WARFARIN, -XABAN, OR -GATRAN?

November 18, 2011 (Orlando, Florida) —Sacc For decades, warfarin has been the best — and pretty much only — oral anticoagulant for stroke prevention in atrial fibrillation (AF).
Despite all the warts of drug–drug and drug–food interactions, the difficulty of keeping patients in therapeutic range, and the burdensome need for regular monitoring of International Normalized Ratios (INR), warfarin is an extremely effective therapy. Still, the most sincere wish of many patients and physicians has been that there should be some other option.
Other oral anticoagulants have tried and failed to beat warfarin; one of these, ximelagatran, made it through phase 3 trials and all the way to an application to the US Food and Drug Administration (FDA) before being scuppered by signals of liver toxicity.
Now, however, the dam has burst. The second of 2 alternative oral anticoagulants for the prevention of stroke or systemic embolism in AF has just been approved by FDA, with a third drug expected to be considered for approval soon.
Dabigatran (Pradaxa, Boehringer Ingelheim), a direct thrombin inhibitor, was the first warfarin alternative approved, in October 2010. Rivaroxaban (Xarelto, Bayer/Johnson & Johnson), a factor Xa inhibitor, was approved by the FDA on November 4. On the strength of 2 positive trials, AVERROES and ARISTOTLE, a third agent, apixaban (Eliquis, Pfizer/Bristol-Myers Squibb), also a factor Xa inhibitor, may not be far behind.
At the American Heart Association (AHA) 2011 Scientific Sessions meeting here, Medscape Medical News spoke to stroke experts about their experience to date with dabigatran, their thoughts on the approval of rivaroxaban, and how they intend to incorporate these new choices in the clinic.
"Great News"
Despite the need to weigh the pros and cons of the new drugs, some of which may not actually yet be known, all welcomed the options they provide.
"It's an exciting time," said Mark Alberts, MD, professor of neurology and director of the Stroke Program at Northwestern University and Northwestern Memorial Hospital in Chicago, Illinois.
"Taking warfarin has always been a challenge for patients, as well as physicians and the healthcare system, and now we have 2 new options that don't have that specific challenge," he said. "There may be other challenges with the newer agents, but net, I think this is good for our patients. I think all these new agents are safer than warfarin, and they'll do a better job in the real world of preventing strokes."
Ralph Sacco, MD, professor and Olemberg Family chair of neurology, executve director of the Evelyn McKnight Brain Institute at the Miller School of Medicine at the University of Miami, Florida, and past-president of the American Heart Association, feels the new agents improve the prospect of having more patients with AF treated because they do not require INR monitoring.
"We've known for years that warfarin is underutilized," Dr. Sacco told Medscape Medical News. "Patients don't like to take it; physicians don't like to prescribe it. We need to do more to reduce the risk of stroke in the nearly 2.6 million atrial fibrillation patients who are out there in the United States, with more to come.
"The good news is that we do have hopefully now more-effective drugs, and drugs that will be used in a larger proportion of the community," he added.
Joseph Broderick, MD, professor and Albert Barnes Voorheis Chair of Neurology at the University of Cincinnati College of Medicine in Ohio, told Medscape Medical News that in his view, "each of the agents has advantages, but clearly, I think, they both have advantages over warfarin.
"It will be great to have another choice," he added. "The problem is, there's no data that makes the comparison of dabigatran and rivaroxaban, to know which one's the best choice."
Issues to Consider
That sentiment was echoed by each of the other neurologists. With 3, and perhaps soon 4, oral anticoagulants to choose from, the problem is how to decide which one to use without the luxury of head-to-head data.
Complicating this decision about rivaroxaban are issues that have been raised about the pivotal phase 3 trial, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF), of rivaroxaban vs warfarin.
Although the dabigatran 150-mg dose regimen was superior to warfarin in reducing stroke and systemic embolism in the RE-LY trial, supporting its approval, rivaroxaban met statistical noninferiority criteria, but did not reach superiority criteria, in the intention-to-treat analysis for both the "during treatment" and "after discontinuation" groups in ROCKET-AF, said Philip B. Gorelick, MD, MPH, John S. Garvin professor and head of the Department of Neurology and Rehabilitation, and director of the Center for Stroke Research, at the University of Illinois College of Medicine at Chicago.
