The benefit of a remotely monitored implantable loop recorder as a first line investigation in unexplained syncope: the EaSyAS II trial

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1 Europace (216) 18, doi:1.193/europace/euv228 CLINICAL RESEARCH Electrocardiology and risk stratification The benefit of a remotely monitored implantable loop recorder as a first line investigation in unexplained syncope: the EaSyAS II trial Neil Sulke 1 *, Conn Sugihara 1, Paul Hong 1, Nik Patel 1, and Nick Freemantle 2 1 Cardiology Research Department, Eastbourne General Hospital, Kings Drive, East Sussex Healthcare NHS Trust, East Sussex BN21 2UD, UK; and 2 Department of Primary Care and Population Health, University College London, London, UK Received 14 October 214; accepted after revision 26 May 215; online publish-ahead-of-print 12 October 215 Aims This prospective randomized controlled study evaluated the first-line use of a novel remotely monitored implantable loop recorder (ILR) in the initial investigation of unexplained syncope, and compared this to conventional therapy and a dedicated Syncope Clinic (SC).... Methods A total of 246 patients (mean age 7.3 years) were randomly allocated to conventional management, SC alone, ILR and results alone, or SC + ILR. Median follow-up was 2 months (IQR months). Time to electrocardiogram (ECG) diagnosis was significantly shorter with ILR alone vs. conventional [hazard ratio (HR) 35.5, P ¼.4] and with SC vs. conventional (HR 25.6, P ¼.2). Seventy-four per cent of first syncopal events documented in the SC groups occurred during provocative tilt testing. Twenty-two per cent of patients who received an ILR were found to have a bradycardia indication for permanent pacing, compared with 3% of patients who did not. Overall, more investigative tests were undertaken in the conventional group than in any other. Only patients who received an ILR had a significant increase in time to second syncope (P ¼.2), suggesting successful diagnosis and management of treatable causes of syncope.... Conclusions Implantable loop recorder monitoring achieved a more rapid diagnosis in unexplained syncope than usual care. Conventional management of syncope failed to achieve an ECG diagnosis despite a large number of investigative tests. Syncope Clinic and provocative tilt testing delivered a rapid ECG diagnosis, but did not prevent recurrent syncope. Implantable loop recorders offered rapid diagnosis, increased the likelihood of syncope being reported, demonstrated a high rate of intermittent bradycardia requiring pacing, and reduced recurrent syncope Keywords Syncope Implantable loop recorder Introduction Syncope is a common and debilitating condition. 1 Many patients who present with syncope can be diagnosed on the basis of a thorough history, clinical examination, and electrocardiogram (ECG). However, in patients with unexplained syncope, the diagnosis relies upon ECG evidence at the time of symptoms. Conventional Holter monitoring and external loop recorders are recognized to have low diagnostic yield. 2,3 Futile investigations and recurrent hospitalizations in these patients have significant health economic consequences. 4 6 Patients with implantable loop recorders (ILRs) are more likely to achieve an ECG diagnosis, 7 and consequently have a better clinical outcome 8 than those investigated with intermittent monitors. However, conventional ILRs achieve a diagnosis in the minority of individuals with syncope. 2 Previous studies have documented that up to 47% of syncopal events go unreported. 3,7 The Sleuth (Transoma Medical Inc., St Paul, MN, USA) device is a remotely monitored ILR, which automatically uploads all patient activations immediately. This is interpreted at a monitoring centre, and all events are notified to the responsible clinician. This allows the direct care team to contact the patient promptly and establish the nature of any associated symptoms. In clinical practice, there is heterogeneity in the expertise of clinicians assessing patients with syncope. Studies have demonstrated the efficacy of a dedicated Syncope Clinic (SC) in the management of patients with unexplained syncope. 5,6 The aim of this study was to evaluate the use of a remotely monitored ILR 9 as a first-line investigation for syncope, compared with * Corresponding author. Tel: ; fax: address: neil.sulke@nhs.net Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 215. For permissions please journals.permissions@oup.com.

