• Thrombotic Disorders
• Cardiology Clinical Trials
• Thromboembolic Disease

• Cardiology & Cardiovascular Medicine
• Thrombotic Disorders
• Cardiology Clinical Trials
• Thromboembolic Disease

Edoxaban was noninferior to warfarin for prevention of recurrent venous thromboembolism (VTE) in patients with acute VTE who were initially treated with heparin. Harry R. Büller, MD, University of Amsterdam, Amsterdam, The Netherlands, presented data from the Comparative Investigation of Edoxaban Tosylate (DU176b) Versus Warfarin in the Treatment of Symptomatic Deep-Vein Clots and/or Lung Blood Clots trial [Edoxaban Hokusai-VTE Study; Büller HR et al. N Engl J Med 2013].

The third most frequent cardiovascular disease, VTE is estimated to affect about 700,000 North Americans annually [White RH. Circulation 2003]. The traditional therapy for VTE, initial treatment with heparin followed by vitamin K antagonists [Kearon C et al. Chest 2012], has been challenged by several novel oral anticoagulants which have been studied either as monotherapy or after initial treatment with heparin in the treatment of VTE [Schulman S et al. N Engl J Med 2009; EINSTEIN Investigators. N Engl J Med 2010, 2012; Agnelli G et al. N Engl J Med 2013]. The Edoxaban Hokusai-VTE Study tested the hypothesis that treatment with edoxaban would be noninferior to warfarin after acute therapy with heparin in patients presenting with acute VTE.

The international Phase 3 Edoxaban Hokusai-VTE trial randomized 8240 patients with acute symptomatic deep-vein thrombosis (DVT) or pulmonary embolism (PE) to receive 60 mg daily edoxaban or warfarin with a target INR of 2–3. Those patients with a creatinine clearance of 30 to 50 mL/min, body weight of <60 kg, or those patients treated with potent P-glycoprotein inhibitors randomized to edoxaban received a reduced dose of 30 mg daily. The duration of therapy was left to the treating physician and ranged from 3 to 12 months [Büller HR et al. N Engl J Med 2013]. Patients were eligible if they were aged ≥18 years, and were diagnosed with either an acute and symptomatic DVT in the popliteal, femoral, or iliac veins, or an acute and symptomatic PE. All patients were initially treated with low molecular weight or unfractionated heparin for at least 5 days. Blinded treatment allocation was maintained through the use of a point-of-care device for INR measurement in all patients that provided sham values for patients who were randomized to edoxaban.

The mean age of trial participants was 56 years and 57% were male. Overall, 4921 patients had DVT and 3391 patients had PE. The 30-mg dose of edoxaban was administered to 18% and 17% of patients in the edoxaban and warfarin arms, respectively. Patients in the warfarin arm had a mean time in the therapeutic window of 63.5%. Approximately 40% of patients were treated for 12 months.

The primary efficacy endpoint was recurrent symptomatic VTE (either DVT or PE). The efficacy analyses were performed in a modified intention-to-treat population consisting of all patients randomized who received at least one dose of the study drug. The upper confidence interval for noninferiority was 1.5. The primary safety endpoint was a composite of clinically relevant major and non-major bleeding.

Rates of recurrent VTE were similar with edoxaban compared with warfarin (3.2% vs 3.5%; HR, 0.89; 95% CI, 0.70 to 1.13; p<0.001 for noninferiority) [Büller HR et al. N Engl J Med 2013]. Similar results were found when limiting the analysis to events which occurred while on treatment (HR, 0.82; 95% CI, 0.60 to 1.14; p<0.001 for noninferiority). In a subgroup of patients with evidence of severe PE (evidence of right ventricular dysfunction or elevated natriuretic peptides), edoxaban reduced recurrent VTE (HR, 0.52; 95% CI, 0.28 to 0.98).

Rates of clinically relevant bleeding (major or nonmajor) were lower with edoxaban compared with warfarin (8.5% vs 10.3%; HR, 0.81; 95% CI, 0.71 to 0.94; p=0.004) [Büller HR et al. N Engl J Med 2013]. Major bleeding was similar with edoxaban compared with warfarin (1.4% vs 1.6%; HR, 0.84, 95% CI, 0.59 to 1.21; p=0.35).

Prof. Büller concluded by noting that the Edoxaban Hokusai-VTE Study confirmed the hypothesis that in patients with acute VTE treated initially with heparin, treatment with edoxaban is noninferior to warfarin for the prevention of recurrent VTE. In addition, he highlighted that edoxaban had similar efficacy as warfarin but did have a lower rate of clinically relevant bleeding and a similar rate of major bleeding when compared with warfarin.

• © 2013 MD Conference Express®