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Original article
Cryptogenic ischemic stroke and prevalence of asymptomatic atrial fibrillation: a prospective study Marcella Jorfidaa, Marina Antolinia, Enrico Cerratoa, Maria Giovanna Capriolib, Davide Castagnoa, Paolo Garronea, Carlo Budanoa, Paolo Cerratob and Fiorenzo Gaitaa Background Atrial fibrillation is responsible for up to onethird of ischemic strokes, and is also associated with silent cerebral infarctions and transient ischemic attacks (TIAs). The self-terminating and often asymptomatic nature of paroxysmal atrial fibrillation (PAF) may lead to its underdiagnosis. A continuous and long-term heart rhythm monitoring can be useful in unmasking PAF episodes. Objective Prevalence of asymptomatic PAF in patients suffering a cryptogenic stroke, at risk for atrial fibrillation but without any history of arrhythmia or palpitations, using a continuous electrocardiographic monitoring. Methods One hundred and forty-two consecutive patients were admitted to the Stroke Unit of ‘Citta` della Salute e della Scienza’ Hospital of Turin between June 2010 and March 2013 and discharged with the diagnosis of ischemic cryptogenic stroke. Sixty fulfilled predefined inclusion criteria. Follow-up was carried on and completed for the 54 patients who consented to implantable loop recorder (ILR) implantation. After ILR implantation, trans-telephonic data were collected monthly. Results Atrial fibrillation episodes lasting more than 5 min were recorded in 25 patients (46%), median detection time
Introduction Ischemic stroke is a frequent disease: the prevalence of stroke varies from 1.5% in Italy to 3% in the UK and USA; it is the third largest cause of death and is responsible for 50% of disabling conditions in survivors (mortality of 253 000 people per year).1,2 The 5-year risk of stroke recurrence after the first event is about 18%.3 Cryptogenic stroke is defined as a stroke caused by unknown, undetermined or unclear causes and accounts for 25–30% percentage of ischemic strokes.4 Atrial fibrillation increases the risk of recurrence of stroke and is associated with a greater disability and mortality.5,6 Atrial fibrillation is a common cause of embolism, but it can be difficult to identify, owing to asymptomatic or paroxysmal episodes. The use of invasive continuous cardiac monitoring by means of an implantable loop recorder (ILR)hasproveneffectiveindetectingparoxysmalarrhythmias. Ideally, in order to diagnose silent arrhythmic events, continuous heart rhythm monitoring would be necessary.7 1558-2027 ß 2014 Italian Federation of Cardiology
was 5.4 months (range 1–18) and median duration of atrial fibrillation episodes was 20 h (range 7 min–8 days) with 19 patients (76%) remaining asymptomatic and the others experiencing weakness and dyspnoea but not palpitations. Conclusion Long-term heart rhythm monitoring is successful in unmasking silent atrial fibrillation in 46% of patients suffering a cryptogenic stroke with concomitant atrial fibrillation risk factors, but without history of arrhythmia or palpitations. J Cardiovasc Med 2014, 15:000–000 Keywords: atrial fibrillation, cardiac monitoring, cryptogenic stroke, implantable loop recorder, supraventricular arrhythmia a
Division of Cardiology, Cardiovascular and Thoracic Department, ‘Citta` della Salute e della Scienza’ Hospital and Department of Medical Sciences and Stroke Unit, ‘Citta` della Salute e della Scienza’ Hospital and University of Turin, Turin, Italy
b
Correspondence to Marina Antolini, MD, Division of Cardiology, Cardiovascular and Thoracic Department, ‘Citta` della Salute e della Scienza’ Hospital and Department of Medical Sciences, University of Turin, C.so A.M. Dogliotti, 14, 10126 Turin, Italy Tel: +390116335571; fax: +390116336015; e-mail: [email protected] Received 7 April 2014 Revised 1 June 2014 Accepted 3 June 2014
Antiplatelet therapy is indicated by current guidelines as secondary prevention after an ischemic stroke.8 Oral anticoagulant therapy (OAT) provides a 40% risk reduction in stroke recurrence and a stroke severity reduction in patients with atrial fibrillation.9,10 The aim of this prospective, single-centre study was to determine the incidence of atrial fibrillation in cryptogenic ischemic stroke by using continuous monitoring of the heart rate over several months, in a population of patients suffering a recent cryptogenic ischemic stroke and having at least one risk factor for atrial fibrillation without history of atrial fibrillation or palpitations.
