There’s a strong chance that my heart skipped a beat when I found out about the FDA’s approval of the new anti-clotting drug, Xarelto®. As one of more than two million Americans suffering from atrial fibrillation, a condition involving erratic heartbeats, I’m just as frustrated as the next person over the endless blood testing required when taking warfarin, so the idea that I could take one pill and forget those monthly doctor visits was incredibly appealing. But then I looked into it a little more, and what I found was not comforting.
The FDA approved Xarelto (generic name: rivaroxaban) as a blood thinner for atrial fibrillation patients in November of 2011. What you don’t read about as often is that, along with a high volume of adverse events being reported, 1) the FDA’s own review of the drug recommended against its approval and 2) Xarelto currently has no antidote.
Xarelto’s current lack of an antidote
What one has to immediately consider when taking an anticoagulant such as rivaroxaban is whether or not the anti-clotting effect can be stopped, and quickly. Apart from the immediate need of stopping a wound or ruptured organ from bleeding out and potentially causing debilitation or death, the possibility of hemorrhage may prevent a patient from receiving immediately needed life-saving surgery.
Two years after it was approved for use in afib patients, Xarelto still does not have an antidote. And while research is being conducted into possible reversal agents, researchers have noted that “there is no firm evidence that these agents will indeed reduce blood loss and improve outcome in patients with anticoagulant-induced bleeding, and it will be very difficult to design clinical trials to systematically address this issue.”
The FDA overrode its reviewers’ recommendation not to approve
Then there’s the question about Xarelto’s strange approval process.
When asked to review and recommend whether or not rivaroxaban should be permitted for use in afib patients, FDA reviewers advised against its approval, stating that during clinical trials, the control drug warfarin (a drug that has been used as an anti-clotting agent in afib patients for more than half a century) was not “used skillfully.”
That is, for warfarin to be optimally effective, it needs to be present in a patient’s blood at certain levels; thus the need for regular blood testing to make sure those levels are where they should be. During the Xarelto trials, however, those control patients taking warfarin were only in that optimal window, or “therapeutic range,” for about 55 percent of the time. Compared to the 63-to-73 percent of the time in therapeutic range in other trials using warfarin as a control, this is pretty low. In fact, according to the reviewers, the trial “does not show convincingly that rivaroxaban [Xarelto] is as effective as warfarin when the latter is used skillfully.”
Another sticking point was “an excess of strokes” in patients taking rivaroxaban as they transitioned to open label warfarin at the end of the study. Since Xarelto’s manufacturer, Janssen Pharmaceuticals, had not developed instructions on how to transition from rivaroxaban to warfarin until after its clinical trials were complete, the reviewers recommended that these instructions be “evaluated or shown to be safe in terms of bleeding risk and embolic risk” before releasing the drug on the market.
The reviewers even questioned the dose amount, pointing out that a twice daily dose of rivaroxaban would help maintain more steady blood levels of the drug than the recommended once daily dose, and might be associated with a better safety profile and improved efficacy. In fact, a lower total daily dose might be just as effective as the current recommended dose.
Finally, when asked by Janssen Pharmaceuticals if it could use “superiority language,” or statements regarding Xarelto’s superiority over warfarin for afib patients, the FDA reviewers soundly rejected it, stating that “superiority language in labeling might induce physicians to switch patients who are doing well on warfarin to rivaroxaban. However, the study data do not support an advantage for such a switch.”
In sum, the FDA reviewers explained that, in their understanding, “new therapy should be as effective as the approved therapy when the approved therapy drug is used skillfully.” Therefore, “if the underlying goal of protecting public health is to be advanced, the logical course is to reject the new therapy because it has not been convincingly demonstrated to be as effective as approved therapy.”
Shortly after this recommendation to turn down Xarelto for afib patients was presented to an FDA advisory panel, Xarelto received that panel’s sound approval in a 9 – 2 vote. Two months later, the FDA issued its approval of the drug with one contingency: that it include the FDA’s strongest warning – a black box warning – basically stating that if you stop taking Xarelto without medical supervision, you increase your risk of stroke.
Why the strong approval after so much seemed to be going against it? Who knows, but it does make a solid case for researching any new drug as much as you can before taking it. As if we need to be reminded in this day and time, it is always wise to be skeptical of drug marketing claims.