Submission for Lancet Protocol Review Title A study ... - NHS Lothian

Submission for Lancet Protocol Review Title A study ... - NHS Lothian

Submission for Lancet Protocol Review


A study to develop and validate a Clinical Decision Rule using history,

examination, electrocardiographic and biochemical markers, to predict one

month outcome for patients presenting with syncope to the Emergency

Department (the ROSE study)

Short Title

Risk stratification Of Syncope in the Emergency department: the ROSE study

Principal Investigators

Dr Matthew Reed, Chief Scientist Office Clinical Academic Research Training

Fellow and Locum Consultant in Emergency Medicine, Department of

Emergency Medicine, Edinburgh Royal Infirmary, Edinburgh, UK.

Dr Alasdair Gray, Consultant and Honorary Reader in Emergency Medicine,

Department of Emergency Medicine, Edinburgh Royal Infirmary, Edinburgh,


Professor David Newby, Professor of Cardiology, Centre for Cardiovascular

Sciences, Edinburgh Royal Infirmary, Edinburgh, UK.

Dr Andrew Coull, Consultant Physician and Honorary Senior Lecturer,

Department of Medicine for the Elderly, Edinburgh Royal Infirmary, Edinburgh,


Professor Robin Prescott, Professor of Statistics, Medical Statistical Unit,

University of Edinburgh.


Mr Robert Lee, Statistician, Medical Statistical Unit, University of Edinburgh.

Main study centre

Department of Emergency Medicine, Edinburgh Royal Infirmary, 51 Little

France Crescent, Edinburgh, EH16 4SA, UK.


We aim to conduct the largest international derivation and validation study of

undifferentiated syncope based in the Emergency Department looking at onemonth

outcome, and the first in the UK. 550 consecutive patients aged 16

years or over will be recruited into the derivation study and 550 into the

validation study over an 18-month period. All patients will undergo a

standardised assessment using 32 historical variables, 14 examination

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variables and 24 ECG based variables. All patients will also have a full blood

count, urea, creatinine, liver function, glucose, electrolytes, high sensitivity

CRP and near-patient BNP tests. Admitted patients and a random selection of

100 discharged derivation group patients will undergo a formal laboratory

based Troponin I at least 12 hours post syncope. Endpoint measures are

serious outcome at 1 month. A Clinical Decision Rule using history,

examination, ECG, and biochemical markers will be developed and validated

to predict 1 month outcome for patients presenting with syncope to the

Emergency Department.

Background and previous research

Syncope is a transient loss of consciousness with an inability to maintain

postural tone followed by a spontaneous recovery [1]. It accounts for 3% of

ED visits and 1-6% of hospital medical admissions, affecting 6 per 1000

people per year [2,3]. Clinical assessment of syncope is difficult due to the

heterogeneous nature of underlying causes, ranging from benign

neurocardiogenic syncope, to potentially fatal arrhythmias.

In 1983, Kapoor et al [4] published the first prospective syncope study. 12month

mortality was 14%. Mortality was greatest in patients in whom a

cardiovascular cause was identified (30%). Subsequent studies have shown

that underlying heart disease in patients with syncope is associated with a

poor prognosis [5]. Recent emphasis has focused on risk stratification of

patients with syncope. Although guidelines have been issued [6-10],

evidence in respect to ED management is sparse.

There are 5 risk stratification studies [11-16]. Most involved small numbers of

patients and used different characteristics and outcome measures in their risk

stratification tools. Only two were prospective and had mixed results [11,13].

Only one study, a US based study looked at short-term adverse outcome

[15,16], which is relevant to emergency medicine practice. There were two

fundamental problems with this study. Firstly, two of the selected predictor

variables included in the rule would usually necessitate immediate hospital

admission (systolic blood pressure less than 90mmHg and a haematocrit of

less than 30%). This greatly reduces the benefit of the rule in ED admission

decision-making. Secondly, the rule was originally derived for 7 day serious

outcome, however later validated for 1 month outcome. No studies have been

examined in a UK population.

