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Apixaban Superior for AF Patients With Previous Stroke, TIA
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free mobile app. Download Now February 8, 2012 (New Orleans, Louisiana) — New data from 2 large phase 3 trials that compared the novel factor Xa inhibitor apixaban (Eliquis, Pfizer/Bristol-Myers Squibb) with warfarin and aspirin, respectively, in patients with atrial fibrillation (AF) show a benefit of apixaban similar to that seen in the main trial results among those with a history of prior stroke or transient ischemic attack (TIA).
Dr. J. Donald Easton
Substudy data on this predefined subgroup from the previously published Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE) and Apixaban vs Acetylsalicylic Acid to Prevent Strokes in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trials were presented here at the American Stroke Association's International Stroke Conference (ISC) 2012. Both trials were funded by Bristol-Myers Squibb and Pfizer Inc.
ARISTOTLE: Apixaban vs Warfarin
The ARISTOTLE trial randomly assigned 18,201 patients with AF and at least 1 other risk factor to receive either apixaban, given in a dose of 5 mg orally twice daily, or warfarin with a target international normalized ratio of from 2.0 to 3.0. After a median follow-up of 1.8 years, results showed that apixaban was associated with a 21% reduction in the risk for stroke or systemic embolism, a 31% reduction in bleeding, and an 11% reduction in all-cause mortality, meeting criteria not only for noninferiority but also for superiority compared with warfarin. The results were published in the New England Journal of Medicine in 2011.
At the meeting here, J. Donald Easton, MD, professor emeritus of neurology at Brown University Alpert Medical School in Providence, Rhode Island, and clinical professor, Department of Neurology, University of California, San Francisco, presented a substudy looking at whether apixaban had the same advantage over warfarin in patients with prior stroke or TIA, as was seen in the overall findings. The primary efficacy outcome for this analysis was the same, stroke or systemic embolism, as was the primary safety outcome, major bleeding by the International Society of Thrombosis and Hemostasis (ISTH) definition.
A total of 3436 patients (19.5%) in this cohort had had a prior stroke or TIA. There were no important differences in baseline characteristics for the prior stroke or TIA group compared with the overall group, Dr. Easton noted, with the exception of the CHADS score indicating overall risk: 92% of this subgroup with prior events had a score of 3 or greater.
"So this is a high-risk group of patients, whereas only 15% of the no-prior-stroke or TIA patients had a CHADS score that high," Dr. Easton noted.
For the primary efficacy outcome, the researchers found that the event rate was considerably higher in the prior stroke patients, "and therefore, the absolute benefit of apixaban is greater in our patients than it is in the overall trial," Dr. Easton said.
Table 1. ARISTOTLE: Efficacy and Safety With and Without Prior Stroke or TIA
Endpoint  Prior Stroke or TIA  No Prior Stroke or TIA  P 
Apixaban, n (rate*)  Warfarin, n (rate*)  HR (95% CI)  Apixaban, n (rate*)  Warfarin, n (rate*)  HR (95% CI) 
Stroke or systemic embolism 73 (2.46) 98 (3.24) 0.76 (0.56 - 1.03) 139 (1.01) 167 (1.23) 0.82 (0.65 - 1.03) .71
ISTH major bleeding 77 (2.84) 106 (3.91) 0.73 (0.55 - 0.98) 250 (1.98) 356 (2.91) 0.68 (0.58 - 0.80) .69
Intracranial bleeding 15 (0.55) 41 (1.49) 0.37 (0.21 - 0.67) 37 (0.29) 81 (0.65) 0.44 (0.30 - 0.66) .60
Death from any cause 129 (4.22) 150 (4.77) 0.89 (0.70 - 1.12) 474 (3.37) 519 (3.75) 0.90 (0.79 - 1.02) .89
*per 1000 patient/years of follow-up.
HR, hazard ratio; CI, confidence interval.
"So treatment with apixaban compared to warfarin in patients with AF and a prior stroke or TIA, we now know from ARISTOTLE, reduces stroke or systemic embolism by 24%, it reduces major bleeding by 27%, it reduces intracranial bleeding by 63%, and it reduces mortality by 11%, again with the P value for interaction being nonsignificant for any of these, indicating that the results in the prior stroke patients are equally beneficial to those in the non–stroke patients."
In patients with AF who have prior stroke or TIA, apixaban given over the course of 1.8 years prevented 15 strokes (including 12 hemorrhagic and 4 ischemic or uncertain etiology strokes), 18 major bleeds, and 9 deaths per 1000 patients treated vs warfarin, the researchers note.
Dr. Easton concluded that the reduction in outcome events seen in these patients with prior stroke or TIA is consistent with those seen in the main ARISTOTLE trial population. "In patients with atrial fibrillation and prior stroke or TIA, apixaban is superior to warfarin at preventing stroke or systemic embolism: It causes less bleeding, especially intracranial bleeding, and it results in lower mortality," he said.
During the discussion, Dr. Easton was asked by an audience member to speculate on why mortality was lower in this trial with apixaban, an effect not achieved by the other recently approved oral anticoagulants, dabigatran (Pradaxa, Boehringer Ingelheim) or rivaroxaban (Xarelto, Bayer/Johnson & Johnson), in trials that were "pretty much contemporary to yours."
