June 20, 2016
4 min read

Edoxaban safe, effective for extended prevention of recurrent VTE

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Extended treatment with the oral anticoagulant edoxaban prevented recurrent venous thromboembolism and led to fewer major bleeding events than warfarin among patients with venous thromboembolism, according to a post-hoc analysis of a randomized trial.

Thus, daily edoxaban (Savaysa, Daiichi Sankyo) may serve as an alternative to warfarin for patients requiring extended anticoagulation for the prevention of recurrent VTE.

“Evidence-based practice guidelines recommend anticoagulant treatment for at least 3 months in patients with VTE, followed by an assessment of the benefits and risks of continued therapy,” Gary Raskob, PhD, professor of medicine and epidemiology in the college of public health at University of Oklahoma Health Sciences Center, and colleagues wrote. “The risk for recurrence is substantial for patients with unprovoked VTE or continuing risk factors, and many of these patients need extended anticoagulation beyond 3 months.”

However, little study has focused on the role of direct oral anticoagulants, as compared with vitamin K antagonists, in patients recommended for extended therapy.

Raskob and colleagues performed a post-hoc analysis of the randomized, noninferiority Hokusai-VTE trial to determine the risk–benefit profile of extended treatment using edoxaban compared with warfarin.

In the trial, 8,292 patients with acute VTE were randomly assigned to edoxaban (n = 3,633) or warfarin (n = 3,594) for at least 3 months and up to 12 months. The researchers documented outcomes at 12 months, irrespective of individual treatment duration.

The incidence of adjudicated symptomatic recurrent VTE at each time interval (3 months, > 3 months to 6 months, > 6 months to < 12 months, and at 12 months) — as well as the cumulative incidence between 3 months and 12 months — served as the primary efficacy endpoints.

The incidence of clinically relevant bleeding — comprised of major or clinically relevant nonmajor bleeding events — served as the primary safety endpoint.

The researchers performed on-treatment and intention-to-treat analyses.

The on-treatment analysis showed a 1.1% incidence of recurrent VTE at 3 months in the edoxaban arm (n = 44 of 4,118), compared with 1.2% (n = 51 of 4,122) in the warfarin arm.

Eighty-seven percent of patients (n = 7,227) continued treatment beyond 3 months.

The VTE incidence among patients on treatment from longer than 3 months to 6 months was 0.7% (n = 8 of 1,076) in the edoxaban arm and 0.5% (n = 5 of 1,084) in the warfarin arm.

The VTE incidence of patients treated for more than 6 months to 12 months was 0.2% (n = 2 of 896) in the edoxaban arm and 0.8% (n = 7 of 851) in the warfarin arm. At 12 months, the edoxaban arm had a VTE incidence rate of less than 0.1% (n = 1 of 1,661) and the warfarin arm had an incidence rate of 0.1% (n = 2 of 1,659).

Patients assigned edoxaban had a cumulative incidence of recurrent VTE of 0.3%, compared with 0.4% in the warfarin arm (HR = 0.78; 95% CI, 0.36-1.72).

The cumulative incidence of clinically relevant bleeding was 3.9% in the edoxaban arm compared with 4.1% in the warfarin arm (HR = 0.97; 95% CI, 0.77-1.22). The cumulative incidence of major bleeding was 0.3% in the edoxaban arm and 0.7% in the warfarin arm (HR = 0.45; 95% CI, 0.22-0.92).

Ten patients assigned edoxaban and nine patients assigned warfarin died. Bleeding caused or contributed to two deaths in the warfarin arm and to no deaths in the edoxaban arm.

The intention-to-treat analysis produced similar results.

The researchers acknowledged that randomization occurring at initiation of anticoagulation may have potentially biased patients treated longer than 3 months, and thus may serve as a study limitation.

“More data are needed on the relative efficacy and safety of direct oral anticoagulants compared with vitamin K antagonists for longer durations of treatment,” Raskob and colleagues wrote. “In conclusion, VTE patients continuing treatment with edoxaban beyond 3 months had a low rate of recurrent VTE, and once-daily edoxaban provides an effective and more convenient alternative to warfarin for extended treatment to prevent recurrent VTE.”

The growing availability of agents for the reversal of bleeding caused by direct oral anticoagulants suggests that they can be used regularly and safely, Jerrold H. Levy, MD, FAHA, FCCM, professor of anesthesiology and co-director of the cardiothoracic ICU at Duke University School of Medicine, and Beverley J. Hunt, MD, FRCP, FRCPath, professor of thrombosis and hemostasis and director of the hemostasis research unit at Guy’s & St. Thomas’ NHS Foundation Trust in London, wrote in an accompanying editorial.

“For dabigatran [Pradaxa, Boehringer Ingelheim]-treated patients, idarucizumab [Praxbind, Boehringer Ingelheim], a monoclonal antibody that binds dabigatran and acutely reverses its anticoagulation effect, is currently approved for major bleeding or for patients requiring emergency procedures, and is available in many countries,” Levy and Hunt wrote. “For the reversal of the Xa inhibitors, andexanet [Portola Pharmaceuticals] and ciraparantag [PER977, Perosphere] are under investigation for acute bleeding episodes.”

Levy and Hunt suggest considering specific reversal strategies when deciding which anticoagulant to use. – by Cameron Kelsall

Disclosure: Daiichi Sankyo funded this study. Raskob reports personal fees from Daiichi Sankyo and Itreas during the conduct of this study, as well as personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Ionis Pharmaceuticals, Janssen, Pfizer and Portola outside the submitted work. Please see the full study for a list of all other researchers’ relevant financial disclosures. Levy reports steering committee roles with Boehringer Ingelheim, CSL Behring, Grifols, Instrumentation Laboratory, Janssen and The Medicines Company. Hunt reports no relevant financial disclosures.