With growing pressures on acute medical beds and an increasingly elderly

population, there is a need for a large study of this common presenting

symptom to identify high-risk populations requiring further investigation, and

low-risk patients who may be discharged safely. Accurate identification of

patients would enable specific targeting of resources and prevent excessive

investigation of patients with benign causes.

No risk stratification studies have investigated the role of biochemical markers

in risk stratification. We hypothesize that Brain Natriuretic Peptide (BNP) and

high sensitivity C-reactive protein (HS-CRP) acting as objective markers of

underlying cardiac disease, may be excellent ED markers of 1 month

outcome. BNP [17,18] is an excellent marker of prognosis in patients with

heart failure or cardiac disease, and several prospective epidemiological

studies from the United States and Europe have demonstrated that HS-CRP

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is a good predictor of future coronary events [19-21]. It is also well

established that prognosis in syncope is related to the presence of underlying

heart disease [5], and all existing syncope CDRs include either a history of

congestive heart failure [11,14,15] or underlying cardiac disease [12,13].

Troponin I (TnI) is commonly measured 12 hours post syncope to rule out

acute myocardial infarction (AMI) and has only been assessed as a

prognostic marker in syncope in one previous study [22]. This study took

Troponin levels as early as four hours after the syncopal episode, when

sensitivity for AMI is poor (0.64) [23]. We hypothesize that a routine TnI is

unnecessary and aim to assess the value of a 12-hour troponin as both an

AMI rule-out marker, and as a syncope prognostic marker.

Results of pilot study

A pilot study was performed between November 2005 and January 2006. 99

consecutive patients with undifferentiated syncope were enrolled (1.6 per

day). 32 patients were high-risk, 51 medium and 16 low according to our

existing departmental syncope guidelines (based on the European Society of

Cardiology [9,10], American College of Physicians [6,7] and American

College of Emergency Physicians guidelines [8]). 72 patients had BNP

measured, 25 (35%) were 100 pg/ml or greater, and 3 were over 1000 pg/ml.

44 patients were admitted to hospital and 55 were discharged from the ED. 30

of those admitted had troponin I measured. Only one of these was raised

(14.40 ng/ml) and this was thought to be due to an AMI. 66 patients had CRP

measured, 16 were raised (>5 mg/l). There were 11 serious outcomes. 5

patients had died by 3 months, and 6 others had an alternative serious

outcome. 8 of the 11 patients had a serious outcome by 1 week. The

percentage risk of serious outcome at 7 days, 1 month and 3 months was

therefore 8.1%, 8.1% and 11.1% respectively. 9 of 11 serious outcome

patients had BNP measured, 6 were >100, 3 were >1000 and all patients with

a BNP >1000 were in the serious outcome group (2 died, 1 AMI) [24]. The

OESIL score, the SFSR and our existing departmental guidelines all showed

some ability to risk stratify syncope patients [25].

Primary aim

To develop and validate a Clinical Decision Rule (CDR) using history,

examination, electrocardiographic (ECG) and biochemical markers, to predict

one month outcome for patients presenting with syncope to the ED.

Research questions

(1) Can a syncope CDR using specific components from the history and

examination, ECG characteristics and biochemical markers (HS-CRP and

BNP) predict one-month outcome in ED patients presenting with syncope?

(2) Can HS-CRP or BNP predict one-month outcome in patients presenting to

the ED with syncope?

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(3) Are biochemical markers in isolation better than history, examination and

ECG characteristics at predicting one-month outcome, or are they more useful

in conjunction with them to improve the accuracy of a CDR in predicting onemonth

outcome in syncope patients presenting to the ED?

(4) How does the validation of this CDR compare with the validation of

existing ED syncope CDRs in the UK ED population?

(5) Is it necessary to measure a 12-hour troponin I level in all patients

presenting to the ED with syncope?

Methods: Setting

The ED of the Royal Infirmary of Edinburgh (85,000 adult attendances per


Target population

From the pilot study it was estimated that there are 1200 patients presenting

to our ED per annum who are eligible for enrolment into the study. With an

improved recruitment strategy we aim to recruit between 800 and 1000

patients per annum.