2 Benefit of a remotely monitored implantable loop recorder 913 What s new? Investigation with a remotely monitored ILR resulted in a more rapid diagnosis of unexplained syncope. Treatment based on ECG diagnoses achieved with ILR monitoring reduced the rate of recurrent syncope. conventional management. The additional effect of a dedicated SC was also investigated. The primary study hypothesis was that remotely monitored ILRs would significantly reduce the time to ECG diagnosis when compared with patients who did not have an ILR. In a secondary analysis, the effect of a dedicated SC was examined. The time of ECG diagnosis was defined as the first time when a patient suffered syncope with a concurrent ECG after study randomization. Secondary outcomes included time to first and second post-randomization syncope, and time to ECG-directed therapy. Methods The second Eastbourne Syncope Assessment (EaSyAs II) trial was a prospective randomized study conducted in a single centre in the UK. Recruitment took place between August 27 and December 28. Patients enrolled presented to the emergency department, to general practitioners in the community as well as to medical, surgical, and orthopaedic wards with a diagnosis of recurrent syncope. Inclusion and exclusion criteria are shown in Figure 1. The study received approval from the national ethics committee and local institutional review board. Written, informed consent was obtained for all trial subjects. All patients had clinical review, cognitive function tests, postural blood pressure, blood tests, and ECG performed. Patients were then randomized into one of four possible groups via computer-generated random number tables: (1) Implantable loop recorder group (ILR) immediate implant of the ILR without hospital admission with remote monitoring activated. All patients attended again 1 week later for wound review. (2) Implantable loop recorder and Syncope Clinic group (ILR + SC) immediate implant of the ILR as above, with attendance at a dedicated SC for follow-up within 2 weeks. (3) Syncope Clinic group (SC) patients were all referred to a dedicated SC with attendance for follow-up within 2 weeks. (4) Conventional group (CONV) patients were managed routinely by the referring physician. These patients were followed-up with complete hospital and general practitioner record review. In addition, all patients underwent three monthly telephone questionnaires, and were encouraged to contact the researchers as soon as possible in the event of syncope. 15 patients screen failed Syncope presenting to emergency department; general practitioners; medical, surgical or orthopaedic wards 396 patients screened 246 randomized Inclusion criteria Age >16 >2 undiagnosed syncopal episodes in last 24 months Normal FBC, U&Es, glucose Exclusion criteria High grade atrioventricular block Significant cognitive impairment Additional pathology requiring admission Remotely monitored ILR implanted without hospital admission Wound review at 1 week No ILR implanted Implantable loop recorder only (ILR) n =66 ILR + Syncope Clinic (ILR + SC) n =59 Syncope Clinic (SC) n =6 Conventional management (CONV) n =61 Follow-up based on ILR-detected arrhythmias/events Specialist outpatient review within 2 weeks of syncope Specialist outpatient review within 2 weeks of syncope Standard investigation and management by admitting physician Figure 1 Study flow chart and inclusion/exclusion criteria.

