A Randomised Trial of Expedited Transfer to a Cardiac Arrest Centre for Non-ST Elevation Out-of-hospital Cardiac Arrest
Phase: NA
Conditions: Out-Of-Hospital Cardiac Arrest
Sponsor: Guy's and St Thomas' NHS Foundation Trust

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A randomised trial of expedited transfer to a cardiac arrest 
centre for non-ST elevation out-of-hospital cardiac arrest 
(ARREST) 
 
Trial Protocol Version 6 
ISRCTN96585404 
 
 
Sponsored by King’s College London 
 
Funded by the British Heart Foundation 
 

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Table of contents 
Table of contents ........................................................................................................................... 2 
 
List of abbreviations ........................................................................................................... 5 
 
A note on terminology ........................................................................................................... 5 
 
Trial summary ..................................................................................................................... 6 
 
Protocol summary .................................................................................................................. 6 
 
Flow diagram ......................................................................................................................... 8 
 
Introduction ....................................................................................................................... 9 
 
Background ............................................................................................................................ 9 
 
The need for a randomised controlled trial ......................................................................... 10 
 
Pilot study results ................................................................................................................ 10 
 
Aim .................................................................................................................................... 11 
 
Endpoints .......................................................................................................................... 11 
 
Primary endpoint ................................................................................................................. 11 
 
Secondary endpoints ........................................................................................................... 11 
 
Power calculations and sample size determination ............................................................ 11 
 
Selection of patients .......................................................................................................... 12 
 
Identification of patients ..................................................................................................... 12 
 
Inclusion criteria .................................................................................................................. 12 
 
Exclusion criteria .................................................................................................................. 12 
 
Eligibility of prisoners ........................................................................................................... 12 
 
Eligibility of patients detained under the Mental Health Act .............................................. 13 
 
Patients entered into observational research ..................................................................... 13 
 
Ethical considerations ........................................................................................................ 13 
 
Consent procedures ............................................................................................................. 13 
 
Consent waiver prior to enrolment ......................................................................... 13 
 
Patient identification in hospital .............................................................................. 13 
 
Informed Consent .................................................................................................... 14 
 
Participants who lack capacity ................................................................................. 14 
8.1.4.1. 
Personal consultee ................................................................................................... 14 
8.1.4.2. 
Professional consultee ............................................................................................. 15 
8.1.4.3. 
Assessment of capacity during follow up ................................................................. 15 
 
Participants that have died before consent can be obtained .................................. 15 
8.1.5.1. 
Process for relatives to gather further information ................................................. 16 
 
Patients that have been discharged before consent can be obtained .................... 16 
 
Advance notification of dissent ............................................................................... 16 
 
Withdrawal .............................................................................................................. 17 
 
Declaration of Helsinki and Good Clinical Practice .............................................................. 17 
 
Ethical committee review .................................................................................................... 17 
 
Confidentiality advisory group ............................................................................................. 17 
 
Trial registration .................................................................................................................. 17 

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Randomisation .................................................................................................................. 18 
 
Randomisation procedure ................................................................................................... 18 
 
Access to randomisation site ............................................................................................... 18 
 
Trial treatment .................................................................................................................. 19 
 Intervention: Direct to CAC .................................................................................................. 19 
 Control: standard of care ..................................................................................................... 19 
 Crossover ............................................................................................................................. 19 
 
Safety reporting ................................................................................................................. 19 
 Definition ............................................................................................................................. 19 
 Expected serious adverse events related to usual clinical care ........................................... 20 
 Unexpected serious adverse events .................................................................................... 20 
 Unexpected non-serious adverse events ............................................................................. 21 
 Reporting unexpected adverse events ................................................................................ 21 
 
Assessment of intensity ........................................................................................... 21 
 
Assessment of causality ........................................................................................... 21 
 
Data collection and follow-up ............................................................................................ 21 
 Trials procedures table ........................................................................................................ 21 
 Data collection ..................................................................................................................... 22 
 Trials procedures ................................................................................................................. 23 
 
Pre-hospital care: ..................................................................................................... 23 
 
In-hospital care: ....................................................................................................... 23 
 
30 days post-randomisation: ................................................................................... 24 
 
3 months post-randomisation: ................................................................................ 24 
 
6-months post-randomisation: ................................................................................ 24 
 
12-months post-randomisation: .............................................................................. 24 
 
Monitoring and auditing .................................................................................................... 24 
 Monitoring ........................................................................................................................... 24 
 
Statistical considerations ................................................................................................... 25 
 Statistical analysis plan ........................................................................................................ 25 
 Statistical analysis ................................................................................................................ 25 
 Intention to treat ................................................................................................................. 25 
 Planned subgroup analysis .................................................................................................. 25 
 Bias ....................................................................................................................................... 26 
 Potential risks and hazards .................................................................................................. 26 
 Early termination of trial ...................................................................................................... 26 
 
Data handling and record keeping ..................................................................................... 26 
 
Insurance ........................................................................................................................... 27 
 