Sample size calculation and statistical power

Statistical advice was sought early during planning of the pilot and main study.

With a sample size of 500 patients, if the one month adverse outcome rate is

10.0% [15,25] at the average value of any predictor variable, then there will

be 80% power of showing that this variable has a statistically significant effect

on ‘serious outcome’ (p

Exclusion criteria

� Patients under 16

� Patients previously recruited

� Patient with a good history of seizure or a prolonged (>15 minutes)

post-ictal phase

� Patients who are unable to give written or verbal consent and who do

not have a relative or guardian to give written assent

� Patients whose collapse is suspected to be due entirely to excessive

alcohol consumption

� Suspected alcoholic/epileptic seizure

� Near-syncope (i.e. no loss of consciousness)

Enrolment into derivation study

Eligible patients will be flagged at the ED high dependency triage area and a

data collection form (DCF) will be placed in the patient’s records. Assessment

of patients will be carried out by routine ED medical staff who will also be

responsible for deciding eligibility. A decision to enrol a patient will not be later

overturned by the study team and enrolled patients will be analysed on an

intention to treat basis.

Because the treating doctor is enrolling eligible patients and completing the

data collection form there is theoretically a possible selection bias. Sicker

patients may be excluded because of the time required to complete study

paperwork. This has been addressed by reducing the paperwork required to

be completed at the time of enrolment to an absolute minimum. The study

researcher (MR) will complete the rest of the data collection i.e. blood results

at a later time. The treating doctor should complete as much as possible of

the DCF at the time of patient enrolment. If for some reason information is not

available they should leave the appropriate part of the form blank. The study

researcher (MR) will review the data collected in the ED and will document

any further information that becomes available later. Data obtained after the

patient’s ED attendance will be marked as retrospectively obtained data for

the purposes of analysis in both the DCF and also in the study database. It is

important that any derived CDR is based on information that is available to the

ED doctor at the time of seeing a patient. It is also important for a CDR to

have as accurate information as possible and therefore the end analysis will

include the opportunity to look at this retrospectively available information.

We aim to have a minimum of 500 patients in the derivation cohort available

for final analysis. Because there will be some patients that are lost to followup,

inevitably some for whom all data is not obtained, and a small proportion

who will be excluded later due to them having an obvious cause necessitating

admission on presentation to the ED, we will aim to recruit 550 patients during

the 9 month derivation study.

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All patients will undergo a standardised assessment using 32 pre-determined

variables (9 focussed on clinical features, 10 on past medical history and 13

concerning current medication) and 14 examination variables. These were

selected after careful systematic review of the literature to identify

characteristics that have previously been shown to be associated with serious


After a full history and examination, all patients will undergo a 12-lead ECG,

lying standing blood pressures and a ‘BM stix’ glucose estimation. All patients

will have two red (2.7ml EDTA KE), one orange (4.7ml Lithium-Heparin-Gel)

and one yellow tube (2.7ml Glucose FE) taken and a full blood count, urea,

creatinine, glucose, electrolytes, liver function and HS-CRP will be formally

measured in the hospital laboratory. One green tube (3ml Coagulation 9 NC)

will also be taken, spun down in the biochemistry laboratory and the plasma

kept for storage. A study label will be placed onto the laboratory request form,

and samples will be sent to the hospital laboratory in the usual manner.

Near-patient BNP testing will be performed using a small quantity of blood

from the other ‘spare’ red (2.7ml EDTA KE) tube using the Biosite Triage®

point of care machine. For any patient in whom the near-patient BNP test has

not been performed (i.e. physician or machine error) this will be performed the

following day using the serum from the patient’s original EDTA sample, which

was taken on the patient’s presentation. This will have been spun down after

testing and stored immediately in the fridge in the biochemistry department.

Treating physicians will not be blinded to the result of the BNP test.

All admitted patients will have a laboratory based Troponin I at least 12 hours

post syncope performed by the admitting team, by the study researcher (MR)

or added onto an existing sample in the laboratory which has been taken

between 12 hours and 7 days after the syncopal episode. Patients still in the

ED at 12 hours post ED arrival will be defined as admitted.

