European Journal of Neurology 2014, 21: 884–889
doi:10.1111/ene.12400
Paroxysmal atrial fibrillation occurs often in cryptogenic ischaemic stroke. Final results from the SURPRISE* study L. M. Christensena, D. W. Kriegera,b, S. Højbergc, O. D. Pedersenc, F. M. Karlsenc, M. D. Jacobsenc, R. Worckc, H. Nielsenc, K. Ægidiusa, L. L. Jeppesena, S. Rosenbauma, J. Marstranda and H. Christensena a
Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospitals, Copenhagen; bDepartment of Neurology, Rigshospitalet, Copenhagen University Hospitals, Copenhagen; and cDepartment of Cardiology, Bispebjerg Hospital, Copenhagen University Hospitals, Copenhagen, Denmark
Keywords:
atrial fibrillation, cardiology, cryptogenic stroke, implantable loop recorder, long-term cardiac monitoring, neurology, paroxysmal atrial fibrillation Received 28 October 2013 Accepted 28 January 2014
Background and purpose: Atrial fibrillation (AF) increases the risk of stroke fourfold and is associated with a poor clinical outcome. Despite work-up in compliance with guidelines, up to one-third of patients have cryptogenic stroke (CS). The prevalence of asymptomatic paroxysmal atrial fibrillation (PAF) in CS remains unknown. The SURPRISE project aimed at determining this rate using long-term cardiac monitoring. Methods: Patients with CS after protocolled work-up including electrocardiography (ECG) and telemetry were included after informed consent. An implantable loop recorder (ILR) was implanted subcutaneously. PAF was defined by events of atrial arrhythmia >2 min with a correlating one-lead ECG confirming the diagnosis. Results: Eighty-five patients were monitored for a mean of 569 days (SD 310). PAF was documented in 18 patients (20.7%) during the study period and detected by ILR in 14 patients (16.1%). In three patients PAF was detected by other methods before or after monitoring and was undiscovered due to device sensitivity in one case. The first event of PAF was documented at a mean of 109 days (SD 48) after stroke onset. PAF was asymptomatic in all cases and occurred in episodes lasting predominantly between 1 and 4 h. Four recurrent strokes were observed, three in patients with PAF; all three patients were on oral anticoagulation (OAC). Conclusions: One in five patients with CS had PAF, which occurred at low burden and long after stroke. Future studies should determine the role of implantable cardiac monitors after stroke and determine the potential therapeutic benefit of OAC treatment of patients with PAF.
Background Atrial fibrillation (AF) is the predominant risk factor for cardioembolic stroke [1] and may convey a 1-year survival as low as 30% after stroke [2]. Oral anticoagulation (OAC) treatment reduces the risk of recurrent stroke by two-thirds [3,4]. The natural history and benefit of OAC underline the importance of identifying AF in patients after stroke, in particular after minor stroke or transient ischaemic attack (TIA). The stroke risk is Correspondence: L. M. Christensen, Department of Neurology, Bispebjerg Hospital, Copenhagen, Denmark (tel.: +45 53620238; fax: +45 35313733; e-mail: [email protected]). *Stroke Prior to Diagnosis of Atrial Fibrillation Using Long-term Observation with Implantable Cardiac Monitoring Apparatus Reveal.
884
considered equivalent in paroxysmal and permanent AF [5,6] stressing the need for a highly sensitive and specific method of monitoring for AF after stroke. Both AF and paroxysmal atrial fibrillation (PAF) are frequently asymptomatic [7], making stroke the first clinical manifestation of AF. Cryptogenic stroke (CS) has been defined as a cerebrovascular event of unknown origin, despite thorough work-up. The implication in everyday practice is continuously debated [8–10], as even in current studies 20%–30% of all ischaemic strokes can be classified as cryptogenic [11–13]. The prevalence of AF in patients with CS is reported to be in the range of 4.9% and 9.2% [14–16]; however, as improved detection techniques have become available the prevalence is suggested to be as high as 25% [17–19]. © 2014 The Author(s) European Journal of Neurology © 2014 EAN
885
Final results from the SURPRISE study
Long-term electrocardiography (ECG) monitoring is used routinely for the detection of arrhythmias in patients with syncope [20]. For this purpose, cardiac monitors are implanted subcutaneously and monitor the heart continuously registering beat-to-beat variability, by measurement of the R-R intervals, for up to 3 years [21,22]. When irregular R-R-intervals are detected, the device stores 2 min of ECG and information regarding time occurring and amount detected, enabling later detailed detection and qualification of AF. The aim of this study was to detect and quantify AF in patients with CS using long-term monitoring.
