Thrombus

Credit: Kevin MacKenzie

Health Canada has approved dabigatran etexilate (Pradaxa) for the treatment and prevention of venous thromboembolism (VTE).

Dabigatran is a novel, reversible, oral direct thrombin inhibitor that has been on the market for more than 5 years and is approved in more than 100 countries.

Health Canada’s latest approval of dabigatran is based on results from four phase 3 trials—RE-MEDY, RE-SONATE, and RE-COVER I and II.

The trials suggested that dabigatran given at 150 mg twice daily can treat and prevent a recurrence of deep vein thrombosis or pulmonary embolism.

RE-COVER I

In the first RE-COVER trial, dabigatran proved noninferior to warfarin for preventing VTE recurrence, and rates of major bleeding were similar between the treatment arms. However, patients were more likely to discontinue dabigatran due to adverse events.

VTE recurred in 2.4% of patients treated with dabigatran and 2.1% of patients who received warfarin (P<0.001 for noninferiority).

Bleeding events occurred in 16.1% of patients who received dabigatran and 21.9% of warfarin-treated patients (P<0.001). Major bleeding occurred in 1.6% and 1.9% of patients, respectively (P=0.38).

The numbers of deaths, acute coronary syndromes, and abnormal liver-function tests were similar between the treatment arms. But adverse events leading to treatment discontinuation occurred in 9.0% of dabigatran-treated patients and 6.8% of patients in the warfarin arm (P=0.05).

Results from RE-COVER were presented at ASH 2009 and published in NEJM.

RE-COVER II

The RE-COVER II trial suggested that dabigatran was noninferior to warfarin for preventing VTE recurrence and related deaths. This outcome occurred in 2.3% of dabigatran-treated patients and 2.2% of warfarin-treated patients (P<0.001 for noninferiority).

Major bleeding occurred 1.2% of patients who received dabigatran and 1.7% of patients who received warfarin. Any bleeding occurred in 15.6% and 22.1% of patients, respectively.

Overall, rates of death, adverse events, and acute coronary syndromes were similar between the treatment arms.

Results from RE-COVER II were published in Circulation in 2013.

RE-MEDY and RE-SONATE

The RE-MEDY and RE-SONATE trials were designed to evaluate dabigatran as extended VTE prophylaxis. Results of both trials were reported in a single NEJM article published in 2013.

The RE-MEDY trial showed that dabigatran was noninferior to warfarin as extended prophylaxis for recurrent VTE, and warfarin presented a significantly higher risk of bleeding.

VTE recurred in 1.8% of patients in the dabigatran arm and 1.3% of patients in the warfarin arm (P=0.01 for noninferiority). And the rate of clinically relevant or major bleeding was lower with dabigatran than with warfarin—at 5.6% and 10.2%, respectively (P<0.001).

Results of the RE-SONATE trial showed that dabigatran was superior to placebo for preventing recurrent VTE, although the drug significantly increased the risk of major or clinically relevant bleeding.

VTE recurred in 0.4% of patients in the dabigatran arm and 5.6% of patients in the placebo arm (P<0.001). Clinically relevant or major bleeding occurred in 5.3% of patients in the dabigatran and 1.8% of patients in the placebo arm (P=0.001).

Safety concerns with dabigatran

Over the years, the safety of dabigatran has been called into question, as serious bleeding events have been reported in patients taking the drug.

However, results of two investigations by the US Food and Drug Administration—one reported in 2012 and one reported this year—have suggested the benefits of dabigatran outweigh the risks.

Recently, a series of papers published in The BMJ raised concerns about dabigatran, claiming the drug’s developer underreported adverse events and withheld data showing that monitoring and dose adjustment could improve the safety of dabigatran without compromising its efficacy. The developer, Boehringer Ingelheim, denied these allegations.

For more information on dabigatran, see its product monograph.

Health Canada approves dabigatran for VTE