Novel Anticoagulant Edoxaban Surpasses Warfarin Across Spectrum of VTE Patients

AMSTERDAM, The Netherlands—Edoxaban, a new oral factor Xa inhibitor, matches the efficacy of warfarin while achieving less bleeding in patients with venous thromboembolism (VTE). Findings from the Hokusai-VTE trial were presented September 1, 2013, at the European Society of Cardiology Congress and simultaneously published in the New England Journal of Medicine.

Harry R. Büller, MD, of Academic Medical Center (Amsterdam, The Netherlands), and colleagues looked at more than 8,000 patients—including 4,921 with DVT and 3,319 with pulmonary embolism—who were treated at 439 centers in 37 countries. Patients were randomly assigned in a double-blind fashion to edoxaban (n = 4,143; 60 mg daily or, in those with creatinine clearance of 30-50 mL/min or body weight < 60 kg, 30 mg daily) or warfarin (n = 4,149; TTR of 63.5%).

Length of study drug treatment ranged from 3 to 12 months, with 40% of patients treated for the full duration. Follow-up was maintained for 12 months.

Similar Efficacy, Better Safety

Edoxaban met noninferiorit criteria compared with warfarin for the primary efficacy outcome of recurrent symptomatic VTE and showed better safety in terms of major and clinically relevant non-major bleeding (table 1). Other adverse events occurred at similar rates in both groups.

Table 1. Primary Outcomes by Intention-to-Treat

 

 

Edoxaban
(n = 4,143)

Warfarin
(n = 4,149)

HR (95% CI)

P Value

Recurrent Symptomatic VTE

3.2%

3.5%

0.89 (0.70-1.13)

< 0.001a

Major/Clinically Relevant Non-Major Bleeding

8.5%

10.3%

0.81 (0.71-0.94)

0.004

aP for noninferiority.

Even at the reduced edoxaban dose, efficacy was preserved and safety was improved compared with warfarin, Dr. Büller reported. He also pointed out that, overall, intracranial and retroperitoneal bleeding events were less common with edoxaban than with warfarin.

“One of the more striking observations,” came from subgroup analyses, he noted. Namely, edoxaban showed superior efficacy in patients with pulmonary embolism who had right ventricular dysfunction as indicated by NT-proBNP levels. In this subgroup, the rate of recurrent VTE was 3.3% with edoxaban and 6.2% with warfarin (HR 0.52; 95% CI 0.28-0.98).

Designed with Practice in Mind

“We designed the study in such a way that it would broaden the applicability to real-world practice,” Dr. Büller said, noting that all patients were initially given the standard treatment of enoxaparin or unfractionated heparin for at least 5 days (median 7 days). After initiation of the study drug, treatment duration was flexible and at physician discretion.

Moreover, the population presented with a broad range of disease severity, he added. Primary pulmonary embolism accounted for 40% of the group, for example, and a similar proportion had venous thrombosis extending into the femoral or iliac vein.

Discussing the trial, Stavros V. Konstantinides, MD, PhD, of Johannes Gutenberg University of Mainz (Mainz, Germany), also praised the design and conduct of Hokusai-VTE. He highlighted the trial’s centralized approach to TTR measurement “to ensure high quality of warfarin treatment” and use of imaging and biomarker assessment “to risk stratify patients with acute [pulmonary embolism] and prove finally the efficacy of edoxaban in this prespecified group.”

Warfarin may be difficult to administer, particularly in the outpatient setting when treating patients with less severe disease, he said.

Edoxaban, meanwhile, is a “patient and physician friendly drug, as it is given once daily and does not require a dose reduction after the first week, as with apixaban, or the third week, as with rivaroxaban,” Dr. Konstantinides commented. “[I]mportantly, physicians having concerns about administering a new drug to their patients right away, in the first critical hours or days, may feel more comfortable starting with low molecular weight heparin, which they have known and trusted for 15 years, and then switch to [edoxaban] after the situation is fully under control, particularly in the 30% of patients with severe [pulmonary embolism].”

 

Source:

Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;Epub ahead of print.

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Disclosures
  • The Hokusai-VTE trial was funded by Daiichi-Sankyo.
  • Dr. Büller reports receiving consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Isis Pharmaceuticals, and ThromboGenics as well as grant support from Bayer and Pfizer.

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