Publications ....................................................................................................................... 27 
 Policy .................................................................................................................................... 27 
 Expected value of results ..................................................................................................... 27 
 Dissemination ...................................................................................................................... 27 
 
Trial organisation ............................................................................................................... 28 

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 Trial and logistics management ........................................................................................... 28 
 Trial steering committee ...................................................................................................... 28 
 Project management group ................................................................................................. 28 
 Data and safety monitoring committee ............................................................................... 29 
 
References ......................................................................................................................... 30 
Appendix A: List of sites and Principal Investigators ...................................................................... 35 
London Ambulance Service ............................................................................................................. 35 
CAC Sites .......................................................................................................................................... 35 
Emergency Departments ................................................................................................................. 35 
Appendix B: EQ-5D-5L ................................................................................................................... 37 
 
 
 

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 List of abbreviations 
APP  
 
 
Advanced paramedic practitioner 
ARR 
 
 
Absolute risk reduction 
CAC 
 
 
Cardiac arrest centre  
CARU  
 
Clinical Audit and Research Unit 
CPC  
 
 
Cerebral performance category score 
CPR  
 
 
Cardiopulmonary resuscitation 
DSMC   
 
Data and safety monitoring committee  
EAPCI  
 
European Association of Percutaneous Cardiovascular Interventions 
ECG  
 
 
Electrocardiogram 
eCRF 
 
 
Electronic case report form 
ICA  
 
 
Immediate coronary angiography 
ILCOR   
 
International Liaison Committee on Resuscitation 
LAS  
 
 
London Ambulance Service 
LSHTM CTU 
 
London School of Hygiene & Tropical Medicine Clinical Trials Unit 
MACCE   
 
Major adverse cardiovascular and cerebrovascular events 
OHCA  
 
Out-of-hospital cardiac arrest 
PCI 
 
 
Percutaneous coronary intervention  
PI 
 
 
Principal Investigator 
PIS 
 
 
Patient information sheet 
STE 
 
 
ST-segment elevation 
 
 
A note on terminology 
The term cardiac arrest centre (CAC) has been used throughout this document in place of heart attack 
centre (HAC) which was used in the pilot study. The term HAC, while used in London, is not in use in 
other parts of the United Kingdom or abroad. As such, it was decided to use CAC to reflect the move 
towards this more commonly accepted term. However, in the patient and consultee information 
sheets the term HAC has been used to avoid any confusion for patients or consultees. 

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 Trial summary 
 
 Protocol summary 
Abbreviated Title 
ARREST 
Full Title 
A randomised trial of expedited transfer to a cardiac arrest centre for 
non-ST elevation out-of-hospital cardiac arrest 
ISRCTN 
ISRCTN96585404 
http://www.controlledtrials.com/ISRCTN96585404/ARREST 
Brief Description 
The aim is to determine the best post-resuscitation care pathway for 
patients without ST-segment elevation (STE). We propose that changes 
to emergency management comprising expedited delivery to a cardiac 
arrest centre (CAC) will reduce mortality in patients without STE 
compared to the current standard of care. 
Trial Type 
Randomised controlled interventional trial 
Condition 
Out-of-hospital cardiac arrest (OHCA) 
Intervention 
Transfer to a CAC 
Trial Arms 
1) Treatment arm: Expedited transfer to a CAC 
2) Control arm: Current standard of care  
Start Date 
Pilot trial: November 2014 
Full trial: 1 May 2017 for set-up, 1 September 2017 for recruitment 
Estimated 
Enrolment 
 
860 patients: 430 in each trial arm 
Estimated 
Completion 
End of recruitment: 31 October 2020 
End of follow-up: 31 October 2021 
Completion of trial: 30 April 2022 
 
 

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Eligibility Criteria 
Inclusion Criteria (all) 
1. Out-of-hospital cardiac arrest (OHCA) 
2. Return of spontaneous circulation (ROSC) 
3. Age 18 or over (known or presumed) 
Exclusion Criteria (any) 
1. Criteria for ST-elevation myocardial infarction on 12-Lead 
electrocardiogram (ECG) 
2. Cardiac arrest suffered after care pathway set and patient en 
route 
3. Do Not Attempt Resuscitation (DNAR) order 
4. Suspected pregnancy 
5. Presumed non-cardiac cause (for example; trauma, drowning, 
suicide, drug overdose) 
6. Presumed significant trauma/injury 
Gender 
Both 
Ages 
Age 18 or over (known or presumed), no upper age limit 
Healthy Volunteers 
No 
Recruitment Status 
Open 
UK Sites & 
Investigators 
 
A list of participating sites and investigators can be found in Appendix A 
Chief Investigator 
Prof Simon R Redwood 
Professor of Interventional Cardiology 
King’s College London/Guy’s and St Thomas’ NHS Foundation Trust 
Email: simon.redwood@gstt.nhs.uk 
Clinical Lead 
Dr Tiffany Patterson 
NIHR Academic Clinical Lecturer and Interventional Fellow 
King’s College London/Guy’s and St Thomas’ NHS Foundation Trust 
Email: tiffany.patterson@gstt.nhs.uk / tiffanypatterson05@gmail.com 
Co-Principal 
Investigators 
St Barts’ Heart Centre: 
 
