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NEJM
Robert G. Hart, M.D. Atrial fibrillation is a common cardiac arrhythmia whose most serious clinical consequence is stroke. Described in pathological studies in the 1940s, uncoordinated atrial contractions result in sluggish blood flow and the formation of thrombus in the atrial appendage: "The immobility of the auricular walls makes them defenceless against thrombotic deposits, as a horse should be against flies without his cutaneous muscles"1 (see Figure). The stasis-precipitated thrombi lead to emboli that are distributed according to cardiac output, but emboli to the brain account for about 80 percent of symptomatic emboli. Because they are larger on average than emboli of valvular origin, emboli to the brain cause disabling and often lethal strokes. Most strokes associated with atrial fibrillation cause substantial neurologic disability, and therefore primary prevention, rather than belated prophylaxis among survivors of an initial stroke, is the only sensible approach.
An estimated 2.3 million Americans have atrial fibrillation, and this number is expected to double during the next two decades. The prevalence of atrial fibrillation increases with age and affects about 5 percent of those 70 years of age or older. The average age of patients with atrial fibrillation is about 75 years. Among the very elderly, atrial fibrillation is the single most important cause of ischemic stroke. The long-term success of electrical and pharmacologic cardioversion in restoring sinus rhythm is inconsistent, and cardioversion does not appear to reduce the risk of stroke. During the past 15 years, a score of randomized clinical trials conducted by investigators around the world and involving 13,843 participants with nonvalvular atrial fibrillation have revolutionized management, demonstrating convincingly the value of antithrombotic therapies for stroke prevention. Anticoagulation with warfarin and congeners reduces the risk of stroke by about 65 percent, according to an intention-to-treat analysis of these clinical trials. Analysis according to treatment received shows a striking 85 percent reduction in the risk of ischemic stroke with the use of oral vitamin K inhibitors; when properly administered, adjusted-dose warfarin therapy virtually eliminates the excess risk of stroke associated with atrial fibrillation. To achieve maximal protection, the intensity of anticoagulation must be optimal, as shown by Hylek and colleagues in this issue of the Journal (pages 1019�1026). International normalized ratios between 2.0 and 3.0 provide maximal protection. Aspirin in doses of 50 to 325 mg per day reduces the risk of stroke by about 20 percent � primarily smaller, noncardioembolic strokes from which elderly, often hypertensive patients with atrial fibrillation are not immune. As compared with aspirin, adjusted-dose warfarin reduces the risk of stroke by about 45 percent. Anticoagulation with warfarin is unequivocally superior to aspirin therapy for the prevention of stroke in patients with atrial fibrillation. Does it then follow that all patients with atrial fibrillation should receive lifelong anticoagulation? No. The risk of stroke varies by a factor of more than 20 among identifiable subgroups of patients with atrial fibrillation. Many patients with nonvalvular atrial fibrillation, including most of those who are younger than 75 years of age, do not benefit sufficiently from anticoagulation to warrant its use instead of aspirin for primary prevention. Trials of primary prevention have shown that about one third of patients with atrial fibrillation have a low risk of stroke (less than 2 percent per year) if given aspirin, about one third have a high risk of stroke (more than 4 percent per year), and the remaining one third are at moderate risk (2 to 4 percent per year). Adjusted-dose warfarin offers large benefits for high-risk patients with atrial fibrillation, whereas aspirin is adequate for low-risk patients. For those at moderate risk, the patient's preference, the individual risk of bleeding during anticoagulation, and access to high-quality anticoagulation monitoring are crucial factors in the decision to use warfarin rather than aspirin. In short, antithrombotic therapies are best tailored according to the individual patient's risk of stroke and of bleeding during anticoagulation. Several approaches to the stratification of the risk of stroke have been developed and independently validated and are suitable for general clinical use. At present, there is no general consensus about which criteria are best. With all approaches, a history of stroke, an age of more than 75 years, and the presence of uncontrolled hypertension and congestive heart failure identify high-risk patients, whereas with some approaches, diabetes mellitus and controlled hypertension are used as criteria to predict the risk of stroke. The rates of stroke associated with chronic (i.e., sustained) atrial fibrillation and recurrent paroxysmal atrial fibrillation are surprisingly similar, and many elderly patients with recurrent paroxysmal atrial fibrillation benefit substantially from anticoagulation. Whether and how transesophageal echocardiographic data add to the clinical features used in the stratification of the risk of stroke remain unsettled. Antithrombotic agents that are more efficacious than aspirin and that are easier to use than adjusted-dose warfarin are needed. Several large, randomized trials are testing novel oral anticoagulants (e.g., ximelagatran) and combinations of antiplatelet agents, and additional options for stroke prevention are on the horizon. Efficacious, well-tolerated antithrombotic therapies to prevent stroke remain underused in clinical practice. During the ongoing epidemic of atrial fibrillation, all clinicians should be aware of this common cause of preventable stroke.
From the Department of Medicine, Division of Neurology, University of Texas Health Science Center, San Antonio. References
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