"At the level of FDA advisory guidance, rivaroxaban met some resistance and controversy, and although it passed through the committee, it was not a 'slam dunk,' " Dr. Gorelick told Medscape Medical News.
Concern was also expressed about the lower percentage of time in therapeutic range (TTR) for INRs in the warfarin group in ROCKET-AF compared with patients receiving warfarin in the dabigatran and apixaban trials, raising the issue of whether better INR control might have affected the results.
Still, Dr. Gorelick said, "in all of the 3 trials, brain bleeding frequency was lower in the respective rivaroxaban, dabigtran, and apixaban treatment groups than observed in the warfarin comparator groups, providing a distinct advantage of all of these drugs over warfarin."
The new agents are welcome options, based on ease of use and safety profiles, Dr. Gorelick added. "Therefore, these newer classes of anticoagulant drugs may fill an important gap and help to provide treatment to many patients who would not be taking an anticoagulant but, rather, an antiplatelet medication for stroke prevention in atrial fibrillation."
Antiplatelet agents generally fall far short of the mark for stroke prevention in AF when compared with oral anticoagulants, he added. "Clinicians are reminded, however, that if high TTR for the INR can be met with warfarin, it is difficult to best warfarin in a head-to-head comparison."
Bruce Ovbiagele, MD, from the Department of Neurosciences, University of California, San Diego, was perhaps the most cautious in his outlook on these agents. In the year since dabigatran was approved, he said, he has prescribed it only when warfarin is not an option.
"I still tend to use warfarin in most of my patients," Dr. Ovbiagele told Medscape Medical News. He is concerned about some safety issues that were raised over the summer with dabigatran, including addition of a black box warning in Japan after 5 deaths there, and a safety advisory issued in Australia about reported bleeding risk in patients starting to receive the drug.
In addition, a revision to the label issued by the FDA on November 9 advises physicians using dabigatran to assess renal function before prescribing the drug, and recommends lower doses for elderly patients who may have renal problems.
A new report issued November 17 by Boehringer Ingelheim noted that to date, there have been 260 fatal bleeds worldwide among patients receiving dabigatran. A statement issued today by the European Medicines Agency notes that it is closely monitoring the issue, but that changes to the drug's current usage instructions "adequately manage the risk of bleeding." The deaths should be viewed in the context of the rapid uptake of dabigatran and increased awareness of its adverse effects, the agency notes.
"I have used it in some patients who have contraindications to warfarin, but it's not my first port of call, so to speak, when I have a patient with [atrial fibrillation]," Dr. Ovbiagele said.
Another consideration is the cost of these new agents vs warfarin, he added. At the county hospital where he also works, dabigatran is not on the formulary, and to obtain it off-formulary, he has to provide some justification. "Even at the [Veterans Administration Hospital], where I work as well, you really have to justify when a person is getting it."
Dr. Alberts said, however, that in his experience, cost has not been the issue that he anticipated it would be. "The cost issue seems to have, I don't want to say 'gone away,' but it doesn't seem to be a major issue for most people, as long as they have pretty decent insurance and/or Medicare," he said.
Drug interactions with dabigatran have been seen since it was approved, he noted, which have also been outlined in the new FDA guidance, including systemic ketoconazole and dronedarone, "which is not used that commonly, but it's something clinicians need to be aware of."
"On the positive side," Dr. Alberts notes, the updated label now says that once opened, dabigatran can be safely stored longer than previous recommendations that it be used within 30 days of opening the bottle.
After a year of experience with dabigatran, clinicians are becoming more comfortable with it, but rivaroxaban is brand new and will raise some important questions, he added.
"One of these is whether it can be given to patients who've already had a stroke and can't swallow," Dr. Alberts said. "Can rivaroxaban be crushed up, can it be given through a feeding tube? Those issues need to be addressed."
Anticoagulation Reversal
One very big issue with all of these new agents has been the fact that at least to date, anticoagulation cannot be immediately reversed for emergent surgical procedures or hemorrhagic complications, for example. It may also rule out use of tissue plasminogen activator (tPA) if the patient has a stroke despite anticoagulation.
"This becomes important to me as a stroke neurologist, because sometimes people come in with bleeding strokes, and if we're using these agents, we need to know how to reverse it, and I think we're making some progress in that area," Dr. Alberts said.
