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Aims

Monitoring capabilities of cardiac implantable electronic devices have revealed that a large proportion of patients present silent atrial fibrillation (AF) detected as atrial high rate episodes (AHREs). Atrial high rate episodes >5 min have been linked to increased risk of clinical stroke, but a high proportion of ischaemic brain lesions (IBLs) could be subclinical.

Methods and results

We prospectively analysed the incidence of AHRE > 5 min in 109 patients (56% men, aged 74 ± 9 years) and the presence of silent IBL on computed tomography (CT) scan. Mean CHADS2 and CHA2DS2VASc scores were 2.3 ± 1.3 and 3.9 ± 1.6, respectively. Seventy-five patients (69%) had no history of AF or stroke/transient ischaemic attack (TIA). After 12 months, 28 patients (25.7%) showed at least one AHRE. Patients with AHREs were more likely to have history of AF. Computed tomography scan showed silent IBL in 28 (25.7%). The presence of IBL was significantly related to older patients, prior history of AF or stroke/TIA, higher CHADS2 or CHA2DS2VASc scores, and the presence of AHRE. Multivariable analysis demonstrated that AHRE was an independent predictor for silent IBL in overall population [hazard ratio (HR) 3.05 (1.06–8.81; P < 0.05)] but also in patients without prior history of AF or stroke/TIA [HR 9.76 (1.76–54.07; P < 0.05)].

Conclusion

Cardiac implantable electronic devices can accurately detect AF as AHRE. Atrial high rate episodes were associated to a higher incidence of silent IBL on CT scan. Atrial high rate episodes represent a kind of silent AF where management recommendations are lacking despite the fact that a higher embolic risk is present.

Atrial fibrillation, Cardiac electronic devices, Silent ischaemic brain lesions, Atrial high rate episodes, Computed tomography.
What's new?

  • Identification of paroxysmal atrial fibrillation (AF), even in the absence of symptoms, is crucial to permit an early intervention avoiding a thrombo-embolic event as first symptom.

  • Multiple studies have shown that atrial high rate episodes (AHREs) detected in cardiac implantable electronic devices (CIEDs) are related to an increased risk of stroke.

  • These studies have evaluated symptomatic events but brain-imaging techniques have shown that silent cerebral infarcts are frequently seen in asymptomatic patients with AF.

  • Subsequently, the embolic risk attributed to AHRE could be underestimated.

  • Our study is the first study that evaluates the relation between the incidence of AHRE and the presence of silent ischaemic brain lesions on computed tomography (CT) scan.

  • Our data also showed that the presence of AHRE > 5 min in this selected population of patients with CIED was an independent risk factor associated to silent ischaemic brain lesions detected on CT scan in patients without prior history of AF or stroke/transient ischaemic attack (odds ratio 5.83).

Introduction

Atrial fibrillation (AF) is recognized as the most prevalent cardiac arrhythmia and is associated with substantial complications and healthcare costs.1,2 Assessment of the prevalence of silent paroxysmal AF represents a challenge, since the arrhythmia may be brief, completely asymptomatic, and difficult to detect. Lack of symptoms from AF should not be equated to lack of risk of thrombo-embolic complications due to AF, which is probably present to the same degree as in symptomatic AF.3 The stroke risk conferred by paroxysmal AF has been considered to be the same as continuous AF.4 Stroke can be the first symptom of a ‘silent’ AF previously unrecognized.5 Cerebral computed tomography (CT) and magnetic resonance imaging (MRI) are useful diagnostic techniques detecting both symptomatic and silent ischaemic brain lesions (IBLs) in patients with AF.6 Identification of short episodes of paroxysmal AF, even in the absence of symptoms, therefore may be important to permit early intervention.

Cardiac implantable electronic devices (CIEDs) have shown reliable AF detection as atrial high rate episodes (AHREs).7 The presence of AHRE has been related to increased risk of stroke and systemic embolism.8–10 These studies have evaluated the occurrence of symptomatic clinical events but the real embolic risk could be underestimated. Silent or subclinical IBL can be detected by CT scan and could help to reflect a more real perspective of the embolic risk these patients are exposed to.

Methods

Patient population

Patients in sinus rhythm, with or without history of previous episodes of AF and with St Jude Medical dual-chamber pacemakers (PMs), implantable cardioverter-defibrillators (ICDs), and devices for cardiac resynchronization therapy (CRT) capable of atrial activity monitoring were included in the study. Baseline patient's characteristics including cardiovascular risk factors, prior heart disease, or atrial tachyarrhythmia, indications for CIED implantation, and medications were recorded.

The study protocol was presented and approved by the Ethics Committee of our Institution. Patients were recruited after implantation or in the scheduled follow-up visits from February 2012. At inclusion, patients were informed of the investigational purpose of the study, asked to perform a brain CT scan examination (Phillips Brilliance 64 CT Scanner). and informed consent was obtained. Scheduled PM check-ups were planned at 3 months after inclusion and every year. All the PM check-up data were downloaded in the patient medical history. No special surveillance was protocolized in patients presenting AHRE during follow-up.