Materials and methods Patients enrolment
We prospectively enrolled all consecutive patients admitted to the Stroke Unit department of ‘Citta` della Salute e della Scienza’ hospital of Turin (Italy) between June 2010 and March 2013 and discharged with the DOI:10.2459/JCM.0000000000000181
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diagnosis of ischemic cryptogenic stroke. Inclusion criteria were age between 18 and 80 years; diagnosis of cryptogenic stroke within the previous 3 months; brain MRI suggestive of embolic cortical infarcts or subcortical lesions according to current definitions;11–13 at least one risk factor for atrial fibrillation: age more than 75 years, hypertension, left ventricular hypertrophy, atrial enlargement, presence of cardiomyopathy, chronic pericarditis, pulmonary diseases, thyroid diseases, diabetes, obesity.14 Previous documented history of atrial fibrillation, other comorbidities requiring OAT and a residual disability impairing the possibility to express an informed consent were the exclusion criteria.15 All consenting patients underwent implantation of a subcutaneous continuous cardiac monitor, although those who refused were followed up with periodical visits. Clinical history and neurological characteristics of every patient enrolled in the registry were independently reviewed by two experienced neurologists, who confirmed the diagnosis of cryptogenic ischemic stroke. All patients were studied with 12-lead ECG, 48 h of inhospital continuous telemetry, 24 h Holter monitoring, transthoracic echocardiography, cerebral computed tomography (CT) or MRI scans, carotid and vertebro-basilar systems ultrasound or angio-MRI, haematological and inflammatory tests in order to assess any cause of stroke. Vascular malformations, intracranial stenosis and dissections were ruled out by intracranial-MRI and/or angio-CT. Hypercoagulable states or haematological disorders were considered as exclusion criteria and were assessed in all patients with the more common specific tests. Atrial fibrillation episodes registered at telemetry or 24 h Holter were the exclusion criteria. Transthoracic echocardiography was performed in all patients and a left atrial volume more than 29 ml/m2 was considered enlarged.16 Transthoracic echocardiography with saline bubble contrast was performed in younger patients (usually 100/day Therapy at admission Acetylsalicylic acid Clopidogrel b-blockers Calcium channel blockers ACE-inhibitor Other antihypertensives
Overall, 54
SR, 29
AF, 25
Univariate P
67.8 9.4 31 (57.4) 145 20 89 16 81 22 10 (18.5) 47 (88.7) 12 (22.6) 8 (14.8) 15 (27.8) 3.4 0.8 4.5 1.2 3.0 0.6 3.6 2.0 6 (11)
65.7 11.5 15 (51.7) 142 18 88 19 78 19 7 (25.0) 23 (82.1) 6 (20.7) 4 (14.8) 6 (20.7) 3.4 1.0 4.4 1.3 2.9 0.6 3.2 2.0 2 (6.8)
70.1 5.8 16 (64.0) 148 21 91 18 83 24 3 (12.0) 24 (96.0) 6 (24.0) 4 (16.0) 9 (36.0) 3.5 0.6 4.7 1.2 3.1 0.7 4.1 1.8 4 (16.0)
0.2 0.4 0.2 0.5 0.09 0.2 0.1 0.8 0.8 0.2 0.6 0.3 0.5 0.1 0.1
13 (24.1) 3 (5.6) 23 (42.6) 16 (29.6) 9 (16.7) 8 (14.8)
5 (17.2) 2 (6.8) 12 (41.4) 8 (27.6) 5 (17.2) 5 (17.2)
4 (16.0) 1 (4.0) 11 (44.0) 8 (32.0) 4 (16.0) 3 (12.0)
0.9 0.6 0.6 0.7 0.9 0.6
ACE, angiotensin-converting enzyme; AF, atrial fibrillation. Values are mean SD or numbers with percentages.
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Fig. 1
fibrillation-group and those in SR-group (Table 3). Left ventricular systolic function was preserved and a mild left atrial volume enlargement was observed in both groups.
Survival function Censored
1.0
In 10 patients (18.5%), transcranic echo-Doppler and/or transesophageal echocardiography revealed a PFO, with no statistically significant differences between the two groups.
Cum AF freedom
0.8
0.6
0.4
Neurological features 0.2
No differences in the anatomical localization of cerebral lesions were observed between the atrial fibrillation and SR-Group (Table 4). In addition, the presence of previous cerebral infarcts was investigated by means of MRI, but no differences were highlighted between the two groups (36.0 vs. 20.7% in the atrial fibrillation and SR-Group, respectively, P ¼ 0.2).
0.0 0
5
10
20
15
25
Observational period (months) Numbers of subjects at risk 36
35
34
33
32
31
30
29
28
27
26
25
24
23
22
21
20
19
18
17
16
14 12 10 8 6 4 2 0 15 13 11 9 7 5 3 1
Kaplan–Meier freedom from atrial fibrillation.
patients (24%) had atrial fibrillation lasting more than 1 day, with a single persistent episode of 20 days. The majority of the atrial fibrillation episodes were paroxysmal [24 out of 25 (96%) patients], and persistent in one case only. Most of the patients experiencing atrial fibrillation occurrence during follow-up remained asymptomatic [19 (76%) patients]. Although no significant differences in mean ventricular rate were observed between symptomatic and asymptomatic patients (120 22 vs. 132 16 bpm, P ¼ 0.1, Table 2), fatigue and dyspnoea were the most frequently reported atrial fibrillation related symptoms, with none of the patients complaining for palpitations. The overall median duration of the longest episode recorded in any patient presenting with atrial fibrillation was 20 h (range 7 min–8 days) (Table 2). During follow-up, one patient underwent electrical cardioversion because of persistent symptomatic atrial fibrillation, whereas another patient developed pathological sinus pauses in the absence of concomitant antiarrhythmic therapy requiring permanent pacemaker implantation. Echocardiographic data
No significant differences in baseline echocardiographic parameters were observed between patients in atrial Table 2
During follow-up, only one patient suffered a recurrent stroke with the ILR showing two episodes of long-lasting (of 32 and 28 h duration, respectively) asymptomatic atrial fibrillation 3 weeks before the clinical event. Univariate and multivariate analysis
At univariate analysis, all clinical, echocardiographic and neurological features were compared without pointing out differences between groups; no clinical or instrumental parameter proved to be significant atrial fibrillation predictors during follow-up. The small sample does not allow an analysis with a multivariable model.
