Oral Rivaroxaban Versus Standard Therapy in the Initial Treatment of Symptomatic Deep Vein Thrombosis and Long-Term Prevention of Recurrent Venous Thromboembolism - EINSTEIN–DVT

Dec 04, 2010
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Bayer Schering Pharma and Ortho-McNeil
Date Presented:
01/01/2010
Date Published:
01/01/2010
Date Updated:
12/04/2010
Original Posted Date:
12/04/2010
References

Description:

The goal of the trial was to evaluate treatment with the oral direct factor Xa inhibitor rivaroxaban compared with enoxaparin/vitamin K antagonist among patients with acute deep venous thromboembolism.

Hypothesis:

Rivaroxaban will be noninferior to enoxaparin/vitamin K antagonist in preventing recurrent symptomatic venous thromboembolism.

Study Design

  • Randomized
  • Parallel

Patient Populations:

  • Patients with acute symptomatic deep venous thromboembolism

    Number of enrollees: 3,449
    Mean patient age: 56 years
    Percentage female: 43%

Exclusions:

  • Acute pulmonary embolism
  • Creatinine clearance <30 ml/minute

Primary Endpoints:

  • Recurrent symptomatic venous thromboembolism (recurrent deep venous thromboembolism, or nonfatal or fatal pulmonary embolism)
  • Major and clinically relevant nonmajor bleeding

Secondary Endpoints:

  • Net clinical benefit
  • Total mortality
  • Cardiovascular events
  • Liver enzyme monitoring

Drug/Procedures Used:

Patients with acute deep venous thromboembolism were randomized to oral rivaroxaban 15 mg twice daily for 3 weeks, then 20 mg daily (n = 1,731) versus enoxaparin 1 mg/kg twice daily ≥5 days, followed by a vitamin K antagonist with target international normalized ratio (INR) 2-3 (n = 1,718). Physicians could decide on treatment duration (3, 6, or 12 months).

Patients who completed 6 to 12 months of therapy with study drug were eligible to participate in an extension study with randomization to rivaroxaban 20 mg daily (n = 602) versus placebo (n = 594) for an additional 6 to 12 months.

Principal Findings:

Overall, 3,449 patients were randomized. In the rivaroxaban group, the mean age was 56 years, 43% were women, body mass index was 28 kg/m2, cause of venous thromboembolism was unprovoked in 61%, recent surgery/trauma in 20%, and immobilization in 15%. The intended treatment duration of 6 months was selected in 63%. In the enoxaparin/vitamin K antagonist group, 58% of patients were at target INR.

The primary efficacy outcome, recurrent symptomatic venous thromboembolism, occurred in 2.1% of the rivaroxaban group versus 3.0% of the enoxaparin/vitamin K antagonist group (p < 0.0001 for noninferiority, p = 0.076 for superiority). Recurrent deep venous thromboembolism occurred in 0.8% versus 1.6%, and nonfatal pulmonary embolism occurred in 1.2% versus 1.0%, respectively.

In the extension study (EINSTEIN–Extension), the primary outcome occurred in 1.3% of the rivaroxaban group versus 7.1% of the placebo group (p < 0.001).

The primary safety outcome, major and clinically relevant nonmajor bleeding, occurred in 8.1% of the rivaroxaban group versus 8.1% of the enoxaparin/vitamin K antagonist group (p = 0.71).

Alanine aminotransferase >3x upper limit of normal (ULN)/bilirubin >2x ULN occurred in 0.1% versus 0.2%, respectively.

Interpretation:

Among patients with acute deep venous thromboembolism, the use of oral rivaroxaban was effective. This therapy was noninferior to subcutaneous enoxaparin followed by a vitamin K antagonist in the prevention of recurrent symptomatic venous thromboembolism. Rivaroxaban was superior to placebo with long-term treatment. Bleeding was similar between the groups and there was no evidence for an increase in hepatic toxicity. This single drug regimen without need for INR monitoring may simplify the treatment of acute deep venous thromboembolism.

References:

The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;Dec 4:[Epub ahead of print.]

Presented by Dr. Harry Buller at the European Society of Cardiology Congress, Stockholm, Sweden, August 2010.

Keywords: Vitamin K, Morpholines, Pulmonary Embolism, Thiophenes, Warfarin, Venous Thromboembolism, Bilirubin, Body Mass Index, Enoxaparin, Venous Thrombosis, Factor Xa


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