Methods The study was approved by the ethics committee of the Capitol Region of Denmark (H3-2010-083) in compliance with the Declaration of Helsinki and was registered at Clinical Trial Registration URL: http:// www.clinicaltrials.gov; unique identifier NCT01498146. The study was conducted in Bispebjerg University Hospital, Copenhagen, Denmark, which shares a catchment area for acute stroke of 1.7 million inhabitants with one other hospital. During the inclusion period from 2010 to 2012 the average number of acute stroke admissions was 946 per year. All new patient files were systematically screened during the study period by one investigator (LC) and patients were also referred from the outpatient clinic. The inclusion criteria were (i) providing informed consent, (ii) an ischaemic vascular event with CT or MRI verified acute ischaemic lesion, (iii) a post-stroke modified Rankin score ≤2, (iv) >18 years of age, (v) no known prior AF or AF documented during the admission period (including continuous telemetric monitoring for 12–24 h) and (vi) a diagnosis of CS based on a standardized work-up (carotid occlusive disease, cardiac sources of embolism, small vessel disease and thrombophilia). Included patients were referred to the cardiologist for implantation of the implantable loop recorder (ILR). Patients were scheduled as soon as possible, usually within a week after completed work-up. The ILR (Reveal XT; Medtronic Inc., Minneapolis, MN, USA) was implanted subcutaneously in a left parasternal position and all patients were instructed to transmit data on a regular basis at least every 2 weeks. Patients with confirmed episodes of AF continued transmitting until the end of the study. The device was programmed to detect AF (Fig. 1) and to store one-lead ECG of all episodes of arrhythmia. AF was defined as irregular R-R intervals (an example is shown in Fig. 1) and no visible p-waves on correlating © 2014 The Author(s) European Journal of Neurology © 2014 EAN
ID# Type 5
AF
Date
Time Duration hh:mm hh:mm:ss Max V. Rate
03-Nov-2009 21:39
04:52:00 176 bpm (340 ms)
Median V. Rate 97 bpm (620 ms)
Detected
Interval (ms) 1500 1200 900 600 400 200
–280 –260 –240 –220 –200 –180 –160 –140 –120 –100 Time (sec)
–80
–60
–40
–20
0
Figure 1 R-R intervals of a transmission. Shows a transmission from regular R-R intervals in sinus rhythm to the scatter in atrial fibrillation; the x-axis is the time in seconds, and the y-axis is the length of R-R intervals in milliseconds.
one-lead ECG transmissions. Only AF events lasting >2 min were recorded by the ILR. All event reports from the ILR were evaluated by two independent cardiologists based on the one-lead ECG. If AF was detected, the patient was recommended OAC. During the first year of the study period, warfarin was the only option; later novel anticoagulants (NOAC) including dabigatran etexilate, rivaroxaban and apixaban were marketed and available. Warfarin treatment was administered by a hospital based outpatient clinic and patients on NOACs were followed up at 3–6 months after which the patient was referred to a general practitioner. The primary endpoint was the incidence of AF. Secondary end-points were (i) time from index cerebrovascular event to detection of AF, (ii) burden of AF during monitoring and (iii) recurrence of stroke or TIA during the study period. Statistical analysis included frequency analysis, Student’s t test and Wilcoxon Mann–Whitney test (where Gaussian distribution could not be assumed), and v2 and logistic regression analysis. All analyses were done using IBM® SPSS® Statistics version 20.0.0 (Armonk, NY, USA).
