Dabigatran's First A Fib Year Starts Warfarin's Decline
By Mitchel L. Zoler

For decades, physicians and patients bemoaned the problems and inconveniences of warfarin to prevent strokes caused by atrial fibrillation. Finding the right dosage was hard and often a moving target, patients needed regular coagulation monitoring, their anticoagulated state often fell out of the ideal range thereby putting them at an increased risk for either a stroke or bleeding complications, and care was needed with diet and other medications to avoid interactions that would throw off the whole delicate balance. A simpler, easier oral anticoagulant was what people wanted and what drove drug companies to try to find alternatives.

The first alternative, dabigatran, received Food and Drug Administration approval for stroke prevention in atrial fibrillation (AF) patients a year ago, in October 2010. Today, at least two other drugs seem on the verge of joining dabigatran on the U.S. market, and a fourth agent may follow in another couple of years.

The initial 12-month experience with AF management in a world with a warfarin alternative showed the eagerness of some physicians and patients to embrace a not-warfarin, but also prompted the grudging recognition that warfarin has attractive features despite its flaws.

Simple numbers show that dabigatran had a good first year. In late August, Boehringer Ingelheim, the company that markets dabigatran (Pradaxa), reported that to that time U.S. physicians had prescribed dabigatran to about 250,000 AF patients, roughly 10% of the total number of U.S. patients with AF. That level of market penetration beat expectations, said Matthew Killeen, Ph.D., an analyst with Decision Resources in Burlington, Mass.

The penetration during the first year "is greater than what we previously forecast," Dr. Killeen said in an interview. Dabigatran "has done remarkably well considering that it represents a completely new treatment strategy. It's a completely new mindset in how physicians treat AF patients." Boehringer Ingelheim "had to lay the groundwork with physician education so that they were comfortable prescribing a pill that doesn't need monitoring or dose adjustment."

But while dabigatran's first year of attempting to eclipse warfarin may have exceeded expectations, it has not been a totally smooth launch, said several cardiologists recently asked about their experiences. Dabigatran succeeded despite some widely acknowledged limitations, some of which have underscored warfarin's strengths, starting with the issue of cost.

Like any new, proprietary drug, dabigatran is expensive, with an average wholesale price in excess of $7 a day (although some pharmacies sell it for as low as about $4.50 per day), compared with an average wholesale price for warfarin of about $0.22 per day. That can put dabigatran out of the picture for patients with no drug coverage, and even for those with a drug plan, the copay often makes dabigatran a financially tough pill to swallow.

"Cost is an issue with dabigatran. I've had patients tell me that they'll stay with warfarin for another couple of years until the new drugs get less expensive," said Dr. Gordon F. Tomaselli, professor of medicine and chief of cardiology at Johns Hopkins University in Baltimore.

"I think there has been limited uptake of dabigatran primarily because of cost. The out-of-pocket cost to patients can be substantial," said Dr. Deepak L. Bhatt, chief of cardiology at the VA Boston Healthcare system and a cardiologist at Brigham and Women's Hospital in Boston. "It can be hard to get patients to agree to the out-of-pocket copay."

But large copays for new, more effective anticoagulants may fade as insurers realize that they can save more money in the long run by having beneficiaries treated with drugs that better prevent ischemic strokes and intracranial hemorrhages. The potential cost saving from cerebrovascular events avoided "will offset the increased drug cost," Dr. Killeen noted.

Another issue that has made physicians think twice about prescribing dabigatran has been the gastrointestinal bleeds it triggers, a 6% rate of major gastrointestinal hemorrhages during each year of treatment, said Dr. Michael D. Ezekowitz, a professor of medicine at Jefferson Medical College, Philadelphia, and one of the researchers who led the clinical trials during dabigatran's development. Increased gastrointestinal bleeds, and an accompanying gastritis, are "the price to pay" for using dabigatran, he said in an interview, though the risk can be reduced through more careful coadministration of antiplatelet drugs, avoiding the drug in patients with gastritis or hemorrhoids, or by cauterizing telangiectasias.

Other critiques of dabigatran include on the lack of an antidote, which has made some physicians wary of prescribing it, an issue that currently limits all of the new oral anticoagulants. A physician can reverse the effect of warfarin with a simple dose of vitamin K, and some find the lack of a similar maneuver for the new drugs disconcerting, but it may not be a significant problem in actual practice, noted Dr. Lars Wallentin, professor of cardiology at Uppsala (Sweden) University and another leader of the dabigatran trials.

