FDA will argue against rivaroxaban's approval...

FDA will argue against rivaroxaban approval for AF indication
September 6, 2011 Michael O'Riordan



Rockville, MD - The Food and Drug Administration (FDA) will recommend against approval of rivaroxaban (Xarelto, Bayer/Johnson & Johnson), an oral factor Xa inhibitor, for the prevention of stroke in atrial-fibrillation patients, when the Cardiovascular and Renal Drugs Advisory Committee meets September 8, 2011, according to documents released Tuesday.

The FDA review states the drug should not be approved because of concerns about dosing in the warfarin arm of ROCKET-AF, the large clinical trial showing that rivaroxaban was noninferior to dose-adjusted warfarin with regard to all-cause stroke and non-central nervous system (CNS) embolism. The FDA is concerned because the warfarin-treated patients spent just 57.8% of the time in therapeutic range (TTR), the time spent at the optimal international normalized ratio (INR), which was lower than in other trials with warfarin.

According to the FDA, any study testing a new anticoagulant that protects atrial-fibrillation patients from the risk of thrombotic events must show that the "new therapy . . . be as effective as an approved therapy when the approved-therapy drug is used skillfully." This is a requirement based on an FDA policy that requires drugs for conditions that are "life-threatening or capable of causing irreversible morbidity (eg, stroke or heart attack)."

In the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial, a study of dabigatran etexilate (Pradaxa, Boehringer Ingelheim) vs warfarin for stroke prevention in patients with atrial fibrillation, the average TTR was 64% and the median TTR 67%. Last October, the FDA voted to approve dabigatran for the prevention of stroke and systemic embolism in patients with atrial fibrillation. The drug is available in two doses, 150 mg twice daily and, for a small subset with severe renal impairment, 75 mg twice daily.

When the ROCKET-AF study was presented last year at the American Heart Association meeting, reported by heartwire at that time, study investigators pointed out that the patients in ROCKET-AF were fairly sick, with 90% of patients hypertensive, 62% having congestive heart failure, and 55% having a prior history of stroke, transient ischemic attack, or non-CNS systemic embolism. In addition, 90% of the patients had a CHADS2 score of 3 or higher, much higher than scores of patients enrolled in comparable studies, and because of these factors, the INR might have been more difficult to manage, said investigators.

In addition to concerns about warfarin dosing, the FDA reviewers are troubled by the excess of strokes in the rivaroxaban arm when the patients were transitioned from the blinded study drug to warfarin at the end of the study. "The sponsor's proposed instructions for the transition from rivaroxaban to warfarin, developed after ROCKET was completed, have not been evaluated or shown to be safe in terms of bleeding risk or embolic risk in a clinical study," according to the reviewers.

In the document, released Tuesday in advance of the committee meeting later this week, the reviewers said there were no other safety concerns with rivaroxaban, especially concerns about bleeding.

Rockville, MD (updated) -

The Food and Drug Administration (FDA) will recommend against approval of rivaroxaban (Xarelto, Bayer/Johnson & Johnson), an oral factor Xa inhibitor, for the prevention of stroke in atrial-fibrillation patients, when the Cardiovascular and Renal Drugs Advisory Committee meets September 8, 2011.

In the FDA briefing documents for the committee, which were posted online Tuesday, the clinical review recommends that a complete response letter (CRL) be issued and that the drug's sponsor conduct additional studies before the FDA approves the latest anticoagulant on the scene for stroke prevention.

The critical FDA review states the drug should not be approved because "there is a lack of substantial evidence that rivaroxaban will have its desired effect when used as recommended in labeling." Specifically, the agency review is concerned about dosing in the warfarin arm of ROCKET-AF, the large clinical trial showing that rivaroxaban was noninferior to dose-adjusted warfarin with regard to all-cause stroke and non-central nervous system (CNS) embolism. The FDA is concerned because the warfarin-treated patients spent just 57.8% of the time in therapeutic range (TTR), the time spent at the optimal international normalized ratio (INR), which was lower than in other trials with warfarin.

According to the FDA, any study testing a new anticoagulant that protects atrial-fibrillation patients from the risk of thrombotic events must show that the "new therapy . . . be as effective as an approved therapy when the approved-therapy drug is used skillfully." This is a requirement based on an FDA policy for drugs for conditions that are "life-threatening or capable of causing irreversible morbidity (eg, stroke or heart attack)."

Rivaroxaban is currently approved by the FDA for prevention of deep venous thrombosis in the setting of knee- or hip-replacement surgery.

In the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial, a study of dabigatran etexilate (Pradaxa, Boehringer Ingelheim) vs warfarin for stroke prevention in patients with atrial fibrillation, the average TTR was 64% and the median TTR 67%. Last October, the FDA voted to approve dabigatran for the prevention of stroke and systemic embolism in patients with atrial fibrillation. The drug is available in two doses, 150 mg twice daily and, for a small subset with severe renal impairment, 75 mg twice daily.

