article249

EINSTEIN-PE

"Rivaroxaban versus Standard Therapy for Pulmonary Embolism Treatment". The New England Journal of Medicine. 2012. ClinicalTrials.gov number, NCT00439777.

Clinical Question

Does rivaroxaban, an oral factor Xa inhibitor, offer a safe and effective single-drug approach to the treatment of pulmonary embolism compared to standard therapy with enoxaparin followed by vitamin K antagonist?

Bottom Line

Rivaroxaban provides similar protection from recurrent venous thromboembolism as standard therapy and may have an improved benefit-risk profile, offering a simplified approach to the treatment of pulmonary embolism.

Major Points

Guidelines

As of the knowledge cutoff in 2023, there were no specific guidelines reflecting the results of this trial.

Design

- Multicenter, randomized, open-label, event-driven, noninferiority trial
- N=4,832 patients with acute symptomatic pulmonary embolism
- Interventions:
- Rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily)
- Standard therapy (enoxaparin followed by adjusted-dose vitamin K antagonist)
- Duration: 3, 6, or 12 months
- Primary efficacy outcome: Symptomatic recurrent venous thromboembolism
- Principal safety outcome: Major or clinically relevant nonmajor bleeding

Population

- Inclusion criteria: Acute symptomatic pulmonary embolism with or without DVT
- Exclusion criteria: Thrombectomy, vena cava filter placement, fibrinolytic agents for the current episode, treatment with more than 48 hours of anticoagulation before randomization, contraindications to enoxaparin, warfarin, or acenocoumarol
- Baseline characteristics: Representative spectrum of patients presenting with symptomatic pulmonary embolism

Interventions

- Rivaroxaban: 15 mg twice daily for 3 weeks, 20 mg once daily thereafter
- Standard therapy: Enoxaparin with transition to warfarin or acenocoumarol; discontinuing enoxaparin once INR of 2.0 or higher was maintained for 2 consecutive days.

Outcomes

- Primary outcome: Recurrent venous thromboembolism occurred in 50 patients (2.1%) in the rivaroxaban group and 44 patients (1.8%) in the standard therapy group (hazard ratio, 1.12; 95% CI, 0.75 to 1.68).
- Principal safety outcome: Clinically relevant bleeding occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard therapy group (hazard ratio, 0.90; 95% CI, 0.76 to 1.07).
- Major bleeding: Observed in 1.1% in the rivaroxaban group vs. 2.2% in the standard therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79).
- Other outcomes: Acute coronary events and liver function abnormalities were low and similar between groups.

Criticisms

- Open-label design could introduce a diagnostic-suspicion bias.
- Brief exposure to low-molecular-weight heparin prior to randomization may affect outcomes, although it is a part of current clinical practice.

Funding

The study was funded by Bayer HealthCare and Janssen Pharmaceuticals.