The
n e w e ng l a n d j o u r na l
of
m e dic i n e
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Heart-Rhythm Monitoring for Evaluation of Cryptogenic Stroke Hooman Kamel, M.D. Observational studies suggest that we often fail to detect paroxysmal atrial fibrillation as the cause of ischemic stroke.1 However, owing to the limitations of existing studies, guidelines have yet to endorse specific strategies for detect ing atrial fibrillation in patients with a new stroke.2,3 The results of two studies published in this issue of the Journal indicate that prolonged monitoring of heart rhythm should now become part of the standard care of patients with crypto genic stroke.4,5 This finding represents an important advance, because typical evaluations fail to determine the cause of one third of ischemic strokes. Crypto genic strokes often seem to arise from distant clots, prompting some to call them embolic strokes of undetermined source.6 What sources of embolism might elude detection during eval uation for stroke? Atrial fibrillation causes em bolism and frequently takes a paroxysmal and asymptomatic form. Even a few minutes of this subclinical form of atrial fibrillation increases the risk of stroke.7 A patient might have sub clinical atrial fibrillation that leads to stroke, but only evidence of sinus rhythm is observed during the ensuing hospitalization. Such a scenario matters, because patients without recognized atrial fibrillation typically receive antiplatelet therapy after stroke, and antiplatelet therapy is inferior to anticoagulant therapy for clinically apparent atrial fibrillation. Therefore, a failure to diagnose atrial fibrillation as the cause of stroke may result in suboptimal antithrombotic therapy. Such misdiagnosis may not be uncom mon, because although the current standard of care requires just 24 hours of cardiac monitor ing after stroke,2,3 several decades’ worth of
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studies suggest that prolonged monitoring may capture previously undiagnosed atrial fibrillation in about 10% of patients.1 What has prevented the adoption of prolonged rhythm monitoring as a standard test for cryptogenic stroke? Most studies have lacked control groups, leaving it unclear whether monitoring improves diagnosis as compared with routine follow-up. Subclinical atrial fibrillation often becomes clinically ap parent atrial fibrillation,7 so why not wait for atrial fibrillation to declare itself? The two randomized trials in this issue of the Journal show that prolonged rhythm moni toring identifies atrial fibrillation that would not have otherwise declared itself.4,5 The Cryptogenic Stroke and Underlying AF (CRYSTAL AF) trial and the 30-Day Cardiac Event Monitor Belt for Recording Atrial Fibrillation after a Cerebral Is chemic Event (EMBRACE) trial enrolled patients with recent cryptogenic stroke or transient is chemic attack and no history of atrial fibrillation. Prior to enrollment, patients underwent at least 24 hours of continuous rhythm monitoring with out evidence of atrial fibrillation. In the CRYSTAL AF trial, patients were assigned to 6 months of monitoring with a subcutaneous implantable loop recorder or to routine follow-up. In the EMBRACE trial, patients were assigned to monitoring with a 30-day external loop recorder or a 24-hour Holter monitor. Approximately 10 patients need ed to be screened with prolonged monitoring to establish one new diagnosis of atrial fibrilla tion. Monitoring increased the diagnostic yield regardless of the age of the patients, but abso lute rates of atrial fibrillation increased with age. This may explain the higher yield of mon itoring relative to its duration in the EMBRACE
n engl j med 370;26 nejm.org june 26, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIV OF UTAH ECCLES on July 7, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
editorial
trial, which included patients 55 years of age or older, as compared with the CRYSTAL AF trial, which included patients 40 years of age or older. At least two relevant questions remain unan swered. First, subclinical atrial fibrillation is clearly not the whole answer to the riddle of cryptogenic stroke. Even after long-term followup involving 3 years of continuous rhythm mon itoring in the CRYSTAL AF trial, less than one third of the patients had evidence of atrial fibril lation. We need to identify additional sources of embolism and better markers of known stroke mechanisms such as nonobstructive atheroscle rosis.8 Second, we need more evidence to guide therapy for subclinical atrial fibrillation. Ran domized trials of antithrombotic therapy have involved patients with a sufficient burden of atrial fibrillation to allow its recognition with out prolonged rhythm monitoring. Whether the proven benefit of anticoagulation in this popu lation extends to patients with subclinical atrial fibrillation must be answered in future trials. In the meantime, how should the results of the CRYSTAL AF and EMBRACE trials change practice? The weight of current evidence sug gests that subclinical atrial fibrillation is a modi fiable risk factor for stroke recurrence, and its presence should be thoroughly ruled out in this high-risk population. Therefore, most patients with cryptogenic stroke or transient ischemic attack should undergo at least several weeks of rhythm monitoring. Relatively inexpensive exter nal loop recorders, such as those used in the EMBRACE trial, will probably be cost-effective9; the value of more expensive implantable loop re corders is less clear. Furthermore, the detection of subclinical atrial fibrillation in these patients
