Abstract
Background
The utility of an implantable loop recorder (ILR) in the evaluation of unexplained syncope or palpitations in young patients in the absence of structural heart disease or ventricular dysfunction is limited. To compare the diagnostic yield of ILR with conventional extended Holter evaluation in the detection of arrhythmias among young patients with a structurally normal heart presenting with unexplained palpitations or syncope.
Methods
Open-label randomised control trial was conducted in a tertiary cardiac care centre among young patients with recurrent unexplained palpitations (≥3 episodes/year) or syncope (≥2 episodes) with normal electrocardiogram and echocardiography, after excluding non-cardiac causes. Patients were block randomised to either ILR implantation or conventional extended Holter monitoring.
Results
Fourteen patients in the ILR group and 16 patients in the conventional group completed the study. The mean age of the patients was 31.9 ± 5.5 and 31.2 ± 5.4 years. Males constituted 78.5% and 75% in the two groups, respectively. Diagnosis was established in 10 (71.5%) patients in the ILR group as compared to only 3 (18.7%) in the conventional group (p = 0.01), with an RR of 0.26 (95% CI 0.089–0.76, p = 0.01). The arrhythmias diagnosed with ILR were narrow complex tachycardia (30%), atrial fibrillation (20%), VPCs (20%), severe bradycardia with asystole due to sinus arrest (10%), VPCs with bigeminy (10%), and ventricular tachycardia (10%).
Conclusion
In young patients with unexplained syncope or palpitations, ILR has a higher diagnostic yield in the accurate detection of arrhythmia compared with conventional Holter strategy, resulting in better management.
Keywords: Implantable loop recorder, Syncope, Palpitations, Structurally normal heart
Introduction
Syncope and palpitations are challenging clinical problems with varied presentations, frequently requiring a multipronged approach in their evaluation and management. Nearly one-third of syncope (36%) are of unknown origin.1 Early identification of the cardiac cause is prudent as the one-year mortality of cardiac origin syncope ranges from 18% to 30%.1,2 Despite thorough routine evaluation of unexplained palpitations, the diagnostic yield is only 50%.3 Ambulatory electrocardiography (ECG) monitoring devices which are implantable under the skin have become one of the important tools for the diagnosis of undiagnosed recurrent palpitations or syncope, wherein rhythm and symptom correlation can be performed effectively.3, 4, 5 The major obstacles to diagnosis are the unpredictable frequency of occurrence of arrhythmias and the high spontaneous remission rate of such arrhythmias.1,5 Implantable loop recorders (ILR) may prove useful in the study of palpitations or syncope in this subset of patients with infrequent occurrences of symptoms or where ECG correlation could not be achieved.2
The role of ILR in the diagnosis of recurrent palpitations or syncope in the young Indian population in the absence of structural heart disease is scarce in the currently available literature. Hence the aim of the current study was to assess the diagnostic utility of ILR compared to conventional Holter monitoring in the detection of arrhythmias among young subjects with structurally normal hearts and unexplained palpitations or syncope.
Material and methods
We conducted this open-label, non-blinded randomised control trial in the cardiac centre of a tertiary care hospital between Nov 2015 and May 2018. The study was approved by the institutional ethics committee, and written informed consent was taken from all the study participants.
A total of 30 patients (15 in each group) were enrolled in the study. The primary endpoint was to determine whether ILR contributed in establishing diagnosis above routine Holter monitoring in patients with unexplained recurrent palpitations or syncope and for ascertaining the type of arrhythmia if feasible. Patients were block randomised using random generation function of MS Excel to either conventional strategy of 24 h and extended Holter monitoring only or to ILR implantation.
Inclusion criteria
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1.
Young patients between 18 and 40 years.
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2.
History of recurrent unexplained palpitations (more than three episodes in a year lasting for at least 10 min, not caused by exercise/anxiety or fever) or syncope (more than two episodes in the past not explained by neural mechanisms), with normal surface ECGs and with echocardiographic evidence of structurally normal hearts.
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3.
Patient giving written informed consent for implantation of ILR and available for device interrogation at three monthly intervals or SOS for at least one-year duration.
Exclusion criteria
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1.
Patients not willing for treatment and follow up.
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2.
Patients with structurally abnormal hearts, ventricular dysfunction (ejection fraction <50%) or coronary artery disease (CAD).