Results A total of 95 patients were eligible and included in the study. Patients’ characteristics are presented in Table 1. Eight patients chose to withdraw consent before implantation and two patients presented with AF at the time of implantation; finally 85 patients were implanted with an ILR. Patients were implanted at a median of 69 days (mean 107, SD 117) after stroke onset. The mean time monitored was 569 days (SD 310). The device was explanted prematurely in five patients
886
L. M. Christensen et al.
Table 1 Patient characteristics
Age in years (mean) Male (%) CHA2DS2-VASC (median) CHADS2 (median) Hypertension (%) Diabetes (%) Smoking (or quit 5.5 h/ day is required to increase future risk of embolic events [25]; another study concluded that an AF burden of 6 min predicted an increased risk [26]. Our data may suggest an effect of a smaller AF burden. However, so far any quantification of arrhythmia burden is based on patients with known significant cardiac disease warranting a pacemaker or ICD unit, and there is no way of knowing if the same applies to patients after stroke with no known cardiac disease. It has been suggested that the AF population could be divided into low and high risk patients based on AF burden and risk factors [27]. The size of our study did not permit such an attempt; larger studies in the future regarding the burden of AF and risk of stroke might clarify this. Despite initiating anticoagulant treatment in patients with detected AF, a higher rate of readmissions and recurrent strokes was observed in this group and no time association between AF events and recurrent stroke was found; the episodes and burden overall were short and asymptomatic and do not appear to have been directly involved in the patients’ cerebrovascular episodes. This may be a chance finding but certainly underlines the question whether results can be extrapolated from randomized controlled trials in thromboprofylaxis in atrial fibrillation to this patient group. Intervention studies are needed to address this question.
Conclusion The study documents that shorter duration PAF is frequent in patients after mild to moderate stroke/ TIA discharged to independent living after guideline work-up concluding CS and corroborate other recent
888
L. M. Christensen et al.
findings in this field. The observed AF events were not only short bursts of AF but also longer lasting bursts. However, the majority of events had a duration from 2 to 10 min and were first detected more than 2 months after the index event; there is no way of knowing if the two were related, and whether low burden PAF identified by an ILR truly carries an equal risk of stroke remains an open question. Anticoagulation as thromboprophylaxis was initiated as a result of AF detection; however, clinical events were not related to AF episodes, and clinical events were more frequent in the AF group. Data from interventional trials are needed to define the role of the ILR in patients after stroke and to determine the treatment strategy in thromboprophylaxis.
Acknowledgements The study was funded by the Capital Region of Denmark (PhD grant for the first author) and research grants from Medtronic Denmark A/S, Sophus Jacobsen’s and the Arvid Nilsson Foundation. Medtronic Denmark A/S had no role in the study design, data collection, data analysis, data interpretation or writing of the manuscript.
6.
7.
8. 9.
10. 11.
12.
13.
14.
15.
Disclosure of conflicts of interest LC has received honoraria and conference attendance grants from Bayer Denmark, Boehringer-Ingelheim Denmark and Medtronic Denmark. DK has received honoraria and conference attendance grants from Medtronic Denmark.
References 1. Mattle HP. Long-term outcome after stroke due to atrial fibrillation. Cerebrovasc Dis 2003; 1: 3–8. 2. Piccini JP, Hammill BG, Sinner MF, et al. Clinical course of atrial fibrillation in older adults: the importance of cardiovascular events beyond stroke. Eur Heart J 2014; 35: 250–256. 3. Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study.. Lancet 1989; 1: 175–179. 4. Liew AY, Eikelboom JW, Connolly SJ, O’Donnell M, Hart RG. Efficacy and safety of warfarin vs. antiplatelet therapy in patients with systolic heart failure and sinus rhythm: a systematic review and meta-analysis of randomized controlled trials. Int J Stroke 2014; 9: 199–206. 5. Hart RG, Pearce LA, Rothbart RM, McAnulty JH, Asinger RW, Halperin JL. Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin
16.
17.
18.
19.
20.
21.
22.