should generally prompt a switch from anti platelet to anticoagulant therapy. At the least, patients should be followed closely in order to detect progression to clinically apparent atrial fibrillation, in which case the evidence unambig uously supports anticoagulant therapy for the secondary prevention of stroke. Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Department of Neurology and the Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York. 1. Kishore A, Vail A, Majid A, et al. Detection of atrial fibrilla
tion after ischemic stroke or transient ischemic attack: a system atic review and meta-analysis. Stroke 2014;45:520-6. 2. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44: 870-947. 3. Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the pre vention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the Ameri can Heart Association/American Stroke Association. Stroke 2011; 42:227-76. 4. Sanna T, Diener H-C, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014;370:247886. 5. Gladstone DJ, Spring M, Dorian P, et al. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med 2014;370:246777. 6. Hart RG, Diener HC, Coutts SB, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014;13:429-38. 7. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fi brillation and the risk of stroke. N Engl J Med 2012;366:120-9. 8. Bang OY, Lee PH, Joo SY, Lee JS, Joo IS, Huh K. Frequency and mechanisms of stroke recurrence after cryptogenic stroke. Ann Neurol 2003;54:227-34. 9. Kamel H, Hegde M, Johnson DR, Gage BF, Johnston SC. Cost-effectiveness of outpatient cardiac monitoring to detect atrial fibrillation after ischemic stroke. Stroke 2010;41:1514-20. DOI: 10.1056/NEJMe1405046 Copyright © 2014 Massachusetts Medical Society.
my nejm in the journal online
Individual subscribers can store articles and searches using a feature on the Journal’s website (NEJM.org) called “My NEJM.” Each article and search result links to this feature. Users can create personal folders and move articles into them for convenient retrieval later.
n engl j med 370;26 nejm.org june 26, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIV OF UTAH ECCLES on July 7, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
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n e w e ng l a n d j o u r na l
of
m e dic i n e
edi t or i a l
Heart-Rhythm Monitoring for Evaluation of Cryptogenic Stroke Hooman Kamel, M.D. Observational studies suggest that we often fail to detect paroxysmal atrial fibrillation as the cause of ischemic stroke.1 However, owing to the limitations of existing studies, guidelines have yet to endorse specific strategies for detect ing atrial fibrillation in patients with a new stroke.2,3 The results of two studies published in this issue of the Journal indicate that prolonged monitoring of heart rhythm should now become part of the standard care of patients with crypto genic stroke.4,5 This finding represents an important advance, because typical evaluations fail to determine the cause of one third of ischemic strokes. Crypto genic strokes often seem to arise from distant clots, prompting some to call them embolic strokes of undetermined source.6 What sources of embolism might elude detection during eval uation for stroke? Atrial fibrillation causes em bolism and frequently takes a paroxysmal and asymptomatic form. Even a few minutes of this subclinical form of atrial fibrillation increases the risk of stroke.7 A patient might have sub clinical atrial fibrillation that leads to stroke, but only evidence of sinus rhythm is observed during the ensuing hospitalization. Such a scenario matters, because patients without recognized atrial fibrillation typically receive antiplatelet therapy after stroke, and antiplatelet therapy is inferior to anticoagulant therapy for clinically apparent atrial fibrillation. Therefore, a failure to diagnose atrial fibrillation as the cause of stroke may result in suboptimal antithrombotic therapy. Such misdiagnosis may not be uncom mon, because although the current standard of care requires just 24 hours of cardiac monitor ing after stroke,2,3 several decades’ worth of
2532
