Stephan Moll, MD writes…
Good news: The large phase 3 clinical trial comparing 3-12 months treatment of Rivaroxaban (Xarelto) with warfarin in patients with newly diagnosed pulmonary embolism was published on 3-26-2012 in the New England Journal of Medicine [reference 1], showing that Rivaroxaban was (a) noninferior to warfarin in its efficacy, (b) caused the same amount of clinically relevant bleeding (composite of major and clinically relevant nonmajor bleeding), and (c) caused less major bleeding.
The Trial
a) Methods
- 4,832 patients with acute symptomatic PE with or without DVT were enrolled and treated either (a) with rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily), or (b) with standard therapy with enoxaparin followed by warfarin target INR 2-3, for 3, 6 or 12 months. This was a non-blinded trial.
- Primary endpoint: symptomatic recurrent VTE (i.e. composite of fatal or nonfatal PE or DVT)
- Principal safety endpoint: clinically relevant bleeding (defined as composite of major or clinically relevant nonmajor bleeding)
b) Results
- VTE recurrence: 2.1 % in Rivaroxaban arm, versus 1.8 % in the warfarin arm (hazard ratio, 1.12; 95 % confidence interval, 0.75-1.68).
- Principal safety outcome (i.e. clinically relevant bleeding): 10.3 % in Rivaroxaban arm, versus 11.4 % in the warfarin arm (hazard ratio, 0.90; 95 % confidence interval, 0.76-1.07).
- Major bleeding: 1.1 % in Rivaroxaban arm, versus 2.2 % in the warfarin arm (hazard ratio, 0.49; 95 % confidence interval, 0.31-0.79; p=0.003).
c) Conclusion
- Fixed-dose rivaroxaban given from the get-go to patients with acute PE was non-inferior to warfarin, with a similar rate of clinically relevant bleeding, but less major bleeding.
My Perspective on Xarelto in VTE
These PE data nicely complement the 2011 Rivaroxaban DVT data: Rivaroxaban is as effective and at least as safe as warfarin for the treatment of acute DVT and PE. No initial bridging with low molecular weight heparin is needed, nor monitoring of anticoagulant effect. It is certainly a convenient way to anticoagulate a patient with VTE. At this point the drug is not FDA approved for VTE treatment. It is, however, available on the U.S. market as 10 mg, 15 mg and 20 mg tablets for other indications. I would not quite jump into treating a patient with newly diagnosed DVT or PE with Rivaroxaban, as I’d prefer to see all data reviewed by the FDA. However, the published data on DVT and PE are encouraging that Rivaroxaban may be a good choice for the acute treatment of DVT and PE.
At this point I would consider switching a patient who has been on warfarin to Xarelto, 20 mg once daily, if he/she is not tolerating warfarin well, i.e. has fluctuating INRs, significant side effects from warfarin (hair loss, fatigue) or difficulty getting to an anticoagulation clinic and monitoring the INR. However, a detailed discussion would need to be held with the patient about this off label use.
The full NEJM article can be read here. A press release from Johnson & Johnson can be found here, containing the Xarelto prescribing information.
The Other New Oral Anticoagulants
The four new oral anticoagulant drugs that are at present of most relevance to the clinician are (a) Pradaxa® (Dabigatran), (b) Xarelto® (Rivaroxaban), (c) Eliquis® (Apixaban), and (d) Savaysa® (Edoxaban). Clinical-practical relevant information on these drugs is discussed in various Clot Connect blogs. A summarizing table of the clinical trials, publications and FDA approval status can be found here (see table here).
References
- The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;pre-published March 26th, 2012 (ahead of print).
- EINSTEIN investigators. Oral Rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499-2510.
Disclosure: I have consulted for OthoMcNeil and Bayer, the companies developing Xarelto.
Last updated: May 6th, 2012
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