3 914 N. Sulke et al. Syncope clinic The dedicated SC was jointly run by cardiologists and elderly care physicians. This included a review of the syncope history, postural blood pressure measurements, and blood tests (urea and electrolytes, renal function, thyroid function). Other investigations including computed tomography (CT) or magnetic resonance imaging (MRI), external loop monitoring, echocardiography, electrophysiological study, and standard implantable loop recorder implantation were available. Where appropriate, rapid onward referral to other specialities, including the Falls Prevention Service, was instituted. All patients randomized to attend the Syncope Clinic (SC and ILR + SC) were offered tilt testing. Tilt testing Head-up tilt (HUT) testing was conducted according to the Italian protocol. 1 Continuous beat-to-beat blood pressure and transthoracic impedance measurements were recorded (CNSystems). Carotid sinus massage was undertaken prior to the start of tilt testing. The test was considered positive if the patient experienced syncope with haemodynamic compromise and diagnosis made according to the modified VASIS criteria. 11 Implantable loop recorder implant and functionality All patients randomized to the ILR and ILR + SC groups had an ILR implanted on the same day as randomization where possible. This was performed by a cardiologist or senior emergency clinician, and the patient wasdischargedhomethesameday.thedeviceusedwasthesleuth (Transoma Medical Inc.). The Sleuth device memory was 2 min, with the activator capable of storing up to 1.5 h of data without requiring upload. The activator, a separate hand-held unit, wirelessly interfaced with a fixed transmission unit in the patients homes to effect data transfer. Scheduled upload occurred every 6 h. All patient activations were uploaded immediately. All data were analysed by a monitoring centre with expert clinician review (Mednet Healthcare Technologies Inc, Ewing, NJ, USA). Any arrhythmia with a heart rate.15 b.p.m. or,6 b.p.m., or pause.2 s was notified to the investigators. Alerts were relayed immediately to the investigators via phone, , and short messaging service (SMS). Statistical analysis We estimated that a trial with 234 subjects, randomized 1:1, with a 4% ECG diagnosis rate in the control group, and assuming the a of 2.5% to account for two primary outcomes, would have 9% power (1 b) to find a hazard ratio (HR) of 5.2 to be statistically significant, with a study wide event rate of 28 ECG diagnoses. Power calculations were based on a primary comparison between patients with or without ILRs. All other reported comparisons are pre-specified secondary analyses. Time to event data were described using Kaplan Meier product limit curves, and heterogeneity in the treatment effect across the time to event data was analysed using Cox proportional hazard models. A P-value of,5% was considered significant. Results Between August 27 and December 28, 396 patients were screened for enrolment. A total of 246 patients (99 male, mean age + SD 7.3 years +18) met the inclusion criteria and were recruited into the study (Table 1). All patients were followed-up for a minimum of 12 months. Final study census was the 18 December 29. Five patients withdrew from the study following enrolment. Four declined to accept ILR implantation. One patient required regular MRI scans for surveillance of a benign brain tumour, so declined the ILR despite the fact that the Sleuth is MR-conditional. One patient requested to have his ILR explanted at 8 months due to intolerance. There were no implant-related complications. Twenty-three patients (18%) required telephone assistance for ILR base station set-up, and 17 (13%) required home visits to help with installation of the base station to their analogue phone lines. Median follow-up time was 2.4 months (IQR 15 27). Primary outcome: time to electrocardiogram diagnosis In total, 62 of 125 ILR patients (5%) achieved an ECG diagnosis within a mean of 95.2 days post-randomization. This compares Table 1 Patient demographics Conventional SC ILR ILR 1 SC P-Value for management difference n Male (%) 29 (47.5%) 23 (38.3%) 25 (37.9%) 22 (37.3%) NS Mean age (SD) 73. (14.6) 63.9 (22.7) 72.1 (16.7) 72. (16.2) NS Ischaemic heart disease NS Diabetes (%) 12 (19.7%) 5 (8.3%) 8 (12.1%) 9 (15.3%) NS Hypertension (%) 3 (49.2%) 21 (35.%) 3 (45.5%) 22 (37.3%) NS Chronic obstructive Pulmonary disease (%) 5 (8.2%) 1 (1.7%) 7 (1.6%) 2 (3.4%) NS Epilepsy (%) 1 (1.6%) 2 (3.3%) 5 (7.6%) 4 (6.8%) NS Aspirin (%) 31 (5.8%) 21 (35.%) 31 (47.%) 23 (39.%) NS Clopidogrel (%) 6 (9.8%) 6 (1.%) 4 (6.1%) 5 (8.5%) NS Beta-blocker (%) 2 (32.8%) 12 (2.%) 13 (19.7%) 1 (17.%) NS ACE inhibitor (%) 21 (34.4%) 9 (15.%) 2 (3.3%) 17 (28.8%) NS ARB (%) 7 (11.5%) 6 (1.%) 7 (1.6%) 7 (11.9%) NS Statin (%) 26 (42.6%) 15 (25.%) 28 (43.1%) 23 (39.%) NS ACE, Angiotensin converting enzyme; ARB, Angiotensin receptor blocker; NS, Non significant.