Device settings

It is the protocol of our Arrhythmia Unit to avoid right ventricular pacing in all the dual-chamber PMs prolonging the AV interval and using other dedicated algorithms when necessary. Implantable cardioverter-defibrillators were programmed with back-up pacing (VDI 40 b.p.m.) conserving atrial sensing. Cardiac resynchronization therapy are programmed with an adequate AV interval to achieve >95% of biventricular pacing.

For the purpose of this investigation, AHRE were defined as episodes of atrial rate ≥225 b.p.m. with a minimum duration of 5 min or more. Intracavitary electrograms acquisition was programmed to confirm AF based on atrial electrograms during the episodes.

Data analysis

We analysed prospectively the incidence of AHRE > 5 min compatible with AF in patients in sinus rhythm with dual-chamber cardiac devices and the presence of IBL on CT scan.

Device and clinical evaluation

From February 2012, all the subsequent scheduled PM check-ups were reviewed. Pacemaker atrial stimulation/sense parameters, atrial lead impedance, percentages of atrial and ventricular pacing, AHRE, automatic mode switch episodes, and noise episodes were recorded.

A clinical evaluation was also performed including symptoms, hospital/emergency department admissions, changes in treatment (antiarrhythmic and antithrombotic treatment), electrocardiogram (ECG) documentation of AF, and mortality.

Brain computed tomography scan evaluation

Brain infarcts are described as focal lesions with roughly the same intensity as cerebrospinal fluid on CT scan. Although sensitivity for infarct detection is better for MRI compared with CT, particularly for small lesions located in the basal ganglia, using MRI in asymptomatic patients with implantable cardiac electronic devices is not recommended and it was not considered in our protocol.

All CT scans were performed at inclusion and evaluated blindly by consultant neuroradiologists in our institution with special attention to the number and size of low-density areas compatible with infarcts. Lesion size was measured and ischaemic lesions on brain CT scan were described as those focal lesions that were 3 mm or larger with sharp demarcation from surrounding tissue. Infarcts were classed as silent if they lack stroke-like symptoms after questioning patient combined with evidence from medical records in the clinical history. In patients with prior clinical stroke/transient ischaemic attack (TIA), the responsible lesions were excluded and only new lesions or when multiple were considered.

Statistical analysis

Data were subjected to descriptive statistical analysis, via frequency measurements (absolute frequencies and percentages) for qualitative variables, and via means and standard deviations for quantitative variables. Univariate analysis of the quantitative variables was performed using the Student's t-test when their distribution was normal and the Mann–Whitney U test when they were not. The qualitative variables were analysed using the χ2 or the Fisher's exact test. Multivariate analysis with logistic regression (backward stepwise) was employed to determine whether the association between the IBL on CT scan and AHRE was influenced by the baseline characteristics of the groups (confounding factors). Interactions could not be evaluated in multivariate analysis owing to the small sample size. From the collection of baseline variables shown in Table 1, those with the potential to act as confounding factors were selected first in terms of their clinical and biological plausibility, and secondly in terms of the statistical criterion of Mickey excluding all those variables that in univariate analysis returned an association with the response reflected by a value of P > 0.20. Due to the strong relation between CHADS2 and CHA2DS2VASc scores (both statistically related to the presence of IBL on CT scan in the univariate analysis), we decided to exclude CHADS2 score in the multivariate analysis to avoid redundant variables, maintaining CHA2DS2VASc score that is considered to provide a better thrombo-embolic risk stratification. Therefore, the variables included in the multivariate analysis performed in the overall study population were: age, high blood pressure, CHA2DS2VASc score, small-vessel disease on CT scan, chronic kidney disease, history of prior AF, prior stroke/TIA, and AHRE > 5 min. The variables included in the multivariate analysis performed in the subgroup of patients without prior history of AF or stroke/TIA were: age, CHA2DS2VASc score, structural heart disease, and AHRE > 5 min. The magnitude of the effects of the variables was expressed in the form of odds ratio (OR) and 95% confidence limits (95% CI).

Table 1
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Baseline characteristics for total population and patients with AHRE vs. those without