Discussion The current American guidelines on stroke recommend an antiplatelet agent, either single or dual antiplatelet therapy, for secondary prevention of patients with a previous cryptogenic stroke.8 The stroke clinical risk factors included in the CHA2DS2VASc score are very similar to atrial fibrillation risk factors, but a high thromboembolic risk does not imply anticoagulant therapy if the patient has no history of atrial fibrillation. On the contrary, OAT is highly recommended for those patients with documented atrial fibrillation episodes, as the cerebrovascular accident carries a high
Anatomical features of cerebral lesions
Anatomical location Parietal Frontal Occipital Temporal Cerebellum Corpus callosum Basal ganglia Internal capsula Left/Right hemisphere Lesion depth Cortical Subcortical
Overall, 54 13 19 14 14 5 3 15 3 31
(24.0) (35.2) (25.9) (25.9) (9.2) (5.5) (27.7) (5.5) (57.4)/22 (40.7) 65 21
SR, 29 6 (20.7) 11 (37.9) 11 (37.9) 6 (20.6) 3 (10.3) 3 (10.3) 8 (27.5) 0 (0) 18 (62.1)/11 (37.9) 37 (56.9) (11 (52.4))
AF, 25 7 8 3 8
P
(28.0) (32.0) (12.1) (32.0) 2 (8.0) 0 7 (28.0) 3 (12.1) 14 (56.0)/11 (44.0)
0.7 0.7 0.1 0.4 0.4 0.09 0.7 0.1 0.7
28 (43.1) 10 (47.6)
0.2 0.3
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Table 3
Atrial fibrillation features and burden P
Patients with AF Asymptomatic First detection (months) Overall AF episodes Overall AF episodes month Episode of AF 5 min Episode of AF 5 min month Overall AF burden (h) Overall AF burden month (h) Longest episode (h) Heart rate (Asymptomatic/ symptomatic patients) Paroxysmal persistent AF
25/54 (46.3%) 19/25 (76%) 5.4 (1–18) 25 (1–380) 1 (0–17) 10 (1–85) 0.3 (0–2.8) 561 (0.5–11750) 18.7 (0.2–392) 20 (7 min–8 days) 12þ22/132þ16
– – – – – – – – – – 0.1
24/25 (96%)–1/25 (4%)
–
AF, atrial fibrillation. Values are median and range or numbers with percentages.
thromboembolic risk: in fact, CHADS2 and CHA2DS2VASc are, by definition, at least two in case of previous ischemic stroke or transient ischemic attack. This point highlights the importance of thoroughly investigating the presence of silent or undiagnosed episodes of atrial fibrillation, which may warrant a more aggressive secondary prevention strategy (i.e. anticoagulation vs. antiplatelet therapy). Stroke recurrences are often more debilitating than the first event. Improving secondary prevention not only increases patient survival and quality of life but also reduces healthcare costs. We assumed that the costs related to a stroke recurrence (new hospitalization and rehabilitation, costs related to the loss of productivity) exceed ILR implantation and management costs in our population. Data about long-term atrial fibrillation monitoring in this subset of patients are highly variable, with an atrial fibrillation incidence ranging from 0 to 25%,21–23 up to 30% in the recently presented data of Crystal AF trial.24 A direct relationship between the ECG monitoring duration and the chance of detecting asymptomatic atrial fibrillation episodes has been highlighted in the past with detection rates ranging from 3.8 to 6.1% with short recordings (1–3 days) to 29% with 30-day recordings.25,26
Table 4
Echocardiographic features
LYEF% LF mass M/F/m2 LVEDV LVESV LAESV Max LAESV Min LAESV Max/m2 RA ES Area Diastolic dysfunction Grade I Patent foramen ovale
Overall, 54
SR, 29
AF, 25
P
60.2 6.1 117 23/88 27 95.0 18.9 38.2 14.0 58.2 13.9 28.2 9.7 32.2 6.6 16.6 3.7 31
59.0 6.0 103 88.4 21.4 36.9 14.6 54.4 22.5 27.5 12.2 31.5 12.0 15.7 3.9 17
61.2 5.3 109 95.5.2 20.8 41.3.0 14.2 63.3 26.7 33.5 9.0 35.9 14.8 18.2 3.1 14
0.4 0.7 0.4 0.9 0.3 0.1 0.4 0.6 0.1
10 (18.5)
4 (13.8)
6 (24.0)
0.3
EF, ejection fraction; LAESV, left atrium end-systolic volume; LVEDV/ESV, left ventricular end-diastolic systolic volume; RA ES Area, right atrium end systolic area. Values are mean SD or percentages.