4 Benefit of a remotely monitored implantable loop recorder 915 Table 2 Frequency of ECG diagnosis Conventional management SC ILR ILR 1 SC Total n Number of patients with ECG diagnoses (%) 1 (1.6) 2 (33.3) 29 (43.9) 33 (55.9) 83 (33.7) with only 21 of 121 patients (17%) without ILRs who achieved an ECG diagnosis (P,.1). The ILR + SC group achieved the highest ECG diagnostic yield with 33 of 59 patients (55.9%) followed by the ILR group with 29 of 66 patients (43.9%). Within the ILR + SC group, ECG diagnosis was made in 28 of 59 (47.5%) patients based on both continuous monitoring during HUT and Sleuth data, with correlation between both modalities in all cases. Five ILR + SC patients had spontaneous events detected by their ILRs. Of the 2 (33.3%) ECG diagnoses from the SC group, 18 were achieved during HUT, and 2 on standard external monitoring. One conventionally managed patient achieved ECG diagnosis on 24-h Holter monitoring (Table 2). In total, 13 of 62 patients (21.%) who received an ILR and had an ECG diagnosis demonstrating sinus rhythm during syncopal events, enabling an arrhythmic cause to be excluded. There was a significantly shorter time to ECG diagnosis for ILR patients compared with conventionally managed patients [HR 35.54, 95% confidence interval (CI) , P ¼.4] (Figure 2). In addition, SC patients also achieved a significantly shorter time to ECG diagnosis when compared with CONV patients (HR 25.58, 95% CI , P ¼.2). However, 18 of 2 (9%) ECG diagnoses in the SC group were achieved during provoked syncope on HUT. Electrocardiogram-directed therapy All patients with a positive HUT and a diagnosis of reflex syncope were offered lifestyle modification advice. Tilt training and medication were advised at follow-up if required. In addition, nine patients received pacemakers for carotid sinus hypersensitivity or asystolic pauses.3 s on HUT. In total, 32 pacemakers were implanted and 4 patients underwent electrophysiological studies and radiofrequency ablation (see Table 3). Twenty-eight of 125 (22.4%) patients who received an ILR required insertion of a permanent pacemaker, significantly more than the 4 of 121 (3.3%) patients who did not have an ILR (P,.1). Secondary outcomes: time to first post-randomization syncope Time to first post-randomization syncope was significantly less in all groups combined compared with the conventionally managed group (P,.1) (Figure 3). Twelve patients (19.6%) in the CONV group reported syncopal events during the follow-up, compared with 24 (4%) in the SC group, 29 (43.4%) in the ILR group, and 33 (55.9%) in the ILR + SC group. However, per protocol, a provoked syncopal event on HUT could be considered the first post-randomization syncope. Proportion of patients without ECG diagnosis (%) Time to ECG diagnosis 3 6 Days from randomization Eighteen of 29 (62.1%) patients in the SC group, and 28 of 33 (84.8%) patients in the ILR + SC group had their first syncopal event documented on HUT. Secondary outcomes: time to second post-randomization syncope Implantable loop recorder patients were less likely to have a second post-randomization syncope compared with conventionally managed patients (HR.38, 95% CI.17.86, P ¼.2) There was no significant difference in time to second syncope between CONV and SC patients (Figure 4). Ten of 61 CONV patients (16.4%) suffered second syncopal events during the follow-up. In the SC group, 1 of 6 patients (16.7%) also had second post-randomization syncopes. Six of 66 (9.1%) ILR patients suffered second syncopal events. One already had a pacemaker in situ for 2:1 atrioventricular block (pacing check revealed normal function and the absence of arrhythmia). The remaining five patients had previously had sinus rhythm detected during syncope. One was diagnosed with epilepsy and was subsequently medically treated. Another was diagnosed with pseudo-syncope and referred for psychiatric assessment. Two of 59 (3.4%) ILR + SC patients suffered second syncopal events; both had diagnoses of reflex syncope on HUT. Investigations per randomized group CONV SC ILR ILR + SC CONV vs SC P =.2 CONV vs ILR P =.4 Figure 2 Time to ECG diagnosis in all the four groups. Investigations requested for syncope management are presented in Table 4. Overall, more investigations were ordered in those managed conventionally than those investigated in SC or with an ILR. 9

