Afib News & Events
Divided Panel Ultimately Recommends FDA Approval of Rivaroxaban (Xarelto) for Stroke Prevention in Atrial Fibrillation (AF or Afib)
FDA Panel Votes for Rivaroxaban (Xarelto): Atrial Fibrillation Patients May Soon Have Two Alternatives to Warfarin for Stroke Prevention
By Jennifer L.W. Fink
- Summary: An FDA panel voted to recommend approval of rivaroxaban (Xarelto) for stroke prevention in atrial fibrillation.
- Approximate reading time: 3–5 minutes
Adelphi, MD, September 8, 2011 — An FDA panel voted 9-2-1 to recommend approval of rivaroxaban (Xarelto) for reducing the risk of stroke in those with atrial fibrillation (afib). The FDA doesn't have to follow the panel's recommendation, but usually does.
Rivaroxaban is a "direct factor Xa (pronounced 10a) inhibitor" that was brought to the panel as a possible alternative to warfarin, the current gold standard for stroke prevention in patients with afib. Unlike warfarin, which has multiple food and drug interactions and requires frequent clinic visits, blood draws and dose adjustments, rivaroxaban is an oral medication with no reported food or drug interactions.
The vote to recommend FDA approval was far from certain, as FDA briefing materials recommended against immediate approval. The FDA reviewers did not seem to believe that the submitted data contained enough evidence to support rivaroxaban’s proposed once daily dosing schedule, or sufficient guidance to help clinicians safely transition patients from rivaroxaban to warfarin or another anticoagulant, if necessary. The reviewers also expressed concern with the design of the ROCKET-AF study, the international study that was used to compare rivaroxaban and warfarin. To learn more about the ROCKET-AF trial results, see Rivaroxaban as Effective as Warfarin for Stroke Prevention in Atrial Fibrillation.
In ROCKET-AF, only 55% of the patients taking warfarin had INR levels within the appropriate range to prevent stroke. The FDA reviewers wanted to see rivaroxaban compared to “skillfully managed” warfarin, which they defined as in the 60% to 70% range, even though only about 55% of patients on warfarin are in the proper INR range at any given time.
The FDA reviewers also wondered if twice-a-day dosing of rivaroxaban might not provide more stable drug levels in the blood. ROCKET-AF only studied once-a-day dosing. The reviewers noted an increase in bleeding episodes after study patients taking rivaroxaban were taken off of it and switched to warfarin, and expressed concern about the lack of a clinically proven way to safely transition patients from one drug to another.
Dabigatran, a recently approved oral alternative to warfarin, was clearly on the minds of the FDA reviewers, especially since many of the panel members participated in both hearings. See FDA Panel Votes for Dabigatran: Good News for Atrial Fibrillation Patients for more about the FDA panel's deliberations on dabigatran last year. Some panel members wondered aloud if being as good as warfarin was enough to recommend approval of rivaroxaban. “If a better drug is available, why is it good enough to be non-inferior to [as good as] warfarin,” asked Thomas Fleming, PhD. He and others argued that rivaroxaban might need to be better than dabigatran to warrant approval.
After nearly eight hours of discussion, the panel voted 9-2-1 (1 member abstained) to recommend the approval of rivaroxaban (Xarelto) for stroke prevention in patients with non-valvular atrial fibrillation. Darren McGuire cast one of the yes votes and noted that “it benefits patients to have competitive therapies.”
If rivaroxaban ultimately gains FDA approval, it will be the second oral alternative to warfarin. The panel was divided on whether or not to recommend rivaroxaban as a first-line medication for stroke prevention, or as an alternative to be tried in patients who are unable to take warfarin or dabigatran.
While the FDA panel voted to recommend approval of rivaroxaban, many questions remain. Among them:
- Rivaroxaban was tested in a group of much sicker patients than most drugs. Many were elderly, most took multiple drugs for other medical conditions, and some reviewers argued that rivaroxaban might work best in this “new population.” The FDA, doctors, and patients may wrestle with the question of whether rivaroxaban is most appropriate for use in sick, elderly patients, or in the general atrial fibrillation population.
- Twice-a-day dosing (not tested in ROCKET-AF) may provide more consistent blood thinning. Doctors and patients may want to consider twice daily dosing, despite the lack of data.
