FDA Approval of Rivaroxaban

Rivaroxaban is the first available direct factor Xa inhibitor and has favorable pharmacologic properties including high oral bioavailability (relative bioavailability ~80%), rapid onset of action, and predictable dose-proportional pharmacokinetics and pharmacodynamics. Its half-life ranges between 5 to 9 hours, and the drug is excreted rapidly by renal elimination predominantly and to a lesser degree by the enterohepatic system. Despite its short half-life, phase I studies in healthy subjects have demonstrated that single doses of rivaroxaban can have pharmacodynamic effects that persist for 24 hours.

In my opinion there are specific areas of concern when considering the use of Rivaroxaban for stroke prevention in patients with atrial fibrillation. The most important is the increased risk of stroke which occurred when patients were transitioned from study drug to alternative anticoagulant therapy, usually warfarin. There is no data nor recommendations regarding how to approach patients requiring bridging or transitioning of anticoagulation prior to procedures requiring discontinuation of the drug. The FDA news release states, “Xarelto has a boxed warning to make clear that people using the drug should not discontinue the drug before talking to their health care professional. Discontinuing the drug can increase the risk of stroke.” In addition, there will be an FDA-required Medication Guide given to patients and health care providers when the medication has been dispensed outlining risks that patients will be facing while using the drug. Neither the box warning nor the FDA-required Medication Guide provides any assistance to the clinician regarding how to approach patients requiring transition or discontinuation of anticoagulation therapy.

Another concern worth mentioning is regarding the appropriate dosing of Rivaroxaban. Compared to Dabigatran, it has a shorter half-life yet it is still dosed as a once daily regimen. And finally, when physicians are polled regarding the limiting factor when considering switching from warfarin to Dabigatran the overwhelming response has been concerns over the cost and insurance coverage of Dabigatran. The estimated cost of Rivaraxaban is approximately $10/day while the cost of Dabigatran is $4-9/day (or $2-5/tablet).

Unlike the unanimous decision by the FDA panel to approve Dabigatran, there was a 9-2 (with 1 abstension) vote for the approval of Rivaroxaban. Among several of those voting in favor of approval, there was an element of caution and lack of enthusiasm regarding the final decision. As clinicians, we also must temper our enthusiasm despite the marketing and media blasts that occur when a new drug is brought to market. It would appear that additional data will be required given the above concerns. Given the recent results from ARISTOTLE demonstrating the superiority of apixaban over warfarin for prevention of stroke, bleeding and mortality clinicians may very soon have a viable reversible direct factor Xa inhibitor alternative.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: Anticoagulants, Atrial Fibrillation, Biological Availability, Half-Life, Insurance Coverage, Stroke

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