In the review, the FDA states that patients might be at a higher risk of harm from stroke and/or bleeding than those taking warfarin at therapeutic doses. For this reason, the review recommends that rivaroxaban not be approved until Bayer/Johnson & Johnson provide more data showing that it is as safe and effective as warfarin in a subgroup of patients where the TTR is greater than 67%. That said, the review also notes that if clinicians are in need of an additional oral anticoagulant, it might make sense to approve rivaroxaban as a second- or third-line agent in atrial fibrillation.

"It might be useful in patients who are poorly controlled on warfarin or refuse to take it," according to the review. "However, given that dabigatran has been shown to be superior to warfarin when it is used reasonably well and robustly noninferior to warfarin when it is used extremely well, it seems advisable to make rivaroxaban a third-line agent, behind both warfarin and dabigatran."

Speaking with heartwire about the FDA review, Dr Anne Curtis (University of Buffalo, NY) said that when ROCKET-AF was presented last year at the American Heart Association meeting, there was a significant buzz in the electrophysiology community about the results for the first Xa inhibitor, with physicians excited to have options other than warfarin for stroke prevention in atrial-fibrillation patients. That said, the concerns about the TTR are valid criticisms of the ROCKET-AF trial, although she said the TTR was not all that far off what was observed in the warfarin-treated patients in RE-LY.

"Clearly, anybody studying these drugs is going to have to be very, very careful about the warfarin groups going forward, that they maximize the opportunities to keep people in the target ranges," said Curtis.

Asked about the clinical need for rivaroxaban and the questions raised by the FDA review, Curtis said more drugs are still needed, especially drugs with different mechanisms of action, as some patients might not be able to tolerate dabigatran. If dabigatran failed, for example, then the clinician and patient are left with no other option except warfarin.

When the ROCKET-AF study was presented, and reported by heartwire at that time, study investigators pointed out that the patients in ROCKET-AF were fairly sick, with 90% of patients hypertensive, 62% having congestive heart failure, and 55% having a prior history of stroke, transient ischemic attack, or non-CNS systemic embolism. In addition, 90% of the patients had a CHADS2 score of 3 or higher, much higher than scores of patients enrolled in comparable studies, and because of these factors, the INR might have been more difficult to manage, said investigators.

Events occurring after discontinuing rivaroxaban

In addition to concerns about warfarin dosing, the FDA review questions the 20-mg once-daily dosing of rivaroxaban, saying the evidence supporting the rationale for evaluating the dose is not strong. In addition, the FDA is troubled by the rebound effect that occurs when patients stop taking rivaroxaban and the sponsor's proposed label instructions for the transition from rivaroxaban to warfarin. The review notes there were an excessive number of strokes in the rivaroxaban arm when the patients were transitioned from the blinded study drug to warfarin at the end of the study, an increased risk that was likely the result of the study design.

At the completion of ROCKET-AF, the blinded study medication was stopped and patients were transitioned to alternative anticoagulant therapy, usually warfarin. However, unlike RE-LY and other studies, patients did not undergo a short-term period of dual anticoagulant therapy—rivaroxaban and warfarin—during the lag period of INR control at the beginning of warfarin therapy. Rivaroxaban has a half-life of six to eight hours, so that a patient starting warfarin the day after rivaroxaban was stopped would not receive adequate anticoagulation for about five days, assuming it would take five days to reach an INR of 2.0.

As a result, there were significantly more strokes in the rivaroxaban study arm compared with warfarin—22 vs six events—from the end of the on-treatment period to day 30, with most events occurring early.

Bayer/Johnson & Johnson are proposing labeling instructions to assist physicians with the transition from rivaroxaban to warfarin, calling for a period of dual therapy with warfarin and rivaroxaban until the INR is under control. However, the FDA review notes that the recommendations are based on pharmacokinetic and pharmacodynamic modeling and have not been tested in studies.

"It seems prudent to require the sponsor to demonstrate in a clinical study in atrial-fibrillation patients receiving rivaroxaban therapy that the proposed transition regimen is safe and effective," the review states.

Regarding safety, particularly bleeding, the review suggests there are no safety concerns with rivaroxaban. Based on the FDA assessment of the data, "there is not a rationale with respect to major bleeding that would prevent an approval decision."

"I think rivaroxaban does what it is supposed to do, and that is prevent strokes," Curtis told heartwire. "I think the Xa inhibitors are needed, and even the FDA said they didn't see a safety concern with bleeding, but it'll be interesting to see how the panel reacts to this."

In terms of predicting how the vote will go, Curtis, who has previously chaired the circulatory system devices advisory panel, suspects the panel members will comprehend the agency's concerns but might vote for approval, given that the drug was shown to be safe and effective in the major clinical-outcomes trial.

For the blow-by-blow account of tomorrow's FDA advisory committee hearing, which will be reported extensively by heartwire, follow theheart.org on Twitter.