A consecutive cohort of 100 derivation study patients who were discharged

from the ED will be selected to return for an interval Troponin I. The patients

will return to the Clinical Research Facility of the Royal Infirmary of Edinburgh

to a special clinic run by one of the facility’s research nurses. Patients will be

given standard travelling expenses of £30. The troponin test will be performed

as soon as possible after ED discharge but no later than 7 days and no

sooner than 12 hours after the episode of syncope. Troponin levels

After formal routine laboratory testing the red (2.7ml EDTA KE), orange (4.7ml

Lithium-Heparin-Gel), yellow (2.7ml Glucose FE) and green tubes (3ml

Coagulation 9 NC) for all enrolled patients will be spun down, separated and

stored initially in a refrigerator in the biochemistry laboratory. The samples

will then be frozen at minus 20 degrees Celsius. Once a week, the previous

week’s samples will be thawed and divided into smaller aliquots and refrozen

at minus 80 degrees Celsius for further analysis (which will include Vidas D-

Dimer and markers inflammation and ischemia) at a later date. These frozen

samples will be stored initially in a research freezer in the ED and later in the

Centre for Inflammation Research, Queen’s building, University of Edinburgh

under the supervision of Dr Matthew Reed, for an indefinite period.

In order to quantify the number of eligible patients not being enrolled into the

study, a daily search of all ED electronic patient records (EPRs) will

conducted throughout the study using Microsoft Business Objects® looking

for the keywords 'syncope', 'collapse', 'faint', 'loss of consciousness' or 'loc'

appearing anywhere on the EPR. All EPRs with one of these terms will then

be hand searched and a decision made from the notes about whether a

patient presented with a possible syncopal event and whether or not they

were eligible for enrolment. Out of those eligible for enrolment, it will be

established how many were successfully enrolled and how many were missed

and for what reason (i.e. missed by doctor, refused consent, consent not able

to be obtained). A database will be compiled of those patients who were

eligible but who were not enrolled along their demographic details and at the

conclusion of the derivation stage, these will be compared to those patients

who are recruited into the study and statistical analysis will be performed.

A Microsoft Access® database has been designed for data entry, which will

be performed by MR. A separate database will be used for derivation and

validation cohorts. A second researcher will check a random selection of 100

patient data collection forms from the derivation study in order to ensure

accuracy of data entry. If errors are found, this check will be extended to the

entire database. The contents of the Microsoft Access® database will be

exported into Microsoft Excel®, SPSS and SAS for statistical analysis. A

patient flow chart will be constructed detailing patient recruitment.

Endpoint measures

Primary outcome: Serious outcome or all cause death at one month

Definition of serious outcome:

� AMI (history of chest pain or ECG changes and troponin I>0.2),

� Life-threatening arrhythmia (as defined prior by expert panel - recorded

episode of VF, sustained VT, ventricular pause greater than 3 seconds,

Mobitz type 2, Wenkebach, bifascicular or complete heart block, or

symptomatic bradycardia

� Insertion of Pacemaker or Internal Cardiac Defibrillator device or a

decision that the patient requires such a device, within 1 month of the

ED attendance.

� Pulmonary embolus (confirmed on VQ/CTPA and requiring treatment),

� Cerebrovascular accident/subarachnoid haemorrhage (CT or LP


� Haemorrhage requiring a blood transfusion of two units or more during

inpatient stay, and an acute surgical procedure or endoscopic

intervention secondary to a suspected cause of syncope.

As part of the data analysis process, two researchers from the expert panel

will independently review notes of all patients who are considered to have

reached endpoint in order to independently agree this. These experts will be

blinded to the presence or absence of all predictor variables.

Secondary outcome: Syncope related death (death due to a recognised

cause of syncope as decided by the expert panel)

Outcome, final discharge diagnosis and information regarding inpatient stay,

investigations, interventions and serious outcome will be identified by way of

ED, hospital, ISD, Registrar General and GP records, death certificates and

post mortem results, and via a structured telephone interview with the patient.