In fact, arrhythmias detection rate can reach 100% only using a continuous cardiac rhythm monitoring system. In a recent study, the number of atrial fibrillation episodes detected in cryptogenic stroke patients was 10-fold higher using ILR than 7-day Holter monitoring.27 Our study confirms the importance of a long-lasting monitoring system. We found the majority of silent atrial fibrillation episodes within the first 6 months of monitoring. The duration of atrial fibrillation episodes may also play a major role in determining which therapeutic strategy should be used, but it is still unclear which is the time threshold to mandate anticoagulation. In the Mode Selection Trial (MOST), atrial high-rate arrhythmic episodes lasting at least 5 min predicted a higher incidence of the composite outcome of death or nonfatal stroke.28 Data from the Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients study and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) showed that an episode of atrial high-rate lasting more than 6 min conferred a relative risk of 2.49 [95% confidence interval (95% CI)] for subsequent ischemic stroke or systemic embolism.29 In addition, Botto et al.30 evaluated the risk of thromboembolic events combining arrhythmia duration with baseline CHADS2 score: in group with CHADS2 score greater than 2, atrial fibrillation episodes lasting more than 5 min increased the risk of stroke from 0.6 to 4%. The correct statement of arrhythmia burden increases CHA2DS2VASC specificity to predict thromboembolic event.31 In accordance with this wealth of data, we decided to choose a cut-off of 5 min to define clinically meaningful atrial fibrillation episodes. Previous studies have investigated the potential diagnostic usefulness of LRI in patients suffering a cryptogenic stroke.32,33 These studies failed to demonstrate the utility of ILR in silent atrial fibrillation episodes detection; in fact no arrhythmic events were detected during followup. The result may be due to a selection bias, as these studies included unselected populations without any specific focus on atrial fibrillation risk factors. Conversely, in a more recent study analysing patients in whom ILRs were used for the diagnostic work-up of cryptogenic stroke documented at brain MRI, atrial fibrillation was observed in 25% of patients.22 In the most recent Crystal AF, a randomized trial including 441 patients with cryptogenic stroke and without history of atrial arrhythmias, atrial fibrillation was detected in 8.9% of patients in ILR group vs. 1.4% in control group at 6 months, and in 30 vs. 3% at 3 years, confirming the utility of a continuous monitoring in this kind of patients.24 We found a prevalence of silent atrial fibrillation of 35% at 6 months and 46% at the end of the study (median follow-up time of 14.5 months). The higher prevalence of atrial fibrillation observed in our population is probably due to the inclusion criteria used, requiring the presence
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of at least one risk factor for atrial fibrillation to be enrolled in our prospective registry. The majority of atrial fibrillation episodes were detected within the first 6 months, suggesting a direct link between the arrhythmic events and stroke occurrence. In addition, patients reporting history of palpitations or documented atrial arrhythmias were excluded in order to focus on undiagnosed/asymptomatic atrial fibrillation episodes that are usually revealed after major complications (e.g. stroke or congestive heart failure). The fact that a high rate of asymptomatic events was observed in our study underlines all the advantages of a continuous monitoring strategy as compared with symptom-triggered ECG recordings. This is especially true if we consider that the thromboembolic risk conferred by atrial fibrillation is independent from symptoms and that paroxysmal episodes share the same risk of persistent or permanent atrial fibrillation.34–36 ILR implantation unmasked atrial fibrillation in six patients with a coexistent PFO. Bonvini et al. demonstrated with a 7-day event-loop recorder a somewhat higher prevalence of atrial fibrillation in patients with cryptogenic stroke and a concomitant PFO, although percutaneous closure did not reduce atrial fibrillation occurrence.37 Furthermore, Cotter et al. did not find a higher prevalence of atrial fibrillation among the patients with a PFO and the presence of a PFO was not associated with an increased risk of atrial fibrillation occurrence as assessed by ILR implantation.22 A PFO was diagnosed in 18.5% of our patients during the initial screening: more than half of these patients showed atrial fibrillation during follow up.38 Taking all these points together, it seems clear that revealing asymptomatic or previously undiagnosed atrial fibrillation episodes in patients with a cryptogenic stroke and a concomitant PFO by means of continuous cardiac monitoring may avoid inappropriate PFO percutaneous closure.
continuous monitoring of all patients with cryptogenic stroke and any atrial fibrillation risk factor, until further studies, including a larger population, could fulfil the gap in our understanding. The purpose of the study is to define the prevalence of atrial fibrillation in patients discharge after a stroke that results cryptogenic after an insightful exclusion of all the potential causes. Thus, the study does not aim and was not powered to estimate potential differences between PFO and not-PFO patients or regarding the finding of previous cerebral infarcts at MRI. Prospective, randomized and multicentric trials should enlist all cryptogenic stroke patients in the early phase of the disease, during hospitalization, without excluding major disabilities. Selection of patients according to atrial fibrillation risk factors should be maintained: the population with atrial fibrillation risk factors has a higher thromboembolic risk and requires a different approach because discovering atrial fibrillation is mandatory to set up a correct secondary prevention.
Conclusion In patients with at least one risk factor for atrial fibrillation suffering a recent cryptogenic stroke, silent arrhythmic events can be detected in almost half of the cases by means of continuous ECG monitoring. This approach may be useful to select potential high-risk patients who may need a more aggressive secondary prevention strategy (i.e. anticoagulation) to avoid debilitating and life-threatening stroke recurrences.
Acknowledgements The authors have no conflicts of interest.
References 1
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Limitations Some limitations should be acknowledged in interpreting the results of the present study. Although continuous ECG monitoring allowed the detection of silent atrial fibrillation episodes in a considerable proportion of patients with a recent cryptogenic stroke, the time elapsed between the neurologic event and ILR implantation may have determined an underestimation of the arrhythmic events.