Baseline CharacteristicsTotal Population (n = 109)Patients with AHRE (n = 28)Patients without AHRE (n = 81)P value
Age, years (SD)74 ± 976 ± 674 ± 100.45
Sex, male (%)61 (56)15 (53)46 (56)0.76
Hypertension, n (%)88 (80)23 (82)65 (80)0.82
Diabetes, n (%)34 (31)7 (25)27 (33)0.40
Prior structural heart disease, n (%)35 (32)8 (28)27 (33)0.63
 Ischaemic cardiomyopathy35 (32)7 (25)18 (22)0.22
 Cardiac valvular prosthesis2 (1.8)0 (0)2 (2)0.30
 Systolic dysfunction (EF < 50%)16 (14.7)3 (10)13 (16)0.59
 Left ventricle hypertrophy (>13 mm)5 (4.6)1 (3)4 (5)0.86
History of heart failure, n (%)11 (10)4 (14)7 (8)0.40
History of AF, n (%)22 (20)11 (39)11 (13)0.005
Prior stroke/TIA, n (%)21 (19)9 (32)12 (14)0.054
Chronic kidney disease, n (%)24 (22)7 (25)17 (21)0.66
CHADS2 score2.3 ± 1.32.5 ± 1.22.2 ± 1.30.32
CHA2DS2VASc score3.9 ± 1.64.2 ± 1.43.8 ± 1.60.22
Treatment, n (%)
 ACE inhibitors/ARB75 (69)21 (75)54 (66)0.40
 Beta-blockers37 (34)7 (25)30 (37)0.23
 Statins62 (57)16 (57)46 (56)0.97
 Aspirin54 (49)13 (46)41 (50)0.70
 Clopidogrel6 (5)2 (7)4 (5)0.66
 Anticoagulation21 (19)9 (32)12 (14)0.054
 Antiarrhythmics15 (14)7 (25)8 (9)0.057
Baseline CharacteristicsTotal Population (n = 109)Patients with AHRE (n = 28)Patients without AHRE (n = 81)P value
Age, years (SD)74 ± 976 ± 674 ± 100.45
Sex, male (%)61 (56)15 (53)46 (56)0.76
Hypertension, n (%)88 (80)23 (82)65 (80)0.82
Diabetes, n (%)34 (31)7 (25)27 (33)0.40
Prior structural heart disease, n (%)35 (32)8 (28)27 (33)0.63
 Ischaemic cardiomyopathy35 (32)7 (25)18 (22)0.22
 Cardiac valvular prosthesis2 (1.8)0 (0)2 (2)0.30
 Systolic dysfunction (EF < 50%)16 (14.7)3 (10)13 (16)0.59
 Left ventricle hypertrophy (>13 mm)5 (4.6)1 (3)4 (5)0.86
History of heart failure, n (%)11 (10)4 (14)7 (8)0.40
History of AF, n (%)22 (20)11 (39)11 (13)0.005
Prior stroke/TIA, n (%)21 (19)9 (32)12 (14)0.054
Chronic kidney disease, n (%)24 (22)7 (25)17 (21)0.66
CHADS2 score2.3 ± 1.32.5 ± 1.22.2 ± 1.30.32
CHA2DS2VASc score3.9 ± 1.64.2 ± 1.43.8 ± 1.60.22
Treatment, n (%)
 ACE inhibitors/ARB75 (69)21 (75)54 (66)0.40
 Beta-blockers37 (34)7 (25)30 (37)0.23
 Statins62 (57)16 (57)46 (56)0.97
 Aspirin54 (49)13 (46)41 (50)0.70
 Clopidogrel6 (5)2 (7)4 (5)0.66
 Anticoagulation21 (19)9 (32)12 (14)0.054
 Antiarrhythmics15 (14)7 (25)8 (9)0.057

Continuous variables are presented as median ± SD.

Categorical variables are presented as number (%).

AHRE, atrial high rate episode; TIA, transient ischaemic attack. Bold values show variables showing a statistically significant relationship.

Table 1
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Baseline characteristics for total population and patients with AHRE vs. those without