Dr Ajay Jain 
King’s College Hospital: 
 
Professor Philip MacCarthy 
Harefield Hospital: 
 
 
Dr Miles Dalby 
St George’s Hospital:  
 
Dr Sami Firoozi 

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Royal Free Hospital:  
 
Dr Roby Rakhit 
Hammersmith Hospital: 
 
Dr Iqbal Malik 
 
Flow diagram 
 
 

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 Introduction 
 
 Background 
Out-of-hospital cardiac arrest (OHCA) is a global public health issue. There are 60,000 cardiac arrests 
per year in the UK, of which resuscitation is attempted in just under half.1, 2 
Resuscitation attempts are successful in up to 30%. However, more than two thirds of patients who 
survive to hospital admission die before discharge. There is wide variation in both regional and inter-
hospital survival rates from OHCA; this disparity is also present across London.2-9 This variation has 
been shown to be attributable to hospital infrastructure, resources and personnel rather than patient 
characteristics.10 Overall survival therefore remains poor, at 7%.11 
OHCA places a substantial burden on the NHS. Healthcare costs (including emergency response, 
hospitalisation and long-term care of survivors) amount to more than £50,000/patient.12-14 
Regionalisation of care into specialist centres has played a vital role in the management of time-critical 
illnesses through concentration of services and greater provider experience.15-20 These organised 
systems of care have the potential to improve survival post-cardiac arrest, with an associated 
reduction in the economic burden.12, 13, 21 
The International Liaison Committee on Resuscitation (ILCOR) suggest transport of the post-arrest 
patient to a cardiac arrest centre (CAC) with 24/7 access to interventional cardiology facilities to 
manage the ensuing cardiovascular dysfunction and diagnose and treat the underlying cause to 
increase the probability of survival.22-25 The coordination of this is complex and close interaction is 
necessary pre-hospital between centres and ambulance services and internally between the 
Emergency Department, Cardiologists, and Critical Care.  
It is well known that the majority of OHCA are secondary to an acute cardiac ischaemic event. Coronary 
artery disease is responsible for more than 70% of OHCA of presumed cardiac cause, with acute 
occlusion demonstrated in 50% of consecutive patients taken for immediate coronary angiography 
(ICA).26 Early cardiopulmonary resuscitation (CPR) and defibrillation, with ICA and percutaneous 
coronary intervention (PCI) in a CAC, prevents re-arrest, preserves myocardial function and has been 
shown to improve post-arrest outcomes in ST-segment elevation (STE).8, 27-32 
It is difficult to conclude which of the components of post-arrest care is essential, given the 
observational nature of studies.3 Targeted temperature management has been shown to improve 

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neurological survival.33, 34 There is also expert consensus that early reperfusion therapy in STE reduces 
mortality (Class I recommendation).35-37 
The management of patients without STE however is controversial, with a delayed approach to 
intervention. Despite recently published data suggesting PCI in non-STE resulted in a two-fold increase 
in favourable outcome27, randomised data are lacking. Emergent reperfusion therapies come with a 
weak recommendation from ILCOR, and a Class IIa recommendation by the American Heart 
Association (AHA) and European Society of Cardiology (ESC), if there is a high suspicion of ongoing 
infarction.36, 38 
The European Association of Percutaneous Cardiovascular Interventions (EAPCI) recommends a prior 
rule-out of non-cardiac cause in the emergency department followed by coronary angiography within 
2 hours.23 It remains unclear if time-critical, definitive hospital based management of the post-arrest 
patient without STE in a specialist centre improves outcomes, and there has been variable uptake of 
this strategy both pre-hospital and amongst the interventional cardiology community. 
 
The need for a randomised controlled trial 
There is an urgent need for a randomised controlled trial examining the benefits of early delivery of 
post-cardiac arrest care in specialist centres, specifically in the absence of STE. Post-arrest care is time-
critical, requires a multi-disciplinary approach and may be more optimally delivered in centres with 
greater provider experience. ILCOR and the EAPCI state that randomised trials are essential in this 
population to determine if timely delivery by the ambulance services to a CAC with organised post-
cardiac arrest care including immediate access to reperfusion therapy improves survival.3, 23 There are 
no randomised trials and only indirect evidence that CAC and systems of care may be effective and 
only two observational studies examining the role of immediate ICA±PCI in the absence of STE. This is 
an important and topical question as there is a drive to regionalise care for all patients into CACs. 
 
 Pilot study results 
The pilot was a feasibility study (that also assessed safety and efficacy outcomes) undertaken by 
London Ambulance Service (LAS), St. Thomas’ Hospital CAC, the London School of Hygiene and Tropical 
Medicine Clinical Trials Unit (LSHTM CTU) and the neighbouring district general hospitals within St 
Thomas’ CAC catchment area.  
40 patients were randomised, 10 patients were recruited between November 2014 to March 2015 
and 30 patients between August 2015 to February 2016, with an increase in recruitment rate during 
the study period. On comparison with independently collected clinical OHCA audit data, 63% of all 
eligible patients were recruited over these time periods. 

