expense of the costly LMWHs before being switched to the new oral anticoagulant.

    Rivaroxaban (Xarelto, Janssen) and apixaban [Eliquis; Bristol-Myers Squibb, Pfizer (FDA approval status pending, see Table)] do not have this limitation. They were used immediately upon the diagnosis of VTE in the phase 3 acute VTE treatment trials, without the need for initial LMWH therapy, giving them a clear advantage in the management of acute VTE over dabigatran and edoxaban. As for the long-term secondary prevention of VTE, dabigatran is also not an attractive treatment option in this situation because of its twice-daily dosing schedule (many patients prefer a once-daily dosing regimen); high renal drug clearance and, thus, its dependence on renal function; and very wide range of inter-individual drug half-life, even in patients with normal renal function, making it impossible to know when prior to surgeries or procedures to stop the drug for effective hemostasis.

    Thus, although this FDA approval is noteworthy, dabigatran is not an attractive option for VTE treatment for the patient and clinician when other, more convenient options are available, such as rivaroxaban at the moment and apixaban once/if it becomes FDA approved for VTE treatment. The only time I would see dabigatran as an option is if there is a financial advantage of the drug to the patient — ie, if it is treated preferentially by an insurance plan and a patient has less of a copay for dabigatran than for another one of the new oral anticoagulants — specifically rivaroxaban and, if/once FDA approved, apixaban. Finally, it is always good to have choices, even if it is only to keep drug prices down when competition exists. Thus, the approval of dabigatran is a welcome addition to our VTE treatment options.

    • Stephan Moll, MD
    • Associate professor, Department of Medicine, Division of Hematology-Oncology University of North Carolina School of Medicine Medical director, Clot Connect

    Disclosures: Moll has been a consultant for Boehinger Ingelheim, Daiichi Sankyo and Janssen.