23.
therapy. Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol 2000; 35: 183–187. Friberg L, Hammar N, Rosenqvist M. Stroke in paroxysmal atrial fibrillation: report from the Stockholm Cohort of Atrial Fibrillation. Eur Heart J 2010; 31: 967–975. Strickberger SA, Ip J, Saksena S, Curry K, Bahnson TD, Ziegler PD. Relationship between atrial tachyarrhythmias and symptoms. Heart Rhythm 2005; 2: 125–131. Finsterer J. Management of cryptogenic stroke. Acta Neurol Belg 2010; 110: 35–47. Liberman AL, Prabhakaran S. Cryptogenic stroke: how to define it? How to treat it? Curr Cardiol Rep 2013; 15: 423. Mohr JP. Cryptogenic stroke. N Engl J Med 1988; 318: 1197–1198. Elijovich L, Josephson SA, Fung GL, Smith WS. Intermittent atrial fibrillation may account for a large proportion of otherwise cryptogenic stroke: a study of 30-day cardiac event monitors. J Stroke Cerebrovasc Dis 2009; 18: 185–189. Kaya D, Yildiz E. Aortic atheromas in stroke subgroups detected by multidetector computed tomographic angiography. Clin Neurol Neurosurg 2009; 111: 415–421. Sacco RL, Ellenberg JH, Mohr JP, et al. Infarcts of undetermined cause: the NINCDS Stroke Data Bank. Ann Neurol 1989; 25: 382–390. Schaer BA, Zellweger MJ, Cron TA, Kaiser CA, Osswald S. Value of routine Holter monitoring for the detection of paroxysmal atrial fibrillation in patients with cerebral ischemic events. Stroke 2004; 35: e68–e70. Jabaudon D, Sztajzel J, Sievert K, Landis T, Sztajzel R. Usefulness of ambulatory 7-day ECG monitoring for the detection of atrial fibrillation and flutter after acute stroke and transient ischemic attack. Stroke 2004; 35: 1647–1651. Gaillard N, Deltour S, Vilotijevic B, et al. Detection of paroxysmal atrial fibrillation with transtelephonic EKG in TIA or stroke patients. Neurology 2010; 74: 1666–1670. Ritter MA, Kochhauser S, Duning T, et al. Occult atrial fibrillation in cryptogenic stroke: detection by 7-day electrocardiogram versus implantable cardiac monitors. Stroke 2013; 44: 1449–1452. Cotter PE, Martin PJ, Ring L, Warburton EA, Belham M, Pugh PJ. Incidence of atrial fibrillation detected by implantable loop recorders in unexplained stroke. Neurology 2013; 80: 1546–1550. Ziegler PD, Glotzer TV, Daoud EG, et al. Incidence of newly detected atrial arrhythmias via implantable devices in patients with a history of thromboembolic events. Stroke 2010; 41: 256–260. Brignole M, Alboni P, Benditt DG, et al. Guidelines on management (diagnosis and treatment) of syncope – update 2004. Europace 2004; 6: 467–537. Hindricks G, Pokushalov E, Urban L, et al. Performance of a new leadless implantable cardiac monitor in detecting and quantifying atrial fibrillation: results of the XPECT trial. Circ Arrhythm Electrophysiol 2010; 3: 141–147. Eitel C, Husser D, Hindricks G, et al. Performance of an implantable automatic atrial fibrillation detection device: impact of software adjustments and relevance of manual episode analysis. Europace 2011; 13: 480–485. Gladstone DJ, Blakely J, Dorian P, et al. Detecting paroxysmal atrial fibrillation after ischemic stroke and
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
Final results from the SURPRISE study
transient ischemic attack: if you don’t look, you won’t find. Stroke 2008; 39: e78–e79. 24. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31: 2369–2429. 25. Daoud EG, Glotzer TV, Wyse DG, et al. Temporal relationship of atrial tachyarrhythmias, cerebrovascular events, and systemic emboli based on stored device data:
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
889
a subgroup analysis of TRENDS. Heart Rhythm 2011; 8: 1416–1423. 26. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012; 366: 120–129. 27. Glotzer TV, Ziegler PD. Silent atrial fibrillation as a stroke risk factor and anticoagulation indication. Can J Cardiol 2013; 29: 14–23.