Baseline CharacteristicsTotal Population (n = 109)Patients with AHRE (n = 28)Patients without AHRE (n = 81)P value
Age, years (SD)74 ± 976 ± 674 ± 100.45
Sex, male (%)61 (56)15 (53)46 (56)0.76
Hypertension, n (%)88 (80)23 (82)65 (80)0.82
Diabetes, n (%)34 (31)7 (25)27 (33)0.40
Prior structural heart disease, n (%)35 (32)8 (28)27 (33)0.63
 Ischaemic cardiomyopathy35 (32)7 (25)18 (22)0.22
 Cardiac valvular prosthesis2 (1.8)0 (0)2 (2)0.30
 Systolic dysfunction (EF < 50%)16 (14.7)3 (10)13 (16)0.59
 Left ventricle hypertrophy (>13 mm)5 (4.6)1 (3)4 (5)0.86
History of heart failure, n (%)11 (10)4 (14)7 (8)0.40
History of AF, n (%)22 (20)11 (39)11 (13)0.005
Prior stroke/TIA, n (%)21 (19)9 (32)12 (14)0.054
Chronic kidney disease, n (%)24 (22)7 (25)17 (21)0.66
CHADS2 score2.3 ± 1.32.5 ± 1.22.2 ± 1.30.32
CHA2DS2VASc score3.9 ± 1.64.2 ± 1.43.8 ± 1.60.22
Treatment, n (%)
 ACE inhibitors/ARB75 (69)21 (75)54 (66)0.40
 Beta-blockers37 (34)7 (25)30 (37)0.23
 Statins62 (57)16 (57)46 (56)0.97
 Aspirin54 (49)13 (46)41 (50)0.70
 Clopidogrel6 (5)2 (7)4 (5)0.66
 Anticoagulation21 (19)9 (32)12 (14)0.054
 Antiarrhythmics15 (14)7 (25)8 (9)0.057
Baseline CharacteristicsTotal Population (n = 109)Patients with AHRE (n = 28)Patients without AHRE (n = 81)P value
Age, years (SD)74 ± 976 ± 674 ± 100.45
Sex, male (%)61 (56)15 (53)46 (56)0.76
Hypertension, n (%)88 (80)23 (82)65 (80)0.82
Diabetes, n (%)34 (31)7 (25)27 (33)0.40
Prior structural heart disease, n (%)35 (32)8 (28)27 (33)0.63
 Ischaemic cardiomyopathy35 (32)7 (25)18 (22)0.22
 Cardiac valvular prosthesis2 (1.8)0 (0)2 (2)0.30
 Systolic dysfunction (EF < 50%)16 (14.7)3 (10)13 (16)0.59
 Left ventricle hypertrophy (>13 mm)5 (4.6)1 (3)4 (5)0.86
History of heart failure, n (%)11 (10)4 (14)7 (8)0.40
History of AF, n (%)22 (20)11 (39)11 (13)0.005
Prior stroke/TIA, n (%)21 (19)9 (32)12 (14)0.054
Chronic kidney disease, n (%)24 (22)7 (25)17 (21)0.66
CHADS2 score2.3 ± 1.32.5 ± 1.22.2 ± 1.30.32
CHA2DS2VASc score3.9 ± 1.64.2 ± 1.43.8 ± 1.60.22
Treatment, n (%)
 ACE inhibitors/ARB75 (69)21 (75)54 (66)0.40
 Beta-blockers37 (34)7 (25)30 (37)0.23
 Statins62 (57)16 (57)46 (56)0.97
 Aspirin54 (49)13 (46)41 (50)0.70
 Clopidogrel6 (5)2 (7)4 (5)0.66
 Anticoagulation21 (19)9 (32)12 (14)0.054
 Antiarrhythmics15 (14)7 (25)8 (9)0.057

Continuous variables are presented as median ± SD.

Categorical variables are presented as number (%).

AHRE, atrial high rate episode; TIA, transient ischaemic attack. Bold values show variables showing a statistically significant relationship.

Results

Study population

From February 2012 to February 2014, 109 consecutive patients (61 men, 56%) were enrolled in the study. We included 97 PMs (89%), 7 ICDs (6%), and 5 CRTs (5%). The main indication for PM implantation was sinus node disease (51%). The mean age was 74 ± 9 years (range 26–94). In 74 patients (68%), there was no evidence of underlying structural heart disease. Prior history of AF was present in 22 patients (20%) and prior stroke/TIA in 21 patients (19%). Seventy-five patients (69%) had no prior history of AF or stroke/TIA. Mean CHADS2 and CHA2DS2VASc scores were 2.3 ± 1.3 and 3.9 ± 1.6, respectively, reflecting a moderately high expected stroke risk. The baseline characteristics of the study population are provided in Table 1.

Atrial high rate episodes

After a mean follow-up of 17 ± 6 months, 28 patients (25.7%) showed at least one AHRE > 5 min. Fifteen patients (13.7%) presented at least one episode at 3 months. Episodes last 5 min to 1 h in 10 patients, 1–12 h in 10 patients, 12–24 h in 2 patients, and >24 h in 6 patients. Patients with AHREs were more likely to have a history of AF, anticoagulation or antiarrhythmic treatment, and prior stroke or TIA than patients without AHRE, Table 1. After excluding patients with prior AF, there were no statistical differences related to the presence of AHRE attending to baseline characteristics.

Ischaemic brain lesions on computed tomography scan

Brain CT scans were evaluated as normal in 81 patients (74.3%). Twenty-eight patients (25.7%) presented one or more small silent IBL. Among these patients, 10 patients (35%) had prior AF and 14 patients (50%) had prior stroke/TIA. On the other hand, 11 patients (39%) had none of both antecedents, Table 2. The presence of IBL on CT scan was significantly related to older patients, prior history of AF or stroke/TIA, higher CHADS2 or CHA2DS2VASc scores, and the presence of AHRE > 5 min at 12 months. There were no differences related to the duration of the AHRE in patients with and without IBL. In 87 patients (80%) without prior history of AF, 8 patients showing AHRE > 5 min (47%) presented one or more IBL on CT scan compared with 10 of 70 patients without AHRE (14%), P = 0.005.