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Feasibility data have been presented and published.39 These data demonstrated no clear safety 
concerns and recruitment rate indicated the feasibility of proceeding to a larger scale trial.  
 Aim 
The aim is to determine the best post-resuscitation care pathway for patients without STE. We 
propose that changes to emergency management comprising expedited delivery to a CAC with 
organised post-cardiac arrest care including immediate access to reperfusion therapy will reduce 
mortality in patients without STE compared to the current standard of care, which comprises 
protracted pre-hospital management of the patient without definitive care plan and delivery to 
geographically closest hospital. 
 Endpoints 
 
 Primary endpoint 
All-cause mortality at 30 days. 
 
Secondary endpoints 
The impact on the following outcomes will be assessed. 
• 
Neurological status at discharge and 3 months 
• 
All-cause mortality at 3, 6 and 12 months 
• 
EQ-5D-5L at discharge 
 Power calculations and sample size determination 
Mortality at 30 days in the control arm is expected to be approximately 60% for the type of patients 
recruited into ARREST. This figure is based on Pan London OHCA data (87% mortality with ROSC at any 
time post cardiac arrest and 73% mortality with ROSC maintained to hospital), registry data and the 
pilot study.  
Observational studies on implementation of treatment bundles have shown absolute risk reductions 
(ARR) of near 30% compared to the baseline comparator and the Parisian group have shown ARR of 
16% following PCI in non-STE.3, 40, 41 If half of the population in question will have a treatable lesion 
and the combined treatment effect of this within a treatment bundle is examined, a 10% ARR will be 
practical from 60% to 50% mortality. 

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A trial of 860 patients (430 in each arm) provides 80% to detect an absolute reduction of 10% (ie 60% 
to 50%) with up to 10% losses to follow-up and a 5% significance level. If the mortality is higher than 
60% then the power will increase to detect a 10% absolute reduction in mortality. 
 Selection of patients 
 
 Identification of patients 
Patients with confirmed cardiac arrest will be assessed for eligibility by the attending LAS paramedic. 
Due to the emergency context of the research, identification cannot be performed in advance. 
Patients who re-arrest after they have been randomised into the trial will not be excluded and will be 
conveyed to an ED or CAC as indicated by their treatment allocation. If the patient re-arrests on scene 
and there is recognition of life extinct by the attending paramedic after randomisation, the patient 
will not be transferred to an ED or CAC. The patient will remain in the trial and patient data will be 
collected as discussed in section 8.1.5. 
 
Inclusion criteria 
Patients must meet all of the following criteria: 
1. Out-of-hospital cardiac arrest (OHCA) 
2. Return of spontaneous circulation (ROSC) 
3. Age 18 or over (known or presumed) 
 
 
 Exclusion criteria 
Patients will be excluded if they meet any of the following criteria: 
1. Criteria for ST-elevation myocardial infarction on 12-Lead electrocardiogram (ECG)  
2. Do Not Attempt Resuscitation (DNAR) Order 
3. Cardiac arrest suffered after care pathway set and patient en route 
4. Suspected pregnancy 
5. Presumed non-cardiac cause (for example; trauma, drowning, suicide, drug overdose) 
6. Presumed significant trauma/injury 
 
Eligibility of prisoners 
Prisoners, defined as any inmate of the prison systems of England and Wales, Scotland and Northern 
Ireland including those under the care of the probationary system, and those in police custody who 

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have not yet been charged are eligible for the ARREST trial providing they meet the inclusion and 
exclusion criteria. 
 
Eligibility of patients detained under the Mental Health Act 
Patients detained under the Mental Health Act (MHA) are eligible for ARREST providing they meet 
the inclusion and exclusion criteria.  
 
Patients entered into observational research 
Patients may be entered into registries or observational studies while also participating in ARREST. 
 Ethical considerations 
 
 Consent procedures 
There are a number of important issues in the consent procedure that have been considered. These 
include the enrolment of patients while they are in cardiac arrest, the handling of data and follow-up 
for patients who are unable to give their consent due to lack of capacity, and the handling of data 
from patients who have died. These considerations are discussed below. 
 Consent waiver prior to enrolment 
Due to the emergency nature of the trial and the immediacy of the intervention, the need for prior 
informed consent has been waived.42  
 Patient identification in hospital 
A research paramedic will contact the named local collaborator/s at the destination hospital (either 
the CAC or emergency department depending on randomised allocation). The named local 
collaborator/s will be a member of the direct care team at the hospital delegated by the local PI.  
Once identified the patient or consultee may then either; 
a) Be approached for consent or to make a declaration on the patient’s behalf by a member of 
the direct care team 
b) Be approached for consent or to make a declaration on the patient’s behalf by a research 
paramedic 
OR  
c) Asked if they can be contacted by a local researcher, a researcher allocated from the local 
research network or a research passport holder. If the patient or consultee agree to this the 

