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RISK FACTORSFORSTROKEIN NONRHEUMATICATRIA1 FIBRILLATION To the Editor: Stroke prevention is a very important health concern. While aspirin reduces stroke or death in men with “threatened stroke” [1,2], it has only been recently that warfarin anticoagulation has been shown in randomized trials to reduce the incidence of strokes in patients with nonrheumatic atrial fibrillation [3-51. However, the benefit of warfarin (that is, prevention of stroke) is bestowed on a small minority of the patients who receive the treatment, while all are subjected to the risk of bleeding complications. Research to identify subgroups of patients with nonrheumatic atrial fibrillation at increased risk for embolic stroke is potentially very useful to identify those likely to benefit more from warfarin therapy. We therefore read with interest the case-control study by Moulton et al [l], whose purpose was to identify risk factors for ischemic stroke among patients with nonrheumatic atria1 fibrillation. The investigators identified a case group of patients discharged from the hospital with diagnoses of nonrheumatic atria1 fibrillation and stroke and a control group of patients admitted during the same time period with nonrheumatic atria1 fibrillation and without a diagnosis of stroke. They compared multiple characteristics of the two groups and found that age and hypertension were risk factors for stroke (defined in their study as “sudden development of a major neurologic deficit that lasted more than 24 hours and correlated with a cerebrovascular territory”) and that these factors should be considered when “deciding upon longterm anticoagulant therapy to prevent stroke in patients with nonrheumatic atria1 fibrillation.” We disagree with the authors’ conclusion for two reasons. First,
the authors were unable to distinguish between embolic stroke and all other causes of stroke. Their case group therefore was necessarily a heterogeneous group. Since the increased risk of stroke in patients with atrial fibrillation is thought to be due to emboli from the heart, the chosen case group appears to be inappropriate for the purpose of the study. Second, while we would agree that age and hypertension are risk factors for stroke, we submit that the findings of the study result primarily from age and hypertension in themselves being risk factors for stroke  as defined by the authors, independent of nonrheumatic atrial fibrillation. We therefore would have been very surprised if the case group had not been older and had not included more patients with hypertension. In fact, the authors would have been wiser, in their selection of cases and controls, to have matched for age and hypertension. Since these results would be expected whether or not the patients studied had atrial fibrillation, the conclusions of the authors appear to be unsubstantiated. JOHN T.~HILBRICK,M.D. DANIELM.BECKER,M.D. KENNETHA.BALLEW,M.D. RALPHS.BUCKLEY,M.D. DANIEL J. DIEKEMA,M.D. PAULA.KOBERNA,M.D. University
School of Medicine Virginia
1. Moulton AW, Singer DE, Haas JS. Risk factors for stroke in patients with nonrheumatic atrial fibrillation: a case-control study. Am J Med 1991; 91: 156-61. 2. The Canadian Cooperative Study Group. A randomized trial of aspirin and sulfinpyrazone in threatened stroke. N Engl J Med 1978; 299: 53-9. 3. Petersen P. Godtfredsen J, Boysen G, Andersen E. Andersen B. Placebo-controlled, randomized trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK Study. Lancet 1980; 1: 175-9. 4. Stroke Prevention in Atrial Fibrillation Study Group Investigators. Preliminary report of the Stroke Prevention in Atrial Fibrillation Study. N Engl J Med 1990; 322: 863-8. 5.The Boston Area Anticoagulation Trial in Atrial Fibrillation Investigators. Theeffect of low-dosewarfarin on the risk of stroke in patients with non-rheumatic atrial fibrillation. N Engl J Med 1990; 323: 1505-11.
6. Wolf PA, Kannel WB, Dawber TR. Prospective investigations: the Framingham study and the epidemiology of stroke. Adv Neurol 1978; 19: 107-20. Submitted
23, 1991, and accepted January 29, 1992
The Reply: The concerns expressed by Philbrick et al about our study [l] rest on the assumption that a substantial fraction of strokes among patients with nonrheumatic atria1 fibrillation (NRAF) are due to mechanisms other than cardiogenic emboli. By their formulation, the risk factors that we identified-increased age, and a history of hypertension-solely raise the risk of such nonembolic strokes. They assume warfarin would not be an effective preventative for such strokes. The detailed mechanism of stroke in patients with NRAF is often elusive, regardless of the sophistication of the medical evaluation. In recognition of this problem, the recent randomized trials have commonly used the aggregate category of “ischemic stroke” as their primary endpoint [2-41. Our study incorporated two features to address this problem. First, we excluded patients with known carotid disease or a history of transient ischemic attacks. Second, we repeated our analysis in the subgroup of patients who we conservatively categorized as having had a probable or definite embolic stroke, and our findings were similar. There is substantial evidence that the overwhelming proportion of strokes with NRAF are due to AF-specific mechanisms. In the Lausanne Stroke Registry study, detailed clinical evaluation estimated 76% of strokes with NRAF were due to embolism from the heart . Reworking of data from the Framingham Heart Study reveals that 80% of strokes with NRAF are attributable to AF, per se, independent of other risk factors . Finally, and perhaps most importantly, the recent clinical trials demonstrate Journal