doi:10.1111/ene.12400
Paroxysmal atrial fibrillation occurs often in cryptogenic ischaemic stroke. Final results from the SURPRISE* study L. M. Christensena, D. W. Kriegera,b, S. Højbergc, O. D. Pedersenc, F. M. Karlsenc, M. D. Jacobsenc, R. Worckc, H. Nielsenc, K. Ægidiusa, L. L. Jeppesena, S. Rosenbauma, J. Marstranda and H. Christensena a
Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospitals, Copenhagen; bDepartment of Neurology, Rigshospitalet, Copenhagen University Hospitals, Copenhagen; and cDepartment of Cardiology, Bispebjerg Hospital, Copenhagen University Hospitals, Copenhagen, Denmark
Keywords:
atrial fibrillation, cardiology, cryptogenic stroke, implantable loop recorder, long-term cardiac monitoring, neurology, paroxysmal atrial fibrillation Received 28 October 2013 Accepted 28 January 2014
Background and purpose: Atrial fibrillation (AF) increases the risk of stroke fourfold and is associated with a poor clinical outcome. Despite work-up in compliance with guidelines, up to one-third of patients have cryptogenic stroke (CS). The prevalence of asymptomatic paroxysmal atrial fibrillation (PAF) in CS remains unknown. The SURPRISE project aimed at determining this rate using long-term cardiac monitoring. Methods: Patients with CS after protocolled work-up including electrocardiography (ECG) and telemetry were included after informed consent. An implantable loop recorder (ILR) was implanted subcutaneously. PAF was defined by events of atrial arrhythmia >2 min with a correlating one-lead ECG confirming the diagnosis. Results: Eighty-five patients were monitored for a mean of 569 days (SD 310). PAF was documented in 18 patients (20.7%) during the study period and detected by ILR in 14 patients (16.1%). In three patients PAF was detected by other methods before or after monitoring and was undiscovered due to device sensitivity in one case. The first event of PAF was documented at a mean of 109 days (SD 48) after stroke onset. PAF was asymptomatic in all cases and occurred in episodes lasting predominantly between 1 and 4 h. Four recurrent strokes were observed, three in patients with PAF; all three patients were on oral anticoagulation (OAC). Conclusions: One in five patients with CS had PAF, which occurred at low burden and long after stroke. Future studies should determine the role of implantable cardiac monitors after stroke and determine the potential therapeutic benefit of OAC treatment of patients with PAF.
Background Atrial fibrillation (AF) is the predominant risk factor for cardioembolic stroke [1] and may convey a 1-year survival as low as 30% after stroke [2]. Oral anticoagulation (OAC) treatment reduces the risk of recurrent stroke by two-thirds [3,4]. The natural history and benefit of OAC underline the importance of identifying AF in patients after stroke, in particular after minor stroke or transient ischaemic attack (TIA). The stroke risk is Correspondence: L. M. Christensen, Department of Neurology, Bispebjerg Hospital, Copenhagen, Denmark (tel.: +45 53620238; fax: +45 35313733; e-mail: [email protected]). *Stroke Prior to Diagnosis of Atrial Fibrillation Using Long-term Observation with Implantable Cardiac Monitoring Apparatus Reveal.
884
considered equivalent in paroxysmal and permanent AF [5,6] stressing the need for a highly sensitive and specific method of monitoring for AF after stroke. Both AF and paroxysmal atrial fibrillation (PAF) are frequently asymptomatic [7], making stroke the first clinical manifestation of AF. Cryptogenic stroke (CS) has been defined as a cerebrovascular event of unknown origin, despite thorough work-up. The implication in everyday practice is continuously debated [8–10], as even in current studies 20%–30% of all ischaemic strokes can be classified as cryptogenic [11–13]. The prevalence of AF in patients with CS is reported to be in the range of 4.9% and 9.2% [14–16]; however, as improved detection techniques have become available the prevalence is suggested to be as high as 25% [17–19]. © 2014 The Author(s) European Journal of Neurology © 2014 EAN
885
Final results from the SURPRISE study
Long-term electrocardiography (ECG) monitoring is used routinely for the detection of arrhythmias in patients with syncope [20]. For this purpose, cardiac monitors are implanted subcutaneously and monitor the heart continuously registering beat-to-beat variability, by measurement of the R-R intervals, for up to 3 years [21,22]. When irregular R-R-intervals are detected, the device stores 2 min of ECG and information regarding time occurring and amount detected, enabling later detailed detection and qualification of AF. The aim of this study was to detect and quantify AF in patients with CS using long-term monitoring.
