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By Matthew E. Fink, MD
Professor and Chairman, Department of Neurology, Weill Cornell Medical College, and Neurologist-in-Chief, New York Presbyterian Hospital
SOURCES: Gladstone DJ, et al, for the EMBRACE Investigators and Coordinators. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med 2014;370:2467-2477.
Kamel H. Editorial. Heart-rhythm monitoring for evaluation of cryptogenic stroke. N Engl J Med 2014;26:2532-2533.
Sanna T, et al, for the CRYSTAL AF Investigators. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014;370:2478-2486.
Ischemic stroke remains a leading cause of death worldwide, and atrial fibrillation is a major risk factor, increasing the risk of ischemic stroke five-fold in those who have a confirmed diagnosis of atrial fibrillation. Of all ischemic strokes, 20-40% have no identifiable cause and are classified as cryptogenic ischemic strokes. Clinically, it has been suspected that many of these cryptogenic ischemic strokes have the features of cardiogenic embolism, but a clear cause has not been identified, and therefore, the most effective treatment for cardiogenic embolism, full anticoagulation with either warfarin or the newer direct thrombin inhibitors, is not used. If in fact these patients have silent or intermittent atrial fibrillation that has not been identified, they remain at increased risk for recurrent stroke, and standard therapy with antiplatelet medication would be inferior to the use of full anticoagulation. Two recently published randomized trials (CRYSTAL AF and EMBRACE) have shed further light on the value of prolonged cardiac monitoring in patients with cryptogenic stroke, in order to diagnose occult or silent atrial fibrillation.
CRYSTAL AF was a randomized controlled study of 441 patients over the age of 40 who had a transient ischemic attack (TIA) or ischemic stroke of undetermined cause, and had long-term monitoring with an insertable cardiac loop ECG monitor that remained in place for a minimum of 6 months. The control group received 24 hours of ECG monitoring within 90 days of the index event. The primary endpoint was the time to first detection of atrial fibrillation, and defined as an episode > 30 seconds within 6 months. Secondary endpoint was time to first detection of atrial fibrillation within 12 months. At 6 months, atrial fibrillation was detected in 8.9% of patients in the monitored group vs 1.4% of patients in the control group (P < 0.001). By 12 months, atrial fibrillation was detected in 12.4% of patients in the monitored group vs 2% of patients in the control group (P < 0.001).
EMBRACE was a study of 572 patients 55 years of age or older, without known atrial fibrillation, who had a TIA or cryptogenic ischemic stroke within the previous 6 months and a negative 24-hour ECG monitoring. The patients were then randomized to a second 24-hour monitoring session, or noninvasive ambulatory ECG monitoring with a 30-day event-triggered recorder. The primary endpoint was newly detected atrial fibrillation lasting > 30 seconds within 90 days after randomization. Secondary outcomes included episodes of atrial fibrillation lasting 2.5 minutes or longer and anticoagulation status at 90 days. In the EMBRACE study, atrial fibrillation was detected in 16.1% of the 30-day monitoring group, compared to 3.2% in the control group (P < 0.001). Atrial fibrillation lasting 2.5 minutes or longer was present in 9.9% of the intervention group, compared to 2.5% in the control group (P < 0.001). By 90 days, oral anticoagulant therapy had been prescribed for more patients who were diagnosed with atrial fibrillation in the monitoring group then in the control group (18.6% vs 11.1%; P < 0.01).
Both of these well-designed and well-executed randomized clinical trials clearly demonstrated a significant identification of atrial fibrillation in patients with cryptogenic stroke if they undergo long-term monitoring anywhere from 30 days to 1 year. It is clear from these studies that long-term monitoring should be the standard of care for patients with cryptogenic stroke, although the actual duration of monitoring has yet to be determined. In addition, the best technique for monitoring has not been clearly determined. We should also recognize that the majority of patients do not have atrial fibrillation identified, and therefore we must continue to look for other causes of cryptogenic stroke. Nevertheless, these findings are a major advance in our knowledge and will help to prevent secondary stroke in patients who have cryptogenic ischemic stroke or TIAs.