Warfarin Superior to Aspirin for Stroke Prevention in AF: BAFTA Trial Published

August 13, 2007 — Results of the Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) trial show that among patients aged 75 years or older with atrial fibrillation (AF), anticoagulation with warfarin was superior to aspirin for prevention of primary stroke. The benefit of treatment did not come at the cost of more major hemorrhage, the rates of which were similar between groups.
The results are published in the August 11 issue of The Lancet. They were presented previously at the 16th European Stroke Conference in Glasgow, Scotland, and were reported by Medscape Medical News at that time.
"In summary, these data lend support to the use of anticoagulation for all people aged over 75 years who have a atrial fibrillation, unless there are contraindications or the patient decides the size of the benefit is not worth the inconvenience of the treatment," BAFTA investigators, with lead author Jonathan W. Mant, MD, from the University of Birmingham, United Kingdom, conclude in their report.
The target international normalized ratio (INR) should be 2 to 3, they add, a range for which there is "clear evidence of benefit and no evidence from this study of harm compared with aspirin. Age itself should not be regarded as a contraindication to anticoagulation therapy."
Elderly Primary Care Population
Warfarin has been shown to be superior to aspirin for the prevention of stroke in patients with AF, but the large trials that established the efficacy of anticoagulation to aspirin therapy generally enrolled younger patients, in whom the risk for bleeding complications is lower, the authors point out.
The majority of strokes associated with AF occurs in people older than 75 years. However, Dr.Mant said, "there are concerns about the applicability of the evidence both to the elderly, where there is concern that the increased risk of bleeding on warfarin might outweigh the benefits, and also in community-based populations such as primary care where, of the 3 trials that have looked at warfarin vs aspirin, 2 have, in fact, been negative."
To address these concerns, the investigators undertook the BAFTA trial. This was a randomized, controlled trial comparing adjusted-dose warfarin with a target INR of 2.5 (range, 2.0 - 3.0) with aspirin at 75 mg daily among elderly patients with AF in primary care settings.
The investigators enrolled 973 patients age 75 years or older with AF from more than 260 general practices in England and Wales. Patients were followed up at 3 months after randomization by their general practitioner, then every 6 months for an average of 2.7 years.
The primary endpoint was fatal or nonfatal disabling stroke, either ischemic or hemorrhagic, or significant arterial embolism. "We deliberately chose quite a hard outcome measure," Dr. Mant said. "Nondisabling stroke was not part of our outcome, but we included hemorrhagic stroke — including intracranial hemorrhage — in our primary outcome, so we could make a clear conclusion."
And the conclusion was clear: a significant reduction in the risk for a primary outcome event (P = .003). There were 24 primary outcome events in the warfarin group, including 24 strokes, 2 other intracranial hemorrhages, and 1 systemic embolus, vs 48 such events in the aspirin group, including 44 strokes, 1 other intracranial hemorrhage, and 3 systemic emboli.
This resulted in a number needed to treat (NNT) of 50 patients treated for 1 year to prevent 1 primary outcome event. The absolute yearly risk reduction was 2% (95% confidence interval [CI], 0.7 - 3.2).
There was no difference in major hemorrhage between the groups, though the CIs were wide for this endpoint because there were only 50 events in all, the authors note. There was also no difference among the other hospital admissions for hemorrhage or the composite of all major hemorrhages including major intracranial hemorrhage.
Although the study was not powered to look at subgroups, the authors point out that the risk for hemorrhage rose with age, "but I would point out it rises just as much in the aspirin group, if not more so, than in the warfarin group," Dr. Mant noted during his presentation of these data. There was no evidence of any interaction with age in the benefit seen with warfarin, or in the harm seen with aspirin, he added, "so it appears the same result is coming through in people aged 85 or older at randomization."
No differences were seen in other secondary outcomes, including all-cause mortality, other vascular mortality, or nonvascular deaths. There were no differences in vascular events between warfarin and aspirin, although 1 endpoint (a composite of major vascular events combining stroke, myocardial infarction, pulmonary embolus, and vascular death), did show a significant reduction with warfarin vs aspirin.
Lack of Difference in Bleeding Risk a Surprise
Dr. Mant speculated on some of the potential reasons for what he called the "most surprising finding of the BAFTA study," the lack of difference in the risk for hemorrhage between the groups. However, previous studies used higher target INR ranges, up to 4.5, "and it may be that we've over-estimated the danger of warfarin because of those studies," he said.
Some 40% of patients in BAFTA had previously been treated with warfarin, which results of the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-W) trial suggested may be associated with a lower bleeding risk. However, Dr. Mant noted, "we did look at that in a secondary subgroup analysis, and in our trial there was no important difference in the risk of hemorrhage between people who were new to warfarin and those who'd been on warfarin for some time."
At the end of the trial, three quarters of patients in the aspirin group were still on their assigned therapy, whereas two thirds assigned to warfarin were still on the drug to which they had been initially assigned. Most of the patients not on their original treatment assignment crossed over to the other trial medication.
The effect of the treatment crossovers would probably have been to underestimate both the benefits of warfarin in preventing ischemic events, and possibly the risk of harm, Dr. Mant noted. "We did do a secondary on-treatment analysis for harm, and that actually made no difference to the results; we still found no difference between warfarin and aspirin when we did an on-treatment analysis looking at hemorrhage as opposed to intention-to-treat."
Important New Information for the Elderly
In an editorial accompanying the publication, David Garcia MD, from the University of New Mexico, Albuquerque, and Elaine Hylek, MD, MPH, from Boston University in Massachusetts, discuss whether these results can be extrapolated to the "real-world" population of elderly patients with AF. Because the study was limited to patients for whom clinicians were uncertain as to the best treatment, this probably encouraged recruitment of patients at a lower risk of stroke, they note.
Compared with other study populations, the BAFTA participants had a lower prevalence of risk factors for stroke, and just over one fifth of patients were excluded because warfarin was the only appropriate treatment. The low prevalence of risk factors and the large population of patients already taking a vitamin K antagonist when they entered the study may explain why thrombotic events were lower than anticipated in this study, they write.
"Nevertheless, the fact that BAFTA showed that warfarin is more effective than aspirin, even in this relatively low-risk group of patients, adds to other evidence that, in patients with atrial fibrillation, anticoagulation protects patients against stroke more effectively than antiplatelet therapy."
The editorialists agree with Dr. Mant and colleagues that the lack of difference in major bleeding between the groups is surprising, and the bleeding rate was significantly lower than rates seen in other studies. They speculate on some of the reasons for this, suggesting that more information on the risk factors for hemorrhage in these subjects would be informative.
"Despite these considerations, BAFTA adds important new information for the care of elderly patients with atrial fibrillation," they write. "Mant and colleagues enrolled an unprecedented number of patients in an age group that that has been largely under-represented in randomised trials. BAFTA firmly establishes the superior efficacy of warfarin as a stroke-prevention strategy in elderly patients with atrial fibrillation."
The Medical Research Council funded the study. Dr. Mant has disclosed no relevant financial relationships. One coauthor has received support from AstraZeneca, Sanofi-Aventis, Bayer, Astellas, and Daiichi-Sanko. Drs. Garcia and Hylek have received research funding from Bristol-Myers Squibb and have acted as consultants for Bristol-Myers Squibb. Dr. Hylek also has received research funding from AstraZeneca.
Lancet. 2007;370:493-503, 460-461.