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appropriate person should be contacted and they will be responsible for gathering consent 
or a consultee declaration. 
A research paramedic, or a member of the direct care team, must make the first approach to the 
patient, their friends or family, or a professional consultee.  
The patient or family member’s wishes regarding further contact will be adhered to without 
affecting the patient’s standard of care in any way. 
 Informed Consent  
If the patient regains capacity following the cardiac arrest, informed consent should be gathered once 
the initial emergency has passed.43, 44 The earliest practicable time is anticipated to be once the patient 
is discharged from ICU (if this was clinically indicated) and is on a hospital ward. 
Consent will be obtained by research paramedics, or by a trained member of staff delegated to do so 
by the site PI. The patient will be given the patient information sheet (PIS) and allowed sufficient 
time to consider it fully and have any questions they may have addressed.  
If patients wish not to be followed up, consent will be sought to gather data from medical records. 
Non-identifiable data up until that point will be retained unless the patient explicitly declines 
permission.  
 Participants who lack capacity 
A consultee should be approached if the patient is alive but does not regain capacity. If the patient 
has died a consultee should not be approached for written consent. Please see section 8.1.5. 
8.1.4.1. 
Personal consultee 
As soon as practicable, and at a time which will cause the least distress to the patient and relatives, a 
friend, partner or relative of the patient should be informed that the patient has been entered into 
the trial. The decision to approach a friend, relative or partner is at the discretion of a research 
paramedic in consultation with the direct care team. If it is felt that this would cause undue distress a 
professional consultee may be contacted instead (see 8.1.4.2). 
If appropriate the friend, relative or partner’s advice should be taken on whether they think the 
patient would wish to be part of the trial, particularly if the patient had expressed any prior wishes or 
advanced decisions. A personal consultee declaration form should be completed, this will be obtained 
by a registered healthcare professional delegated to do so by the site PI. 

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8.1.4.2. 
Professional consultee 
A professional consultee may be used in cases where either a family member or friend is unwilling or 
unable to act as a personal consultee, or the family or friends are not present or available.   
This may either be; 
a) A doctor or healthcare provider responsible for the medical treatment provided to the 
patient, as long as that person is independent of the trial. 
OR 
b) A person independent of the trial nominated by the doctor or healthcare provider primarily 
responsible. 
Their advice should be taken on whether they think the patient would wish to be part of the trial. A 
professional consultee declaration form should be completed, this will be obtained by a registered 
healthcare professional delegated to do so by the site PI. 
Regardless of whether a professional consultee declaration has been collected, if a personal 
consultee becomes available and it is appropriate to approach them then their advice should be 
sought on the continued involvement of the patient.  
If the patient regains capacity before the one year follow-up visit, the patient should be 
approached to give informed consent regardless of whether a consultee declaration form has been 
completed.  
8.1.4.3. 
Assessment of capacity during follow up 
At the follow-up time points the personal or professional consultee will be contacted. They will be 
asked if the researcher may speak to the patient.  
• 
If on assessment it is found that the patient still lacks capacity the consultee will be asked to 
respond on behalf of the patient.  
• 
If the patient is found to have capacity then the patient information will be provided about 
the trial and consent sought.  
 Participants that have died before consent can be obtained 
If a patient does not regain capacity and dies before it is possible to gather written consent, mortality 
data available to LAS will be collected, without patient identifiable data, on the trial database.  

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8.1.5.1. 
Process for relatives to gather further information 
It is not appropriate to actively inform relatives that the deceased patient has been entered into the 
trial due to the risk that the receipt of that information may cause additional stress at a traumatic 
time. There are also practical barriers to providing the information, the sudden and unexpected 
nature of cardiac arrest will mean relatives may not be present or identifiable.  
A website containing details of the trial will be set up with details of the trial and a contact number, 
email address and postal address to contact for more information. Relatives can therefore make a 
choice themselves about whether they wish to seek further information, and at a time that suits 
them. This method has been used successfully on the PARAMEDIC-2 trial.  
 Patients that have been discharged before consent can be obtained 
If the patient is discharged from hospital before contact can be established the research paramedics 
will first verify that the patient is alive.  
• 
If the patient is found to have died then mortality data will be gathered by LAS (see 8.1.5.) 
• 
If the patient is alive an invitation letter and information sheet will be posted to their 
discharge address as soon as possible.  
If there is no response after two weeks the research paramedic will try to contact the patient by 
telephone (if a contact number a known) or by a second letter. The patient will be given the option 
of replying by phone, email or by returning a reply slip. The patient will either then be contacted to 
complete a consent form or their withdrawal will be recorded.  
Non-identifiable data will be collected using mortality tracking, review of patient notes, and data 
linkage where appropriate on those patients for which no reply has been received. 
 Advance notification of dissent 
Information regarding the trial will be given on the websites of participating organisations and on 
posters displayed at the hospitals. Patients who wish to not take part in the trial can contact the 
LSHTM CTU to register their dissent. Due to the emergency nature of the trial, it will not be possible 
to prevent patients from being randomized into the trial by LAS. However, patients, or their families, 
who are enrolled in ARREST but have previously registered their dissent using this mechanism will 
not be contacted by any study staff. 
The list of patients who have notified the trial that they do not want to be contacted will be shared 
between the LSHTM CTU and the LAS to ensure that patients are not approached. 

