Edoxaban Versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism - Hokusai-VTE

Sep 01, 2013
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Hokusai-VTE
Date Presented:
01/01/2013
Date Published:
01/01/2013
Date Updated:
09/01/2013
Original Posted Date:
09/01/2013
References

Description:

Recent studies have demonstrated the potential to dramatically change the management strategy for acute venous thromboembolism (VTE). Agents such as rivaroxaban and apixaban have shown similar efficacy as warfarin with reduction in bleeding in these patients. The current trial sought to study the safety and efficacy of edoxaban, another oral direct factor Xa inhibitor, as compared with warfarin for the treatment of acute VTE.

Hypothesis:

Edoxaban would be noninferior to warfarin for the treatment of acute VTE.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Age ≥18 years
  • Objectively diagnosed acute symptomatic DVT (iliac, femoral or popliteal) or PE

    Number of enrollees: 8,240
    Duration of follow-up: 1 year
    Mean patient age: 55.8 years
    Percentage female: 43%

Exclusions:

  • Contraindication to heparin or warfarin
  • Treatment for >48 hours with therapeutic doses of heparin
  • >1 dose of vitamin K antagonist
  • Known cancer with anticipated treatment with LMWH
  • Another indication for warfarin
  • Aspirin >100 mg or dual antiplatelet therapy
  • Creatinine clearance <30 ml/min

Primary Endpoints:

  • Primary efficacy outcome: Recurrent symptomatic VTE at 1 year
  • Primary safety outcome: Major or clinically relevant nonmajor bleeding at 1 year

Secondary Endpoints:

  • Recurrent symptomatic VTE + mortality at 1 year

Drug/Procedures Used:

All patients received open-label unfractionated heparin (UFH) or low molecular weight heparin (LMWH) for 5 days. Patients then received either edoxaban 60 mg daily (30 mg if glomerular filtration rate was 30-50 ml/min or body weight was <60 kg), or warfarin to achieve an international normalized ratio (INR) of 2-3.Treatment was continued for 3-12 months.

Principal Findings:

A total of 8,240 patients were randomized, 4,118 to edoxaban and 4,122 to warfarin. Baseline characteristics were fairly similar between the two arms. Approximately 60% had deep-vein thrombosis (DVT), 16% had pulmonary embolism (PE), and 24% had both. The majority of patients had intermediate or extensive DVT. Nearly two thirds were unprovoked VTEs; cancer was presented in 9% of the patients. In patients with PE, nearly 35% had evidence of right ventricular (RV) dysfunction (i.e., were submassive PEs). Time in therapeutic range for warfarin was 63.5%.

The primary endpoint of recurrent VTEs was similar between the edoxaban and warfarin arms (3.2% vs. 3.5%, hazard ratio 0.89, 95% confidence interval 0.70-1.13; p for noninferiority < 0.001). Fatal or nonfatal PE during follow-up was noted in 2% of all patients. Results were similar in patients with DVT or PE on presentation. In patients with known RV dysfunction, edoxaban demonstrated a significant reduction in the primary endpoint (3.3% vs. 6.2%).

The primary safety outcome of first major or clinically relevant nonmajor bleeding was significantly lower in the edoxaban arm (8.5% vs. 10.3%, p = 0.004 for superiority). This was mostly driven by a reduction in clinically significant nonmajor bleeding (7.2% vs. 8.9%, p = 0.004). Fatal bleeding was similar (<0.1% vs. 0.2%), including intracranial bleeding (0% vs. 0.1%). Other side effects were similar between the two arms, including acute coronary events (0.5% vs. 0.4%).

Interpretation:

The results of the Hokusai-VTE study indicate that in-hospital heparin for 5 days followed by edoxaban 60 mg daily is noninferior to warfarin in reducing recurrent VTEs in patients with acute VTE, and results in lower bleeding. This is an important study, and adds to data from studies such as EINSTEIN-PE, RE-COVER, and AMPLIFY. A difference from these studies is that the current trial required an initial parenteral course of heparin. All of these agents have the potential to significantly simplify the management of patients with acute VTE. They might even allow outpatient management in selected patients. Cost-effectiveness analyses are eagerly awaited.

References:

The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369:1406-15.

Presented by Dr. Harry Buller at the European Society of Cardiology Congress, Amsterdam, Holland, September 1, 2013.

Keywords: International Normalized Ratio, Follow-Up Studies, Heparin, Low-Molecular-Weight, Pulmonary Embolism, Warfarin, Body Weight, Venous Thromboembolism, Thiazoles, Pyridines, Glomerular Filtration Rate, Confidence Intervals, Factor Xa


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