Methods The study was approved by the ethics committee of the Capitol Region of Denmark (H3-2010-083) in compliance with the Declaration of Helsinki and was registered at Clinical Trial Registration URL: http:// www.clinicaltrials.gov; unique identifier NCT01498146. The study was conducted in Bispebjerg University Hospital, Copenhagen, Denmark, which shares a catchment area for acute stroke of 1.7 million inhabitants with one other hospital. During the inclusion period from 2010 to 2012 the average number of acute stroke admissions was 946 per year. All new patient files were systematically screened during the study period by one investigator (LC) and patients were also referred from the outpatient clinic. The inclusion criteria were (i) providing informed consent, (ii) an ischaemic vascular event with CT or MRI verified acute ischaemic lesion, (iii) a post-stroke modified Rankin score ≤2, (iv) >18 years of age, (v) no known prior AF or AF documented during the admission period (including continuous telemetric monitoring for 12–24 h) and (vi) a diagnosis of CS based on a standardized work-up (carotid occlusive disease, cardiac sources of embolism, small vessel disease and thrombophilia). Included patients were referred to the cardiologist for implantation of the implantable loop recorder (ILR). Patients were scheduled as soon as possible, usually within a week after completed work-up. The ILR (Reveal XT; Medtronic Inc., Minneapolis, MN, USA) was implanted subcutaneously in a left parasternal position and all patients were instructed to transmit data on a regular basis at least every 2 weeks. Patients with confirmed episodes of AF continued transmitting until the end of the study. The device was programmed to detect AF (Fig. 1) and to store one-lead ECG of all episodes of arrhythmia. AF was defined as irregular R-R intervals (an example is shown in Fig. 1) and no visible p-waves on correlating © 2014 The Author(s) European Journal of Neurology © 2014 EAN
ID# Type 5
AF
Date
Time Duration hh:mm hh:mm:ss Max V. Rate
03-Nov-2009 21:39
04:52:00 176 bpm (340 ms)
Median V. Rate 97 bpm (620 ms)
Detected
Interval (ms) 1500 1200 900 600 400 200
–280 –260 –240 –220 –200 –180 –160 –140 –120 –100 Time (sec)
–80
–60
–40
–20
0
Figure 1 R-R intervals of a transmission. Shows a transmission from regular R-R intervals in sinus rhythm to the scatter in atrial fibrillation; the x-axis is the time in seconds, and the y-axis is the length of R-R intervals in milliseconds.
one-lead ECG transmissions. Only AF events lasting >2 min were recorded by the ILR. All event reports from the ILR were evaluated by two independent cardiologists based on the one-lead ECG. If AF was detected, the patient was recommended OAC. During the first year of the study period, warfarin was the only option; later novel anticoagulants (NOAC) including dabigatran etexilate, rivaroxaban and apixaban were marketed and available. Warfarin treatment was administered by a hospital based outpatient clinic and patients on NOACs were followed up at 3–6 months after which the patient was referred to a general practitioner. The primary endpoint was the incidence of AF. Secondary end-points were (i) time from index cerebrovascular event to detection of AF, (ii) burden of AF during monitoring and (iii) recurrence of stroke or TIA during the study period. Statistical analysis included frequency analysis, Student’s t test and Wilcoxon Mann–Whitney test (where Gaussian distribution could not be assumed), and v2 and logistic regression analysis. All analyses were done using IBM® SPSS® Statistics version 20.0.0 (Armonk, NY, USA).