5 916 N. Sulke et al. Table 3 Electrocardiogram-directed therapy Conventional SC ILR ILR 1 SC P-Value for management difference n Invasive interventions Permanent pacemaker (PPM) insertion ,.1 [PPM for symptomatic bradycardia,4 b.p.m.] [] [] [5] [6] [PPM for intermittent atrioventricular block] [1] [3] [8] [9] Electrophysiology study + ablation 2 2 NS Total invasive interventions (%) 1 (1.6%) 3 (5.%) 15 (22.7%) 17 (28.8%),.1 Non-invasive interventions Specialist referral 1 1 NS Medication adjustment Lifestyle modification and counter-measures Total non-invasive interventions (%) 15 (24.6%) 22 (36.7%) 11 (16.7%) 17 (28.8%) NS Total interventions (%) 16 (26.2%) 25 (41.7%) 26 (39.3%) 34 (57.6%).6 Proportion of patients without first syncope (%) Time to first post-induction syncope CONV SC ILR ILR + SC P <.1 CONV vs the rest Proportion of patients without first syncope (%) Time to second post-induction syncope ILR + SC ILR SC CONV ILR vs CONV P =.2 Syncope clinic vs CONV P = Days from randomization Days from randomization 9 Figure 3 Time to first post-randomization syncope. Figure 4 Time to second post-randomization syncope. Discussion This is the first randomized study comparing the efficacy of a remotely monitored ILR and/or SC with conventional management for recurrent unexplained syncope. All patients with diagnosis for their syncope at presentation (e.g. persistent bradycardia and severe aortic stenosis) were excluded. Patients with recurrent unexplained syncope pose the greatest diagnostic and therapeutic challenge for clinicians. Primary and secondary endpoints The primary endpoint was time to ECG diagnosis. An initial diagnostic approach focussing on investigating arrhythmias has been shown to have high yield. 12 An ECG at the time of syncope allows for a definitive diagnosis and appropriate management. This study found that patients with unexplained syncope who underwent HUT were more likely to have an ECG diagnosis of neurally mediated syncope than those managed conventionally. Patients who had ILRs were more likely to have an ECG diagnosis of bradycardic syncope. This was unexpected given the randomized nature of the study design: the observed prevalence of arrhythmic and neurocardiogenic syncope should have been similar in all groups. The time to second syncope highlights the therapeutic effect of management decisions. Without an ECG diagnosis, only empiric therapy is feasible in unexplained syncope. After an ECG diagnosis is made, the management plan is modified by this new information. The ISSUE 3 trial demonstrated that even in neurally mediated syncope, permanent pacemakers are effective in reducing syncope. 13 Successful interventions based on an ECG diagnosis should increase the time to second syncope. 8,13,14 In patients who reported a second syncopal event, only subjects who received an ILR had a significant increase in the time to second syncope. However, patients managed by the SC had no significant therapeutic effect detected. Conventional management Patients managed conventionally had poor outcomes, with only one (3.3%) patient achieving an ECG diagnosis, in spite of more investigative tests being performed on this group than any other. Patients

6 Benefit of a remotely monitored implantable loop recorder 917 Table 4 Investigations ordered for unexplained syncope Conventional management SC ILR ILR 1 SC 24 h Holter External loop recorder 25 2 ILR 1 N/A N/A Tilt tests h blood pressure monitor 2 Echocardiogram Stress echocardiogram 3 Myocardial perfusion scan Exercise tolerance test CT angiogram 1 Coronary angiogram 1 2 Carotid Doppler 3 2 CT head MRI head 7 1 Electromyogram 1 Electroencephalogram 2 1 Sleep studies 1 Total randomized to this group also had a significantly longer time to first reported syncope than any other group. This is most likely due to under-reporting of syncope in the CONV group. Forty-six of 119 (38.7%) patients randomized to attending SC had their first syncope documented