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Original article
Cryptogenic ischemic stroke and prevalence of asymptomatic atrial fibrillation: a prospective study Marcella Jorfidaa, Marina Antolinia, Enrico Cerratoa, Maria Giovanna Capriolib, Davide Castagnoa, Paolo Garronea, Carlo Budanoa, Paolo Cerratob and Fiorenzo Gaitaa Background Atrial fibrillation is responsible for up to onethird of ischemic strokes, and is also associated with silent cerebral infarctions and transient ischemic attacks (TIAs). The self-terminating and often asymptomatic nature of paroxysmal atrial fibrillation (PAF) may lead to its underdiagnosis. A continuous and long-term heart rhythm monitoring can be useful in unmasking PAF episodes. Objective Prevalence of asymptomatic PAF in patients suffering a cryptogenic stroke, at risk for atrial fibrillation but without any history of arrhythmia or palpitations, using a continuous electrocardiographic monitoring. Methods One hundred and forty-two consecutive patients were admitted to the Stroke Unit of ‘Citta` della Salute e della Scienza’ Hospital of Turin between June 2010 and March 2013 and discharged with the diagnosis of ischemic cryptogenic stroke. Sixty fulfilled predefined inclusion criteria. Follow-up was carried on and completed for the 54 patients who consented to implantable loop recorder (ILR) implantation. After ILR implantation, trans-telephonic data were collected monthly. Results Atrial fibrillation episodes lasting more than 5 min were recorded in 25 patients (46%), median detection time
Introduction Ischemic stroke is a frequent disease: the prevalence of stroke varies from 1.5% in Italy to 3% in the UK and USA; it is the third largest cause of death and is responsible for 50% of disabling conditions in survivors (mortality of 253 000 people per year).1,2 The 5-year risk of stroke recurrence after the first event is about 18%.3 Cryptogenic stroke is defined as a stroke caused by unknown, undetermined or unclear causes and accounts for 25–30% percentage of ischemic strokes.4 Atrial fibrillation increases the risk of recurrence of stroke and is associated with a greater disability and mortality.5,6 Atrial fibrillation is a common cause of embolism, but it can be difficult to identify, owing to asymptomatic or paroxysmal episodes. The use of invasive continuous cardiac monitoring by means of an implantable loop recorder (ILR)hasproveneffectiveindetectingparoxysmalarrhythmias. Ideally, in order to diagnose silent arrhythmic events, continuous heart rhythm monitoring would be necessary.7 1558-2027 ß 2014 Italian Federation of Cardiology
was 5.4 months (range 1–18) and median duration of atrial fibrillation episodes was 20 h (range 7 min–8 days) with 19 patients (76%) remaining asymptomatic and the others experiencing weakness and dyspnoea but not palpitations. Conclusion Long-term heart rhythm monitoring is successful in unmasking silent atrial fibrillation in 46% of patients suffering a cryptogenic stroke with concomitant atrial fibrillation risk factors, but without history of arrhythmia or palpitations. J Cardiovasc Med 2014, 15:000–000 Keywords: atrial fibrillation, cardiac monitoring, cryptogenic stroke, implantable loop recorder, supraventricular arrhythmia a
Division of Cardiology, Cardiovascular and Thoracic Department, ‘Citta` della Salute e della Scienza’ Hospital and Department of Medical Sciences and Stroke Unit, ‘Citta` della Salute e della Scienza’ Hospital and University of Turin, Turin, Italy
b
Correspondence to Marina Antolini, MD, Division of Cardiology, Cardiovascular and Thoracic Department, ‘Citta` della Salute e della Scienza’ Hospital and Department of Medical Sciences, University of Turin, C.so A.M. Dogliotti, 14, 10126 Turin, Italy Tel: +390116335571; fax: +390116336015; e-mail: [email protected] Received 7 April 2014 Revised 1 June 2014 Accepted 3 June 2014
Antiplatelet therapy is indicated by current guidelines as secondary prevention after an ischemic stroke.8 Oral anticoagulant therapy (OAT) provides a 40% risk reduction in stroke recurrence and a stroke severity reduction in patients with atrial fibrillation.9,10 The aim of this prospective, single-centre study was to determine the incidence of atrial fibrillation in cryptogenic ischemic stroke by using continuous monitoring of the heart rate over several months, in a population of patients suffering a recent cryptogenic ischemic stroke and having at least one risk factor for atrial fibrillation without history of atrial fibrillation or palpitations.