Results A total of 95 patients were eligible and included in the study. Patients’ characteristics are presented in Table 1. Eight patients chose to withdraw consent before implantation and two patients presented with AF at the time of implantation; finally 85 patients were implanted with an ILR. Patients were implanted at a median of 69 days (mean 107, SD 117) after stroke onset. The mean time monitored was 569 days (SD 310). The device was explanted prematurely in five patients
886
L. M. Christensen et al.
Table 1 Patient characteristics
Age in years (mean) Male (%) CHA2DS2-VASC (median) CHADS2 (median) Hypertension (%) Diabetes (%) Smoking (or quit 5.5 h/ day is required to increase future risk of embolic events [25]; another study concluded that an AF burden of 6 min predicted an increased risk [26]. Our data may suggest an effect of a smaller AF burden. However, so far any quantification of arrhythmia burden is based on patients with known significant cardiac disease warranting a pacemaker or ICD unit, and there is no way of knowing if the same applies to patients after stroke with no known cardiac disease. It has been suggested that the AF population could be divided into low and high risk patients based on AF burden and risk factors [27]. The size of our study did not permit such an attempt; larger studies in the future regarding the burden of AF and risk of stroke might clarify this. Despite initiating anticoagulant treatment in patients with detected AF, a higher rate of readmissions and recurrent strokes was observed in this group and no time association between AF events and recurrent stroke was found; the episodes and burden overall were short and asymptomatic and do not appear to have been directly involved in the patients’ cerebrovascular episodes. This may be a chance finding but certainly underlines the question whether results can be extrapolated from randomized controlled trials in thromboprofylaxis in atrial fibrillation to this patient group. Intervention studies are needed to address this question.
Conclusion The study documents that shorter duration PAF is frequent in patients after mild to moderate stroke/ TIA discharged to independent living after guideline work-up concluding CS and corroborate other recent
888
L. M. Christensen et al.
findings in this field. The observed AF events were not only short bursts of AF but also longer lasting bursts. However, the majority of events had a duration from 2 to 10 min and were first detected more than 2 months after the index event; there is no way of knowing if the two were related, and whether low burden PAF identified by an ILR truly carries an equal risk of stroke remains an open question. Anticoagulation as thromboprophylaxis was initiated as a result of AF detection; however, clinical events were not related to AF episodes, and clinical events were more frequent in the AF group. Data from interventional trials are needed to define the role of the ILR in patients after stroke and to determine the treatment strategy in thromboprophylaxis.
Acknowledgements The study was funded by the Capital Region of Denmark (PhD grant for the first author) and research grants from Medtronic Denmark A/S, Sophus Jacobsen’s and the Arvid Nilsson Foundation. Medtronic Denmark A/S had no role in the study design, data collection, data analysis, data interpretation or writing of the manuscript.
6.
7.
8. 9.
10. 11.
12.
13.
14.
15.
Disclosure of conflicts of interest LC has received honoraria and conference attendance grants from Bayer Denmark, Boehringer-Ingelheim Denmark and Medtronic Denmark. DK has received honoraria and conference attendance grants from Medtronic Denmark.
References 1. Mattle HP. Long-term outcome after stroke due to atrial fibrillation. Cerebrovasc Dis 2003; 1: 3–8. 2. Piccini JP, Hammill BG, Sinner MF, et al. Clinical course of atrial fibrillation in older adults: the importance of cardiovascular events beyond stroke. Eur Heart J 2014; 35: 250–256. 3. Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study.. Lancet 1989; 1: 175–179. 4. Liew AY, Eikelboom JW, Connolly SJ, O’Donnell M, Hart RG. Efficacy and safety of warfarin vs. antiplatelet therapy in patients with systolic heart failure and sinus rhythm: a systematic review and meta-analysis of randomized controlled trials. Int J Stroke 2014; 9: 199–206. 5. Hart RG, Pearce LA, Rothbart RM, McAnulty JH, Asinger RW, Halperin JL. Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin
16.
17.
18.
19.
20.
21.
22.
