FDA Reviewers Recommend Complete Response Letter for Rivaroxaban (Xarelto)

FDA reviewers have recommended against the approval of rivaroxaban (Xarelto, Johnson & Johnson), which will be the subject of a Cardiovascular and Renal Drugs Advisory Committee meeting on Thursday. The recommendation comes as a surprise, as many physicians and analysts had expected an easy approval for the drug.

The bottom line from the FDA reviewers is that the pivotal ROCKET trial failed to demonstrate that rivaroxaban was as effective as warfarin, since warfarin was not “used skillfully” in the trial. The reviewers note that the time in the therapeutic range (TTR) for warfarin-treated patients was lower in ROCKET than in similar trials with other drugs. The mean TTR for warfarin in ROCKET was 55%, compared to 63%-73% in other recent warfarin-controlled studies, according to the reviewers. Thus, although the trial was technically a success because it demonstrated that rivaroxaban was noninferior to warfarin, this finding does “not take into account other factors, such as the quality of anticoagulation in the warfarin arm.”

The FDA explained its recommendation:

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.

The FDA also raised concerns about the safety of rivaroxaban, noting “an excess of strokes in the rivaroxaban arm during the transition from blinded study drug to open label warfarin at the end of the study.”

The single daily dose of rivaroxaban was also criticized. The FDA reviewers noted that clinical pharmacology studies had suggested that twice daily dosing might have been more safe and effective. (At the press conference for the ARISTOTLE trial at the ESC the investigators noted that the pharmacology of apixaban, which is given twice-daily, is not substantially different from that of rivaroxaban.)

The FDA reviewers said a single study could be performed that would address all the major issues raised by the review. No other safety concerns were raised by the reviewers.

It comes as no surprise then that the FDA reviewers strongly rejected J&J’s request for a superiority claim:

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.

The reviewers did hold out hope that rivaroxaban might gain approval with a weak second or third line indication:

…if the medical community is currently in great need of an additional oral anticoagulant for use in AFib patients, it might not be unreasonable to approve rivaroxaban as second or third line treatment. It might be useful in patients who are poorly controlled on warfarin or refuse to take it. However, given that dabigatran has been shown to be superior to warfarin when it [is] used reasonably well, and robustly non-inferior to warfarin when it is used extremely well, it seems advisable to make rivaroxaban a third-line agent, behind both warfarin and dabigatran.

The advisory committee meeting will undoubtedly feature some heated discussion, especially since both Steve Nissen, the noted industry skeptic, and Sanjay Kaul, a tough critic of clinical trials, will be members of the panel. Duke’s Rob Califf will present and defend the ROCKET results for J&J. It should be noted that Califf has clashed with Nissen in the past, most notably during the rosiglitazone (Avandia) controversy.

Here are links to the FDA briefing documents:



  1. sylvia martinez says

    I just started on xarelto 4 days ago iam not sure i want to take it. i have been in afib less then 10 times since the late 1980s the bleeding part is a big concern since iam a diabetic. what to do? could i stop taking it now.?


  1. […] Posts FDA Reviewers Recommend Complete Response Letter for Rivaroxaban (Xarelto)FDA Reviewers Recommend Against Approval of Rivaroxaban (Xarelto)Stenting Worse Than Medical Therapy […]

  2. […] 2011 in Orlando: Late-Breaking Clinical TrialsThe Rivaroxaban FDA Panel and Large Pragmatic TrialsFDA Reviewers Recommend Complete Response Letter for Rivaroxaban (Xarelto)Pradaxa (dabigatran) Pricing Starts to EmergeApixaban (Eliquis) Meets Primary Endpoint in […]

  3. […] Tom Burton notes that in approving rivaroxaban for this indication the FDA overruled its own staff recommendation to issue a complete response letter to J&J’s […]

  4. […] fibrillation indication.  A detailed discussion with reasons for the recommendation can be found here.  The main reason: It has not been shown that rivaroxaban is as effective as well-managed […]

Speak Your Mind