Materials and methods Patients enrolment
We prospectively enrolled all consecutive patients admitted to the Stroke Unit department of ‘Citta` della Salute e della Scienza’ hospital of Turin (Italy) between June 2010 and March 2013 and discharged with the DOI:10.2459/JCM.0000000000000181
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diagnosis of ischemic cryptogenic stroke. Inclusion criteria were age between 18 and 80 years; diagnosis of cryptogenic stroke within the previous 3 months; brain MRI suggestive of embolic cortical infarcts or subcortical lesions according to current definitions;11–13 at least one risk factor for atrial fibrillation: age more than 75 years, hypertension, left ventricular hypertrophy, atrial enlargement, presence of cardiomyopathy, chronic pericarditis, pulmonary diseases, thyroid diseases, diabetes, obesity.14 Previous documented history of atrial fibrillation, other comorbidities requiring OAT and a residual disability impairing the possibility to express an informed consent were the exclusion criteria.15 All consenting patients underwent implantation of a subcutaneous continuous cardiac monitor, although those who refused were followed up with periodical visits. Clinical history and neurological characteristics of every patient enrolled in the registry were independently reviewed by two experienced neurologists, who confirmed the diagnosis of cryptogenic ischemic stroke. All patients were studied with 12-lead ECG, 48 h of inhospital continuous telemetry, 24 h Holter monitoring, transthoracic echocardiography, cerebral computed tomography (CT) or MRI scans, carotid and vertebro-basilar systems ultrasound or angio-MRI, haematological and inflammatory tests in order to assess any cause of stroke. Vascular malformations, intracranial stenosis and dissections were ruled out by intracranial-MRI and/or angio-CT. Hypercoagulable states or haematological disorders were considered as exclusion criteria and were assessed in all patients with the more common specific tests. Atrial fibrillation episodes registered at telemetry or 24 h Holter were the exclusion criteria. Transthoracic echocardiography was performed in all patients and a left atrial volume more than 29 ml/m2 was considered enlarged.16 Transthoracic echocardiography with saline bubble contrast was performed in younger patients (usually 100/day Therapy at admission Acetylsalicylic acid Clopidogrel b-blockers Calcium channel blockers ACE-inhibitor Other antihypertensives
Overall, 54
SR, 29
AF, 25
Univariate P
67.8 9.4 31 (57.4) 145 20 89 16 81 22 10 (18.5) 47 (88.7) 12 (22.6) 8 (14.8) 15 (27.8) 3.4 0.8 4.5 1.2 3.0 0.6 3.6 2.0 6 (11)
65.7 11.5 15 (51.7) 142 18 88 19 78 19 7 (25.0) 23 (82.1) 6 (20.7) 4 (14.8) 6 (20.7) 3.4 1.0 4.4 1.3 2.9 0.6 3.2 2.0 2 (6.8)
70.1 5.8 16 (64.0) 148 21 91 18 83 24 3 (12.0) 24 (96.0) 6 (24.0) 4 (16.0) 9 (36.0) 3.5 0.6 4.7 1.2 3.1 0.7 4.1 1.8 4 (16.0)
0.2 0.4 0.2 0.5 0.09 0.2 0.1 0.8 0.8 0.2 0.6 0.3 0.5 0.1 0.1
13 (24.1) 3 (5.6) 23 (42.6) 16 (29.6) 9 (16.7) 8 (14.8)
5 (17.2) 2 (6.8) 12 (41.4) 8 (27.6) 5 (17.2) 5 (17.2)
4 (16.0) 1 (4.0) 11 (44.0) 8 (32.0) 4 (16.0) 3 (12.0)
0.9 0.6 0.6 0.7 0.9 0.6
ACE, angiotensin-converting enzyme; AF, atrial fibrillation. Values are mean SD or numbers with percentages.
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Fig. 1
fibrillation-group and those in SR-group (Table 3). Left ventricular systolic function was preserved and a mild left atrial volume enlargement was observed in both groups.
Survival function Censored
1.0
In 10 patients (18.5%), transcranic echo-Doppler and/or transesophageal echocardiography revealed a PFO, with no statistically significant differences between the two groups.
Cum AF freedom
0.8
0.6
0.4
Neurological features 0.2
No differences in the anatomical localization of cerebral lesions were observed between the atrial fibrillation and SR-Group (Table 4). In addition, the presence of previous cerebral infarcts was investigated by means of MRI, but no differences were highlighted between the two groups (36.0 vs. 20.7% in the atrial fibrillation and SR-Group, respectively, P ¼ 0.2).
0.0 0
5
10
20
15
25
Observational period (months) Numbers of subjects at risk 36
35
34
33
32
31
30
29
28
27
26
25
24
23
22
21
20
19
18
17
16
14 12 10 8 6 4 2 0 15 13 11 9 7 5 3 1
Kaplan–Meier freedom from atrial fibrillation.
patients (24%) had atrial fibrillation lasting more than 1 day, with a single persistent episode of 20 days. The majority of the atrial fibrillation episodes were paroxysmal [24 out of 25 (96%) patients], and persistent in one case only. Most of the patients experiencing atrial fibrillation occurrence during follow-up remained asymptomatic [19 (76%) patients]. Although no significant differences in mean ventricular rate were observed between symptomatic and asymptomatic patients (120 22 vs. 132 16 bpm, P ¼ 0.1, Table 2), fatigue and dyspnoea were the most frequently reported atrial fibrillation related symptoms, with none of the patients complaining for palpitations. The overall median duration of the longest episode recorded in any patient presenting with atrial fibrillation was 20 h (range 7 min–8 days) (Table 2). During follow-up, one patient underwent electrical cardioversion because of persistent symptomatic atrial fibrillation, whereas another patient developed pathological sinus pauses in the absence of concomitant antiarrhythmic therapy requiring permanent pacemaker implantation. Echocardiographic data
No significant differences in baseline echocardiographic parameters were observed between patients in atrial Table 2
During follow-up, only one patient suffered a recurrent stroke with the ILR showing two episodes of long-lasting (of 32 and 28 h duration, respectively) asymptomatic atrial fibrillation 3 weeks before the clinical event. Univariate and multivariate analysis
At univariate analysis, all clinical, echocardiographic and neurological features were compared without pointing out differences between groups; no clinical or instrumental parameter proved to be significant atrial fibrillation predictors during follow-up. The small sample does not allow an analysis with a multivariable model.
