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Edoxaban after initial heparin found noninferior to standard therapy
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AMSTERDAM — Once-daily edoxaban administered after initial treatment with low–molecular-weight heparin was noninferior to standard therapy and associated with less bleeding in patients with venous thromboembolism, including those with severe pulmonary embolism, according to findings from the Hokusai-VTE study.
The randomized, double blind, noninferiority study included 3,319 patients with pulmonary embolism (PE) and 4,921 with deep vein thrombosis (mean age, 57 years). All patients received initial subcutaneous low–molecular-weight heparin and were then randomly assigned to daily edoxaban (Daiichi-Sankyo) 60 mg or 30 mg for those at a perceived higher bleeding risk, due to low body weight or renal impairment, or to warfarin per standard of care. Patients received the study drugs for 3 to 12 months.
According to data presented at ESC Congress 2013 by Harry R. Büller, MD, edoxaban, a direct inhibitor of activated factor X, was noninferior to warfarin for the primary efficacy outcome of recurrent symptomatic venous thromboembolism (VTE; 3.2% vs. 3.5%; HR=0.89; 95% CI, 0.7-1.13; P<.001 for noninferiority). In patients who qualified for the 30-mg dose, recurrent VTE occurred in 3% compared with 4.2% assigned warfarin (HR=0.73; 95% CI, 0.42-1.26). In a subgroup of patients with PE and evidence of right ventricular dysfunction, efficacy was superior with edoxaban (3.3% vs. 6.2%; HR=0.52; 95% CI, 0.28-0.98).
“The regimen tested in Hokusai-VTE is noninferior to standard therapy for the prevention of recurrent VTE,” Büller, professor of vascular medicine at Academic Medical Center, Amsterdam, said at a press conference.
For the principal safety outcome of major or clinically relevant nonmajor bleeding, edoxaban was superior to warfarin (8.5% vs. 10.3%; HR=0.81; 95% CI, 0.71-0.94; P=.004 for superiority). Major bleeding occurred in 1.4% of the edoxaban group vs. 1.6% of the warfarin group (HR=0.84; 95% CI, 0.59-1.21). Among the subgroup of patients at high risk for bleeding, efficacy of the 30-mg edoxaban dose was maintained with significantly less bleeding than observed with warfarin, according to Büller. Clinically relevant bleeding occurred in 7.9% of the high-risk edoxaban subgroup vs. 12.8% of the warfarin group (HR=0.62; 95% CI, 0.44-0.86).
Adverse event rates were similar between the edoxaban and warfarin groups. In total, 938 patients with PE had right ventricular dysfunction. In this subgroup, the rate of recurrent VTE was 3.3% with edoxaban vs. 6.2% with warfarin (HR=0.52; 95% CI, 0.28-0.98). The rate of acute coronary events was 0.5% with edoxaban vs. 0.4% with warfarin.
In addition, the researchers also observed less intracranial bleeds with the use of edoxaban, Büller said.
“The message here is that patients [who] receive low–molecular-weight heparin and edoxaban and have severe PE are really better off,” he said at the press conference.
“Our findings are likely to be generalizable,” the researchers wrote in The New England Journal of Medicine. “In this global study, we included patients with both provoked and unprovoked VTE, and treatment durations varied from 3 to 12 months at the discretion of the treating physician. Loss to follow-up was very low (<0.2%) as was the rate of withdrawal of consent (<0.9%).”
The trial was conducted at 439 centers in 37 countries between January 2010 and October 2012. – by Katie Kalvaitis
For more information:
Büller HR. Hot Line I: Late breaking trials on thrombosis. Presented at: the European Society of Cardiology Congress; Aug. 31-Sept. 4, 2013; Amsterdam.
The Hokusai-VTE investigators. N Engl J Med. 2013;doi:10.1056/NEJMoa1306638.
Disclosure: The study was supported by Daiichi-Sankyo. Buller reports receiving consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Isis Pharmaceuticals and ThromboGenics, and grant support from Bayer and Pfizer.