August 2, 2012 — The American Heart Association/American Stroke Association has released a new scientific advisory on use of the new oral antithrombotic agents to prevent stroke in patients with nonvalvular atrial fibrillation (AF).
The update recommends that along with warfarin and dabigatran (Pradaxa, Boehringer Ingelheim), already recommended for this indication, rivaroxaban (Xarelto, Janssen Pharmaceuticals/Bayer) and apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) are indicated to prevent first or recurrent stroke in patients with nonvalvular AF.
"This update talks about the addition of several new agents that appear to be as good if not better than warfarin, in terms of preventing embolic stroke and preventing hemorrhage," said Karen L. Furie, MD, neurologist-in-chief at Rhode Island Hospital, and chair and professor of neurology at Alpert Medical School at Brown University, Providence. Dr. Furie co-chaired the writing committee for the new advisory, along with Larry B. Goldstein, MD, director of the Duke Stroke Center at Duke University Medical Center in Durham, North Carolina.
"They have a better safety profile than warfarin and are at least as efficacious. These agents represent a significant improvement in our armamentarium," Dr. Furie told Medscape Medical News. The new agents offer "a much simpler approach to management," she added, because they do not require regular international normalized ratio (INR) testing, as warfarin does, and they are dosed once or twice daily, "so it is a major advance in stroke prevention."
The advisory is published online August 2, and will appear in the October issue of Stroke. The American Academy of Neurology endorsed the value of the document "as an educational tool for neurologists."
Simpler Approach to Management
On the strength of 2 positive trials, AVERROES and ARISTOTLE, a third agent, apixaban, also a factor Xa inhibitor, is widely expected to be approved in the near future, but many were surprised when the company was issued a complete response letter June 25 by the US Food and Drug Administration (FDA). The Agency is requesting additional information on data management and verification from the ARISTOTLE trial.
Still, the writing committee took the somewhat unusual step of recommending apixaban, even though it is not yet approved.
"The FDA is appropriately conservative, so the fact that they wanted more information is not surprising. Since it is likely to be approved in the future, including it made sense," Dr. Furie said. "Since it is likely to become one of the drugs that people could choose from, we thought it was important to include it in this document."
None of the new agents is recommended over the others at this point, because they have not yet been compared head to head, she noted.
"There are opportunities for clinicians to tailor the selection of a drug to an individual patient. There remain caveats about the long-term safety of these therapies. Clinicians are going to have to pay attention to the qualifications for using these drugs, particularly in people with renal insufficiency, and be mindful that unlike warfarin, they can't be easily reversed and their potency can't be measured with blood tests, so you're not always sure with these drugs whether the patient is deriving optimal benefit," she said.
In addition, if the patient does come to hospital with an ischemic stroke or a hemorrhage, "you may be limited in terms of your management options."
To this end, the writing committee is not recommending the use of these newer agents over warfarin in all patients. "There are patients who have been well controlled on warfarin for many years who remain in the therapeutic range, have no complications, and are happy remaining on the warfarin," Dr. Furie said. "For those patients, we're not recommending that they all necessarily be transitioned to this new class of drugs that have adverse potential and cost considerations."
"These are early days yet, and everyone is trying to gain experience with these drugs, and I think it'll probably be a few years before neurologists are completely comfortable with selecting drugs for patients and dealing with some of the management," she added.
Another issue discussed in the document is the recent report of bleeding with dabigatran. "It's still at the level of case reports, and it's something that the FDA is tracking," Dr. Furie noted. "Examining these drugs in an idealized clinical trial situation can be very different than the real-life experience, and so postmarketing surveillance with a particular focus on hemorrhage with these drugs is going to be critical. Right now, there's not enough of a concern to really raise a significant safety alarm, but certainly enough to warrant collection of these cases and scrutiny by the FDA."
Some of the new recommendations include the following:
Warfarin, dabigatran, apixaban, and rivaroxaban are all indicated for the prevention of first and recurrent stroke in patients with nonvalvular AF. "The selection of an agent should be individualized on the basis of risk factors, cost, tolerability, patient preference, potential for drug interactions, and other clinical characteristics, including time in INR therapeutic range if the patient has been taking warfarin."
Dabigatran 150 mg twice daily is an "efficacious alternative" to warfarin for the prevention of first and recurrent stroke in patients with nonvalvular AF and at least 1 additional risk factor, who have creatinine clearance (CrCl) greater than 30 mL/minute.
