Rivaroxaban approved for stroke prevention in atrial fibrillation

Earlier today, representatives from the US Food & Drug Administration (FDA) announced that the agency had approved the oral factor Xa inhibitor rivaroxaban (Xarelto^®) for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). The decision follows several months of controversy, as FDA reviewers initially recommended against its approval in atrial fibrillation while the FDA Cardiovascular and Renal Drugs Advisory Committee voted in its favor.

The approval is based on the results of the ROCKET-AF trial, which found that rivaroxaban was just as effective (i.e., non-inferior) to warfarin for the prevention of stroke and systemic embolism in patients with non-valvular AF. Bleeding events were comparable between the two agents, although patients on rivaroxaban had less severe bleeding events, including fewer intracranial hemorrhages and fewer cases of fatal bleeding.

The results of ROCKET-AF have been the subject of harsh criticism, including the fact that patients randomized to warfarin had a time in therapeutic range (TTR) of only 55%. While no official threshold exists, most consider TTR > 60-65% as being the gold standard when making comparisons to warfarin. Critics of the trial have also expressed concerns over the increased incidence of thromboembolic events in patients who discontinued therapy or were transitioned from rivaroxaban to another anticoagulant.

Given that rivaroxaban is no more effective than warfarin and probably less effective than dabigatran (although the two have not been compared head-to-head), I anticipate Johnson & Johnson will market the drug based on its convenience (e.g., once daily dosing and no need for lab monitoring). The once daily dosing strategy still perplexes me, especially given that the drug's half life is only about 5-9 hours. Rivaroxaban is dosed twice daily in the management of deep venous thrombosis and pulmonary embolism, although it has not yet been approved for these indications in the US.

In terms of comparing it to existing alternatives, I would put rivaroxaban at a distant third, considering it primarily for those patients in whom compliance may be a limiting factor. However, the "rebound" effects observed in ROCKET-AF are troubling, so I would still make this recommendation with some trepidation. Another proposed advantage (details in a previous post) is that the effects of rivaroxaban can be reversed by prothrombin complex concentrate (PCC), a prohemostatic agent comprised of factors II, VII, IX, and X. However, whether the reversal of laboratory measurements (e.g., prothrombin time, endogenous thrombin potential) correlates with a clinically meaningful improvement in bleeding events is still unknown at this time.

The excitement over rivaroxaban will likely be eclipsed by the approval of apixaban, another factor Xa inhibitor and the latest to be compared to warfarin in patients with AF. Although apixaban is dosed twice daily, it was shown to be safer and more effective than warfarin, two features that have yet to be matched by any other anticoagulant to date. While no official word on its approval is currently available, I imagine it will only be a matter of time.