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 Withdrawal 
A patient may decide to withdraw from the trial at any time without prejudice to their future care.  
If the patient has previously consented, NHS records will continue to be used to gather endpoint data 
unless the patient explicitly denies permission for us to do this.  
 
Declaration of Helsinki and Good Clinical Practice 
The trial will conform to the spirit and the letter of the declaration of Helsinki, and in accordance with 
the Good Clinical Practice guidelines. 
 
 Ethical committee review 
The trial was granted ethical approval (Pan-London) by the National Research Ethics Committee (REC 
13/LO/1508) in January 2014.  
 
Confidentiality advisory group 
Due to the nature of the trial, there are three possible instances where patient identifiers in the 
absence of consent will need to be accessed by researchers.  
1. During the identification process LAS research paramedics will access LAS records in order to 
identify patients.  
2. Patients who are entered into the trial but do not regain the capacity to consent and die 
shortly after enrollment before a consultee declaration can be gathered. In these cases it is 
key that the trial is able to retain the non-identifiable data for analysis.  
3. Patients for whom there is no consent or consultee declaration, have been transferred to 
another hospital and have not replied to multiple contact attempts from the research team. 
In these cases it is key that the trial is able to track mortality data on these patients for the 
primary endpoint and retain non-identifiable data for analysis.  
Permission has been granted by CAG to allow the use of identifiable data as outlined above. The CAG 
reference number is 17/CAG/0151 
 
Trial registration 
The trial was prospectively registered with the International Standard Randomised Controlled Trials 
Registry (ISRCTN98596585404). 

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 Randomisation 
 
 Randomisation procedure 
Designated LAS staff at the Advanced Paramedic Practitioner (APP) dispatch desk will randomise 
patients into the intervention arm or control arm using the following procedure:  
• 
Paramedics attending a suspected OHCA will assess the patient for eligibility. Once eligibility 
is confirmed, the on-site paramedic will ask the APP desk to randomise the patient into the 
trial.  
• 
The on-site paramedics will call the APP dispatch desk to provide the patient details required 
to complete randomisation.  
• 
The APP desk staff will access the randomisation site, enter the required details, and generate 
a study ID and treatment allocation. Patients will be randomised either to an expedited 
transfer to a CAC (see section 10.1) or to receive standard of care (see section 10.2). 
• 
The APP desk will inform the on-site paramedic which group the patient has been randomised 
to, and the on-site paramedic will proceed as appropriate.  
• 
The APP desk will provide the necessary information to the Clinical Audit and Research Unit 
(CARU) at LAS for them to track the patient report form (PRF) to gain clinical data. 
 
Access to randomisation site 
Access to the randomisation site sealedenvelope.com will be strictly controlled and available only to 
delegated staff of the APP desk at LAS that have received appropriate training. Delegation and training 
logs will be recorded both at LAS and at the LSHTM CTU. Each staff member will have a unique account 
for accessing the randomisation site, and will not share these details of their account with other staff 
members.  
If a staff member is unable to access their account, they should contact the LSHTM CTU to request an 
account reset. APP desk staff will log in to their accounts at the beginning of each shift and remain 
logged in for the duration of the shift. Each session will time out after 12 hours. The daily login to the 
account will mitigate the risk of staff forgetting their login details and losing access to the 
randomisation service. 

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 Trial treatment 
 
Intervention: Direct to CAC  
The intervention arm consists of activation of the pre-hospital triaging system currently in place for 
post-arrest STE patients. This involves pre-alert of the CAC and strategic delivery of the patient to the 
catheter laboratory (24 hours a day, 7 days a week). Patients will receive definitive post-resuscitation 
care: intubation and ventilation, where necessary, targeted temperature management, and goal-
directed therapies including evaluation and identification of underlying cause of arrest with access to 
immediate reperfusion if necessary.24, 45 Prognostication will occur no earlier than 72 hours post-
cardiac arrest to prevent premature withdrawal of life-sustaining treatment.46 Transfer times 
estimated from the 40-patient pilot are anticipated to be 100 minutes (median; IQR 75 to 113) from 
time of arrest to the designated centre. 
 
Control: standard of care 
The control arm comprises the current standard of pre-hospital advanced life support (ALS) care 
management for patients with ROSC following cardiac arrest of suspected cardiac aetiology. The 
patient is conveyed to the geographically closest emergency department. Management thereafter will 
be as per standard hospital protocols however as in the intervention arm, prognostication is to be 
delayed in trial patients until at least 72 hours post arrest.46 
 
Crossover 
This likelihood of crossover is anticipated to be low in patients with ROSC in the absence of STE on the 
ECG. If a clinical decision is made either by the paramedic staff or the in-hospital care team that the 
patient in the standard of care arm should receive urgent coronary angiography, this will not be 
considered crossover. 
Extensive paramedic training will be provided to prevent inappropriate crossover, however if this does 
happen the patient will remain in the trial (in the arm they were randomly assigned to) as part of the 
intention to treat (ITT) analysis. 
 Safety reporting 
 
Definition 
Events that are collected on the electronic case report form (eCRF) or are part of the usual 
complications post cardiac arrest do not need to be reported for this trial. Unexpected adverse events 
should however be reported to the ARREST CTU.  