studies suggest that prolonged monitoring may capture previously undiagnosed atrial fibrillation in about 10% of patients.1 What has prevented the adoption of prolonged rhythm monitoring as a standard test for cryptogenic stroke? Most studies have lacked control groups, leaving it unclear whether monitoring improves diagnosis as compared with routine follow-up. Subclinical atrial fibrillation often becomes clinically ap parent atrial fibrillation,7 so why not wait for atrial fibrillation to declare itself? The two randomized trials in this issue of the Journal show that prolonged rhythm moni toring identifies atrial fibrillation that would not have otherwise declared itself.4,5 The Cryptogenic Stroke and Underlying AF (CRYSTAL AF) trial and the 30-Day Cardiac Event Monitor Belt for Recording Atrial Fibrillation after a Cerebral Is chemic Event (EMBRACE) trial enrolled patients with recent cryptogenic stroke or transient is chemic attack and no history of atrial fibrillation. Prior to enrollment, patients underwent at least 24 hours of continuous rhythm monitoring with out evidence of atrial fibrillation. In the CRYSTAL AF trial, patients were assigned to 6 months of monitoring with a subcutaneous implantable loop recorder or to routine follow-up. In the EMBRACE trial, patients were assigned to monitoring with a 30-day external loop recorder or a 24-hour Holter monitor. Approximately 10 patients need ed to be screened with prolonged monitoring to establish one new diagnosis of atrial fibrilla tion. Monitoring increased the diagnostic yield regardless of the age of the patients, but abso lute rates of atrial fibrillation increased with age. This may explain the higher yield of mon itoring relative to its duration in the EMBRACE
n engl j med 370;26 nejm.org june 26, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIV OF UTAH ECCLES on July 7, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
editorial
trial, which included patients 55 years of age or older, as compared with the CRYSTAL AF trial, which included patients 40 years of age or older. At least two relevant questions remain unan swered. First, subclinical atrial fibrillation is clearly not the whole answer to the riddle of cryptogenic stroke. Even after long-term followup involving 3 years of continuous rhythm mon itoring in the CRYSTAL AF trial, less than one third of the patients had evidence of atrial fibril lation. We need to identify additional sources of embolism and better markers of known stroke mechanisms such as nonobstructive atheroscle rosis.8 Second, we need more evidence to guide therapy for subclinical atrial fibrillation. Ran domized trials of antithrombotic therapy have involved patients with a sufficient burden of atrial fibrillation to allow its recognition with out prolonged rhythm monitoring. Whether the proven benefit of anticoagulation in this popu lation extends to patients with subclinical atrial fibrillation must be answered in future trials. In the meantime, how should the results of the CRYSTAL AF and EMBRACE trials change practice? The weight of current evidence sug gests that subclinical atrial fibrillation is a modi fiable risk factor for stroke recurrence, and its presence should be thoroughly ruled out in this high-risk population. Therefore, most patients with cryptogenic stroke or transient ischemic attack should undergo at least several weeks of rhythm monitoring. Relatively inexpensive exter nal loop recorders, such as those used in the EMBRACE trial, will probably be cost-effective9; the value of more expensive implantable loop re corders is less clear. Furthermore, the detection of subclinical atrial fibrillation in these patients
should generally prompt a switch from anti platelet to anticoagulant therapy. At the least, patients should be followed closely in order to detect progression to clinically apparent atrial fibrillation, in which case the evidence unambig uously supports anticoagulant therapy for the secondary prevention of stroke. Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Department of Neurology and the Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York. 1. Kishore A, Vail A, Majid A, et al. Detection of atrial fibrilla
tion after ischemic stroke or transient ischemic attack: a system atic review and meta-analysis. Stroke 2014;45:520-6. 2. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44: 870-947. 3. Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the pre vention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the Ameri can Heart Association/American Stroke Association. Stroke 2011; 42:227-76. 4. Sanna T, Diener H-C, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014;370:247886. 5. Gladstone DJ, Spring M, Dorian P, et al. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med 2014;370:246777. 6. Hart RG, Diener HC, Coutts SB, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014;13:429-38. 7. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fi brillation and the risk of stroke. N Engl J Med 2012;366:120-9. 8. Bang OY, Lee PH, Joo SY, Lee JS, Joo IS, Huh K. Frequency and mechanisms of stroke recurrence after cryptogenic stroke. Ann Neurol 2003;54:227-34. 9. Kamel H, Hegde M, Johnson DR, Gage BF, Johnston SC. Cost-effectiveness of outpatient cardiac monitoring to detect atrial fibrillation after ischemic stroke. Stroke 2010;41:1514-20. DOI: 10.1056/NEJMe1405046 Copyright © 2014 Massachusetts Medical Society.
my nejm in the journal online
Individual subscribers can store articles and searches using a feature on the Journal’s website (NEJM.org) called “My NEJM.” Each article and search result links to this feature. Users can create personal folders and move articles into them for convenient retrieval later.
n engl j med 370;26 nejm.org june 26, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIV OF UTAH ECCLES on July 7, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
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