Table 2
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Baseline characteristics of the patients according to brain CT scan findings

Baseline characteristicsNormal CT scan (n = 81)IBLs (n = 28)P value
Age, years (SD)73 ± 1079 ± 50.007
Sex, male (%)45 (55)16 (57)0.88
Hypertension, n (%)63 (77)25 (89)0.16
Diabetes, n (%)23 (28)11 (39)0.29
Prior structural heart disease, n (%)24 (29)11 (39)0.35
History of heart failure, n (%)9 (11)2 (7)0.53
History of AF, n (%)12 (14)10 (35)0.02
Prior stroke/TIA, n (%)7 (8)14 (50)<0.001
Chronic kidney disease, n (%)15 (18)9 (32)0.14
CHADS2 score1.9 ± 1.13.3 ± 1.1<0.001
CHA2DS2VASc score3.4 ± 1.55.1 ± 1.0<0.001
Treatment, n (%)
 Aspirin35 (43)19 (67)0.023
 Anticoagulation12 (14)9 (32)0.054
 Antiarrhythmics7 (8)8 (28)0.013
Presence of small-vessel disease on CT scan30 (37)15 (53)0.12
AHRE at 12 months16 (19)12 (42)0.019
Baseline characteristicsNormal CT scan (n = 81)IBLs (n = 28)P value
Age, years (SD)73 ± 1079 ± 50.007
Sex, male (%)45 (55)16 (57)0.88
Hypertension, n (%)63 (77)25 (89)0.16
Diabetes, n (%)23 (28)11 (39)0.29
Prior structural heart disease, n (%)24 (29)11 (39)0.35
History of heart failure, n (%)9 (11)2 (7)0.53
History of AF, n (%)12 (14)10 (35)0.02
Prior stroke/TIA, n (%)7 (8)14 (50)<0.001
Chronic kidney disease, n (%)15 (18)9 (32)0.14
CHADS2 score1.9 ± 1.13.3 ± 1.1<0.001
CHA2DS2VASc score3.4 ± 1.55.1 ± 1.0<0.001
Treatment, n (%)
 Aspirin35 (43)19 (67)0.023
 Anticoagulation12 (14)9 (32)0.054
 Antiarrhythmics7 (8)8 (28)0.013
Presence of small-vessel disease on CT scan30 (37)15 (53)0.12
AHRE at 12 months16 (19)12 (42)0.019

Continuous variables are presented as median ± SD.

Categorical variables are presented as number (%).

AHRE, atrial high rate episode; TIA, transient ischaemic attack.

Bold values show variables showing a statistically significant relationship.

Table 2
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Baseline characteristics of the patients according to brain CT scan findings

Baseline characteristicsNormal CT scan (n = 81)IBLs (n = 28)P value
Age, years (SD)73 ± 1079 ± 50.007
Sex, male (%)45 (55)16 (57)0.88
Hypertension, n (%)63 (77)25 (89)0.16
Diabetes, n (%)23 (28)11 (39)0.29
Prior structural heart disease, n (%)24 (29)11 (39)0.35
History of heart failure, n (%)9 (11)2 (7)0.53
History of AF, n (%)12 (14)10 (35)0.02
Prior stroke/TIA, n (%)7 (8)14 (50)<0.001
Chronic kidney disease, n (%)15 (18)9 (32)0.14
CHADS2 score1.9 ± 1.13.3 ± 1.1<0.001
CHA2DS2VASc score3.4 ± 1.55.1 ± 1.0<0.001
Treatment, n (%)
 Aspirin35 (43)19 (67)0.023
 Anticoagulation12 (14)9 (32)0.054
 Antiarrhythmics7 (8)8 (28)0.013
Presence of small-vessel disease on CT scan30 (37)15 (53)0.12
AHRE at 12 months16 (19)12 (42)0.019
Baseline characteristicsNormal CT scan (n = 81)IBLs (n = 28)P value
Age, years (SD)73 ± 1079 ± 50.007
Sex, male (%)45 (55)16 (57)0.88
Hypertension, n (%)63 (77)25 (89)0.16
Diabetes, n (%)23 (28)11 (39)0.29
Prior structural heart disease, n (%)24 (29)11 (39)0.35
History of heart failure, n (%)9 (11)2 (7)0.53
History of AF, n (%)12 (14)10 (35)0.02
Prior stroke/TIA, n (%)7 (8)14 (50)<0.001
Chronic kidney disease, n (%)15 (18)9 (32)0.14
CHADS2 score1.9 ± 1.13.3 ± 1.1<0.001
CHA2DS2VASc score3.4 ± 1.55.1 ± 1.0<0.001
Treatment, n (%)
 Aspirin35 (43)19 (67)0.023
 Anticoagulation12 (14)9 (32)0.054
 Antiarrhythmics7 (8)8 (28)0.013
Presence of small-vessel disease on CT scan30 (37)15 (53)0.12
AHRE at 12 months16 (19)12 (42)0.019

Continuous variables are presented as median ± SD.

Categorical variables are presented as number (%).

AHRE, atrial high rate episode; TIA, transient ischaemic attack.

Bold values show variables showing a statistically significant relationship.

