Daily Rivaroxaban as Effective as Enoxaparin for Pulmonary Embolism
CHICAGO, IL—A fixed dose of the oral factor X inhibitor rivaroxaban is noninferior to standard therapy with enoxaparin and a vitamin K antagonist in patients with acute symptomatic pulmonary embolism with or without deep-vein thrombosis (DVT). In a presentation March 26, 2012, at the annual American College of Cardiology/i2 Scientific Session, researchers said the twice daily therapy shows a potentially improved benefit-risk profile, which could have significant implications for simplifying treatment and reducing length of stay.
The study was simultaneously published online in the New England Journal of Medicine.
Harry R. Büller, MD, of Academic Medical Center (Amsterdam, the Netherlands) presented data from EINSTEIN-PE, an open-label safety and efficacy trial conducted at 283 centers in 38 countries from March 2007 through March 2011. Patients were randomly assigned to 1 of 2 arms:
- Oral rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily)
- Standard therapy with enoxaparin (1.0 mg/kg body weight twice daily and either warfarin or acenocoumarol, started within 48 hours after randomization and discontinued when the INR was 2.0 or more for 2 consecutive days and the patient had received at least 5 days of enoxaparin); vitamin K antagonist for 3, 6, or 12 months adjusted to maintain an INR of 2.0 to 3.0
Aspirin at a dose of no more than 100 mg/day and clopidogrel 75 mg/day or both were permitted.
The median duration of enoxaparin treatment was 8 days and the INR at the end of treatment was 2.0 or more in 83%.
Similar Recurrence, Bleeding Rates
Overall, rivaroxaban was noninferior to enoxaparin for the primary endpoint of recurrent thromboembolism at 1 year, while major or clinically relevant bleeding was similar in both groups and any major bleeding was less frequent with rivaroxaban (table 1).
Table 1. Clinical Outcomes
|
|
Rivaroxiban |
Enoxaparin |
Hazard Ratio (95% CI) |
P Value |
|
Recurrent Thromboembolism |
2.1% |
1.8% |
1.12 (0.75-1.68) |
0.003a |
|
Major or Clinically Relevant Bleeding |
10.3% |
11.4% |
0.90 (0.76-1.07) |
0.23 |
|
Any Major Bleeding |
1.1% |
2.2% |
0.49 (0.31-0.79) |
0.003 |
a P value for noninferiority.
Dr. Büller noted that the curves for major bleeding started to separate in the initial 5 to 10 days, suggesting that the combination of enoxaparin and vitamin K leads to greater early bleeding that levels off but remains “something we need to pay more attention to.”
By day 21, the end of the twice-daily rivaroxaban treatment, recurrent thromboembolism had occurred in 0.7% in the rivaroxaban group compared with 0.9% in the enoxaparin group. In patients with anatomically limited, intermediate or extensive pulmonary embolism at baseline, recurrence rates were 1.6%, 2.5% and 1.7%, respectively in the rivaroxaban group and 1.3%, 2.2% and 1.4% in the enoxaparin group.
Net clinical benefit (a composite of recurrence and major bleeding) was 3.4% in the rivaroxaban group and 4.0% in the enoxaparin group (HR 0.85; 95% CI 0.63-1.14; P = 0.28). Additionally, there was a low incidence of acute coronary events both during treatment and in the 30-day post treatment period in both groups. The incidence of liver toxicity also was low and equivalent, with 0.2% of patients in both treatment groups experiencing high alanine aminotransferase and bilirubin levels.
Dr. Büller said a subgroup analysis is planned to try to identify a risk profile for those most likely to experience bleeding.
Cost Effectiveness Forthcoming
In July 2011, rivaroxaban (Xarelto; Johnson & Johnson, New Brunswick, NJ) was approved by the United States Food and Drug Administration for the prevention of DVT in patients undergoing knee or hip replacement surgery. It also is approved to reduce the risk of stroke in patients with nonvalvular atrial fibrillation.
C. Michael Gibson, MD, of Beth Israel Deaconess Medical Center (Boston, MA), asked Dr. Büller if there were any occurrences of life-threatening bleeding such as intracranial hemorrhage or retroperitoneal hemorrhage among the cohort.
Dr. Büller responded that there was 1 case of intracranial hemorrhage with rivaroxaban vs. 10 with enoxaparin and 1 case of retroperitoneal hemorrhage with rivaroxaban vs. 7 with enoxaparin.
“That’s very impressive,” Dr. Gibson said, noting the high costs attached to bleeding.
Dr. Büller said his group is in the process of conducting cost analyses and looking at the clinical impact of the specific bleeding events. He added that he believes the growing data on rivaroxaban support the suggestion that patients eventually will be able to spend less time in the hospital, with some even treated on an outpatient basis due to the simpler strategy provided by the novel oral agent.
Source:
The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;Epub ahead of print.
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L.A. McKeown is a Senior Medical Journalist for TCTMD, the Section Editor of CV Team Forum, and Senior Medical…
Read Full BioDisclosures
- The study was sponsored by Bayer Healthcare and Janssen Pharmaceuticals.
- Dr. Büller reports serving as a consultant to and serving on the advisory boards of Bayer HealthCare, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Isis, Pfizer, Roche, Sanofi-Aventis, and Thrombogenics.
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