- Many patients experienced a bleeding episode when going off of rivaroxaban. The FDA is expected to recommend an additional study of how to safely transition patients off of rivaroxaban and onto another blood thinner, if necessary.
- The panel agreed that rivaroxaban is a good alternative for patients who don’t do well on warfarin or dabigatran. It’s still not clear if rivaroxaban is a good first choice for stroke prevention in patients with atrial fibrillation.
What does this mean for atrial fibrillation patients? Potentially, if the FDA does follow the advice of the panel (and they don't have to), then there will be a second alternative to warfarin for those with atrial fibrillation. That's great news, because if you have problems with one medication, you would still have more options available. To understand more about how to decide which medication to choose, see Rivaroxaban as Effective as Warfarin for Stroke Prevention in Atrial Fibrillation.
With rivaroxaban's results in this older population, where medications are not always taken on schedule, this could potentially have positive implications for success with younger patients who often do take medications more consistently and might have even better results. But this is something that would have to be studied.
For more information about rivaroxaban (Xarelto), or other alternatives to warfarin (Coumadin), see:
- Rivaroxaban as Effective as Warfarin for Stroke Prevention in Atrial Fibrillation
- Rivaroxaban comparable to warfarin in preventing stroke and other complications of irregular heartbeat
- FDA Approves Pradaxa as Alternative to Warfarin for Stroke Prevention in Atrial Fibrillation
Jennifer L.W. Fink is a freelance writer and Registered Nurse who writes frequently about health and wellness.
Please note that StopAfib.org does not endorse particular medications, but we do provide you information about new things happening that could impact you. Stroke prevention is the most critical issue for anyone with atrial fibrillation.
StopAfib.org would also like to give kudos to Debbe McCall, who represented you as the atrial fibrillation patient representative on the panel. She did an awesome job of bringing the experience of our atrial fibrillation community to the panel. Great job, Debbe, and thanks for doing this.
Author's Real-time Tweets from the FDA Hearing:
To better understand the discussion and thinking at the FDA hearing, here are the Twitter tweets that Jennifer sent during the hearing. Start reviewing them at the bottom of the list, which was the start of the meeting, and work up the list to the end of the meeting.
- Is anyone surprised by the FDA panel's decision to recommend approval of #rivaroxaban for #stroke prevention in #afib?
- FDA panel agrees OK for sponsor to study proposed bridging from #rivaroxaban to other anti-coag. after the product hits the market #afib
- FDA panel OK w/ #rivaroxaban as an option for pts who've failed other anticoagulants, not sure if it should be an alternative to warfarin
- FDA panel members finally seem to be acknowledging that many pts have problems w/ warfarin #rivaroxaban #afib
- Dr. Couker: Nothing that says #rivaroxaban should be 1st line therapy, concerned marketing efforts may push it that way
- Dr. Kaul voted yes for #rivaroxaban b/c he believes it should be avail. as an alternative to pts
- Nissen: "We owe pts the best therapy we can get." Admitted he might view it differently if dabigatran was not out. #rivaroxaban #xarelto
- Dr. Nissen voted no — "I am worried we may have the wrong dose administration for this drug." also worries about "creeping non-inferiority"
- Yes vote — b/c there is "tremendous unmet medical need for new therapies" #rivaroxaban #afib
- Abstaining member: What was imp. here wasn't the vote, but the "great discussion" that occurred #rivaroxaban
- Vote was 9 to 2 w/ 1 member abstaining #rivaroxaban #xarelto
- FDA panel votes to APPROVE #rivaroxaban for #stroke prevention in pts. w/ non-valvular atrial fibrillation
- FDA panel getting ready to vote re #rivaroxaban for #stroke prevention in #afib
- FDA panel seems to be leaning toward recommending an additional, sm. study to test appropriate transitioning from #rivaroxaban
- Dr. McGuire: "the reality is that we don't have any idea how to transition from one anticoagulant to another" #rivaroxaban
- FDA now addressing lack of guidelines re proper transitioning from #rivaroxaban to something else #fdacv #afib
- Dr. McGuire "I think it benefits pts to have competitive therapies" #rivaroxaban #xarelto
- Another consideration: Dabigatran hasn't been proven in the sicker pop. used to test #rivaroxaban
- ...it's non-inferior to warfarin, which is an inferior treatment. #rivaroxaban #xarelto #afib
- Dr. Fleming: Is there sufficient data to say dabigatran is superior? If so, can't really approve #rivaroxaban on grounds that....