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Safety reporting for each patient should commence from time of randomisation to completion of 
follow up at one year after randomisation.  
 
Expected serious adverse events related to usual clinical care 
These events are recognised complications of cardiac arrest. They will be recorded on the eCRF but 
do not need to be reported separately on an SAE form: 
1. Death 
2. Myocardial Infarction 
3. Stroke 
4. Neurological complications 
5. Multi-organ failure 
The following are considered expected adverse events for cardiac arrest patients undergoing routine 
clinical care and as such do not need to be reported: 
1. Vascular complications 
2. Emergency surgery 
 
Unexpected serious adverse events 
Any untoward medical occurrence/effect that:  
1. Results in death 
2. Is life-threatening*  
3. Requires hospitalisation or prolongation of existing inpatient’s hospitalisation  
4. Results in persistent or significant disability or incapacity 
*Life-threatening in the definition of a serious adverse event refers to an event in which the patient 
was at risk of death at the time of event; it does not refer to an event which hypothetically might have 
caused death if it were more severe.  
SAEs should be reported to the CTU within 7 days. The report should include an assessment of 
causality by the Principal Investigator (PI) at each site. The Chief Investigator (CI) will be responsible 
for the prompt notification of findings that could adversely affect the health of patients or impact on 
the conduct of the trial. Notification of confirmed unexpected and related SAEs will be to the sponsor, 
the Research Ethics Committee (REC) and the Data and Safety Monitoring Committee (DSMC).  

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Unexpected non-serious adverse events 
The PI or research nurse should evaluate unexpected non-serious adverse events. This should include 
an assessment of causality and intensity and reports made within 14 days. The CTU will keep detailed 
records of all unexpected adverse events reported. The CI will review reports to consider intensity, 
causality and expectedness. As appropriate, these will be reported to the sponsor, the DSMC and the 
REC.  
 
Reporting unexpected adverse events 
Investigators will make their reports of all unexpected adverse events, whether serious or not, to the 
ARREST CTU by email to arrest@LSHTM.ac.uk or by secure fax to 020 7927 2189. 
 Assessment of intensity 
Mild: The patient is aware of the event or symptom, but the event or symptom is easily tolerated.  
Moderate: The patient experiences sufficient discomfort to interfere with or reduce his or her usual 
level of activity.  
Severe: Significant impairment of functioning; the patient is unable to carry out usual activities and/or 
the patient’s life is at risk from the event. 
 Assessment of causality 
Probable: A causal relationship is clinically / biologically highly plausible and there is a plausible time 
sequence between onset of the adverse event and the treatment 
Possible: A causal relationship is clinically / biologically plausible and there is a plausible time sequence 
between onset of the adverse event and the treatment 
Unlikely: A causal relationship is improbable and another documented cause of the adverse event is 
most plausible.  
Unrelated: A causal relationship can definitely be excluded and another documented cause of the 
adverse event is most plausible.   
 Data collection and follow-up 
 
Trials procedures table 
  
Pre-
hospital 
On 
arrival 
In 
hospital 
30 days 
3 
months 
6 
months 
12 
months 

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to 
hospital 
Review of eligibility 
criteria 
X 
 
 
 
  
  
  
ROSC assessment 
X 
X 
 
 
  
  
  
Randomisation 
X 
 
  
 
  
  
  
Transfer to CAC or 
hospital 
X 
 
 
 
 
 
 
PIS & Informed consent 
/ Personal Consultee / 
Professional Consultee 
 
 
X 
 
  
  
  
Neurological status 
 
 
X 
 
X 
 
 
Mortality status 
 
X 
X 
X 
X 
X 
X 
EQ-5D-5L 
  
  
 
X 
 
 
 
Service use 
questionnaire 
 
 
 
X 
X 
 
 
SAE / NSAEs 
X 
X 
X 
X 
X 
 
 
 
 
Data collection 
The research paramedics at LAS will collect data for pre-hospital care from the patient report form 
(PRF) until the patient is consented. If the patient dies before consent is obtained research 
paramedics will collect mortality data. Delegated research nurses will collect data for in-hospital care 
and the 30-day and 3-month follow up time points. Delegated research nurses at St Thomas’ will 
collect mortality data for the 6-month and 12-month follow-up time points. 
 
