Warfarin, Move Over: Dabigatran Gets Unanimous Thumbs-up From FDA Advisory Panel

September 20, 2010

September 20, 2010 ( Updated September 21, 2010) (Silver Spring, Maryland) One of cardiology's fondest wishes moved closer to fulfillment as an FDA advisory panel unanimously recommended approval of a potential replacement for warfarin in one of the most common heart disorders. Barring any unforeseen damning revelations about the drug, for which the agency had already expressed support, its approval of the oral thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim) for stroke prevention in atrial fibrillation (AF) is all but certain.

"I think it's a tremendous advance; people have been looking for a replacement for warfarin for decades," Dr A Michael Lincoff (Cleveland Clinic, OH), acting chair of the FDA's Cardiovascular and Renal Drugs Advisory Committee, observed for heartwire after the meeting adjourned. In the key dabigatran clinical trial it considered, the drug came out ahead of warfarin in multiple ways, he said: ease of administration, associated risk of intracranial hemorrhage, "and it's somewhat better at preventing stroke."

The panel, with its nine voting members, made its decision based on what's generally seen as the well-designed, solidly executed 18 000-patient Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial, which showed that dabigatran was noninferior to warfarin at a lower dosage and superior at a higher one for preventing thromboembolic stroke in paroxysmal or permanent AF.

As previously reported by heartwire , RE-LY compared dabigatran at 110 mg twice daily and 150 mg twice daily against a conventional warfarin regimen, all in open-label fashion. Patients who took the higher dosage showed a 34% falloff in stroke risk compared with those on warfarin (p<0.001) over a median of two years.

"All in all, I think it's a plus for our patients," panelist Dr Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA) said for heartwire with some circumspection. "I think the major issue here is going to be how [Boehringer Ingelheim] is going to price it. To me, that is the elephant in the room."

In Canada, Europe, and other places that the drug is available, "the cost is anywhere from $8 to $12 per day," Kaul said. It's that high because the indication is prophylaxis after hip and knee surgery, "which is a limited duration, maybe 35 days. But you can't have a drug priced at $8 to $12 when patients have to take it lifelong. So they'll have to get their act right on the price issue."

Rat Poison

Warfarin, a vitamin-K antagonist, is distinguished in being one of the oldest, most widely used, most effective, and most disliked drugs in cardiology: it dramatically cuts ischemic stroke risk in AF but generally requires regular anticoagulation monitoring to get the dosage right, which can be arduous for patients and the healthcare system. Patients must also watch their intake of a lot of healthy, vitamin-K–containing foods.

Some physicians express their low opinion of warfarin by referring to it according to its primary use before it became a medicine, which was inducing fatal hemorrhage in Rattus norvegicus.

The kicker with dabigatran, even when "noninferior" to warfarin, is that it doesn't require anticoagulation monitoring--or major diet changes, for that matter. And as the trial suggested and panelists agreed, at the higher dose it was significantly although only modestly more stroke-preventive than warfarin.

"It's a milestone. Warfarin has been around for a very long time, and no one has been able to replace it for most of the indications for warfarin. It's a hard drug to use, it has a lot of warts," panelist Dr Steven Nissen (Cleveland Clinic) said to heartwire .

"This one [dabigatran] is a little bit cleaner, and the fact that you don't have to monitor [anticoagulation] is an advantage if you think about patients who have to go in and get stuck for an INR--some of them as often as once a week," he observed.

"The difficulties in using warfarin are really the biggest issue, and in fact its [associated] bleeding [risk] stems in part from that," according to Lincoff, "because the patients with the poorest [anticoagulation] control are the ones who bleed, in many cases."

Confronting What Controversy There Was

Debate among the advisory panel throughout the day was tame; there were few criticisms of the RE-LY trial's design, little real disappointment in the results, and clear enthusiasm for replacing warfarin for such a widespread indication. But there were a few bones to pick.

During the deliberations, Nissen pressed the concern that RE-LY's open-label nature made it more likely that the three patient groups would be managed differently. "You can't be entirely comfortable with any open-label trial involving drugs of this importance that's going to be taken by this number of people, given that there may be biases we can't even measure or understand in trials. There's a reason that, historically, we've always done double-blind trials, and that reason is a good reason."

He called the way the trial was executed "reasonable but not optimal." Several others on the panel seemed easy to forgive the open-label design, if not see it as a plus.

Yes, double-blind trials are conducted to minimize bias, agreed panelist Dr James D Neaton (University of Minnesota, Minneapolis), a biostatistician. "But I think this [design] actually is far more informative to clinical practice in terms of what the drug really can do under real-life circumstances than a very artificial trial that would be set up to do it double blind. So I'm not convinced it wasn't optimal in this particular situation."

The other biostatistics expert on the panel, Dr Scott Emerson (University of Washington, Seattle), concurred. So did Lincoff, agreeing that a double-blind approach would have forced the dabigatran group to be monitored for anticoagulation status, which would have introduced bias of different kinds.

To heartwire , Kaul agreed that RE-LY's design "was somewhat in keeping with the realities of daily practice. The investigators, despite the challenges of conducting an open-label noninferiority study, did a pretty good job of minimizing and controlling biases."

The FDA didn't charge the panel with voting on a question that provided some of the only suspense throughout the day, whether the approval should cover only the higher dose that was "superior" to warfarin, the lower dose that was "noninferior," or perhaps both. The agency was already on record as favoring approval of only the higher dosage.

Dosing Do-Si-Do

"A number of us argued that giving clinicians the choice of [the higher dose along with] a little bit less effective dose that one could use in certain patients was the right thing to do," Nissen said when interviewed. The lower dose, their reasoning goes, might be selected for patients at special risk for bleeding complications, such as the very elderly. If that happens, he cautioned, the labeling should at least specify a preference for the higher dose. His concern, Nissen stated during the meeting, is that if a doctor is hesitant to risk bleeding complications by giving the higher dose, and there is no lower dose, the patient will get neither.

But Lincoff and several other panelists adamantly preferred approval for only the higher dose. Given evidence for a more effective treatment than standard warfarin therapy--that is, dabigatran at 150 mg twice daily--the 110-mg twice-daily dose that is comparable to warfarin in effectiveness shouldn't be part of the approval. To make it so would be to allow clinicians to trade efficacy against ischemic stroke for a lower bleeding risk, which is usually a bad deal.

And, Lincoff observes, the high-bleeding-risk patients who might be suitable for the lower dose also tend to be those at high risk of ischemic stroke, who might most benefit from the higher dose.

"I think we need to be a lot more careful about what we're trying to avoid in terms of bleeding complications," he said when interviewed. "A stroke can be devastating even in its mildest form."

Kaul agreed. "I felt that if the lower dose is approved with the claim it may have a better bleeding profile, most physicians are more likely to prescribe the lower dose, which to my mind is an inferior standard."

Despite no mandate to vote on dosing, the panel nonetheless did so informally, with those preferring to allow both dosages edging out those favoring only the higher dose.

Assuming approval, dabigatran's monopoly as the easier, more effective warfarin alternative in AF may not last very long. Other oral anticoagulants in various stages of development include apixaban (Bristol-Myers Squibb/Pfizer), rivaroxaban (Xarelto, Bayer/Johnson & Johnson), edoxaban (Daiichi-Sankyo), and betrixaban (Portola Pharmaceuticals/Merck).

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