- Dr. Fleming: if a better drug is available, why is it sufficient to be non-inferior to warfarin? #rivaroxaban
- Question before the FDA: does #rivaroxaban need to be "as effective" as warfarin or "something else?" (dabigatran)
- Possible lesson to drug co. from #rivaroxaban hearing: It might be best to be the FIRST to come out with an alternative to an existing drug
- FDA commenter: Dabigatran irrelevant to discussion, b/c was not available when #rivaroxaban was compared to warfarin #afib
- Nissen commends ROCKET -AF researchers for studying a sicker pop, but says they don't constitute a new population #rivaroxaban
- FDA panel will now debate meaning of "as effective as" re the approval of new drugs. #rivaroxaban #xarelto #afib
- FDA panel considering #rivaroxaban has considered 3 of 9 discussion questions. Taking a 10 min. break.
- Dr. Nissen describes warfarin as "forgiving" if pts. go off it for some reason, worries pts. will be at increased risk if stop #rivaroxaban
- FDA panel member points out that we're not living in Lake Wobegon where everyone is above average #rivaroxaban #afib #xarelto
- Kaul and Rose: Well-managed warfarin looks better than #rivaroxaban #fdacv #afib
- "At what pt. do we say being non-inferior is no longer effective? "Believes new drugs should be held to high standards to benefit pts #xarelto
- Dr. Nissen concerned about "the slippery slope of creeping non-inferiority" #rivaroxaban #afib #xarelto
- FDA hearing re #rivaroxaban for #stroke prevention in pts. w/ atrial fibrillation scheduled to be done in 1 hr. I predict it runs long.
- McGuire believes the warfarin anticoagulation in ROCKET-AF study is comparable to real-life practice #rivaroxaban #fdacv
- FDA panel seems split, half n half on whether once/day dosing of #rivaroxaban study
- ouch! FDA: "My concern was that the dose was chosen more for marketing advantages than scientific reasons" #rivaroxaban
- 2 yeses, 1 no and some comments re "was warfarin strategy reasonable?" #rivaroxaban
- Lincoff: "In the real world, warfarin is used inadequately" #rivaroxaban #fdacv
- Panel members will now comment on design of ROCKET-AF. Was warfarin management strategy reasonable? #rivaroxaban
- FDA beginning panel discussion portion on #rivaroxaban hearing. 3 hrs. available for discussion. #afib
- JNJ: twice a day dosing may lead to higher bleeding rates. #rivaroxaban #fdacv
- Dr. Fox: "Let's not forget the 14,000 ppl who donated their time & mortality & morbidity to this study" #rivaroxaban #afib #stroke
- FDA: "You can't avoid the fact that dabi (dabigatran) exists" #rivaroxaban #xarelto #afib
- 20 hours ago Favorite Reply Delete
- Dabigatran = the ghost in the room at the FDA hearing re #rivaroxaban. #afib #fdacv
- Lots of sophisticated statistical debate at the FDA hearing re #rivaroxaban for #stroke prevention in pts w/ atrial fibrillation
- Dr. Kaul points out the "as effective as" also needs to consider "ancillary advantages" such as cost, ease of use #rivaroxaban #afib
- This is the good part of the #rivaroxaban debate: what standard should new drugs be held to? #fdacv
- Dr. Kaul seems to disagree #rivaroxaban #afib
- Dr. Rose response: "robust non-inferiority to warfarin when used well" #rivaroxaban #afib
- Dr. Kaul quizzing FDA on def. of "as effective as" #rivaroxaban #afib
- Dr. Rose speculating that pts. were withdrawn from ROCKET study b/c they had low INR numbers on #rivaroxaban #fdacv #afib
- Says #rivaroxaban does not meet that test #fdacv #afib
- FDA reviewer Rose arguing that #rivaroxaban should have to meet same standard as dabigatran — robust noninferiority to well-managed warfarin
- FDA reviewer recommends that such a study be done prior to drug approval for #rivaroxaban to prevent #stroke in pts. with #afib
- FDA very concerned re proposed transition strategy from #rivaroxaban. Says clinical study may be needed. #fdacv #afib
- FDA: INR control in ROCKET worse than in other recent trials, potentially bias in favor of #rivaroxaban #afib
- FDA reviewer: Geography affects warfarin management. Time in therapeutic range better is US, W. Europe than in Asia, E. Europe #fdacv #afib
