EINSTEIN–Pulmonary Embolism (PE) Study - EINSTEIN–PE

Mar 26, 2012
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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 Healthcare, Janssen Pharmaceuticals
Date Presented:
01/01/2012
Date Published:
01/01/2012
Date Updated:
03/26/2012
Original Posted Date:
03/26/2012
References

Description:

The goal of the trial was to evaluate treatment of the oral direct factor Xa inhibitor, rivaroxaban, compared with standard therapy among patients with symptomatic pulmonary embolism (PE).

Hypothesis:

Rivaroxaban will reduce symptomatic recurrent venous thromboembolism.

Study Design

  • Randomized
  • Parallel
  • Stratified

Patient Populations:

  • Patients with acute symptomatic PE with/without deep vein thrombosis

    Number of enrollees:4,833
    Duration of follow-up: approximately 9 months
    Mean patient age: 58 years
    Percentage female: 46%

Exclusions:

  • Treatment with low molecular weight heparin, unfractionated heparin, or fondaparinux for >48 hours or treatment with >1 dose of a vitamin K antagonist prior to randomization
  • Performance of thrombectomy
  • Placement of vena cava filter
  • Use of fibrinolytic therapy
  • Contraindication to any study medication
  • Another indication for a vitamin K antagonist
  • Renal insufficiency
  • Significant liver disease
  • Bacterial endocarditis
  • Active bleeding or high risk for bleeding
  • Systolic blood pressure >180 mm Hg
  • Pregnancy
  • Use of a cytochrome P-450 inhibitor
  • Limited life expectancy

Primary Endpoints:

  • Symptomatic recurrent venous thromboembolism, defined as fatal/nonfatal PE or deep vein thrombosis
  • Major or clinically relevant nonmajor bleeding

Drug/Procedures Used:

Patients with symptomatic PE were randomized to rivaroxaban 15 mg twice daily for 3 weeks, then 20 mg daily (n = 2,420) versus usual care with enoxaparin 1 mg/kg twice daily, then a vitamin K antagonist with goal international normalized ratio (INR) 2-3 (n = 2,413).

Intended treatment duration of 3, 6, or 12 months was determined by the treating physician prior to randomization.

Concomitant Medications:

Low-dose aspirin <100 mg daily, clopidogrel 75 mg daily, or both were allowed; however, nonsteroidal anti-inflammatory drugs were discouraged.

Principal Findings:

Overall, 4,833 patients were randomized. The mean age was 58 years, and 46% were women. PE was unprovoked in 65%, due to recent surgery or trauma in 17%, immobilization in 16%, estrogen therapy in 9%, and active cancer in 5%. PE was extensive (multiple lobes) in 25% of patients. Intended treatment duration was 3 months in 5%, 6 months in 57%, and 12 months in 37%. The percentage of time that INR was in the therapeutic range was 63%. Mean study drug duration was 216 days.

The primary efficacy outcome, recurrent venous thromboembolism, occurred in 2.1% of the rivaroxaban group versus 1.8% of the usual care group (p for noninferiority = 0.003).

The primary safety outcome, major or clinically relevant nonmajor bleeding, occurred in 10.3% of the rivaroxaban group versus 11.4% of the usual care group (p = 0.23).

Major bleeding: 1.2% versus 2.2% (p = 0.003), respectively.

Net clinical benefit (venous thromboembolism plus major bleeding): 3.4% versus 4.0% (p = 0.28), major bleeding: 1.1% versus 2.2% (p = 0.003), respectively.

Interpretation:

Among patients with acute symptomatic PE, the use of fixed-dose rivaroxaban was noninferior to usual care with enoxaparin/vitamin K antagonist in the prevention of recurrent venous thromboembolism. Bleeding was similar or slightly reduced with rivaroxaban. Rivaroxaban represents a simpler management approach to the treatment of acute PE.

References:

The EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;Mar 26:[Epub ahead of print].

Presented by Dr. Harry Buller at ACC.12 & ACC-i2 with TCT, Chicago, IL, March 24, 2012.

Keywords: Vitamin K, Neoplasms, Morpholines, Enoxaparin, Thiophenes, Pulmonary Embolism, Estrogens, Venous Thromboembolism, Venous Thrombosis, Factor Xa


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