during HUT, when an investigator was present to document the symptoms. It is not surprising that the time to first detected syncope was shorter in this group than in the conventionally managed group. All 29 of 66 (43.9%) patients in the ILR group reported spontaneous syncope. This was both significantly more likely and occurred more quickly than in the conventionally managed group. However, the Sleuth ILR had the advantage of rapid detection, transmission, and analysis. This meant that investigators were able to contact the patient within 24 h of an arrhythmia (such as asystole) occurring. This increased the likelihood that syncope would be reported. It appears that the vast majority of spontaneous syncopal events went unreported in the conventional management group. Furthermore, the time to second syncope, a surrogate measure for the efficacy of initial medical intervention, was very poor in the conventionally managed group. Similar findings have previously been reported. 7 Remotely monitored implantable loop recorder The Sleuth ILR proved to be safe and effective for use in patients with recurrent unexplained syncope. It was implanted by cardiologists and emergency physicians, avoiding hospital admission, without complication. Immediate insertion of an ILR at the time of presentation with recurrent unexplained syncope is feasible in standard clinical practice. Patients who had an ILR had a significantly shorter time to ECG diagnosis than those managed conventionally. Overall, the ILR detected a bradycardia pacing indication in 22% of this population. Following pacemaker implantation, there was a significantly longer time to second syncope, demonstrating the therapeutic benefit of this intervention. Patients who did not receive an ILR had no significant therapeutic benefit observed. Only 3% of these patients were found to have a bradycardia indication for pacing. The high proportion of bradycardia detected in the ILR subgroups suggests that many patients who did not receive an ILR had an undiscovered bradycardic aetiology for their syncope. Conventional investigation and SCs appear to underestimate the prevalence of bradycardic syncope amenable to cardiac pacing. Syncope Clinic Syncope Clinics offer streamlined, specialist, outpatient assessment, and management for patients with unexplained syncope. Subjects randomized to attend SC had a significantly shorter time to ECG diagnosis and fewer investigations than those managed conventionally. However, the majority (74%) of first ECG diagnoses documented in this group was during provoked syncope on HUT. It is not clear that provoked syncope on HUT is equivalent to the spontaneous recurrent syncope that resulted in initial presentation. In our study, patients seen in SC were less likely to receive a diagnosis of arrhythmic syncope, more likely to be managed conservatively, and less likely to receive a pacemaker than patients who had an ILR. There was no observed effect on time to recurrent syncope seen in patients managed in SC compared with conventional management. Syncope Clinic has been shown to be cost-effective in previous studies. 5,6 However, although SC was comparable

7 918 N. Sulke et al. with ILR for achieving an ECG diagnosis, we did not show that SC resulted in similarly effective therapies. Study limitations Head-up tilt-induced syncope may not be the same as the clinical syncope resulting in patient presentation. In this study, SC management was strongly influenced by the results of HUT testing. No improvement in symptoms was seen in patients whose management was directed by this investigation. This may reflect the limitations of HUT testing, rather than the concept of SC in general. Further research is required to distinguish whether SC with or without HUT is beneficial. In common with all similar studies with long follow-up, it is the case that ILR technology has rapidly evolved since the inclusion of the first patient in this study. The cost-effectiveness of the various management strategies tested in this study has not been assessed and is the subject of ongoing study. Conclusions Conventional management of syncope resulted in largely