"In the trials [of both dabigatran and apixaban] not having an antidote was not an issue. We've seen no concerns" by not having an antidote. "I don't think it's a large problem. I think we have overestimated the bleeding risk produced by anticoagulants," he said in an interview.

For dabigatran there are also convenience issues for patients. It's a b.i.d. drug, compared with warfarin's once-daily dosing, and dabigatran also has the unusual problem of a very short half-life once removed from its special, desiccant-containing packaging. Once out of the package, "the efficacy of the drug goes away literally within days," noted Dr. Tomaselli. That means that patients can't set up their dabigatran pills in advance in a Monday-Sunday pill box, something many of them like to do.

What all these limitations have meant for prescribing dabigatran seems to vary. "I use dabigatran sparingly because of the issues with copays and because patients need to understand they can't take the drug out of the packs in advance," Dr. Tomaselli said. But an alternative take came from Dr. Christopher B. Granger, professor of medicine and director of the cardiac care unit at Duke University in Durham, N.C. "I think dabigatran is an excellent drug, and I think the cardiology community has embraced it because it is a really important advance. My mother is on dabigatran," he said in an interview.

Dabigatran's drawbacks have reminded physicians about warfarin's pluses, despite finicky dosing and monitoring: it's inexpensive, easily reversed, administered once daily, effective when used correctly, and people are experienced and comfortable with it. "There are lots of limitations with warfarin, but it's also familiar and cheap, and with a good warfarin clinic and a compliant patient it works pretty well," noted Dr. Bhatt.

Though dabigatran launched a new anticoagulant era for AF management, the revolution will grow more firmly entrenched and will further marginalize warfarin when more new oral anticoagulants come to market. FDA approvals for apixaban (Eliquis) and rivaroxaban (Xarelto) are expected during the next 12 months. While the pivotal trial for rivaroxaban showed that the drug was noninferior to warfarin it failed to prove that rivaroxaban has superior efficacy, but rivaroxaban has the advantages of once-daily dosing and stability. Apixaban may outshine all the competition, as results reported in August in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial showed that apixaban had both superior efficacy and safety compared with warfarin, including a significant improvement in all-cause mortality in AF patients, and it's stable out of its packaging. Apixaban's only drawbacks seem to be b.i.d. dosing, a likely high price, and its lag behind dabigatran onto the U.S. market by more than a year.

"Apixaban seems to tick all the major changes that physicians are looking for in a new oral anticoagulant," said Dr. Killeen. We at Decision Resources expect that apixaban will emerge as the sales leader for new oral anticoagulants by 2020." Another advantage for apixaban is the result from the Apixaban Versus Acetylsalicylic Acid [ASA] to prevent Stroke in Atrial Fibrillation Patients Who Have Failed or are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) study, which proved the drug's safety and efficacy in AF patients who were warfarin intolerant, giving apixaban documented efficacy and safety for the entire range of AF patients, he added.

Dr. Killeen also noted a fourth drug in development that might be in the mix by 2013, edoxaban. Edoxaban's pivotal AF trial against warfarin in more than 20,000 patients, making it the largest study of a new oral anticoagulant in AF patients to date, is scheduled to finish during the first half of 2012. Presuming the trial results are positive for safety and efficacy compared with warfarin, edoxaban will also offer once-daily dosing, stability, and possible availability at multiple dosages (part of the pivotal trial design), features that will make it unique and perhaps very attractive, he said.

Reduced pricing is, of course, another marketing tool that companies can wield, a potent way to counterbalance perceived inequities in efficacy and convenience as well as the time when a drug enters the market relative to its rivals.

"Companies will compete at multiple levels, including price. They will price their drugs to be competitive," Dr. Ezekowitz predicted.

Dr. Tomaselli said he had no disclosures. Dr. Bhatt said that he has received research grants from AstraZeneca,Bristol-Myers Squibb, Eisai, Medtronic,Sanofi-Aventis and the Medicines Company. He also served on the steering committee for the APPRAISE-2 trial of apixaban, and on the executive committee for the ATLAS-2 trial of rivaroxaban. Dr. Ezekowitz has been a consultant to and/or has received grants from Boehringer Ingelheim, Daiichi Sankyoand Janssen. He was also a coprincipal investigator for the RE-LY study of dabigatran, on the executive committee of Engage AF, and lead investigator for betrixaban. Dr. Wallentin said that he has received grants and consultant fees from Bristol-Myers Squibb,Pfizer, AstraZeneca and Boehringer Ingelheim. Dr. Granger said that he has received grants and consultant fees or research grants from several drug and device firms, including Boehringer Ingelheim.

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