Discussion The current American guidelines on stroke recommend an antiplatelet agent, either single or dual antiplatelet therapy, for secondary prevention of patients with a previous cryptogenic stroke.8 The stroke clinical risk factors included in the CHA2DS2VASc score are very similar to atrial fibrillation risk factors, but a high thromboembolic risk does not imply anticoagulant therapy if the patient has no history of atrial fibrillation. On the contrary, OAT is highly recommended for those patients with documented atrial fibrillation episodes, as the cerebrovascular accident carries a high
Anatomical features of cerebral lesions
Anatomical location Parietal Frontal Occipital Temporal Cerebellum Corpus callosum Basal ganglia Internal capsula Left/Right hemisphere Lesion depth Cortical Subcortical
Overall, 54 13 19 14 14 5 3 15 3 31
(24.0) (35.2) (25.9) (25.9) (9.2) (5.5) (27.7) (5.5) (57.4)/22 (40.7) 65 21
SR, 29 6 (20.7) 11 (37.9) 11 (37.9) 6 (20.6) 3 (10.3) 3 (10.3) 8 (27.5) 0 (0) 18 (62.1)/11 (37.9) 37 (56.9) (11 (52.4))
AF, 25 7 8 3 8
P
(28.0) (32.0) (12.1) (32.0) 2 (8.0) 0 7 (28.0) 3 (12.1) 14 (56.0)/11 (44.0)
0.7 0.7 0.1 0.4 0.4 0.09 0.7 0.1 0.7
28 (43.1) 10 (47.6)
0.2 0.3
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Table 3
Atrial fibrillation features and burden P
Patients with AF Asymptomatic First detection (months) Overall AF episodes Overall AF episodes month Episode of AF 5 min Episode of AF 5 min month Overall AF burden (h) Overall AF burden month (h) Longest episode (h) Heart rate (Asymptomatic/ symptomatic patients) Paroxysmal persistent AF
25/54 (46.3%) 19/25 (76%) 5.4 (1–18) 25 (1–380) 1 (0–17) 10 (1–85) 0.3 (0–2.8) 561 (0.5–11750) 18.7 (0.2–392) 20 (7 min–8 days) 12þ22/132þ16
– – – – – – – – – – 0.1
24/25 (96%)–1/25 (4%)
–
AF, atrial fibrillation. Values are median and range or numbers with percentages.
thromboembolic risk: in fact, CHADS2 and CHA2DS2VASc are, by definition, at least two in case of previous ischemic stroke or transient ischemic attack. This point highlights the importance of thoroughly investigating the presence of silent or undiagnosed episodes of atrial fibrillation, which may warrant a more aggressive secondary prevention strategy (i.e. anticoagulation vs. antiplatelet therapy). Stroke recurrences are often more debilitating than the first event. Improving secondary prevention not only increases patient survival and quality of life but also reduces healthcare costs. We assumed that the costs related to a stroke recurrence (new hospitalization and rehabilitation, costs related to the loss of productivity) exceed ILR implantation and management costs in our population. Data about long-term atrial fibrillation monitoring in this subset of patients are highly variable, with an atrial fibrillation incidence ranging from 0 to 25%,21–23 up to 30% in the recently presented data of Crystal AF trial.24 A direct relationship between the ECG monitoring duration and the chance of detecting asymptomatic atrial fibrillation episodes has been highlighted in the past with detection rates ranging from 3.8 to 6.1% with short recordings (1–3 days) to 29% with 30-day recordings.25,26
Table 4
Echocardiographic features
LYEF% LF mass M/F/m2 LVEDV LVESV LAESV Max LAESV Min LAESV Max/m2 RA ES Area Diastolic dysfunction Grade I Patent foramen ovale
Overall, 54
SR, 29
AF, 25
P
60.2 6.1 117 23/88 27 95.0 18.9 38.2 14.0 58.2 13.9 28.2 9.7 32.2 6.6 16.6 3.7 31
59.0 6.0 103 88.4 21.4 36.9 14.6 54.4 22.5 27.5 12.2 31.5 12.0 15.7 3.9 17
61.2 5.3 109 95.5.2 20.8 41.3.0 14.2 63.3 26.7 33.5 9.0 35.9 14.8 18.2 3.1 14
0.4 0.7 0.4 0.9 0.3 0.1 0.4 0.6 0.1
10 (18.5)
4 (13.8)
6 (24.0)
0.3
EF, ejection fraction; LAESV, left atrium end-systolic volume; LVEDV/ESV, left ventricular end-diastolic systolic volume; RA ES Area, right atrium end systolic area. Values are mean SD or percentages.
