New Drugs and Devices From 2011 – 2012 That Might Change Your Practice

Joe Lex, MD

Disclosures

Western J Emerg Med. 2013;14(6):619-628. 

In This Article

Xarelto® (Rivaroxaban)

This one you're going to hear about. Rivaroxaban is an oral anticoagulant that inhibits both free and bound Factor Xa. It is highly selective for this factor and has a rapid onset of action, reaching therapeutic levels in less than 4 hours. By inhibiting Factor Xa, both intrinsic and extrinsic pathways of the blood coagulation cascade are affected; thus, thrombin formation is blocked and clots are less likely to develop. It does not however inhibit thrombin (activated Factor II), and has no effects on platelets. Rivaroxaban has a flat dose response across an eightfold dose range (5–40 mg), so it theoretically allows predictable anticoagulation without dose adjustments and coagulation monitoring. Its half-life requires it to be taken twice daily to be effective.

Early in 2011, the United States (U.S.) Food and Drug Administration (FDA) approved rivaroxaban for prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in adults undergoing hip and knee replacement surgery; later in the year, the FDA approved it for stroke prophylaxis in patients with non-valvular atrial fibrillation (AF). Then on November 2, 2012, rivaroxaban was approved for the treatment of patients with DVT and PE and for longterm treatment to prevent recurrence. In other words, we now have an oral agent we can start in the emergency department (ED) to treat stable outpatients diagnosed with venous thromboembolic disease (VTE); as a bonus, it requires no bridging with heparin and no long-term monitoring.

While we will not be prescribing rivaroxaban for its first 2 indications, we will definitely be encouraged to use it for this most recent indication. Already, full-color 8-page glossy Temple University School of Medicine, Department of Emergency Medicine, Philadelphia, Pennsylvania ads are showing up in our journals and monthly specialtyspecific newspapers. Let's admit it – the prospect of treating a stable patient with VTE as an outpatient simply by writing a prescription is difficult to ignore.

Does it work? Yes, it is at least as effective as the routine regimen of low molecular weight heparin (LMWH) and warfarin. The EINSTEIN-DVT study for treatment and secondary prevention of VTE was an unblinded, randomized, noninferiority study comparing oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (usually warfarin) for 3, 6, or 12 months in patients with acute, symptomatic DVT. As so often happens in real life, the INR was in the therapeutic range (2.0 to 3.0) for only 57.7% of the time. The number of recurrent clots was similar in both groups and the principal safety outcome of major bleedings was not different.

In the EINSTEIN–Pulmonary Embolism Study rivaroxaban was also noninferior to usual care (LMWH and warfarin) as far as recurrent VTE and bleeding in patients with symptomatic PE.

While warfarin is dirt cheap, rivaroxaban costs $8–9 a day…compared to $25 to $50 a day for generic enoxaparin. Somehow, somewhere, someone will determine that this is "cost effective."

One big downside: As with dabigatran (Pradaxa®), there is no specific antidote for rivaroxaban in an exsanguinating patient. An antidote is, however, in development. Rivaroxaban's half-life is only 5–13 hours, so withholding it may be enough. One study used Prothrombin Complex Concentrates (PCC) (50 IU/kg) in 12 healthy patients and showed reversal of the prolonged prothrombin time. However this may not correlate with hemostasis or patient-centered improved outcomes. Recall the excitement generated in studies using Recombinant Factor VIIa to limit the size of hemorrhage in cerebral bleeding, but which had no effect on patient-oriented outcomes, such as survival. Nonetheless, a trial of PCC is warranted in the exsanguinating patient anticoagulated with rivaroxaban. Because of its high protein binding, dialysis will not help. Protamine and vitamin K would not be expected to help.

Rivaroxaban is just the first drug of the xaban category to be approved for outpatient therapy of VTE. Many more will soon follow: apixaban (Eliquis®) is now also available and has been used in Europe since May 2012. Betrixaban, edoxaban, and otamixaban are all in various stages of human trials.

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