Dabigatran's First A Fib Year Starts Warfarin's Decline

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 (Pradaxa), received Food and Drug Administration approval for stroke prevention in atrial fibrillation (AF) patients about a year ago, in October 2010. Just this month, on Nov. 4, rivaroxaban (Xarelto) joined dabigatran on the U.S. market with its FDA approval for the same indication, and two more agents may follow in the next 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 350,000 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, chef of cardiology at the Veterans Affairs 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.