The results of the univariate analysis are shown in Table 3. The presence of IBL on CT scan was associated to the age, CHADS2 or CHA2DS2VASc scores, and prior history of AF or stroke/TIA. The presence of AHRE > 5 min was associated with an increased risk of IBL in both overall population [OR 3.04 (1.20–7.70; P < 0.05)] and patients without prior history of AF or stroke/TIA [OR 5.83 (1.44–26.63; P < 0.05)].

Table 3
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Risk of IBLs on CT scan in the overall study population and in the subgroup of patients without prior history of AF or stroke/TIA

ORCI 95%P value
Overall study population
Age1.091.02–1.17<0.05
Sex (male)1.060.44–2.530.88
CHADS2 score2.671.71 ± 4.16<0.001
CHAD2S2VASc score2.281.56 ± 3.33<0.001
High blood pressure2.380.64 ± 8.790.19
Diabetes1.630.66 ± 4.010.28
Structural heart disease1.530.62 ± 3.760.34
History of heart failure0.610.12 ± 3.030.55
History of stroke/TIA10.573.61 ± 30.88<0.001
History of AF3.191.19 ± 8.56<0.05
Chronic kidney disease2.080.78 ± 5.500.13
Small-vessel disease1.960.82 ± 4.670.12
AHRE > 5 min3.041.20 ± 7.70<0.05
Patients without prior history of AF or stroke/TIA
Age1.070.97–1.180.13
Sex (male)2.210.53–9.090.27
CHADS2 score2.291.06 ± 4.97<0.05
CHAD2S2VASc score1.741.03 ± 2.94<0.05
High blood pressure3.610.43 ± 30.410.23
Diabetes1.580.41 ± 6.080.50
Structural heart disease2.840.77 ± 10.450.11
History of heart failure1.180.12 ± 11.180.88
Chronic kidney disease1.070.20 ± 5.650.93
Small-vessel disease1.250.33 ± 4.780.73
AHRE > 5 min5.831.44 ± 23.63<0.05
ORCI 95%P value
Overall study population
Age1.091.02–1.17<0.05
Sex (male)1.060.44–2.530.88
CHADS2 score2.671.71 ± 4.16<0.001
CHAD2S2VASc score2.281.56 ± 3.33<0.001
High blood pressure2.380.64 ± 8.790.19
Diabetes1.630.66 ± 4.010.28
Structural heart disease1.530.62 ± 3.760.34
History of heart failure0.610.12 ± 3.030.55
History of stroke/TIA10.573.61 ± 30.88<0.001
History of AF3.191.19 ± 8.56<0.05
Chronic kidney disease2.080.78 ± 5.500.13
Small-vessel disease1.960.82 ± 4.670.12
AHRE > 5 min3.041.20 ± 7.70<0.05
Patients without prior history of AF or stroke/TIA
Age1.070.97–1.180.13
Sex (male)2.210.53–9.090.27
CHADS2 score2.291.06 ± 4.97<0.05
CHAD2S2VASc score1.741.03 ± 2.94<0.05
High blood pressure3.610.43 ± 30.410.23
Diabetes1.580.41 ± 6.080.50
Structural heart disease2.840.77 ± 10.450.11
History of heart failure1.180.12 ± 11.180.88
Chronic kidney disease1.070.20 ± 5.650.93
Small-vessel disease1.250.33 ± 4.780.73
AHRE > 5 min5.831.44 ± 23.63<0.05

Bold values show variables showing a statistically significant relationship.

AHRE, atrial high rate episode; TIA, transient ischaemic attack.

Table 3
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Risk of IBLs on CT scan in the overall study population and in the subgroup of patients without prior history of AF or stroke/TIA

ORCI 95%P value
Overall study population
Age1.091.02–1.17<0.05
Sex (male)1.060.44–2.530.88
CHADS2 score2.671.71 ± 4.16<0.001
CHAD2S2VASc score2.281.56 ± 3.33<0.001
High blood pressure2.380.64 ± 8.790.19
Diabetes1.630.66 ± 4.010.28
Structural heart disease1.530.62 ± 3.760.34
History of heart failure0.610.12 ± 3.030.55
History of stroke/TIA10.573.61 ± 30.88<0.001
History of AF3.191.19 ± 8.56<0.05
Chronic kidney disease2.080.78 ± 5.500.13
Small-vessel disease1.960.82 ± 4.670.12
AHRE > 5 min3.041.20 ± 7.70<0.05
Patients without prior history of AF or stroke/TIA
Age1.070.97–1.180.13
Sex (male)2.210.53–9.090.27
CHADS2 score2.291.06 ± 4.97<0.05
CHAD2S2VASc score1.741.03 ± 2.94<0.05
High blood pressure3.610.43 ± 30.410.23
Diabetes1.580.41 ± 6.080.50
Structural heart disease2.840.77 ± 10.450.11
History of heart failure1.180.12 ± 11.180.88
Chronic kidney disease1.070.20 ± 5.650.93
Small-vessel disease1.250.33 ± 4.780.73
AHRE > 5 min5.831.44 ± 23.63<0.05
ORCI 95%P value
Overall study population
Age1.091.02–1.17<0.05
Sex (male)1.060.44–2.530.88
CHADS2 score2.671.71 ± 4.16<0.001
CHAD2S2VASc score2.281.56 ± 3.33<0.001
High blood pressure2.380.64 ± 8.790.19
Diabetes1.630.66 ± 4.010.28
Structural heart disease1.530.62 ± 3.760.34
History of heart failure0.610.12 ± 3.030.55
History of stroke/TIA10.573.61 ± 30.88<0.001
History of AF3.191.19 ± 8.56<0.05
Chronic kidney disease2.080.78 ± 5.500.13
Small-vessel disease1.960.82 ± 4.670.12
AHRE > 5 min3.041.20 ± 7.70<0.05
Patients without prior history of AF or stroke/TIA
Age1.070.97–1.180.13
Sex (male)2.210.53–9.090.27
CHADS2 score2.291.06 ± 4.97<0.05
CHAD2S2VASc score1.741.03 ± 2.94<0.05
High blood pressure3.610.43 ± 30.410.23
Diabetes1.580.41 ± 6.080.50
Structural heart disease2.840.77 ± 10.450.11
History of heart failure1.180.12 ± 11.180.88
Chronic kidney disease1.070.20 ± 5.650.93
Small-vessel disease1.250.33 ± 4.780.73
AHRE > 5 min5.831.44 ± 23.63<0.05

