BAFTA: Warfarin bests aspirin for stroke prevention in elderly AF patients

Susan Jeffrey

May 31, 2007

Glasgow, Scotland - Results of the Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) trial show that even among elderly patients with atrial fibrillation (AF), anticoagulation with warfarin was superior to aspirin for primary stroke prevention[1].

The benefit of treatment was not at the cost of more major hemorrhage, the rates of which were similar between groups. The results were presented here at the 16th European Stroke Conference.

"Use of anticoagulation rather than aspirin in over-75s in our study will prevent one primary event for every 50 patients treated for a year, or 25 treated for two years," Dr Jonathan W Mant (University of Birmingham, UK) told attendees here. "Our conclusion is that warfarin could be safely used much more widely in the elderly than it is at the moment, and age itself should not be regarded as a contraindication to warfarin 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 over 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 occur among those over the age of 75 years. However, 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 three trials that have looked at warfarin vs aspirin, two have in fact been negative."

To address these concerns, the BAFTA trial was undertaken, a randomized, controlled trial comparing adjusted-dose warfarin with a target international normalized ratio (INR) of 2.5 (range, 2.0 - 3.0) with aspirin in a dose of 75 mg daily among elderly AF patients taken from primary-care settings.

The study enrolled 973 patients with AF over the age of 75 years from more than 260 general practices in England and Wales. Patients were followed up at three months after randomization by their general practitioner (GP), then every six months for an average of 2.7 years.

The most common reason for exclusion of patients from randomization was the lack of clinical equipoise for the enrolling GP, Mant noted; in most of these cases, the GP thought the patient should be on warfarin.

At the end of the trial, three quarters of patients in the aspirin group were still on their assigned therapy, while two thirds of patients assigned to warfarin were still on the drug to which they had been initially assigned; most of those not on their original treatment assignment crossed over to the other trial medication.

The primary end point was fatal or nonfatal disabling stroke, either ischemic or hemorrhagic, or significant arterial embolism. "We deliberately chose quite a hard outcome measure," Mant said. "Nondisabling stroke was not part of our outcome, but we included hemorrhagic stroke - including intracranial hemorrhage [ICH] - 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, with a number needed to treat (NNT) of 56 patients treated for one year to prevent one primary outcome event.

BAFTA: Primary analysis

End point Warfarin (%/annum) Aspirin (%/annum) Hazard ratio (95% CI) NNT
Fatal or nonfatal disabling stroke or significant arterial embolism 1.8 3.8 0.48 (0.28-0.80) 50

A secondary outcome was major extracranial hemorrhage, where they saw no difference between the groups, although, he noted, the confidence intervals were wide for this end point. Similarly, there was no difference between other hospital admissions for hemorrhage or the composite of all major hemorrhages, including major ICH.

BAFTA: Bleeding complications with warfarin vs aspirin in AF patients >75 years

End point Warfarin Aspirin Hazard ratio (95% CI)
Major extracranial hemorrhage 1.4 1.6 0.87 (0.43-1.73)
All major hemorrhages 1.9 2.2 0.96 (0.53-1.75)

Although the study was not powered to look at subgroups, he noted 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," Mant noted. 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 one end point, a composite of major vascular events combining stroke, myocardial infarction, pulmonary embolism, and vascular death, did show a significant reduction with warfarin vs aspirin.

Lack of difference in bleeding risk a surprise

Mant speculated on some of the potential reasons for the "most surprising finding of the BAFTA study," the lack of difference in hemorrhage risk between the groups.

Previous studies, for example, used higher target-INR ranges, up to 4.5, "and it may be that we've overestimated the danger of warfarin because of those studies," he speculated.

Some 40% of patients in BAFTA had previously been treated with warfarin, which results of the ACTIVE-W trial suggested may be associated with a lower bleeding risk. However, he 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."

Finally, 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 for harm, he 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."

A strong argument for anticoagulation

Asked for comment on these findings, session cochair and member of the European Stroke Conference program committee Dr Bo Norrving (University of Lund, Sweden) said that the BAFTA results represent important new data.

Although elderly patients are at high risk for stroke in AF, it has not been clear that they benefit as much as younger patients from warfarin treatment and may have increased bleeding risk, so many clinicians have been very reluctant to treat them, Norrving said. "But AF is very much a problem of the elderly, and this is where we have the dilemma."

However, BAFTA showed that "even into the highest age groups, warfarin was still very effective, there was no increased bleeding risk with age, and it was clearly better than aspirin," Norrving said. "This is a very strong argument to use warfarin more often in elderly patients."

He speculated that one of the reasons that warfarin was so safe in this group was that blood pressure control may have been particularly good, rendering warfarin use generally safer than seen in previous trials.

Overall, though, Norrving added, "It's one of the most important pieces of information coming out of this meeting, and it has a great general-health impact."

The study was funded by the Medical Research Council.

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