- Dr. Rose says community clinics in US are getting warfarin in therapeutic range up to 70% of the time #afib #fdacv
- Dr. Rose: "using warfarin well" is a hard concept to define #afib #rivaroxaban #fdacv
- Dr. Rose pointing out that FDA and sponsor used different ways to calculate warfarin pts' time in therapeutic range #rivaroxaban #xarelto
- FDA and sponsor agree that superiority claims for #rivaroxaban and warfarin re #stroke prevention in #afib are "off the table" #fdacv
- FDA seems to believe that #rivaroxaban for #stroke prevention in atrial fibrillation pts would be safer if given twice per day vs. once
- Dr. Dunnmon: #rivaroxaban more effective w/ fewer serious side effects when given twice a day #afib #stroke #fdacv
- FDA is now beginning their presentation at approval hearing for #rivaroxaban for stroke prevention in pts with atrial fibrillation #afib
- FDA questioner asking why there were triple the number of deaths in the intent to treat group in ROCKET-AF study #afib #fdacv
- Sponsor defending decision 2 study #rivaroxaban in hi-risk pop. — “We think it's time to begin doing trials in sick ppl" #fdacv #afib #stroke
- FDA hearing re #rivaroxaban for #stroke prevention in pts. w/ atrial fibrillation running long #afib
- Point: a pt's education, socioeconomic status may affect warfarin use and management #rivaroxaban #afib #fdacv
- Sponsor reply: It's not the drs do a bad job of managing warfarin, it's that it's a hard drug to use #rivaroxaban
- Dr. Nissen asking why researchers didn't provide guidelines and education re how to manage warfarin and INR #rivaroxaban #fdacv
- Dr. Califf taking FDA to task to comparing ROCET-AF and RELY, says cross-study comparisons are dangerous #rivaroxaban #fdacv #afib
- #rivaroxaban approval hearing also touching on drug approval standards in 2011 #afib #stroke #fdacv
- Dr. Califf: biologic factors can affect warfarin time in therapeutic range.(TTR) Being a woman has 3% impact in TTR. #rivaroxaban
- Dr. Califf: "Pt. adherence is critical & the idea that a Dr. can control that is far flung" #fdacv #afib #stroke #xarelto
- Dr. Califf: Warfarin time in therapeutic range doesn't necessarily correlate to adverse events. #afib #stroke #rivaroxaban
- Dr. Califf — Most ppl with atrial fibrillation don't live in the US #afib #stroke #rivaroxaban #xarelto
- Dr Califf :"we don't currently think this drug should be held to a higher standard than other treatments" #fdacv #rivaroxaban #afib
- Dr. Califf reminds FDA panel that docs don't currently know best procedure to discontinue warfarin or dabigatran #fdacv #afib #rivaroxaban
- Johnson & Johnson making every effort to address FDA's concerns re #rivaroxaban for atrial fibrillation stroke prevention #afib #fdacv
- Dr. Califf: "#rivaroxaban has a favorable benefit risk balance compared to warfarin" #afib #stroke #fdacv
- Dr. Califf: "Would hate if the msg. from this proceeding was 'don't study hi-risk pts'" #fdacv #afib #xarelto
- Dr. Califf — ave. ROCKET -AF pt. was also on 9 other meds for other conditions. #afib #fdacv #rivaroxaban
- Dr. Califf reminds FDA "many pts do not receive effective or optimal management" #afib, #fdacv #rivaroxaban
- C Nessel — Fewer pts. on #rivaroxaban experienced adverse events that included death #fdacv #afib #xarelto
- Dr. C. Nessel downplaying GI bleeds in pts. on #rivaroxaban — pts. less likely to die from GI bleed & rivaroxaban decreased brain bleeding
- Dr. R. Califf defends decision to include hi-risk atrial fibrillation pts. -"population in greatest need"— in ROCKET-AF #fdacv #xarelto
- Sponsor issue at FDA hearing for #rivaroxaban: Warfarin is often sub-optimally managed in US, w/ time in therapeutic ranges 51-64% of time
- Sponsor presentation beginning at FDA hearing regarding potential approval of #rivaroxaban to prevent #stroke in pts w/ #afib #fdacv
- FDA "will be asked how good a new drug for stroke prevention needs to be in 2011" #afib #fdacv #stroke #Xarelto
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