On the basis of pharmacokinetic data, use of dabigatran 75 mg twice daily in patients with AF and at least 1 additional risk factor who have low CrCl, in the range of 15 to 30 mL/minute, may be considered, but its safety and efficacy have not been established. Dabigatran is not recommended in patients with more severe renal failure (CrCl less than 15 mL/minute).
Apixaban 5 mg twice daily is an "efficacious alternative" to aspirin in patients with nonvalvular AF deemed unsuitable for vitamin K antagonist therapy who have at least 1 additional risk factor and no more than 1 of the following characteristics: age greater than 80 years, weight less than 60 kg, or serum creatinine greater than 1.5 mg/dL.
Although its safety and efficacy have not been established, apixaban 2.5 mg twice daily may be considered as an alternative to aspirin in patients with nonvalvular AF deemed unsuitable for vitamin K antagonist therapy who have at least 1 additional risk factor and meet more than 2 of the following criteria: age greater than 80 years, weight less than 60 kg, or serum creatinine greater than 1.5 mg/dL.
Apixaban 5 mg twice daily is a "relatively safe and efficacious alternative" to warfarin in patients with nonvalvular AF deemed appropriate for vitamin K antagonist therapy who have at least 1 additional risk factor and no more than 1 of the following characteristics: age greater than 80 years, weight less than 60 kg, or serum creatinine greater than 1.5 mg/dL.
Although its safety and efficacy have not been established, apixaban 2.5 mg twice daily may be considered as an alternative to warfarin in patients with nonvalvular AF deemed appropriate for vitamin K antagonist therapy who have at least 1 additional risk factor and meet more than 2 of the following criteria: age greater than 80 years, weight less than 60 kg, or serum creatinine greater than 1.5 mg/dL. Apixaban should not be used if CrCl is less than 25 mL/minute.
In patients with nonvalvular AF who are at moderate to high risk of stroke (prior history of TIA, stroke, or systemic embolization, or more than 2 additional risk factors), rivaroxaban 20 mg/day "is reasonable" as an alternative to warfarin.
In patients with renal impairment and nonvalvular AF who are at moderate to high risk of stroke (prior history of TIA, stroke, or systemic embolization, or more than 2 additional risk factors), with CrCl of 15 to 50 mL/minute, 15 mg of rivaroxaban daily may be considered, but its safety and efficacy have not been established. Rivaroxaban should not be used if CrCl is less than 15 mL/minute.
The safety and efficacy of combining dabigatran, rivaroxaban, or apixaban with an antiplatelet agent have not been established.
Asked for comment on the new advisory, Philip B. Gorelick, MD, medical director of the Hauenstein Neuroscience Center and Department of Translational Science and Molecular Medicine at Michigan State University College of Human Medicine, in Grand Rapids, called it "timely" and a "well-done, evidence-based update."
"Overall, the authors conclude that warfarin, dabigatran, apixaban, [and] rivaroxaban are all indicated for prevention of first or recurrent stroke for patients with [nonvalvular] AF," Dr. Gorelick notes. "The choice of use of one of the newer non–vitamin K antagonists should be made based on patient risk factors, cost, potential for tolerability, patient preference, potential for drug interactions, and other clinical characteristics such as success in maintaining the INR in therapeutic range if one is taking warfarin."
These new agents, he said, are easy to use, have few drug-drug interactions, and currently have no point-of-care test to monitor, "but one must be mindful of renal function, as dose adjustments may be necessary, or contraindications may exist to administration of these classes of drugs, depending on creatinine clearance level."
The hope with these warfarin alternatives has been that with less complex management, more patients will receive treatment. "Concerns, however, have been voiced by physicians about heightened bleeding risks with the newer drugs, and regulatory agencies are tracking such information," Dr. Gorelick pointed out.
A recent report by the European Medicines Agency found in postmarketing surveillance that fatal bleeding associated with dabigatran is significantly less than that seen in clinical trials, he said.
"As these newer drugs are anticoagulants, one must be cautious as with all drugs of the oral anticoagulant category, as there is elevated risk of bleeds," he concludes. "Interestingly, all of the newer oral anticoagulants, when compared to warfarin, have been associated with a lower risk of brain bleeds according to phase 3 clinical trial experience."
Dr. Furie has disclosed no relevant financial relationships. Full disclosures are available in the advisory document. Dr. Gorelick serves as a member of a speaker's bureau on dabigatran for Boehringer Ingelheim.
Stroke. Published online August 2, 2012.
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Cite this: AHA/ASA Advisory on Stroke Prevention in Atrial Fibrillation - Medscape - Aug 02, 2012.