"There seems to be a consensus forming that activated prothrombin complex concentrates (PCCs), seem to be effective for at least reversing the clotting abnormality seen with these newer agents," he said. "Whether that's going to translate into clinical benefit, we're not 100% certain, but the general feeling, and again this is more a feeling as opposed to based on the data, is that I think we're getting a handle on this."
Some of the companies are also starting to look at specific reversal agents for the factor Xa inhibitors, he added. For the moment, however, "we're stuck with using the activated PCCs, as well as just giving them fluids and diuresing them, especially for dabigatran, since it's heavily renally excreted."
Faced with the need for reversal, "right now our protocols are to get fresh frozen plasma on board, and do other things we can to stop the bleeding," including recombinant activated factor VII and PCCs, Dr. Sacco said.
In certain circumstances it is still possible to do a partial thromboplastin time (PTT) to determine how anticoagulated a patient is, he noted. "You can also in certain circumstances do a thrombin time. They're a little harder to get quickly, but you can get it, and that would be another measure to know if you're over-anticoagulated."
The half-life of these newer drugs is also relatively short, and they clear the system fairly rapidly when they are stopped, but at this time, there is no way to reverse them acutely, he said.
In general, in the case of an ischemic stroke, having dabigatran or rivaroxaban on board may rule out treatment with tPA, he said. "If someone came in with a stroke, and they said they were taking the medicine, I would be reluctant to use tPA. I would do my best to get a PTT and a thrombin time if I could, but knowing that you have less than 4 and half hours, I think it would be tricky," Dr. Sacco said.
"My preference in those cases would be to get them to a comprehensive stroke center and probably do mechanical clot retrieval to remove a clot with the idea that they probably are anticoagulated."
There may be in future some point of service tests that would let the treating physician know immediately how anticoagulated the patient is, he said.
"Many times they're not fully anticoagulated, because we know patients aren't always compliant," he noted. "You'd hate to deprive them of tPA if it turns out they weren't taking this new anticoagulant like they should have, and weren't fully anticoagulated, and therefore would have been a candidate for tPA."
What to Do for a New Patient?
Asked how they will approach treatment of patients with AF with these new options available, all of the stroke neurologists interviewed agreed that they would probably not switch a patient already stable on warfarin.
Dr. Broderick said he would be reluctant to switch a stable patient, "but there are lots of reasons you'd want to be on one of these medications rather than warfarin, just because of ease of use and the issues of diet."
"Once they get some of the [anticoagulation] testing available for these agents, which is going to happen, I think there'll be more of a push toward using them," he said. "The major thing is they're more expensive, but I think both of them have a strong case."
Dr. Sacco also said he would be reluctant to switch someone doing well on warfarin, possibly for many years, unless they had a history of problems with bleeding or wanted to change because of diet limitations or problems getting in to have INRs checked. "Sometimes we don't like to rock the boat if a patient is doing okay," he said. However, he added, "when faced with a new patient, I think that is a different story.
"Now we know from these studies...that these new drugs are as good or better in certain circumstances than warfarin," he said. "They're easier to use, they don't require monitoring, they have less food interactions and less drug–drug interactions. They have actually very acceptable, and in some cases even lower, bleeding risks, including with dabigatran, even lower intracranial bleeding risks, and they can be as good or better than warfarin."

Choosing between dabigatran and rivaroxaban is a more difficult question. Although it may be tempting to do so, he said, "I urge us not to make indirect comparisons, because every time we've made indirect comparisons we've been proven wrong when we do a direct-comparison trial."
The phase 3 studies of these agents, for example, were in slightly different populations: patients in ROCKET-AF were higher risk than in the dabigatran and apixaban trials, making such indirect comparisons treacherous.
"I think in the long run, it may become a matter of physicians getting comfortable with these drugs," Dr. Sacco said. Similar to the array of antihypertensive medications available, for example, there may be subtle differences that become clear over time and would provide some direction on which drug to use with which patient.
Dr. Alberts' approach with the new options will be again to discuss the options with patients, "but I think we're moving away from starting new patients on warfarin," he said. "I think the conversation for new patients is between these 2 new agents."
He discusses the advantages of these agents, the cost, and the need for compliance, "because one of the good things about these agents is that they have rapid onset, but one of the bad things is they have rapid offset," he said. "If patients miss a dose or 2, they're not going to be protected, so the patients do need to be compliant, as opposed to warfarin, where if you miss a dose or 2, you'll probably be protected, assuming that you're therapeutic."