23.
therapy. Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol 2000; 35: 183–187. Friberg L, Hammar N, Rosenqvist M. Stroke in paroxysmal atrial fibrillation: report from the Stockholm Cohort of Atrial Fibrillation. Eur Heart J 2010; 31: 967–975. Strickberger SA, Ip J, Saksena S, Curry K, Bahnson TD, Ziegler PD. Relationship between atrial tachyarrhythmias and symptoms. Heart Rhythm 2005; 2: 125–131. Finsterer J. Management of cryptogenic stroke. Acta Neurol Belg 2010; 110: 35–47. Liberman AL, Prabhakaran S. Cryptogenic stroke: how to define it? How to treat it? Curr Cardiol Rep 2013; 15: 423. Mohr JP. Cryptogenic stroke. N Engl J Med 1988; 318: 1197–1198. Elijovich L, Josephson SA, Fung GL, Smith WS. Intermittent atrial fibrillation may account for a large proportion of otherwise cryptogenic stroke: a study of 30-day cardiac event monitors. J Stroke Cerebrovasc Dis 2009; 18: 185–189. Kaya D, Yildiz E. Aortic atheromas in stroke subgroups detected by multidetector computed tomographic angiography. Clin Neurol Neurosurg 2009; 111: 415–421. Sacco RL, Ellenberg JH, Mohr JP, et al. Infarcts of undetermined cause: the NINCDS Stroke Data Bank. Ann Neurol 1989; 25: 382–390. Schaer BA, Zellweger MJ, Cron TA, Kaiser CA, Osswald S. Value of routine Holter monitoring for the detection of paroxysmal atrial fibrillation in patients with cerebral ischemic events. Stroke 2004; 35: e68–e70. Jabaudon D, Sztajzel J, Sievert K, Landis T, Sztajzel R. Usefulness of ambulatory 7-day ECG monitoring for the detection of atrial fibrillation and flutter after acute stroke and transient ischemic attack. Stroke 2004; 35: 1647–1651. Gaillard N, Deltour S, Vilotijevic B, et al. Detection of paroxysmal atrial fibrillation with transtelephonic EKG in TIA or stroke patients. Neurology 2010; 74: 1666–1670. Ritter MA, Kochhauser S, Duning T, et al. Occult atrial fibrillation in cryptogenic stroke: detection by 7-day electrocardiogram versus implantable cardiac monitors. Stroke 2013; 44: 1449–1452. Cotter PE, Martin PJ, Ring L, Warburton EA, Belham M, Pugh PJ. Incidence of atrial fibrillation detected by implantable loop recorders in unexplained stroke. Neurology 2013; 80: 1546–1550. Ziegler PD, Glotzer TV, Daoud EG, et al. Incidence of newly detected atrial arrhythmias via implantable devices in patients with a history of thromboembolic events. Stroke 2010; 41: 256–260. Brignole M, Alboni P, Benditt DG, et al. Guidelines on management (diagnosis and treatment) of syncope – update 2004. Europace 2004; 6: 467–537. Hindricks G, Pokushalov E, Urban L, et al. Performance of a new leadless implantable cardiac monitor in detecting and quantifying atrial fibrillation: results of the XPECT trial. Circ Arrhythm Electrophysiol 2010; 3: 141–147. Eitel C, Husser D, Hindricks G, et al. Performance of an implantable automatic atrial fibrillation detection device: impact of software adjustments and relevance of manual episode analysis. Europace 2011; 13: 480–485. Gladstone DJ, Blakely J, Dorian P, et al. Detecting paroxysmal atrial fibrillation after ischemic stroke and
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
Final results from the SURPRISE study
transient ischemic attack: if you don’t look, you won’t find. Stroke 2008; 39: e78–e79. 24. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31: 2369–2429. 25. Daoud EG, Glotzer TV, Wyse DG, et al. Temporal relationship of atrial tachyarrhythmias, cerebrovascular events, and systemic emboli based on stored device data:
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
889
a subgroup analysis of TRENDS. Heart Rhythm 2011; 8: 1416–1423. 26. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012; 366: 120–129. 27. Glotzer TV, Ziegler PD. Silent atrial fibrillation as a stroke risk factor and anticoagulation indication. Can J Cardiol 2013; 29: 14–23.