In fact, arrhythmias detection rate can reach 100% only using a continuous cardiac rhythm monitoring system. In a recent study, the number of atrial fibrillation episodes detected in cryptogenic stroke patients was 10-fold higher using ILR than 7-day Holter monitoring.27 Our study confirms the importance of a long-lasting monitoring system. We found the majority of silent atrial fibrillation episodes within the first 6 months of monitoring. The duration of atrial fibrillation episodes may also play a major role in determining which therapeutic strategy should be used, but it is still unclear which is the time threshold to mandate anticoagulation. In the Mode Selection Trial (MOST), atrial high-rate arrhythmic episodes lasting at least 5 min predicted a higher incidence of the composite outcome of death or nonfatal stroke.28 Data from the Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients study and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) showed that an episode of atrial high-rate lasting more than 6 min conferred a relative risk of 2.49 [95% confidence interval (95% CI)] for subsequent ischemic stroke or systemic embolism.29 In addition, Botto et al.30 evaluated the risk of thromboembolic events combining arrhythmia duration with baseline CHADS2 score: in group with CHADS2 score greater than 2, atrial fibrillation episodes lasting more than 5 min increased the risk of stroke from 0.6 to 4%. The correct statement of arrhythmia burden increases CHA2DS2VASC specificity to predict thromboembolic event.31 In accordance with this wealth of data, we decided to choose a cut-off of 5 min to define clinically meaningful atrial fibrillation episodes. Previous studies have investigated the potential diagnostic usefulness of LRI in patients suffering a cryptogenic stroke.32,33 These studies failed to demonstrate the utility of ILR in silent atrial fibrillation episodes detection; in fact no arrhythmic events were detected during followup. The result may be due to a selection bias, as these studies included unselected populations without any specific focus on atrial fibrillation risk factors. Conversely, in a more recent study analysing patients in whom ILRs were used for the diagnostic work-up of cryptogenic stroke documented at brain MRI, atrial fibrillation was observed in 25% of patients.22 In the most recent Crystal AF, a randomized trial including 441 patients with cryptogenic stroke and without history of atrial arrhythmias, atrial fibrillation was detected in 8.9% of patients in ILR group vs. 1.4% in control group at 6 months, and in 30 vs. 3% at 3 years, confirming the utility of a continuous monitoring in this kind of patients.24 We found a prevalence of silent atrial fibrillation of 35% at 6 months and 46% at the end of the study (median follow-up time of 14.5 months). The higher prevalence of atrial fibrillation observed in our population is probably due to the inclusion criteria used, requiring the presence
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of at least one risk factor for atrial fibrillation to be enrolled in our prospective registry. The majority of atrial fibrillation episodes were detected within the first 6 months, suggesting a direct link between the arrhythmic events and stroke occurrence. In addition, patients reporting history of palpitations or documented atrial arrhythmias were excluded in order to focus on undiagnosed/asymptomatic atrial fibrillation episodes that are usually revealed after major complications (e.g. stroke or congestive heart failure). The fact that a high rate of asymptomatic events was observed in our study underlines all the advantages of a continuous monitoring strategy as compared with symptom-triggered ECG recordings. This is especially true if we consider that the thromboembolic risk conferred by atrial fibrillation is independent from symptoms and that paroxysmal episodes share the same risk of persistent or permanent atrial fibrillation.34–36 ILR implantation unmasked atrial fibrillation in six patients with a coexistent PFO. Bonvini et al. demonstrated with a 7-day event-loop recorder a somewhat higher prevalence of atrial fibrillation in patients with cryptogenic stroke and a concomitant PFO, although percutaneous closure did not reduce atrial fibrillation occurrence.37 Furthermore, Cotter et al. did not find a higher prevalence of atrial fibrillation among the patients with a PFO and the presence of a PFO was not associated with an increased risk of atrial fibrillation occurrence as assessed by ILR implantation.22 A PFO was diagnosed in 18.5% of our patients during the initial screening: more than half of these patients showed atrial fibrillation during follow up.38 Taking all these points together, it seems clear that revealing asymptomatic or previously undiagnosed atrial fibrillation episodes in patients with a cryptogenic stroke and a concomitant PFO by means of continuous cardiac monitoring may avoid inappropriate PFO percutaneous closure.
continuous monitoring of all patients with cryptogenic stroke and any atrial fibrillation risk factor, until further studies, including a larger population, could fulfil the gap in our understanding. The purpose of the study is to define the prevalence of atrial fibrillation in patients discharge after a stroke that results cryptogenic after an insightful exclusion of all the potential causes. Thus, the study does not aim and was not powered to estimate potential differences between PFO and not-PFO patients or regarding the finding of previous cerebral infarcts at MRI. Prospective, randomized and multicentric trials should enlist all cryptogenic stroke patients in the early phase of the disease, during hospitalization, without excluding major disabilities. Selection of patients according to atrial fibrillation risk factors should be maintained: the population with atrial fibrillation risk factors has a higher thromboembolic risk and requires a different approach because discovering atrial fibrillation is mandatory to set up a correct secondary prevention.
Conclusion In patients with at least one risk factor for atrial fibrillation suffering a recent cryptogenic stroke, silent arrhythmic events can be detected in almost half of the cases by means of continuous ECG monitoring. This approach may be useful to select potential high-risk patients who may need a more aggressive secondary prevention strategy (i.e. anticoagulation) to avoid debilitating and life-threatening stroke recurrences.
Acknowledgements The authors have no conflicts of interest.
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Limitations Some limitations should be acknowledged in interpreting the results of the present study. Although continuous ECG monitoring allowed the detection of silent atrial fibrillation episodes in a considerable proportion of patients with a recent cryptogenic stroke, the time elapsed between the neurologic event and ILR implantation may have determined an underestimation of the arrhythmic events.
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