"I think that's a very important and difficult question," he replied. "How much of it was play of chance, how much of it was difference in patient selection, and how much of it might be that apixaban truly is a more effective Xa inhibitor, I think we're not going to know for a while."
AVERROES: Apixaban vs Aspirin
In a separate presentation given here, a similar predefined subanalysis was presented by researchers in the AVERROES trial that compared apixaban vs aspirin in patients with AF and previous stroke or TIA.
These results were also published online February 1 in Lancet Neurology to coincide with their presentation here.
Dr. Hans-Christoph Diener
The main trial looked at the use of aspirin (81 - 324 mg daily) vs apixaban (5 mg twice daily) in patients with AF who were thought to be unsuitable for warfarin therapy. During a mean follow-up of 1.1 years, apixaban reduced the risk for stroke or systemic embolism by 55% compared with aspirin, without increasing the risk for major bleeding. The overall AVERROES results were also published in 2011 in the New England Journal of Medicine.
Of a total of 5599 patients, 764 had a prior stroke or TIA. "In this subgroup of about 15% of the patients who had a prior TIA or stroke, the relative benefit of apixaban over aspirin was much bigger than it was in the primary prevention group, and there was no increase in bleeding risk," lead author Hans-Christoph Diener, MD, from the Department of Neurology at University Hospital Essen, Germany, told Medscape Medical News.
Table 2. AVERROES: Efficacy With and Without Prior Stroke or TIA
Endpoint  Prior Stroke or TIA  No Prior Stroke or TIA  P 
Apixaban, n (%year)  Aspirin, n (%/year)  HR (95% CI)  Apixaban, n (%year)  Aspirin, n (%/year)  HR (95% CI) 
Stroke or systemic embolism 10 (2.39) 33 (9.16) 0.29 (0.15 - 0.60) 41 (1.68) 80 (3.06) 0.51 (0.35 - 0.74) .17
Major bleeding was more frequent in the patients with a history of stroke or TIA than in those without a prior event (HR, 2.88; 95% CI, 1.77 - 4.55), but this increase was not significantly different than that seen with aspirin in these patients.
"So the absolute benefit is quite obviously higher in these high-risk patients compared to primary prevention, and this is expressed in the number needed to treat," he added (16 for secondary stroke prevention vs 74 for primary prevention).
"I think there is no longer a place for aspirin," Dr. Diener asserted. "In secondary stroke prevention, it was never superior to placebo anyway, and now that [apixaban] has been shown that it's clearly superior to aspirin, and has the same bleeding risk, there is no place anymore for aspirin."
He also pointed out that this comparison vs aspirin has not been done for either dabigatran or rivaroxaban.
During the moderated poster presentation, however, attendees pointed out that this new drug will cost considerably more than aspirin, and that the number of patients treated with it for now is low, and follow-up still relatively short.
Still, although he made sure these questions about apixaban were raised during the discussion, poster session moderator Chung Y Hsu, MD, PhD, from National Taiwan University School of Medicine in Taichung, summed it up: "This is better than aspirin, for sure."
More Real-World Experience
Asked for comment on these findings, Larry B. Goldstein, MD, director of the Duke Stroke Center, Durham, North Carolina, and a spokesperson for the American Stroke Association, was also somewhat cautious on this point, suggesting more real-world experience might be in order before making that conclusion about apixaban.
Apixaban has not yet gone through US Food and Drug Administration (FDA) review, he pointed out. "When the FDA reviews data, we very often learn things that we didn't know from the published clinical trials, and it hasn't been used clinically yet at all."
He also pointed to new information on bleeding risks with dabigatran that have emerged since its approval. "What that means is not entirely clear, but again, other drugs, when they were being used in the real world, were having potential side effects that were either unanticipated or happening at a frequency different than anticipated based on clinical trials."
Nevertheless, he expects that these agents will have a major effect on treatment of these patients.
Mark Alberts, MD, professor of neurology at Northwestern University Feinberg School of Medicine, Chicago, Illinois, pointed out that the big surprise in the overall AVERROES data was not that apixaban was more effective than aspirin, but that it was just as safe.
"We all expected that apixaban would beat aspirin in efficacy, but to say that an anticoagulant is as safe as an antiplatelet agent is remarkable," he said.
In this new subgroup analysis of those with previous stroke or TIA, the efficacy and safety were similar, he noted. "So this is good: This is what we've seen in other studies of the novel oral anticoagulants, is that they work just as well in a high-risk group as in a low-risk group."
The ARISTOTLE and AVERROES trials were funded by Bristol-Myers Squibb and Pfizer Inc. Dr. Easton reports he is on an advisory board or consultant for AstraZeneca, Bristol-Myers Squibb, sanofi-aventis, and Genentech. Dr. Diener reports he has received compensation from Abbott, AstraZeneca, Bayer Vital, Bristol-Myers Squibb, Boehringer Ingelheim, CoAxia, D-Pharm, Fresenius, GlaxoSmithKline, and others. Dr. Alberts is a member of the editorial advisory board for Medscape Neurology.
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