September 11, 2009 — A contemporary assessment of the real-world clinical care of patients with atrial fibrillation (AF) has identified those who will gain the most benefit from taking warfarin therapy [1]. Dr Daniel E Singer (Massachusetts General Hospital, Boston, MA) and colleagues report their findings, taken from the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) cohort, in the September 1, 2009, issue of the Annals of Internal Medicine.

Existing guidelines for warfarin therapy are based on "old data—randomized clinical trials completed in the 1990s, for the most part," Singer explained to heartwire , "and they don't completely take into consideration the risk of intracranial hemorrhage [ICH]. We were looking to see, 'What is the net benefit of warfarin?'—the good things, ie, a reduction in clot strokes—vs the bad things, ie, increased bleeding into and around the brain."

They found that the net benefit of warfarin was highest among patients with the highest untreated risk for stroke, because the absolute increase in risk for ICH due to warfarin remains fairly stable across thromboembolic risk categories. These included those with a history of ischemic stroke and those in the highest CHADS₂ category (where patients score 1 point each for congestive heart failure, hypertension, age, and diabetes and 2 points for stroke). Those with a CHADS₂ score of 0 or 1 gained no benefit from warfarin, with net benefit being seen in those with a CHADS₂ score of 2 or greater.

Notably, the benefit was greater the older the patient, Singer said, so one of the important messages of this study is that age should not be a barrier to warfarin treatment, as long as the patient "is not falling and is not terribly demented. We can't go out and anticoagulate everyone over 85, but if you think they are reasonable candidates, the data suggest they will benefit."

In an accompanying editorial [2], Drs Robert G Hart (University of Texas Health Science Center, San Antonio) and Jonathan L Halperin (Mount Sinai Medical Center, New York) say: "These new observations underscore the importance of risk stratification to identify patients who are likely to benefit most from long-term anticoagulation. These results challenge us to reconsider the benefit of warfarin for a substantial proportion of patients with AF."

ATRIA: A Large, Contemporary Cohort

One of the strengths of this observational analysis, said Singer, is that the ATRIA database is large, with six years and more than 66 000 person-years of follow-up from a large cohort of 13 000 patients with AF. "We accumulated 1000 ischemic strokes and multiple hundreds of ICHs, so we had enough events to look at both sides of the equation."

Singer said they found that, in general, the background rates of ischemic stroke in this population were "much lower than had previously been reported, by as much as a half," and that this is in line with findings from other recent studies of those with AF.

The net clinical benefit of warfarin was defined in the study as the reduction in ischemic stroke and systemic embolism balanced against the increase in ICH (the latter weighted by a factor of 1.5 because of the severity of the health consequences of intracranial bleeding).

The researchers did not include extracranial bleeding, because 90% of deaths attributed to warfarin involve ICH, but the editorialists say they believe this to be an oversight that may have led to an overestimation of the net clinical benefit of anticoagulation.

Those with a history of stroke, the very elderly, benefit most

The patient groups with the largest net benefit from warfarin were those with a history of ischemic stroke (number needed to treat for one year to prevent one ischemic stroke equivalent=40) and those older than 85 (number needed to treat for one year to prevent one ischemic stroke equivalent=43).

Singer stressed to heartwire , however, that patients must be compliant with warfarin therapy to achieve these benefits: "Anticoagulation is highly dependent on the quality of warfarin management. Patients should be in the INR [international normalized ratio] range of 2 to 3 for 60% or more of the time. We had 65% of our patients in INR 2 to 3, which is good-quality anticoagulation."

Despite their findings, Singer says, "What we really need going forward is better ways to stratify patients. The things we are using are fairly crude risk predictors. What we'd really like to get to is those at the very highest risk: if your risk is 10% per year of having an ischemic stroke and we can get you on anticoagulation, focused very carefully, then we can spare some of the people at lower risk."

He also noted that the whole field is likely to be shaken up by a host of new oral anticoagulants that don't need monitoring in the way that warfarin does, such as dabigatran etexilate (Boehringer-Ingelheim). RE-LY, a landmark study showing that this new agent prevents strokes and peripheral embolic events in patients with AF at least as well as warfarin, with better safety, was reported at the European Society of Cardiology 2009 Congress, in Barcelona, Spain.

The editorialists agree: "New oral anticoagulants are on the horizon, and the net clinical benefit at different levels of intrinsic stroke risk will need to be assessed for these agents."

Singer reports being a consultant for Boehringer-Ingelheim, Bayer, AstraZeneca, Sanofi-Aventis, Daiichi Sankyo, and Johnson & Johnson and receiving honoraria from Bristol-Myers Squibb and Pfizer and grants from Daiichi Sankyo. The editorialists have disclosed no relevant financial relationships.

References

1. Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med 2009; 151: 297-305.
2. Hart RG and Halperin JL. Do current guidelines result in atrial fibrillation? Ann Intern Med 2009; 151: 355-356.