Bold values show variables showing a statistically significant relationship.

AHRE, atrial high rate episode; TIA, transient ischaemic attack.

Multivariable analysis demonstrated that the presence of AHRE > 5 min [hazard ratio 3.05 (1.06–8.81; P < 0.05)] and CHA2DS2VASc score [hazard ratio 2.29 (1.55–3.37; P < 0.001)] were independent predictors of IBL in overall population. In the subgroup of patients without prior history of AF or stroke/TIA, AHRE > 5 min was also an independent predictor of IBL [hazard ratio 9.76 (1.76–54.07; P < 0.05)].

During the follow-up, new diagnosed AF was documented on ECG in five patients. In three of them AF was asymptomatic and was detected in a routinary check-up, in one patient after a syncope episode and in the other patient after a stroke. In all these patients AF was correctly identified and registered as AHRE in the CIED.

Discussion

Population ageing and broader indications are the main reasons for the continuous increase in the use of PM, ICD, and CRT devices in the USA and Europe.11,12 On the other hand, an increasing aged population with underlying heart disease and the improvement of diagnosis techniques have led to report a high prevalence of AF in those over 70 years old.1 Therefore, patients receiving CIED share co-morbidities (age, cardiovascular risk factors, heart disease, etc.) associated also to an increased rate for AF.

Atrial fibrillation presents a two-fold mortality risk and a four- to five-fold risk for stroke.2 It is usually recognized by the onset of symptoms such as palpitations, dysponea, etc. However, in at least one-third of patients, AF is associated with no obvious symptoms. As a result, the initial manifestation of this ‘silent’ AF could be a stroke or systemic embolism.3 It is not uncommon that AF is found incidentally on admission for cerebral infarct. About 25–30% of patients presenting with strokes present AF that was not previously recognized. Magnetic resonance imaging studies revealed that up to 40% of patients with AF had one or many silent cerebral infarcts.6 Improvements in prevention and early diagnosis techniques are needed to identify these episodes of paroxysmal AF, even in the absence of symptoms.

Today's CIED diagnostics accurately detects AHRE when the atrial rate exceeds the programmed arrhythmia detection rate during a programmable number of beats. A critical issue is validating these AHRE as AF. Multiple studies have reported that AHRE > 200–250 b.p.m. and >5 min in duration had a high correlation with atrial tachyarrhythmias validated by simultaneous stored intracardiac electrograms.13,14 But even more important is to assess the clinical significance of these episodes. In the Atrial Diagnostics Ancillary Study of the MOde Selection Trial (MOST), patients with at least one AHRE exceeding 5 min were more likely to have adverse clinical outcomes, including a higher incidence of stroke, death, and subsequent AF than were patients without AHRE.8 TRENDS was a prospective, observational study enrolling 2486 patients with ≥1 stroke risk factor (heart failure, hypertension, age ≥65 years, diabetes, or prior thrombo-embolic event) receiving PM or ICD that monitor atrial tachycardia (AT)/AF burden (defined as the longest total AT/AF duration on any given day during the prior 30-day period). An AT/AF burden ≥5.5 h on any given day during the antecedent 30 days appeared to confer a doubling of thrombo-embolic risk.9 Finally, results of the Asymptomatic AF and Stroke Evaluation in Pacemaker Patients and the AF Reduction Atrial Pacing Trial (ASSERT) showed that, in this population of PM patients with hypertension but no history of AF nor anticoagulation, episodes of device-detected AT>6 min were found in approximately one-third over almost 3 years of mean follow-up. Furthermore, these arrhythmias were associated with a 2.5-fold increase in the risk of ischaemic stroke and systemic embolism.10 Data from the ASSERT and TRENDS studies are supported by several smaller, prospective trials that have also examined the relationship between AHRE and embolic events. In the study by Capucci et al.,15 AHRE lasting >5 min did not increase embolic risk, while episodes lasting >24 h did (OR 3.1). All these trials have shown AHRE to be an independent predictor of thromboembolism, including ischaemic stroke. Furthermore, there was a clear difference in embolic risk that became apparent only when AHRE duration exceeded certain thresholds. Future studies will be required to identify certain high-risk patients on the basis of an AHRE duration threshold as well as the presence of individual risk factors.