With the advantages, however, of no routine INR testing and no need for dose manipulation except in patients with renal dysfunction, "I think clearly the net benefit is in favor of using these new agents as opposed to warfarin," Dr. Alberts said.
When it comes to choosing between dabigatran and rivaroxaban, and perhaps apixaban in the near future, it is probably unlikely that direct comparison trials will be available any time soon, Dr. Sacco said. "I think it will be difficult in the short term to do direct comparisons because somebody has to invest in them," he said. Shrinking research dollars at the National Institutes of Health means they may not take this on as a question, and companies take a risk investing in head-to-head trials.
"In the past I was involved when a company tried this, in the PROFESS trial, when they decided they were going to compare clopidogrel vs extended-release dipyridamole and aspirin," he pointed out. Dr. Sacco was co-principal investigator of the PROFESS trial, funded by Boehringer Ingelheim. "When they got the result, it wasn't exactly the result they wanted, so companies may be reluctant to do this on their own."
"I think in the short-run, we need to start doing more atrial fibrillation registries, recording people on these different agents so we get a better handle on bleeding risk, as well as efficacy, in community patients," he said. "Registries will allow us to potentially use comparative effectiveness research to evaluate some subtle differences."
Meta-analyses and phase 4 surveillance studies may also provide more comparative information in the absence of direct comparison trials.
Stroke and ACS Prevention With Rivaroxaban?
At the meeting here, results of a trial called ATLAS ACS 2 TIMI 51 were presented, showing a benefit of a low dose of rivaroxaban, 2.5 mg twice daily, in addition to standard therapy with low-dose aspirin and clopidogrel (Plavix, Bristol-Myers Squibb/sanofi-aventis) in patients with acute coronary syndrome (ACS).
The results, which were simultaneously published in The New England Journal of Medicine, showed a reduction in overall and cardiovascular mortality vs placebo, despite an increased risk for bleeding and intracranial hemorrhage. Of note, patients with a history of stroke or transient ischemic attack were excluded.
Still, Dr. Sacco said, "the ATLAS trial could be relevant because that's in patients with acute coronary syndrome, many of them already on multiple antiplatelets. They added a low dose of rivaroxaban and actually showed for longer term 2-year prevention, a lower risk of [myocardial infarction], stroke, and cardiovascular death.
"So, could there be other indications in a wider vascular population beyond that of atrial fibrillation?" he speculated. "I think that story still needs to unfold. Apixaban didn't work [in ACS] in a different study population, a different design, and I think there will be other studies coming out, perhaps even in other stroke patients."
Dr. Ovbiagele also mentioned the ATLAS ACS results as an indication that rivaroxaban may have an effect beyond just patients with AF to those with ACS.
"But of course the issue, the challenge there was that it wasn't a stroke trial, and there was a high incidence of intracranial hemorrhage, which of course is something we neurologists have to worry quite a bit about," he added. "Every time we try to translate data from the cardiac literature to stroke patients, when we actually do our trials, we find that there's a big difference in outcomes, especially when it comes to intracerebral hemorrhage."
At the meeting here, Dr. Broderick was awarded the American Heart Association's Clinical Research Prize 2011 for his role in establishing tPA in the treatment of acute ischemic stroke, among other contributions. He is the first stroke investigator to receive this clinical research prize, the association notes, which is awarded "for exemplary contributions to advances in stroke treatment and patient care that have changed medical practice as we know it."
Dr. Sacco reports he served on the data and safety monitoring board for the AVERROES trial of apixaban, sponsored through the Population Health Research Institute at McMaster University, Hamilton, Ontario. Dr. Broderick receives study medications from Genentech for two ongoing NINDS studies and from Schering-Plough for one NINDS study. He has received payment as a consultant for a Genentech-sponsored meeting in 2010 and has been reimbursed for travel to meetings by EV3 and Genentech. Dr. Gorelick reports he is on the speakers bureau for Boehringer Ingelheim. Dr. Alberts reports he has received honoraria and is a consultant to Boehringer Ingelheim, Bristol-Myers Squibb Company, and Pfizer Inc, among other disclosures, and is a member of the editorial advisory board for Medscape LLC.
American Heart Association (AHA) 2011 Scientific Sessions.