Endpoint review

� An expert committee will be convened to review all patients who are

suspected of having a primary outcome to determine agreement.

� All patients whose cause of syncope was known to the treating ED

physician at the time of enrolment and whose underlying cause

necessitated admission will be removed from the final analysis after

expert committee review:

o Suspected AAA rupture with SBP < 90mmHg,

o AMI - chest pain with ST elevation >1mm in any lead,

o Severe onset of headache with CT or LP diagnosis of SAH in


o Recorded episode of VF, sustained VT, CHB or symptomatic


Statistical analysis

After derivation data collection, multivariate logistical regression analysis will

be performed to determine factors associated with the endpoints, and a CDR

will be developed. Previous syncope risk stratification models have either

used a stepwise multiple linear logistic regression model, a stepwise Cox

proportion hazards model or recursive partitioning. The stepwise procedures

can be criticised because they are automatic methods, based on the

independent statistical significance of the potential risk factors. Thus a

relevant variable may be excluded if it has a moderate correlation with a

variable already in the model. Conversely, the large number of risk factors

considered also raises issues of multiple testing and the possibility of

detecting false positive associations. Recursive partitioning has an even

greater risk from false positive findings as the method, in effect, allows for

complex interactions among the potential risk factors. Our approach will utilise

multiple linear logistic regression but model development will not be


In a preliminary stage of analysis, we will attempt to reduce the number of

variables using principal component analysis to identify ‘factors’ among the

set of contender variables. Thus variables that tend to be mutually correlated

will be combined into single variables. Subsequent logistic regression

modelling will take a knowledge-based approach, incorporating widely

accepted risk factors regardless of their statistical significance, while requiring

a high level of significance for variables that other studies have found to be

unimportant. The biochemical markers will be assessed primarily on their

ability to add value to the risk stratification based on conventional risk factors,

but their effects will also be assessed univariately.

Troponin will be analysed in admitted patients and in 100 consecutive

discharged derivation cohort patients. Troponin I will not be included as a

predictor variable for the purposes of the derivation of the CDR due to the

result not being available to the admitting doctor at the time of ED decision


Models will be developed for all of the main outcome variables, from which

practical CDRs will be formulated. The subjective elements in the model

derivation make it particularly important that the models are validated


The validation dataset will be obtained while the deviation dataset is being

analysed, and no data from it will be released until the CDR has been

finalised. The prospective data collection in this study should minimise the

amount of missing data, but for model development, analysis of all subjects is

important. For any categorical variables ‘missing’ will be considered as a

category, while for continuous variables mean imputation will be used in

conjunction with a binary dummy variable to indicate whether or not the

numerical variable has been imputed.

Prospective validation

We aim to have 500 patients available for final analysis and therefore we will

aim for 550 to be recruited as above in an attempt to validate the developed

CDR. Statistical analysis will be used to assess the CDR performance.

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A separate further study is planned that will assess the impact of using the

CDR on admission rate, outpatient follow-up rate and detection of serious

outcomes. A separate cost benefit analysis study will also be performed.

Ethics Committee approval

This study received full ethical approval from the MREC for Scotland A Ethics

committee (Reference: 06/MRE00/107) and Lothian REC (Reference:

06/S11ADMIN/151) on January 8 th 2007, and a submitted substantial

amendment was approved on 22 nd February 2007. Lothian R&D

management approval was also obtained on 24 th January 2007 (Reference:


Informed consent and information sheet

MREC approval has been obtained for the study Patient Information Sheet,

Patient Information Sheet for Relatives, Patient Consent Form, Patient

Consent Form for Relatives and GP Information Sheet.


It is anticipated that the study results will be submitted for to a internationally

renown peer reviewed journal and presented at both national and international

meetings and conferences.


Chief Scientist Office of the Scottish Executive (Reference No: CSO/CAF/01)

Start date (recruitment): March 2007

Finish Date (18 months recruitment): July 2008

Finish Date (1 month follow up): August 2008

Expected Reporting Date: November 2008

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Key references

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The Risk stratification Of Syncope in the Emergency department

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