The development of sophisticated brain-imaging techniques, initially with CT and subsequently with MRI, has shown that vascular disease manifesting as infarcts can result in injury to the brain in the absence of symptoms.16 Silent cerebral infarcts are frequently seen in asymptomatic patients with AF.17 Recent studies have shown that cortical/subcortical and deep white matter silent cerebral infarcts are more frequent in non-valvular AF patients compared with control subjects and CHADS2 score was an effective scheme not only in stroke risk but also in risk of silent cerebral infarct.18 Moreover, brief episodes of subclinical AF (<48 h) documented by Holter monitoring have been associated with a significantly increased risk of silent cerebral infarct and stroke.19

Our data show that a high proportion of patients with CIED (25% at 12 months) present AHRE > 5 min during the follow-up, especially in those with previous AF (50% at 12 months) but also in a high proportion of patients where AF has not yet been documented (19%). The presence of AHRE was associated to a higher incidence (42 vs. 19%) of silent IBL on CT scan. Apart from age, hypertension and small-vessel disease are the most widely accepted risks factors strongly associated with silent brain infarcts in most studies.16 Our findings were consistent with all these studies showing an increased risk of silent IBLs on CT scan in older patients, in patients with higher CHADS2 and CHA2DS2VASc scores, patients with previous AF or prior stroke/TIA etc. But our data also showed that the presence of AHRE > 5 min in this selected population of patients with CIED was an independent risk factor associated to silent IBL detected on CT scan, both in overall population (OR 3.04) and in patients without prior history of AF or stroke/TIA (OR 5.83).

Silent AF has the same poor prognostic impact as symptomatic AF. Atrial high rate episodes represent a kind of silent AF where management recommendations are lacking despite the fact that a higher embolic risk is present. Recently, 2014 AHA/ACC/HRS Guideline for the management of patients with AF has point out the relevant role of CIED in the diagnosis of silent AF but authors conclude that further studies are needed to clarify the relation of AHRE and stroke before providing treatment recommendations.20 Our findings support to consider these AHRE as documented episodes of AF and to evaluate different management alternatives regarding the individual's risk of stroke and thromboembolism of these patients. The routinary application of anticoagulation therapy is as yet unclear and challenging in the absence of randomized studies. To date, the only prospective, randomized trial to address this question was the IMPACT study, which was stopped prematurely and not published.21 Further studies are needed to establish the role of anticoagulation in these patients. In this aspect, the recently designed ARTESIA study will determine if treatment with apixaban, compared with aspirin, will reduce the risk of ischaemic stroke and systemic embolism in PM patients with subclinical AF and additional risk factors for stroke.22 Future guidelines should also deal with this peculiar AF scenario to make professionals that routinely perform CIED follow-ups aware of these relevant episodes but also to provide highly needed recommendations.

Limitations

The present study has the limitations associated to observational single-centre studies. On the other hand, the study includes a ‘real life’ highly reproducible PM population where an exhaustive evaluation of the CIED diagnostic data have been performed, without interfering in other settings of the devices attending to the clinical characteristics of the patients, and where brain CT scan has been obtained and blindly analysed. Due to the relatively small population analysed, our results should be corroborated in future studies.

Only St Jude Medical devices were included in our study to homogenize the parameters programmed and the detection algorithms that could be different in devices from other companies. On the other hand, our results are translatable to the great majority of CIEDs that use similar detection criteria.

Sensitivity for infarct detection is better for MRI compared with CT, particularly for small lesions located in the basal ganglia. Studies using CT scan to detect silent brain infarcts will, therefore, most probably report lower frequencies than those using a more sensitive technique for small lesions as MRI. Therefore our data regarding the thrombo-embolic risk associated to AHRE could be underestimated. This aspect makes our results more clinically relevant and more demanding for management recommendations.

Conclusions

Cardiac implantable electronic device can accurately detect AHRE compatible with silent AF. These AHRE are really prevalent in patients receiving dual-chamber devices, especially in those with previously documented AF, but also in those patients with no history of AF. The presence of AHRE has been associated to a high risk of stroke and systemic embolism but our data also show that these patients present a higher incidence of silent IBL on CT scan. Atrial high rate episodes represent a kind of silent AF where management recommendations are lacking despite the fact that a higher embolic risk is present.

Conflict of interest: none declared.

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