"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.
Dr. Christopher Granger
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 approval for apixaban (Eliquis) 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 (N. Engl. J. Med. 2011;365:883-91).
Apixaban may outshine all the competition, as results reported in August in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) 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.
"[Dabigatran] ... represents a completely new treatment strategy. It’s a completely new mindset in how physicians treat AF patients."
"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 AVERROES (Apixaban vs. Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment) study (N. Engl. J. Med. 2011;364:806-17), 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 Sankyo, and 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.