ineffective over-investigation. More than one in seven patients managed conventionally continued to report recurrent syncope during follow-up. The SC significantly reduced the time to ECG diagnosis, which was mainly driven by diagnoses made on provocative tilt testing. Syncope Clinic offered consistent, streamlined care in an expert outpatient setting, and utilized fewer unnecessary investigations. Patients seen in SC were more likely to have a diagnosis of neurally mediated syncope and less likely to have interventional therapy. However, SC-based management was not shown to reduce the incidence of recurrent syncope. The remotely monitored ILR proved safe and straightforward to use in an urgent care setting. Patients with this type of ILR were contacted rapidly after arrhythmias were detected, and so were significantly more likely to report recurrent syncope. Implantable loop recorder-based management had a higher rate of pacemaker insertion, and a significant reduction in recurrent syncope compared with conventional or SC management. This study shows that a remotely monitored ILR implanted as soon as possible following a recurrent syncopal episode is the investigation of choice to improve the management of patients with unexplained syncope. Acknowledgements The authors would like to thank Mr Utham Shanker and Mr Salim Shubber for their data collection and device implant from Accident and Emergency Department, Eastbourne Hospital, East Sussex Healthcare NHS Trust, UK. They also are grateful to Jacqueline Hunt for her data collection and analysis from Cardiology Research Department, Eastbourne Hospital, East Sussex Healthcare NHS Trust, UK. Funding This study was part funded by an unrestricted grant from Transoma Medical Inc. The majority of funding was from the Eastbourne Cardiology Research Charity Fund. Conflict of interest: none declared. References 1. Management of Transient Loss of Consciousness: National Institute for Health and Clinical Excellence Guideline. Ann Intern Med 211;155:I. 2. Brignole M, Vardas P, Hoffman E, Huikuri H, Moya A, Ricci R et al. Indications for the use of diagnostic implantable and external ECG loop recorders. Europace 29;11: Krahn AD, Klein GJ, Yee R, Takle-Newhouse T, Norris C. Use of an extended monitoring strategy in patients with problematic syncope. Circulation 1999;99: Sun BC, Emond JA, Camargo CA. Direct medical costs of syncope-related hospitalizations in the United States. Am J Cardiol 25;95: Kenny RA. Impact of a dedicated syncope and falls facility for older adults on emergency beds. Age Ageing 22;31: Brignole M. Standardized-care pathway vs. usual management of syncope patients presenting as emergencies at general hospitals. Europace 26;8: Farwell DJ, Freemantle N, Sulke AN. Use of implantable loop recorders in the diagnosis and management of syncope. Eur Heart J 24;25: Farwell DJ, Freemantle N, Sulke N. The clinical impact of implantable loop recorders in patients with syncope. Eur Heart J 26;27: Paruchuri V, Adhaduk M, Garikipati NV, Steinberg JS, Mittal S. Clinical utility of a novel wireless implantable loop recorder in the evaluation of patients with unexplained syncope. Heart Rhythm 211;8: Moya A, Sutton R, Ammirati F, Blanc J-J, Brignole M, Dahm JB et al. Guidelines for the diagnosis and management of syncope (version 29): The Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology (ESC). Eur Heart J 29;3: Brignole M. New classification of haemodynamics of vasovagal syncope: beyond the VASIS classification Analysis of the pre-syncopal phase of the tilt test without and with nitroglycerin challenge. Europace 2;2: Moya A, Garcia-Civera R, Croci F, Menozzi C, Brugada J, Ammirati F et al. Diagnosis, management, and outcomes of patients with syncope and bundle branch block. Eur Heart J 211;32: Brignole M, Menozzi C, Moya A, Andresen D, Blanc JJ, Krahn AD et al. Pacemaker therapy in patients with neurally mediated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial. Circulation 212;125: Brignole M. Early application of an implantable loop recorder allows effective specific therapy in patients with recurrent suspected neurally mediated syncope. Eur Heart J 25;27: