Diagnostic Yield of an Ambulatory Patch Monitor in Emergency Department Syncope Patients Unexplained After Emergency Department Evaluation: A Pilot Study (PATCH-ED)
Phase: NA
Conditions: Syncope
Sponsor: NHS Lothian

 
 
 
 
 
 
 
 
PATCH-ED 
  
 
 
 
 
Diagnostic yield of an ambulatory patch monitor in 
Emergency Department syncope patients unexplained 
after Emergency Department evaluation – a pilot study 
 
 
 
 
 
Version: 1.3 
 
Date: 02/04/2015 
 
 
 
 
 

 
 
 
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Diagnostic yield of an ambulatory patch monitor in Emergency 
Department syncope patients unexplained after Emergency Department 
evaluation – a pilot study (PATCH-ED). 
 
Sponsor: This study is sponsored by NHS Lothian. 
Funding: Applications will be made to Chest, Heart and Stroke Scotland and the Royal 
College of Emergency Medicine. Ambulatory patches will be provided by iRhythm 
Technologies, Inc. San Francisco, CA. BNP strips will be provided by Alere. 
Authorisations and Approvals: This study will be registered with the NIHR research 
portfolio. 
IRAS Project ID:  179127 
 
 
Chief Investigator:  
Dr Matthew Reed 
Consultant, NHS Career Research Fellow & Honorary Senior 
Lecturer in Emergency Medicine.  
Emergency Medicine Research Group Edinburgh (EMeRGE), 
Department of Emergency Medicine,  
Royal Infirmary of Edinburgh,  
51 Little France Crescent, Edinburgh, EH16 4SA, UK. 
E-mail: matthew.reed@nhslothian.scot.nhs.uk 
 
Co-Investigator:   
Professor Alasdair Gray  
Professor of Emergency Medicine.  
Emergency Medicine Research Group Edinburgh (EMeRGE), 
Department of Emergency Medicine,  
Royal Infirmary of Edinburgh,  
51 Little France Crescent, Edinburgh, EH16 4SA, UK. 
E-mail: alasdair.Gray@nhslothian.scot.nhs.uk 
 
Co-Investigator:   
Dr Neil Grubb 
Consultant in Cardiology and Cardiac Electrophysiology. 
Department of Cardiology,  
Royal Infirmary of Edinburgh,  
51 Little France Crescent, Edinburgh, EH16 4SA, UK. 
E-mail: neil.grubb@nhslothian.scot.nhs.uk 
 
Co-Investigator:   
Dr Chris Lang 
Consultant in Cardiology and Cardiac Electrophysiology. 
Department of Cardiology,  
Royal Infirmary of Edinburgh,  
51 Little France Crescent, Edinburgh, EH16 4SA, UK. 
E-mail: chris.lang@nhslothian.scot.nhs.uk 
 
 
 

 
 
 
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Study Co-ordination 
 
Lead Research Nurse:  
Kirsty Simpson 
Emergency Medicine Research Group Edinburgh (EMeRGE), 
Department of Emergency Medicine,  
Royal Infirmary of Edinburgh,  
51 Little France Crescent,  
Edinburgh, EH16 4SA, UK. 
E-mail: Kirsty.Simpson@nhslothian.scot.nhs.uk 
 
Statistician:  
 
Dr Christopher J. Weir 
 
 
` 
 
 
MRC Hub for Trials Methodology Research 
 
 
 
 
Centre for Population Health Sciences 
 
 
 
 
University of Edinburgh Medical School 
 
 
 
 
Teviot Place, Edinburgh EH8 9AG 
 
 
 
 
E-mail: Christopher.Weir@ed.ac.uk 
 
Contents 
Contents………………………………………………………………………………..… 3 
1.Short project summary……………………………………………………………..… 4 
2. Aims……………………………………………………………………………….…... 4 
3. Existing research……………………………………………………………….…..... 4 
Syncope……………………………………………………………………...…… 4 
Cardiac arrhythmia investigation……………………………………….……... 5 
Ambulatory patch monitoring………………………………………………...... 6 
Biomarkers……………………………………………………………………….. 7 
4. Research methods…………………………………………………………………… 8 
Study design…………………………………………………………………….. 8 
Study setting…………………………………………………………………….. 8 
Study population……………………………………………………………….... 8 
Inclusion criteria……………………………………………………………….… 8 
Exclusion criteria…………………………………………………………….….. 8 
Patient enrolment and consent…………………………………………….….. 8 
Data Collection………………………………………………………..……..….. 9 
Study assessments…………………………………………………….………. 10 
Ambulatory patch……………………………………………………….…..….. 11 
Study endpoints…………………………………………………………...……. 12 
Primary endpoint…………………………………………………………...…… 12 
Secondary endpoints……………………………………………………..…….. 12 
Data analysis and statistics……………………………………………….……. 13 
5. Research Governance……………………….……………………………………… 13 
6. Duration of study and Project timelines……………………….…………………… 13 
7. Project Management and oversight arrangements……………………………….. 14 
8. References……………………….…………………………………………………… 18 
 
 

 
 
 
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1. Short project summary: Syncope is a common Emergency Department (ED) 
presentation but the underlying diagnosis is not apparent in 60% of patients after 
assessment and serious adverse event rate is 7% at one month with most having acute 
cardiovascular events, also more likely to be unexplained after ED assessment. Many 
cardiovascular events are due to arrhythmia, difficult for clinicians to diagnose, as 
examination and Electrocardiogram (ECG) findings may both be normal and symptoms have 
resolved by the time the patient gets to the ED. Currently establishing a cardiac arrhythmia 
as the cause of syncope rests on correlating the arrhythmia with symptoms using monitoring 
devices such as Holter but these all have significant drawbacks. The clinical challenge in the 
ED is therefore to identify the moderate and high-risk patients and refer them for further 
investigation and monitoring if appropriate. The logistics of arranging follow up within a timely 
period of the patient’s ED visit is often problematic for a variety of reasons including 
availability of timely specialty outpatient appointments, a lack of consensus of the specialty 
to whom the syncope patient should be referred (cardiology, medicine, neurology, general 
practice) and availability of Holter and other monitoring devices. For this reason most high 
and medium risk patients are admitted to hospital.  
 
Previous syncope clinical decision rules have not been well adopted due to their lack of 
sensitivity and specificity probably due to the varied and heterogeneous nature of potentially 
serious causes. However, the majority of patients with syncope have no serious underlying 
pathology and do not require hospitalisation. Rather than continued attempts at risk 
stratification of outcome based on presentation, more research is required into how we can 
better improve diagnosis and therefore treatment in order to provide improved patient 
benefit. We believe that ambulatory patch monitoring will allow better and earlier arrhythmia 
detection and plan to assess the ability of a 14-day ambulatory patch to detect serious 
arrhythmic outcomes at 90 days.  
 
2. Aims: To investigate the diagnostic yield, prevalence of events, patient satisfaction, patch 
compliance and influence on subsequent treatment of an ambulatory patch monitor in ED 
syncope patients unexplained after ED evaluation – a pilot study. 
 
3. Existing research 
 
Syncope: There are around 650,000 ED syncope presentations a year in the UK [1]. 
Serious underlying conditions can present with syncope and one-month serious adverse 
outcome is around 7% [2] with 50% being cardiovascular [1,2]. The treating ED clinician is 
not always able to rule out serious pathology as the patient is commonly fully recovered on 
arrival in the ED, despite the underlying cause being potentially life threatening should it 
recur again. Whilst most patients do not have a serious underlying cause and therefore do 
not require hospitalisation, the concern of the ED clinician about missing a serious 
underlying cause (especially cardiovascular ones) means that 50% of syncope patients are 
admitted to hospital [1].  
 
Despite research identifying high-risk demographic, historical and examination variables, 
clinical decision rules [3-10] have not been well adopted due to their lack of sensitivity and 
specificity probably due to the varied and heterogeneous nature of potentially serious 

 
 
 
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causes. Rather than continued attempts at risk stratification of outcome based on 
presentation, more research is required into how we can better improve diagnosis and 
therefore treatment in order to provide improved patient benefit. 
 
Cardiovascular causes of syncope fall into two main categories, arrhythmia (e.g. ventricular 
tachycardia (VT), 2nd degree Mobitz II, 3rd degree AV Block or symptomatic bradycardia) 
and structural (e.g. aortic stenosis). It is arrhythmia that is most difficult for the ED clinician to 
diagnose in the ED as examination and presenting Electrocardiogram ECG may both be 
normal. It is for this reason that arrhythmia makes up a large number of subsequent serious 
outcomes in syncope patients whose syncopal cause is unexplained after ED assessment.  
 
The current main method for establishing a cardiac arrhythmia as the cause of syncope rests 
on the correlation of the arrhythmia with symptoms (which will have resolved by the time the 
patient gets to the ED). The clinical challenge in the ED is therefore to identify the moderate 
and high-risk patients and refer them for further investigation and monitoring if appropriate. 
The logistics of arranging follow up within a timely period of the patient’s ED visit is often 
problematic for a variety of reasons including availability of timely specialty outpatient 
appointments, a lack of consensus of the specialty to whom the syncope patient should be 
referred (cardiology, medicine, neurology, general practice) and availability of Holter and 
other monitoring devices. For this reason most high and medium risk patients are admitted to 
hospital. 
 
Cardiac arrhythmia investigation: The investigation of cardiac arrhythmias is usually 
initiated with the Holter monitor which uses a continuous recording over a 24 or 48-hour 
period. The Holter allows detection of baseline rhythm, arrhythmia and conduction 
abnormalities. Holters however are bulky and inconvenient for the patient to wear, the 
transmission of data is not patient dependent and non-compliance with both device use and 
maintaining a written symptom log, limits its diagnostic utility. The lack of extended 
monitoring reduces diagnostic yield to typically less than 20% [11]. Bass reported a 
diagnostic yield of 15% with 24-hour Holter monitoring that did not increase even if the 
device was applied for 72 hours [12].  
For these reasons, the use of Holter monitors is not universal in medium and high-risk 
syncope patients. In one UK ED study, only 158 of 540 (29%) admitted syncope patients 
underwent 24 hour monitoring (which in the majority comprised ward telemetry rather than 
Holter) [13]. There are other devices available to the Cardiologist to investigate syncope 
patients who are classified as European Society of Cardiology (ESC) medium and high-risk 
[14] and whose Holter investigation is unrevealing. Event recorders do not record a 
continuous ECG but require patient activation at the time of symptoms and must be applied 
to the chest wall at the time of the event and must be activated by the patient. A brief, 
typically 90-second, single lead ECG recording is captured and stored. Because of limited 
data storage capability, data must be transmitted to a monitoring centre for validation and 
analysis. Event recorders can be used for cardiac monitoring over longer periods of time but 
the big drawback is that they must be activated following symptom onset, which may be 
difficult to achieve if the patient has suffered syncope or an injury related to the event. 
Finally, these devices cannot be used to document asymptomatic arrhythmias. 
 

 
 
 
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External continuous loop recorders are attached to the patient by chest electrodes or a 
wristband. They continuously record the ECG but only save data if activated by the patient. 
The continuous looping memory feature allows the device to store a fixed length of pre-
activation and post-event ECG data. Mobile cardiac telemetry systems provide up to 30 days 
of real-time continuous cardiac monitoring without the need for patient activation or data 
transmission. These devices are expensive, require electrodes and bulky recording devices, 
and produce a large amount of data, which requires sifting. Implantable loop recorders are 
surgically implanted subcutaneous devices that continuously record single-lead ECG signal 
through 2 electrodes. They are very expensive and necessitate an invasive surgical 
procedure. For patients admitted to hospital and who are placed on telemetry, there is also 
lack of consensus on the optimal duration of monitoring. Typically higher risk patients are 
monitored for 24 hours and discharged without a diagnosis if their ECG tracing has been 
uneventful during this time period. 
 
Ambulatory patch monitoring: In order to solve these problems, a novel ambulatory 
cardiac monitoring device that can easily be applied to ED patients has recently been 
developed. The ZIO®XT Patch (iRhythm Technologies, Inc. San Francisco, CA; 
http://www.irhythmtech.com/zio-services.php) is non-invasive, water-resistant, has no leads 
or wires, is discrete to wear and has been approved for clinical use in the UK. It continuously 
monitors the heart for up to 14 days including during sleep, in the shower, and during 
moderate exercise and has a large button on top for patients to capture symptomatic events. 
When patients reach the end of their monitoring period, they simply mail the device back to 
the company where analysis is undertaken.  
 
The ZIO®XT Patch is well tolerated for prolonged monitoring and compliance is excellent 
with studies demonstrating a mean monitoring wear time of 10.8 days (range 4–14 days) 
[15] and 10.9 days (median 13.0 days) [16]. Barrett et al showed that 80% of patients who 
had worn a Holter monitor for 24 hours, and a ZIO®XT Patch for up to 14 days, preferred the 
ZIO Patch [17]. Single channel ECG data quality is also excellent with one study showing 
more than 98% of the total recording time was analysable [18], and a second study showing 
a median analysable time of 99% of the total wear time [19]. Compliance with returning the 
device is also good. In a study of 174 ED with indications for monitoring (syncope, dizziness 
and palpitations), all patients mailed back their devices [19].   
 
Several studies have shown that ZIO®XT Patch has a higher diagnostic yield for arrhythmias 
than traditional 24–48 hour Holter monitoring and importantly can also efficiently 
characterise symptomatic patients without significant arrhythmia. The absence of an 
arrhythmia during syncope, palpitations or a triggered event does not by itself provide a 
definitive diagnosis but does allow the clinician to exclude an arrhythmia as a potential cause 
and is thus clinically useful. Over half of patients (53.4%) in one study did not have an 
arrhythmia despite a triggered event. This allows the clinician to potentially exclude an 
arrhythmia as an etiology of the patient’s symptoms and potentially avoid further cardiac 
evaluation [19].   
 
Camm et al showed in a study on patients with ARVD, that over the total wear time of both 
devices, the ZIO®XT Patch detected more premature ventricular contraction events than a 

 
 
 
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24 hour Holter monitor [20]. Barrett et al showed ZIO®XT Patch had a 57% greater 
diagnostic yield than a 24 hour Holter monitor [17], and Schreiber at al demonstrated an 
overall diagnostic yield of 63% in ED patients with indications for monitoring. This study also 
showed that 48% of patients had ≥1 arrhythmia and 10% were symptomatic at the time of 
their arrhythmia. Median time to first arrhythmia was 1.0 days (IQR 0.2–2.8) and median time 
to first symptomatic arrhythmia was 1.5 days (IQR 0.4–6.7). 54% of symptomatic patients did 
not have any arrhythmia during their triggered events [18]. 
 
In a study looking at ZIO®XT Patch use in outpatients with clinical indications for monitoring 
(15% of whom had syncope), of the 60% of patients who had an arrhythmia detected, 30% 
had their first arrhythmia and 51% had their first symptom-triggered arrhythmia occur after 
the initial 48-hour period. Mean time to first arrhythmia was 1.7 days (median 0.8) and mean 
time to first symptomatic arrhythmia was 3.0 days (median 2.1) [19]. 
 
This novel ambulatory cardiac monitoring device should allow much earlier arrhythmia 
detection in more patients allowing better diagnosis and subsequent treatment. 
 
Biomarkers: Previous work on cardiac biomarkers by our group has shown they may have 
good prognostic value in the ED assessment of syncope [1,21,22]. In the process of deriving 
and validating the ROSE (Risk Stratification of Syncope in the ED) clinical decision rule, we 
demonstrated that plasma brain natriuretic peptide (BNP) concentrations ≥300 ng/L were an 
independent predictor of serious outcome and death with an odds ratio (OR) of 7.3 and a 
negative predictive value (NPV) of 95.4% (93.0-97.0) [1].  
 
Furthermore, we measured troponin I concentrations using a contemporary sensitive assay 
(ARCHITECTSTAT troponin I assay; Abbott Laboratories, Abbott Park, IL) in 338 of 528 
syncope patients admitted to hospital as part of the ROSE study. Troponin was measureable 
above the limit of detection (10 ng/L) in 77% of patients and above the limit of quantification 
(50 ng/L; coefficient of variation (CV) <10%) in 19% of patients.  
 
Higher troponin concentrations were associated with increased risk of all-cause death, 
serious outcome including death, and MACE including cardiac death. None of the 77 
patients with troponin concentrations less than the limit of detection (10 ng/L; 23% of 
patients enrolled) had any serious outcome at one month [21] and only 4 (2%) of the 162 
patients with a troponin concentration <20 ng/L (48% of patients enrolled) had a serious 
outcome at one month. Only one of 85 (1.2%) patients with a troponin <20 ng/L and 
BNP<100 ng/L had Major Adverse Cardiac Events at 1 month equating to a NPV of 98.8%. 
 
Since these studies, troponin assays have been developed with even greater analytical 
sensitivity and precision [23], and accurate quantification of troponin is possible even at very 
low concentrations. The novel ARCHITECTSTAT high-sensitivity troponin I assay (Abbott 
Laboratories, Abbott Park, IL) can quantify troponin concentrations in >98% of healthy 
persons and has the potential to greatly improve discrimination in patients with syncope. 
Unexplained syncope is rarely due to Myocardial Infarction (MI) [22]. We hypothesise that 
elevated troponin and BNP concentrations in patients with syncope are likely to reflect 
secondary myocardial injury due to myocardial oxygen supply and demand imbalance or 

 
 
 
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reduced cardiac output in severe arrhythmia or structural abnormality. 
 
4. Research methods 
 
Study design: Prospective cohort study. 
 
Study setting: Single centre, teaching hospital ED. 
 
Study population 
Inclusion criteria: 100 consecutive patients aged 16 years or over presenting within 6 hours 
of an episode of syncope and whose syncope remains unexplained after ED assessment will 
be prospectively consented and enrolled by the attending clinician and/or study research 
nurse.  
 
Syncope will be defined as a transient loss of consciousness (TLOC) with inability to 
maintain postural tone and immediate complete spontaneous recovery without medical 
intervention (to preexisting mental status and neurologic function) [24].  
 
Exclusion criteria 
• Obvious underlying cause after ED assessment,  
• Alcohol or illicit drugs as presumptive cause of TLOC [24],  
• Epileptic seizure as presumptive cause of TLOC (seizure activity with a >15 min 
witness reported post-ictal phase) [24],  
• Stroke ⁄ transient ischemic attack as presumptive cause of TLOC [24],  
• Head trauma followed by TLOC [24],  
• Hypoglycemia as presumptive cause of TLOC [24],  
• No consent i.e. patient lacking capacity,  
• Previous recruitment into the study, 
• Patient in custody or prison. 
 
Obvious underlying causes will be defined as:  
• Clinical history of vasovagal syncope i.e. pre-syncope symptoms and low-risk patient 
according to current ESC guidelines [14],  
• Arrhythmia on ED ECG thought to have caused syncope,  
• Arrhythmia on pre-hospital ECG causing syncope,  
• Pulmonary embolism diagnosed on CTPA (or equivalent e.g. symptoms of PE plus 
positive leg USS/VQ/echo),  
• Postural hypotension (postural drop >20 mmHg in ED with symptoms during test and 
suggestive history),  
• Myocardial Infarction [25],  
• CT brain or clinical signs/symptoms in ED showing cerebrovascular accident or 
subarachnoid haemorrhage,  
• Evidence of haemorrhage in ED thought to have caused syncope,  
• Other obvious cause of syncope apparent in ED. 
 

 
 
 
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Patient enrolment and consent 
Potentially eligible patients will be identified by medical and nursing staff in the ED and also 
by the EMERGE research nurse (part of the patient’s direct care team) screening in 
accordance with EMERGE Research Governance: Data protection and Confidentiality SOP 
version 1.1; dated 08/03/2015. 
 
After ED assessment, potentially eligible patients will be assessed for study inclusion by the 
attending clinician. If the patient fulfils the study eligibility criteria, written consent will be 
taken by the treating clinician or by a member of the study research team. A decision to 
enrol a patient will not later be overturned. 
 
We have extensive experience of seeking informed consent from acutely ill patients in the 
Emergency Department setting (3CPO, 3Mg, RATPAC, SNAP, TRIGGER, LAVAS, HALT-IT, 
HIghSTEACS, ExPRES-SEPSIS studies). 
 
We will use the following process for seeking consent and will take into account the opinions 
of ethics committee review after ethics submission. 
 
The patient is assessed by the recruiting doctor or member of the Emergency Department 
research team to establish if he/she is competent or has ‘capacity’ to consent. This 
assessment of capacity will be documented.  
 
Patients lacking capacity who are unable to provide consent will not be approached to take 
part in the study. 
 
The patient (and if present and appropriate their accompanying relative) will be given a 
Patient Information Sheet, which will explain the aims of the trial and the potential risks and 
benefits of the study procedures/tests. 
 
The patient will be given enough time to consider the trial and ask questions regarding their 
participation in the trial. For some patients this could be as much as an hour but for others 
may only be 10-15 minutes. If the patient agrees informed consent will be confirmed with a 
signature on the study consent form.  
 
Potential, eligible participants who are able to express their consent and able to complete 
the consent form will be asked to provide written consent. The recruiting doctor or member of 
the research team will do this. 
 
Data Collection 
Patients will have a Data Collection Form (DCF) completed in the ED, comprising 
demographic, historical and examination characteristics, 12-lead ECG, and radiology and 
standard laboratory investigations. Patient contact details will also be confirmed. These 
criteria are based on recent Standardized Reporting Guidelines for Emergency Department 
Syncope Risk Stratification Research [24]. The ECG and DCF will be stored in paper form 
and archived for up to 5 years after the last patient is enrolled into the study to allow the 
potential for 1 and 5 year follow-up (and for which patients will be consented). The 

 
 
 
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information on the DCF will be entered into a specially designed electronic database which 
will be stored on a secure password protected ‘S’ drive which is held within NHS Lothian in 
accordance with EMERGE Research Governance: Data protection and Confidentiality SOP 
version 1.1; dated 08/03/2015. 
Study Assessments 
Written patient consent will include retrieval of leftover patient’s baseline (admission) routine 
haematology (EDTA) and biochemistry (Li Heparin Gel) samples from the Royal Infirmary of 
Edinburgh laboratory and its quantification for hs-troponin I (ARCHITECTSTAT high-sensitivity 
troponin I assay performed in RIE laboratory) and BNP (ALERE TRIAGE point-of-care BNP 
test; ALERE, San Diego, USA; www.alere.co.uk performed in ED). The results of these tests 
will not be reported to the clinician. 
 
One 2.7ml (half teaspoon) EDTA and one 4.7ml (just less than one teaspoon) Li Heparin Gel 
sample will be taken 3 hours after admission. The 4.7ml (just less than one teaspoon) Li 
Heparin Gel sample will be used to measure troponin (ARCHITECTSTAT high sensitivity 
troponin I) in the RIE laboratory and the 2.7ml (half teaspoon) EDTA sample will be used to 
measure BNP (ALERE TRIAGE point-of-care BNP test; ALERE, San Diego, USA; 
www.alere.co.uk performed in ED). The results of these tests will not be reported to the 
clinician. Both the left over baseline samples and the 3-hour research venous blood samples 
will be stored in an annotated bio resource for an unlimited period and for later further testing 
of other future potential biomarkers. 
 
ED tests not part of the study protocol will be ordered at the discretion of the treating doctor, 
and patients will be admitted, referred for outpatient investigation, or discharged according to 
current ED protocols and at the discretion of the treating clinician. If a patient is admitted 
then the reason for admission decision will be recorded.  
 
Ambulatory patch 
All enrolled patients will be fitted with a novel ambulatory patch (ZIO® XT Patch), which 
continuously records heartbeats for up to 14 days. This will be placed on the patient in the 
ED by a trained research team member, and will be left on for 2 weeks. The study participant 
will also be given a diary in which to record any symptomatic episodes occurring during the 
time the patch is worn e.g. light-headedness/dizziness, syncope/presyncope, and a patch 
satisfaction questionnaire. 
 
The study participant will be given details of the PATCH-ED research team in case of any 
patch problems. At the end of the patch period, the patient will send the patch back to the 
research team in a pre-paid envelope. The PATCH-ED team will then forward this onto the 
iRhythm Clinical Centre for data processing by a certified Electrocardiographic Technician 
specialized in advanced arrhythmia detection.  
 
IRhythm will not receive any personal/identifiable data. Study participants will be registered 
with iRhythm in a blinded format, using only their study ID. The completed patch reports will 
be posted by iRhythm and retrieved by the PATCH-ED study team via a secure website 
(www.zioreports.com) accessed only by a secure login known to the PATCH-ED study team. 

 
 
 
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The completed patch report will then be saved in a PDF format on a secure password 
protection dedicated ‘S’ drive on the NHS Lothian computer system and viewed immediately 
by the study team. 
 
Any study participant with a serious significant arrhythmia on the patch report will be 
contacted immediately and appropriately referred to the RIE cardiac electrophysiology 
service.  
 
Serious significant arrhythmia will be defined as:  
• 
Ventricular fibrillation (VF),  
• 
Ventricular tachycardia (VT) >120 beats per minute for 30 seconds,  
• 
Symptomatic ventricular tachycardia, 
• 
Complete or 3rd degree heart block,  
• 
Symptomatic second degree heart block type II,  
• 
Pause >6 seconds, 
• 
Symptomatic bradycardia <40 beats per minute for >30 seconds  
 
Study endpoints: Patients will be followed up at 90 days after presentation through hospital 
and General Practitioner (GP) Electronic Patient Record (EPR) systems. Patient contact and 
NHS Information Services Division (ISD) linkage did not add any further information in the 
ROSE study [1] so are not planned to be utilised in this study. Patients who have left the 
NHS Lothian area after one month (<1% in ROSE study) will be assigned as ‘lost to follow 
up’ and excluded from subsequent data analysis. Consent will be obtained to allow potential 
follow up at 1 and 5 years. 
 
Serious significant arrhythmia (see above) and significant arrhythmia will be defined based 
on Standardized Reporting Guidelines for Emergency Department Syncope Risk 
Stratification Research [23].  
 
Significant arrhythmia will be defined as: 
• Non-symptomatic ventricular tachycardia < 30 seconds, 
• Symptomatic sinus bradycardia < 60 beats/minute (but >40 or less than 30 seconds), 
• Asymptomatic sinus bradycardia < 40 beats/minute, 
• Sick sinus syndrome with alternating sinus bradycardia and tachycardia,  
• Sinus pause > 3 seconds (but less than 6 seconds), 
• Symptomatic Mobitz type I atrioventricular heart block, 
• Junctional/idioventricular rhythm, 
• Symptomatic supraventricular tachycardia with rate > 100/minute, 
• Symptomatic atrial flutter/fibrillation with ventricular rate >100/min, 
• Symptomatic atrial flutter/fibrillation with ventricular rate <60/min, 
 
Arrhythmias will also be defined as symptomatic (i.e. concurrent light-headedness/dizziness, 
syncope/presyncope with arrhythmia) or asymptomatic. Any significant symptomatic 
arrhythmia will also be discussed with the RIE cardiac electrophysiology service. 
 

 
 
 
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Patient consent will include 5-year follow up, blood sample storage for an unlimited period 
and further testing of blood samples for other future potential biomarkers.  
 
Selection bias: Non-recruited but potentially eligible patients will be identified by a daily 
search of all ED EPRs to assess for potential selection/recruitment bias.  
 
Primary endpoint: Diagnostic yield of the ambulatory patch monitor for significant 
symptomatic arrhythmia at 90-day follow-up versus standard care strategies. 
 
Secondary endpoints:  
1. Median time to detection of significant symptomatic arrhythmia by ambulatory patch 
monitor compared to historical standard care strategies [1]. 
2. Prevalence of arrhythmia, serious significant arrhythmia, significant arrhythmia and 
symptomatic arrhythmia in ED syncope patients unexplained after ED evaluation. 
3. Patient patch satisfaction (postal questionnaire). 
4. Patch compliance (median device wear time/ median device analysable time). 
5. Number of patients with significant underlying arrhythmic pathology on ambulatory 
patch monitoring requiring referral.  
6. All cause serious outcome at 90 days. 
 
All cause serious outcome will be a composite of:  
• All cause death,  
• Major adverse cardiac events [MACE] 
o Myocardial infarction [25],  
o Significant arrhythmia [25], 
o Significant Structural Heart Disease [23],  
o Positive Electrophysiology Study Findings [25] 
o Permanent pacemaker or defibrillator placement,  
o Coronary artery bypass graft or coronary artery stent,  
o Cardiac valve surgery,  
o Elective 
cardioversion 
in 
the 
absence 
of 
objective 
evidence 
that 
tachyarrhythmia is responsible for the syncope,  
o Balloon-pump insertion,  
o Heart transplant,  
o Initiation of anti-arrhythmia medical therapy,  
o Ventricular assist device 
 
Data analysis and statistics: Two consultants will independently review all clinical data and 
assign endpoints with any disagreements resolved by consensus. Descriptive statistics will 
be used where appropriate. A decision to enroll 100 patients was made to enable sufficient 
data to inform our primary and secondary aims and our proposed subsequent RCT. Data 
analysis and statistics will be conducted by the EMERGE research group. 
 
Adverse Events 
Since the only interventions in this trial are peripheral venous blood sampling 3 hours post 
presentation to the ED and the ambulatory patch, we will only collect and record data with 

 
 
 
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regards to Adverse Events that are related to these interventions. These are likely to be 
infection, haematoma formation or minor skin irritation secondary to the patch monitor. 
 
If any of these adverse events meet the criteria of Serious they will be reported to the 
Sponsor as per Sponsor SOP (ACCORD SOP CR006).  
 
A Serious Adverse Event is defined as the following: 
• Results in death of the clinical trial participant 
• Is life-threatening 
• Requires inpatient hospitalisation or prolongation of existing inpatient hospitalisation 
• Results in persistent or significant disability or incapacity 
• Consists of a congenital anomaly or birth defect 
 
Unexpected serious adverse events related to either the research blood sampling procedure 
or to the application or wearing of the ambulatory patch monitor should be reported to the 
study team within 24 hours. 
 
We will not collect any other adverse events data. 
 
5. Research Governance: 
NHS Lothian will act as sponsors for the study. The study will be carried out under the 
research governance frameworks of the Emergency Medicine Research Group Edinburgh 
(EMERGE) and NHS Lothian ACCORD.  
 
6. Duration of study and Project timelines:  
 
Duration of set up: 
2 months (to obtain all ethical/regulatory approvals, prepare 
essential documents and study database and initiate RIE site) 
Duration of recruitment: 
The study will recruit over 3 months, based on an average 
recruitment rate of 7-8 patients a week.  
Duration of follow-up for each participant will be 90 days. 
 
Duration of study close out: 2 months to complete all data cleaning and statistical analysis. 
The planned total study duration is 10 months. Patient data will be kept for up to 5 years 
after the last patient is enrolled into the study to allow the potential for 1 and 5 year follow-
up. 
 
June 2015 
 
 
 
Ethics and NRS approvals.  
August - October 2015  
 
Patient enrollment. 
November - January 2016  
90-day follow-up and analysis. 
February - March 2016 
 
Data cleaning and statistical analysis. 
April 2016 
 
 
 
End of study and Study dissemination. 
 
 
 

 
 
 
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7. Project Management and Oversight Arrangements 
 
Project Management Group 
The project will be managed under the supervision of Dr Matt Reed (Consultant Emergency 
Physician, Emergency Department, Royal Infirmary of Edinburgh). The project will be 
coordinated and supported by clinical, academic, research, managerial and administrative 
support within the EMeRGE group.  
 
Data Monitoring Committee 
Since this is a single site observational study involving techniques that are commonly used 
at this centre we believe this is a low risk study and as such there will be no Data Monitoring 
Committee. 
 
Inspection of Records 
The Investigators and institution involved in the study will permit study related monitoring 
and audits on behalf of the sponsor and REC (Research Ethics Committee) review as 
required.  In the event of an audit or monitoring, the Investigator agrees to allow the 
representatives of the sponsor direct access to all study records and source documentation. 
 
Study Monitoring and Audit 
The Investigator site may be risk assessed by the ACCORD (Academic and Clinical Central 
Office for Research & Development) QA Manager, or designee, in order to determine if audit 
by the ACCORD QA group is required. 
 
Good Clinical Practice 
 
Ethical Conduct 
The study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki. The study will be carried out in accordance with the principles of 
the International Conference on Harmonisation Tripartite Guideline for Good Clinical Practice 
(ICH GCP). 
 
A favourable ethical opinion will be obtained from the appropriate REC and local R&D 
(Research and Development) approval will be obtained prior to commencement of the study. 
 
Investigator responsibilities 
The Investigator is responsible for the overall conduct of the study at the site and compliance 
with the protocol and any protocol amendments.  In accordance with the principles of ICH 
GCP, the following areas listed in this section are also the responsibility of the Investigator.  
Responsibilities may be delegated to an appropriate member of study site staff. 
 
Delegated tasks must be documented on a Delegation Log and signed by all those named 
on the list prior to undertaking applicable study-related procedures. 
 
 
 

 
 
 
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Informed consent 
The Investigator is responsible for ensuring informed consent is obtained before any protocol 
specific procedures are carried out.  The decision of a participant to participate in clinical 
research is voluntary and should be based on a clear understanding of what is involved. 
 
Participants must receive adequate oral and written information – appropriate Participant 
Information and Informed Consent Forms will be provided.  The oral explanation to the 
participant will be performed by the Investigator or qualified delegated person, and must 
cover all the elements specified in the Participant Information Sheet and Consent Form. 
 
The participant must be given every opportunity to clarify any points they do not understand 
and, if necessary, ask for more information.  The participant must be given sufficient time to 
consider the information provided.  It should be emphasised that the participant may 
withdraw their consent to participate at any time without loss of benefits to which they 
otherwise would be entitled. 
 
The participant will be informed and agree to their medical records being inspected by 
representatives of the sponsor(s) but understand that their name will not be disclosed 
outside the hospital. 
 
The Investigator or delegated member of the study team and the participant will sign and 
date the Informed Consent Form(s) to confirm that consent has been obtained.  The 
participant will receive a copy of this document and a copy filed in the Investigator Site File 
(ISF) and participant’s medical notes. 
 
Study site staff 
The Investigator will be familiar with the protocol and the study requirements.  It is the 
Investigator’s responsibility to ensure that all staff assisting with the study are adequately 
informed about the protocol and their study related duties. 
 
Data Recording, Management and Security 
Data will be initially collected into a paper CRF and then entered onto a research database 
specific to this study as anonymised data. This database will be stored on a secure, 
password protected location on the hospital computer shared drive, accessible only to 
EMeRGE research staff. All unidentifiable research data will be kept in this research 
database in this location. Identifiable information will be kept in a separate database which 
will not be accessible outside the immediate research team. This data will be linked by study 
number to the anonymised research database. 
 
The personal data of the participant will be kept in a locked filing cabinet in the EMeRGE 
office. This is a locked office in the Royal Infirmary of Edinburgh hospital, with access 
restricted to named research staff. Any personal data held on the research database will be 
stored on the hospital internal computer network in a password protected area only 
accessible to relevant staff. 
 
 

 
 
 
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Once the data collection has been completed, data analysis will be conducted by the 
EMERGE group meaning no patient data will be transferred outwith the NHS Lothian 
hospital computer shared drive. 
 
The Principle Investigator will be responsible for the quality of the data recorded in the CRF 
as well as data stored on research database. 
 
GCP training 
All study staff will hold evidence of appropriate GCP training. 
 
Confidentiality 
The research database will contain anonymised data that will be stored on the NHS Lothian 
internal computer network in a password protected area only accessible to relevant staff. 
Identifiable data will be stored in a separated controlled database. 
 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain participant confidentiality.  All records will be kept in a secure 
storage area with limited access. 
 
Data Protection 
All Investigators and study site staff involved with this study will comply with the 
requirements of the Data Protection Act 1998 with regard to the collection, storage, 
processing and disclosure of personal information and will uphold the Act’s core principles. 
Access to collated participant data will be restricted to those clinicians treating the 
participants. 
 
Computers used to collate the data will have limited access measures via user names and 
passwords. 
 
Published results will not contain any personal data that could allow identification of 
individual participants. 
 
Study Conduct Responsibilities 
 
Protocol Amendments 
Any changes in research activity, except those necessary to remove an apparent, immediate 
hazard to the participant in the case of an urgent safety measure, must be reviewed and 
approved by the Principal Investigator. 
 
Amendments to the protocol must be submitted in writing to the appropriate REC and local 
R&D for approval prior to participants being enrolled into an amended protocol. 
 
Study Record Retention 
All study documentation will be kept for a minimum of 5 years from the protocol-defined end 
of study point. This is to comply with the minimum retention period as set out in the Sponsor 
SOP on archiving where guidance is given on retention periods for non-CTIMP studies and 

 
 
 
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also to allow the possibility of future 1 and 5-year patient follow-up.  The minimum period 
may be increased if the Sponsor(s) stipulates a longer period of time.  When the minimum 
retention period has elapsed, study documentation will not be destroyed without permission 
from the sponsor. We will keep the fully anonymised research dataset on a secure research 
database indefinitely to help with future research. 
 
End of Study 
The end of study is defined as 1 April 2016. The study will stop sooner than this at the 
discretion of the REC, Sponsor or if advised by the Project Management Group. 
 
Insurance and Indemnity 
The Sponsor is responsible for ensuring proper provision has been made for insurance or 
indemnity to cover their liability and the liability of the Principal Investigator and staff. 
 
The following arrangements are in place to fulfil the Sponsor’s responsibilities: 
 
The Protocol has been designed by the Principal Investigator and researchers employed by 
NHS Lothian.  The Site participating in the study will be liable for clinical negligence and 
other negligent harm to individuals taking part in the study and covered by the duty of care 
owed to them by the sites concerned.  The Site as part of the United Kingdom's Nation 
Health Service will have the benefit of NHS Indemnity. 
 
 
Reporting, Publications and Notification of Results 
 
The results of our research will be disseminated in the following ways: 
 
1. Summary disseminated to NHS Lothian communication systems  
2. A media summary  
3. Summary on EMeRGE intra- and internet sites  
4. Presentation at local and national educational, clinical and research meetings  
5. Presentation at international research meetings  
6. Publication in peer reviewed journals  
7. Research report disseminated to NHS Lothian R&D, NHS Research Scotland.  
 
 
 

 
 
 
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8. References 
 
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department: The ROSE study. J American College Cardiology 2010; 55 (8): 713-721.  
[2] Reed MJ, Henderson SS, Newby DE, et al. One-year prognosis after syncope and the 
failure of the ROSE decision instrument to predict 1 year adverse events. Ann Emerg Med 
2011; 58 (3): 250-6. 
[3] Martin TP, Hanusa BH, Kapoor WN.  Risk stratification of Patients with Syncope.  Ann 
Emerg Med 1997; 29 (4): 459-466. 
[4] Oh JH, Hanusa BH, Kapoor WN, et al.  Do Symptoms Predict Cardiac Arrhythmias and 
Mortality in Patients With Syncope?  Arch Intern Med 1999; 159: 375-380. 
[5] Colivicchi F, Ammirati F, Melina D, et al.  Development and prospective validation of a 
risk stratification system for patients with syncope in the emergency department: the OESIL 
risk score.  European heart journal 2003; 24: 811-819. 
[6] Sarasin FP, Hanusa BH, Perneger T, et al.  A Risk Score to Predict Arrhythmias in 
Patients with Unexplained Syncope.  Acad Emerg Med 2003; 10 (12): 1312-1317. 
[7] Quinn JV, Stiell IG, McDermott DA, et al.  Derivation of the San Francisco syncope rule to 
predict patients with short-term serious outcomes.  Ann Emerg Med 2004; 43: 224-232. 
[8] Quinn JV, McDermott DA, Stiell IG et al. Prospective Validation of the San Francisco 
Syncope Rule to Predict Patients With Serious Outcomes. Ann Emerg Med 2006; 47: 448-
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[9] Costantino G, Perego F, Dipaola, et al.  Short and Long-term prognosis of syncope, risk 
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Syncope) study. J American College Cardiology 2008; 51(3): 276-283. 
[10] Del Rosso A, Ungar A, Maggi R et al.  Clinical predictors of cardiac syncope at initial 
evaluation in patients referred urgently to a general hospital: the EGSYS score. Heart 2008: 
94: 1620-1626. 
[11] Cheung CC1, Kerr CR, Krahn AD. Comparing 14-day adhesive patch with 24-h Holter 
monitoring. Future Cardiol. 2014; 10(3): 319-22. 
[12] Bass EB, Curtiss EI, Arena VC, et al. The duration of Holter monitoring in patients with 
syncope. Is 24 hours enough? Arch Intern Med. 1990; 150: 1073-1078. 
[13] Tattersall L, Reed MJ. The Inpatient Management of Syncope. Emerg Med J. 2010; 27: 
870-872. 
[14] Guidelines for the diagnosis and management of syncope (version 2009). The Task 
Force for the Diagnosis and Management of Syncope of the European Society of Cardiology 
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[15] Rosenberg MA, Samuel M, Thosani A, Zimetbaum PJ. Use of a noninvasive continuous 
monitoring device in the management of atrial fibrillation: a pilot study. Pacing Clin 
Electrophysiol. 2013; 36(3): 328-33. 
[16] Tung CE, Turakhia MP, Lansberg MG. Diagnostic Yield of Extended Cardiac Patch 
Monitoring in Patients with Stroke or TIA. Front. Neurol. 2014; 5: 266. 
[17] Barrett P, Komatireddy R, Haaser S et al. Comparison of 24 hour Holter monitoring 
versus 14 day novel adhesive patch electrocardiographic monitoring. Am J Med. 2014; 127: 
95. e11-95. e17. 

 
 
 
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[18] Schreiber D, Sattar A, Drigalla D, Higgins S. Ambulatory Cardiac Monitoring for 
Discharged Emergency Department Patients with Possible Cardiac Arrhythmias. Western 
Journal of Emergency Medicine 2014; 15 (2): 194. 
[19] Turakhia MP, Hoang DD, Zimetbaum P, Miller JD, Froelicher VF, Kumar UN, Xu X, 
Yang F, Heidenreich PA. Diagnostic utility of a novel leadless arrhythmia monitoring device. 
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[20] Camm CF, Tichnell C, James CA, Murray B, Porterfield F, Te Riele AS, Tandri H, 
Calkins H.J Premature Ventricular Contraction Variability in Arrhythmogenic Right Ventricular 
Dysplasia/Cardiomyopathy. J Cardiovasc Electrophysiol 2015; 26 (1): 53-7. 
[21] Reed MJ, Mills NL, Weir CJ. Sensitive Troponin Assay Predicts Outcome in Syncope. 
Emerg Med J 2012; 29 (12): 1001-3.  
[22] Reed MJ, Newby DE, Coull AJ, et al. Diagnostic and prognostic utility of troponin 
estimation in patients presenting with syncope: a prospective cohort study.  Emerg Med J 
2010: 27(4): 272-276. 
[23] Keller T, Zeller T, Peetz D, et al. Sensitive Troponin I Assay in Early Diagnosis of Acute 
Myocardial Infarction. N Engl J Med 2009; 361: 868-877. 
[24] Sun BC, Thiruganasambandamoorthy V, Dela Cruz J, et al. Standardized Reporting 
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