Intern Emerg Med (2014) 9:887–888 DOI 10.1007/s11739-014-1137-9
THE CUTTING EDGE: RESEARCH UPDATE
Atrial fibrillation detection after cryptogenic stroke Maddalena Alessandra Wu • Emanuela Scannella • Gruppo di Autoformazione Metodologica (GrAM)
Received: 17 September 2014 / Accepted: 19 September 2014 / Published online: 2 October 2014 Ó SIMI 2014
Background Ischemic stroke is a significant cause of mortality and of serious long-term morbidity. It is estimated that cryptogenic stroke (stroke whose underlying causes remain unknown despite a complete work-up,) accounts for about 20–40 % of all ischemic events, one quarter of which tend to be recurrent [1]. Paroxysmal and persistent atrial fibrillation (AF) is a well-recognized cause of ischemic stroke, and the risk may be reduced with anticoagulation. However, only 5 % of patients are diagnosed to have AF after an ischemic stroke. Indeed the use of traditional monitoring techniques may not detect episodes of asymptomatic paroxysmal AF, which might underlie some apparently ‘‘cryptogenic’’ strokes. Therefore, the most effective duration of ECG monitoring has not been determined by current guidelines [2]. Nowadays, external and implanted loop recorders may allow identification of silent AF, thus increasing AF detection rate. However, the effectiveness of prolonged heart rhythm monitoring in patients with cryptogenic stroke is still unproved [3, 4].
Summary The Cryptogenic Stroke and Underlying AF (CRYSTAL AF) trial [5] is a prospective, multicenter randomized
M. A. Wu (&) E. Scannella Division of Medicine, Department of Biomedical and Clinical Sciences ‘‘L. Sacco’’, L. Sacco Hospital, University of Milan, via GB Grassi 74, 20157 Milan, Italy e-mail: [email protected] E. Scannella e-mail: [email protected]
controlled trial conducted between June 2009 and April 2012, aimed at assessing whether long-term monitoring with an implanted cardiac monitor (ICM) is more effective than conventional follow-up for detecting episodes of AF after cryptogenic stroke. Patients 40 years of age or older with a diagnosis of cryptogenic stroke or transient ischemic attack (TIA) within the previous 90 days were included. Stroke was defined as cryptogenic if an extensive etiologic evaluation (including 12-lead ECG, 24 h or more of ECG monitoring, transesophageal echocardiography, screening for thrombophilic states, and magnetic resonance angiography, computed tomographic angiography, or catheter angiography of the head and neck,) did not reveal a clear cause. A history of AF, an indication or contraindication for permanent oral anticoagulant therapy, and an indication for a pacemaker or implantable cardioverter–defibrillator were the main exclusion criteria. The primary end point was the time to first detection of AF (lasting [30 s) within 6 months. Secondary end points were the time to first detection of AF within 12 months, the recurrences of stroke or TIA, and the change in use of oral anticoagulant drugs. A total of 441 patients were randomized to receive conventional follow-up (including scheduled and unscheduled visits in case of symptoms occurrence) or long-term monitoring with an ICM. Patients and physicians were aware of the study-group assignments. Data were analyzed according to the intention-to-treat principle. By 6 months, AF had been detected in 8.9 % of patients in the ICM group (19 patients) versus 1.4 % of patients in the control group (3 patients) (hazard ratio 6.4; 95 % confidence interval [CI] 1.9–21.7; P \ 0.001.) The median time from randomization to AF detection was 41 days in the ICM group and 32 days in the control group. AF was
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asymptomatic in 74 % of the episodes in the ICM group and in 33 % of cases in the control group. By 12 months, AF had been detected in 12.4 % of patients in the ICM group (29 patients) versus 2.0 % of patients in the control group (4 patients) (hazard ratio 7.3; 95 % CI 2.6–20.8; P \ 0.001.) With respect to the other secondary end points, there was a 5.2 % rate of ischemic recurrences in the ICM group as compared to a 8.6 % rate in the control group at 6 months from randomization, and a 7.1 vs 9.1 % rate at 12 months. The rate of use of oral anticoagulants was 10.1 % in the ICM group versus 4.6 % in the control group at 6 months (P = 0.04) and 14.7 vs 6.0 % at 12 months (P = 0.007.) On the basis of these results, the authors conclude that ECG monitoring with an ICM is superior to conventional follow-up for detecting AF after cryptogenic stroke.
Strengths and weaknesses of the study The study proves that ICMs are able to increase the rate of AF detection in cryptogenic stroke. However, the fact that a prolonged observation leads to a higher diagnostic rate would be expected. More clinically relevant questions would be whether there is a cause-effect relationship between stroke and newly discovered AF, and whether anticoagulants prevent stroke recurrences. Unfortunately, these issues are not addressed by the study.
Question marks It would be interesting to know the temporal relation between AF episodes and ischemic recurrences, as well as the number and duration of AF episodes in each patient. Should a strong link between AF burden and subsequent stroke relapses be observed, a causal relationship between paroxysmal AF and cryptogenic stroke would be more robust. It would be interesting to compare the rate of stroke relapses in controls, anticoagulated and non-anticoagulated ECG-monitored patients. This could provide indirect clues about the real clinical benefit of detecting (and treating) asymptomatic paroxysmal AF to prevent stroke relapses, although the small number of subjects would not allow one to draw definite conclusions.
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Intern Emerg Med (2014) 9:887–888
Sponsorship The CRYSTAL AF trial was funded by Medtronic, which had non-voting membership on the steering committee, assisted in the design of the study, data collection, and data analysis, proposed technical content for the manuscript, and contributed to manuscript review, but had no role in the decision to submit the manuscript for publication.
Clinical bottom line Long-term ECG monitoring with an ICM is superior to conventional follow-up to detect asymptomatic AF episodes, which could be linked to cryptogenic strokes. More evidence is needed to identify whether patients’ clinical outcome may be improved by the use of ICMs after cryptogenic stroke. The optimal length and method of monitoring remain unclear. Conflict of interest
None.
References 1. Amin H, Greer DM (2014) Cryptogenic stroke-the appropriate diagnostic evaluation. Curr Treat Options Cardiovasc Med 16:280. doi:10.1007/s11936-013-0280-3 2. Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk BM, Khatri P, McMullan PW Jr, Qureshi AI, Rosenfield K, Scott PA, Summers, Wang DZ, Wintermark M, Yonas H, American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Peripheral Vascular Disease; Council on Clinical Cardiology (2013) 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 44:870–947. doi:10.1161/ STR.0b013e318284056a 3. Lazzaro MA, Krishnan K, Prabhakaran S (2012) Detection of atrial fibrillation with concurrent holter monitoring and continuous cardiac telemetry following ischemic stroke and transient ischemic attack. J Stroke Cerebrovasc Dis 21:89–93. doi:10.1016/j.jstroke cerebrovasdis.2010.05.006 4. Kishore A, Vail A, Majid A, Dawson J, Lees KR, Tyrrell PJ, Smith CJ (2014) Detection of atrial fibrillation after ischemic stroke or transient ischemic attack: a systematic review and meta-analysis. Stroke 45:520–526. doi:10.1161/STROKEAHA.113.003433 5. Sanna T, Diener HC, Passman RS, Di Lazzaro V, Bernstein RA, Morillo CA, Rymer MM, Thijs V, Rogers T, Beckers F, Lindborg K, Brachmann J, CRYSTAL AF Investigators (2014) Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 26(370):2478–2486. doi:10.1056/NEJMoa1313600
THE CUTTING EDGE: RESEARCH UPDATE
Atrial fibrillation detection after cryptogenic stroke Maddalena Alessandra Wu • Emanuela Scannella • Gruppo di Autoformazione Metodologica (GrAM)
Received: 17 September 2014 / Accepted: 19 September 2014 / Published online: 2 October 2014 Ó SIMI 2014
Background Ischemic stroke is a significant cause of mortality and of serious long-term morbidity. It is estimated that cryptogenic stroke (stroke whose underlying causes remain unknown despite a complete work-up,) accounts for about 20–40 % of all ischemic events, one quarter of which tend to be recurrent [1]. Paroxysmal and persistent atrial fibrillation (AF) is a well-recognized cause of ischemic stroke, and the risk may be reduced with anticoagulation. However, only 5 % of patients are diagnosed to have AF after an ischemic stroke. Indeed the use of traditional monitoring techniques may not detect episodes of asymptomatic paroxysmal AF, which might underlie some apparently ‘‘cryptogenic’’ strokes. Therefore, the most effective duration of ECG monitoring has not been determined by current guidelines [2]. Nowadays, external and implanted loop recorders may allow identification of silent AF, thus increasing AF detection rate. However, the effectiveness of prolonged heart rhythm monitoring in patients with cryptogenic stroke is still unproved [3, 4].
Summary The Cryptogenic Stroke and Underlying AF (CRYSTAL AF) trial [5] is a prospective, multicenter randomized
M. A. Wu (&) E. Scannella Division of Medicine, Department of Biomedical and Clinical Sciences ‘‘L. Sacco’’, L. Sacco Hospital, University of Milan, via GB Grassi 74, 20157 Milan, Italy e-mail: [email protected] E. Scannella e-mail: [email protected]
controlled trial conducted between June 2009 and April 2012, aimed at assessing whether long-term monitoring with an implanted cardiac monitor (ICM) is more effective than conventional follow-up for detecting episodes of AF after cryptogenic stroke. Patients 40 years of age or older with a diagnosis of cryptogenic stroke or transient ischemic attack (TIA) within the previous 90 days were included. Stroke was defined as cryptogenic if an extensive etiologic evaluation (including 12-lead ECG, 24 h or more of ECG monitoring, transesophageal echocardiography, screening for thrombophilic states, and magnetic resonance angiography, computed tomographic angiography, or catheter angiography of the head and neck,) did not reveal a clear cause. A history of AF, an indication or contraindication for permanent oral anticoagulant therapy, and an indication for a pacemaker or implantable cardioverter–defibrillator were the main exclusion criteria. The primary end point was the time to first detection of AF (lasting [30 s) within 6 months. Secondary end points were the time to first detection of AF within 12 months, the recurrences of stroke or TIA, and the change in use of oral anticoagulant drugs. A total of 441 patients were randomized to receive conventional follow-up (including scheduled and unscheduled visits in case of symptoms occurrence) or long-term monitoring with an ICM. Patients and physicians were aware of the study-group assignments. Data were analyzed according to the intention-to-treat principle. By 6 months, AF had been detected in 8.9 % of patients in the ICM group (19 patients) versus 1.4 % of patients in the control group (3 patients) (hazard ratio 6.4; 95 % confidence interval [CI] 1.9–21.7; P \ 0.001.) The median time from randomization to AF detection was 41 days in the ICM group and 32 days in the control group. AF was
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asymptomatic in 74 % of the episodes in the ICM group and in 33 % of cases in the control group. By 12 months, AF had been detected in 12.4 % of patients in the ICM group (29 patients) versus 2.0 % of patients in the control group (4 patients) (hazard ratio 7.3; 95 % CI 2.6–20.8; P \ 0.001.) With respect to the other secondary end points, there was a 5.2 % rate of ischemic recurrences in the ICM group as compared to a 8.6 % rate in the control group at 6 months from randomization, and a 7.1 vs 9.1 % rate at 12 months. The rate of use of oral anticoagulants was 10.1 % in the ICM group versus 4.6 % in the control group at 6 months (P = 0.04) and 14.7 vs 6.0 % at 12 months (P = 0.007.) On the basis of these results, the authors conclude that ECG monitoring with an ICM is superior to conventional follow-up for detecting AF after cryptogenic stroke.
Strengths and weaknesses of the study The study proves that ICMs are able to increase the rate of AF detection in cryptogenic stroke. However, the fact that a prolonged observation leads to a higher diagnostic rate would be expected. More clinically relevant questions would be whether there is a cause-effect relationship between stroke and newly discovered AF, and whether anticoagulants prevent stroke recurrences. Unfortunately, these issues are not addressed by the study.
Question marks It would be interesting to know the temporal relation between AF episodes and ischemic recurrences, as well as the number and duration of AF episodes in each patient. Should a strong link between AF burden and subsequent stroke relapses be observed, a causal relationship between paroxysmal AF and cryptogenic stroke would be more robust. It would be interesting to compare the rate of stroke relapses in controls, anticoagulated and non-anticoagulated ECG-monitored patients. This could provide indirect clues about the real clinical benefit of detecting (and treating) asymptomatic paroxysmal AF to prevent stroke relapses, although the small number of subjects would not allow one to draw definite conclusions.
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Intern Emerg Med (2014) 9:887–888
Sponsorship The CRYSTAL AF trial was funded by Medtronic, which had non-voting membership on the steering committee, assisted in the design of the study, data collection, and data analysis, proposed technical content for the manuscript, and contributed to manuscript review, but had no role in the decision to submit the manuscript for publication.
Clinical bottom line Long-term ECG monitoring with an ICM is superior to conventional follow-up to detect asymptomatic AF episodes, which could be linked to cryptogenic strokes. More evidence is needed to identify whether patients’ clinical outcome may be improved by the use of ICMs after cryptogenic stroke. The optimal length and method of monitoring remain unclear. Conflict of interest
None.
References 1. Amin H, Greer DM (2014) Cryptogenic stroke-the appropriate diagnostic evaluation. Curr Treat Options Cardiovasc Med 16:280. doi:10.1007/s11936-013-0280-3 2. Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk BM, Khatri P, McMullan PW Jr, Qureshi AI, Rosenfield K, Scott PA, Summers, Wang DZ, Wintermark M, Yonas H, American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Peripheral Vascular Disease; Council on Clinical Cardiology (2013) 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 44:870–947. doi:10.1161/ STR.0b013e318284056a 3. Lazzaro MA, Krishnan K, Prabhakaran S (2012) Detection of atrial fibrillation with concurrent holter monitoring and continuous cardiac telemetry following ischemic stroke and transient ischemic attack. J Stroke Cerebrovasc Dis 21:89–93. doi:10.1016/j.jstroke cerebrovasdis.2010.05.006 4. Kishore A, Vail A, Majid A, Dawson J, Lees KR, Tyrrell PJ, Smith CJ (2014) Detection of atrial fibrillation after ischemic stroke or transient ischemic attack: a systematic review and meta-analysis. Stroke 45:520–526. doi:10.1161/STROKEAHA.113.003433 5. Sanna T, Diener HC, Passman RS, Di Lazzaro V, Bernstein RA, Morillo CA, Rymer MM, Thijs V, Rogers T, Beckers F, Lindborg K, Brachmann J, CRYSTAL AF Investigators (2014) Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 26(370):2478–2486. doi:10.1056/NEJMoa1313600