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3.
Patients with known ECG abnormalities like pre-excitation, Brugada syndrome, bundle branch blocks or Long QT syndrome.
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4.
Patients with a family history of sudden cardiac death (SCD).
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5.
Presence of anemia, thyroid disorders, pheochromocytoma.
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6.
Psychiatric ailments.
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7.
Pregnancy.
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8.
Significant alcohol abuse.
Patients who satisfied the criteria underwent thorough history taking, clinical examination, ECG, echocardiography and routine biochemical and hematological laboratory investigations in order to exclude palpitations of non-cardiac origin, according to Weber and Kapoor’s criteria.3 Detailed history of palpitations, including perceived rate, rhythm, onset and offset, and accompanying other symptoms were noted. Patients with loss of consciousness suggesting syncopal episodes were interviewed for the duration, premonition, aura, whether related with exercise, occurrences of tonic-clonic convulsions, postictal state and relationship with palpitations. All patients underwent a routine electroencephalogram (EEG) to rule out a seizure disorder. A head-up tilt test (HUTT) was performed in all cases to rule out neurally mediated syncope. All patients subsequently underwent two 24hr ECG monitoring using Schiller Medilog FD12 Holter system as a baseline to rule out already existing or frequently occurring arrhythmia. These patients were subsequently alternately assigned in the two groups based on a random number generated from MS Excel.
Conventional group
In this group, the patients were evaluated with 24 h Holter monitoring on two occasions, followed by an extended Holter monitoring of seven days. During follow-up, all patients had undergone three monthly extended seven-day Holter monitoring. The detection of arrhythmia was considered significant if it correlated with the occurrence of symptoms.
Implantable loop recorders (ILR) group
In this group, after obtaining written informed consent, the patients underwent ILR implantation (Reveal Plus, Medtronic Inc., Minneapolis, Minnesota, a small USB sized device) as in-patients and were monitored for at least 12 months with three monthly or SOS device interrogation. Under local anaesthesia, taking all sterile aseptic precautions in the cardiac catheterisation laboratory, a subcutaneous tunnel of approximately 2 cm in length was made in the left pectoral or parasternal region. Correct implant position was checked using Reveal Vector Check, and the device was secured to the underlying tissue within the pocket using non-absorbable sutures. The incision was subsequently closed with non-absorbable sutures/staplers. A satisfactory electrogram was verified with the help of the programming device. All patients received prophylactic antibiotics post-implantation. Implantable loop recorder monitoring was regarded as diagnostic only when a symptom–rhythm correlation was established during episodes of symptomatic spontaneous palpitations or occurrence of syncope, resembling those prior to enrolment.
Patients in both groups were followed up for at least one-year duration with three monthly reviews or whenever symptomatic with a history suggestive of palpitations or occurrence of syncope. In case of ILR demonstrating any arrhythmia, which requires specific therapy, the patients were advised to undergo the same. The implantable loop recorder was removed from the patient once a follow-up period of at least one year of diagnosis of arrhythmia was made (whichever was earlier).
Sample size
In patients under evaluation for syncope or palpitations of unexplained or unknown origin, the estimated diagnostic yield was 80% and 20%, in the ILR and the conventional group, respectively.6 The calculated sample size with a 90% power and a 5% alpha error for a two sided test, allowing for a 10% drop out, was 14. We, however, recruited 15 patients in each group.
Statistical analysis
Numerical variables were summarised by mean and standard deviation, median and interquartile range and categorical variables were summarised by proportions as applicable. The mean of the difference between the two groups was analysed using the Students t-test, and the z-test was used for comparison of proportions. Categorical variables were compared with the Chi-square test and Fisher’s exact test. Two-tailed tests were used, and a p-value of less than 0.05 was considered to be statistically significant. SPSS version 19 was used for statistical analysis.
Results
We screened a total of 46 patients with recurrent unexplained palpitations or syncope for possible enrolment in the study (Fig. 1). After the complete initial evaluation and excluding structural heart diseases or ventricular dysfunction, 32 patients were identified as eligible candidates for enrolment. Two patients refused consent for follow-up/refused implantation of Implantable loop recorder. Subsequently, 30 patients were enrolled in the study and were randomised into two groups. One patient (6.7%) in the ILR group had device pocket infection within one month of implantation; hence, ILR was explanted. However, he was followed up for the study period, and his data was analysed with the conventional group. The implantation of the ILR device was successful in 93.3% of cases in the first group, and all cases were followed up as per schedule. There were no cases of device malfunction. All patients were available at the end of the study for analysis.
Fig. 1.
Recruitment and follow up of patients in the study.
Table 1 shows the baseline demographic and clinical characteristics of patients in the two groups, which were comparable.
Table 1.
Baseline characteristics of the two groups.
| ILR group (n = 14) n (%) | Conventional group (n = 16) n (%) | p value | |
|---|---|---|---|
| Age in years (Mean ± SD) | 31.9 ± 5.5 | 31.2 ± 5.4 | 0.37 |
| Male | 11 (78.5%) | 12 (75%) | 0.82 |
| Co-morbidities | 0.71 | ||
| Diabetes | 1 (6.7%) | 01 (6.3%) | |
| Hypertension | 1 (6.7%) | 02 (12.5%) | |
| Nil | 13 (86.7%) | 13 (81.3%) | |
| Palpitations | 14 (100%) | 16 (100%) | |
| Duration (years) (Mean ± SD) (range) | 2 ± 1.5 (1.1–5) | 1.9 ± 1.5 (1.2–5) | 0.95 |
| Total Number of Episodes (Mean ± SD) | 3 ± 1.7 | 2.9 ± 1.7 | 0.92 |
| Regular | 11 (78.5%) | 13 (81.2%) | 0.73 |
| Irregular | 03 (21.5%) | 03 (18.8%) | |
| Rapid | 13 (92.9%) | 16 (100%) | 0.47 |
| Onset - Sudden | 14 (100%) | 16 (100%) | – |
| Postpalpitations diuresis | 3 (21.4%) | 3 (18.75%) | 0.85 |
| Syncope following palpitations | 14 (100%) | 16 (100%) | – |
| Syncope without palpitations | 4 (28.5%) | 6 (37.5%) | 0.60 |
| Total episodes of syncope (Mean ± SD) | 2.8 ± 1.3 | 2.3 ± 1.2 | 0.35 |
| Duration of syncope (months) (Mean ± SD) | 5.8 ± 2.9 | 4.6 ± 2.8 | 0.32 |
| Follow up period post recruitment (months) (Mean ± SD) (range) | 11.71 ± 2.4 (7–15) | 13.5 ± 1.1 (12–15) | 0.01 |
During the follow-up period, in the ILR group, out of 14 patients, eight patients had at least one episode of syncope (mean 1.6 ± 0.5) associated with palpitations, while four patients had episodic palpitations without any syncope (mean 2.7 ± 0.5), one patient had symptoms suggestive of seizures and one patient did not report any cardiac complaints. In the conservative group, out of 16 patients, during the follow-up period, seven patients had a single episode of syncope associated with palpitation, however these episodes did not occur when the extended Holter was on. Five patients had complaints of multiple episodes of palpitations (mean 3.2 ± 0.8) when extended Holter was recording. Two patients had episodic palpitations when Holter was not attached, and two were absolutely asymptomatic.
At the end of the study, the diagnosis was established in 10 (71.5%) patients in the ILR group, as compared to only 3 (18.7%) in the conventional group (p = 0.01), demonstrating an efficient diagnostic yield in the ILR group, with a risk ratio (RR) (in favour of ILR) of 0.26, 95% CI 0.089 to 0.76 (p = 0.01) (Table 2). The arrhythmias diagnosed in both groups are shown in Table 3. There were no significant symptomatic arrhythmias seen in four (28.5%) patients in the ILR group and in 13 (81.3%) in the conventional group. The time course of detection of arrhythmia in the ILR group were none in the first 3 months, 2 (14.3%) in 3–6 months, 4 (28.6%) in 6–9 months and 4 (28.6%) beyond 9 months. In the conventional group, one (6.3%) diagnosis was made at 6 months of extended Holter test, while two (12.5%) were made at 15 months of evaluation. The efficacy of ILR in diagnosing arrhythmias as compared to conventional workup as seen in our study was compared with other studies in the form of the risk ratio of non-events and has been represented in the Forest plot in Fig. 2.
Table 2.
Comparison of outcomes at the end of follow-up period.
| Diagnosis n (%) | No diagnosis n (%) | p value | |
|---|---|---|---|
| ILR group (n = 14) | 10 (71.42%) | 04 (28.58%) | RR (non-event) = 0.26 95%CI (0.089–0.76) p = 0.01 |
| Conventional group (n = 16) | 03 (18.75%) | 13 (81.25%) |
Table 3.
ECG correlation with events.
| ILR group (n = 14) n (%) | Conventional group (n = 16) n (%) | |
|---|---|---|
| Total diagnosis of events | 10 | 03 |
| Supraventricular Tachycardia | 03 (30%) | – |
| Atrial Fibrillation | 02 (20%) | 01 (33.3%) |
| Ventricular premature complexes | 02 (20%) | 01 (33.3%) |
| VPCs with bigeminy | 01 (10%) | 01 (33.3%) |
| Bradycardia with asystole (10 s) | 01 (10%) | – |
| Ventricular tachycardia | 01 (10%) | – |
Fig. 2.
Forest plot depicting the efficacy of ILR in diagnosing arrhythmias among different studies.
The patients who had positive ILR recording of arrhythmias were followed up and electrophysiological studies/appropriate treatments were performed for these patients. Two patients of SVT had atrioventricular re-entrant tachycardia (AVRT) with concealed pathway, one patient had atypical atrioventricular nodal re-entrant tachycardia (AVNRT), the patient with a record of ventricular tachycardia had right ventricular outflow tract VT, which was also successfully ablated, and the patient who had syncope and recorded bradycardia with prolonged asystole underwent successful placement of a dual-chamber pacemaker. One patient in the ILR group, who had no documented arrhythmias in the follow-up period, had one documented episode of seizure-like activity, and was subsequently started on anti-epileptics.
Discussion
The primary outcome of a diagnosis of infrequent arrhythmias in young patients with a structurally normal heart with unexplained palpitations or syncope was achieved in a significantly higher number of patients with the use of ILR as compared to the conventional Holter monitoring.
Over the last two decades, ILR has been compared to conventional strategies in the evaluation of unexplained syncope among different populations and has uniformly shown better outcomes. Krahn et al7 demonstrated yield of ILR in 52% vs 20% (p = 0.012) among 66 patients with one-year monitoring while Farwell et8 of the Early alve replacement in severe ASYmptomatic Aortic Stenosis (EASY-AS) trial showed 33% of ILR vs 4% of the conventional group (p < 0.0001) had an appropriate diagnosis in 201 patients. The FRESH study demonstrated that in a population without any underlying heart disease, ILR was diagnosed accurately in 46% of patients, compared to 5% in conventional evaluation.9 In the International Study on Syncope of Uncertain Etiology (ISSUE) study, ILR implantation provided ECG correlation with symptoms in 23–28% of patients with structurally normal hearts.10 Compared to these studies, our study has shown a higher diagnosis of symptom-related arrhythmias due to significantly better follow up in both groups and also that these patients were completely evaluated prior to inclusion in the study to rule out other non-cardiac causes and exclude structural heart disease.
The diagnostic utility of ILR in our study was 71.4% over a period of one year follow up. This is in concordance with the RUP study (recurrent unexplained palpitations study) where ILR was compared over conventional evaluation of Holter and event recorder monitoring and EPS in the evaluation of a small cohort of patients with infrequent palpitations, and showed a high diagnostic yield (73% vs 21%) with ILR.11
In the Cochrane meta-analysis, 579 patients from four randomised studies were analysed with a mean follow up period ranging from 12 to 20 months. The primary outcome of all-cause mortality did not differ between the patients who were implanted ILR compared to those who were managed conventionally. The aetiological diagnoses showed a highly significant difference between the two groups crediting the use of ILR, without notable heterogeneity (137/292 vs 36/287; RR (in favor of ILR) 0.61, 95% CI 0.54 to 0.68).12 We also report similar findings with an RR of 0.26 (95% CI 0.089–0.76), indicating the advantage ILR offers in the early diagnoses of unexplained syncope or palpitations.
In the prospective randomised single centre Eastbourne Syncope Assessment (EaSyAS II) trial, 246 patients either underwent ILR implantation or conventional management, with or without syncope clinic monitoring in both groups. This study clearly demonstrated that ILR enabled early diagnosis (mean 95 days) (HR 35.54,95% CI (4.84–261.01, p = 0.0004), higher rates of pacemaker implantation (22.4% vs 3.3%, p < 0.001) and lesser incidence of subsequent episodes of syncope during follow up (HR 0.38,95% CI 0.17–0.86,p = 0.02), as compared to the conventional group.13
The mean age group in our study was around 31 years. In the Cochrane analysis of four studies of ILR, the mean ages ranged between 66 and 74 years.12 This difference is primarily due to the inclusion criteria of the present study to diagnose unexplained syncope or palpitations in this specific population. Our population also consisted of more than 75% males, while in the Cochrane study, the range of males was between 40% and 55%.12 The higher proportion of males in our study is explained by the fact that this tertiary care cardiac centre caters to serving personnel of the Indian Armed forces, hence with more representation.
In our study, the most common arrhythmia leading to unexplained recurrent symptoms of syncope or palpitations was narrow complex tachycardia (21%), which is in contrast to several studies that demonstrated bradycardia with asystole/sinus pause as a common cause of syncope (22%–70%) followed by complete heart block (5.9%–10.4%).14,15 This could be due to our cohort that presented with syncope preceded by palpitations. In patients with palpitations alone, ILR detected atrioventricular nodal reentrant tachycardia (AVNRT) in 16.7%, atrial fibrillation (AF) in 16.7%, complete heart block (CHB) in 12.5%, and ventricular tachycardia in 8.3% cases.14 Our study has comparable differentiation of various arrhythmias; however, sinus node dysfunction and CHB were less in incidence because our study involved the younger population. Narrow complex tachycardia, such as AVRT and AVNRT, can also cause syncope if the ventricular rates are very high. Syncope in AF, especially in paroxysmal AF, can be due to prolonged bradycardia during the recovery period or in vagally mediated AF or when associated with WPW syndrome with the concealed pathway.16
The duration of palpitations in our study was around two years in both groups, while in the RUP study, the duration of symptoms was 30 (15–66) and 44 (15–100) months (median, IQR).11 The duration of syncope in our study patients was 5.75 (2.98) and 4.67 (2.87) months (Mean + SD), while the duration of symptoms of syncope in the study by Farwell et al was 12–18 months.8 This is due to the fact that the clientele involved in our study have easily accessible medical facilities where they are encouraged to report symptoms and then are worked up extensively. The follow-up period in our study was 11.7 ± 2.4 and 13.5 ± 1.1 months in the two groups, respectively, which is comparable to almost all the studies to provide reliable and comparable results.7,8
The failure rate of implantation of ILR in the present study is 6.7%, due to device infection. The literature mentions a risk of pocket site infections, either during the peri-implantation period or during follow up of around 1%–5%, which may necessitate explantation of the device.17 Other common complications as seen by a retrospective analysis were implant site infection (1.5%), non-infectious implant site pain requiring device explantation/pocket revision (1.5%), hypertrophic scar (0.2%) and device malfunction (0.2%).15 These complications were not seen in our study follow up.
This study further reiterates the role of implantable loop recorders as a supplementary and superior addition to the armamentarium of investigations in achieving a diagnosis in suspected cases of cardiac arrhythmias that are transient and could not be recorded in routine surface ECG during emergency visits, in patients with structurally normal hearts with unexplained recurrent syncope and palpitations.
Study limitations
Our study focused on highly selective patients, young and with structurally normal hearts. Thereby, the relatively small sample size may not be adequate to generalise the results to the general population with unexplained palpitations or syncope, particularly those with frequent symptoms, or with structural heart disease. Given the possible placebo effect of invasive procedures in the ILR arm, the open-label structure of the study is considered a limitation.
Conclusion
Thus, in young individuals with unexplained syncope or palpitations, ILR demonstrates a higher yield in the accurate diagnosis of arrhythmia compared with conventional Holter strategy, resulting in better management.
Disclosure of competing interest
The authors have none to declare.
Acknowledgements
This paper is based on Armed Forces Medical Research Committee Project No. 4609/2015 granted and funded by the office of the Directorate General Armed Forces Medical Services and Defence Research Development Organization, Government of India.
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