 

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Trials procedures 
 Pre-hospital care: 
• 
Group assignment (Intervention or Control) 
• 
Time of arrest 
• 
Location of arrest 
• 
Arrival time of first responder 
• 
CPR start time 
• 
Ambulance arrival time 
• 
Time of first LAS defibrillation 
- Total number of shocks 
• 
Time of first public access defibrillation (PAD) 
- Total number of shocks 
• 
Cardiac arrest drugs administered 
• 
ROSC pre-hospital 
• 
12 Lead ECG 
• 
Type of rhythm (initial) 
• 
Use of mechanical CPR 
• 
Survival to hospital 
• 
Time LAS left scene 
• 
Name of first hospital 
• 
Arrival time at first hospital 
• 
Confirmation that treatment allocation was carried out as randomised 
• 
AVPU scale on arrival 
• 
Cerebral performance category (CPC) or mRS score on arrival 
• 
Glasgow coma score (GCS) on arrival 
• 
Advanced airway management (i-gel or endotracheal tube) 
• 
Ventilated 
 In-hospital care: 
• 
Angiogram completed 
- Date and time 
- Extent of coronary artery disease (CAD) 
• 
Revascularisation 
- PCI or CABG 
- If PCI, which artery 
- Call to balloon 
- Door to balloon 
- PCI success 
• 
Complications 
- Troponin elevation 
- Myocardial infaction 
- Stroke 
- Repeat revascularisation 
- Bleeding 
- Mechanical CPR related complications 
- Need for dialysis/haemofiltration 
- Creatinine collected 
- eGFR collected 

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- Sepsis 
- Vascular complications 
- Other complications 
• 
LV function on echo 
• 
Chest x-ray findings 
• 
Implantable cardioverter defibrillator inserted 
• 
Service use 
• 
Patient mortality 
• 
CPC or mRS score at discharge 
• 
Date of discharge 
• 
Quality of life (EQ-5D-5L) at discharge (capped at 30 days) 
 30 days post-randomisation: 
• 
Patient mortality 
• 
30 day hospitalisation status 
 3 months post-randomisation: 
• 
Patient mortality 
• 
CPC or mRS score by telephone 
• 
Service use questionnaire by telephone 
 6-months post-randomisation: 
• 
Patient mortality 
 12-months post-randomisation: 
• 
Patient mortality 
 Monitoring and auditing 
 
Monitoring 
The conduct of the trial will be supervised by trained staff from the LSHTM CTU. The trial will be 
monitored on a regular basis using central statistical monitoring. On site monitoring will take place if 
considered necessary by the LSHTM CTU or if requested by the trial site.  
Local investigators shall ensure that all trial data are available for trial related monitoring, audits and 
research ethics committee review. 
The CTU will periodically monitor consent forms and consultee declarations obtained by LAS research 
paramedics to ensure that the consent procedure is being correctly followed.  

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 Statistical considerations 
 
Statistical analysis plan 
A detailed statistical analysis plan will be produced prior to any analysis of the data by treatment 
groups. 
 
Statistical analysis 
The primary analysis will be a comparison of all-cause mortality 30 days after randomisation between 
the two arms. A risk ratio together with a 95% confidence interval and p-value will be calculated 
together with the risk difference in all-cause mortality at 30 days. Similarly, these analyses will be 
undertaken for all-cause mortality at 3, 6 and 12 months. Kaplan-Meier curves will be produced to 
show all-cause mortality to 30 days and to 12 months. Survival techniques will be used to compare in 
hospital MACCE given the differing lengths of time patients might be in-hospital. Hazard ratios will be 
presented from Cox proportional hazards modelling. Neurological status will also be compared at 3 
months using the CPC score (an ordinal score from 1 (normal neurological status) to 5 (dead), 
according to the most commonly used post-resuscitation outcome measurement for this purpose.47 
Ordered logistic regression will be used to compare the two treatments and a trend test computed. 
Although the subjectivity of this scoring system and its agreement with other markers of neurological 
status has been questioned, it remains the most commonly used and standard outcome measure of 
neurological status in post-cardiac arrest survivors.48-50 
 
Intention to treat 
Intention to treat (ITT) analysis will be performed as the primary statistical method; this includes all 
randomised patients in the groups to which they were randomly assigned, regardless of their 
adherence with the entry criteria, treatment they actually received, and subsequent withdrawal from 
treatment or deviation from the protocol.51 
 
Planned subgroup analysis 
A limited number of subgroup analyses on the primary endpoint will be undertaken using logistic 
regression including an interaction between the characteristic and the intervention with effect 
estimates and confidence intervals produced. In addition, a subgroup analysis will be undertaken by 
developing a model using logistic regression and categorizing patients according to their underlying 
risk of dying within 30 days. This simultaneously accounts for the multiple risk factors a patient may 
have at baseline and will assess whether intervention is more effective at higher underlying risk again 
using interactions tests. 

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Bias 
The major sources of bias in this trial are potentially a differential loss to follow up in the two arms 
and unblinding of patients and clinicians due to the radically different pathways.  
It is not anticipated bias will affect the primary outcome of all-cause mortality as this is an objective 
measure. 
 
Potential risks and hazards 
A potential risk is the inclusion of patients with non-cardiac causes of arrest. This will be mitigated by 
exclusion of non-obvious cardiac cause during eligibility assessment. 30-day all-cause mortality and 
in-hospital MACCE will enable identification of such risk with DSMC interim analysis. 
 
Early termination of trial 
A fully independent DSMC will be established to monitor the safety of patients in the trial and a 
detailed Data Monitoring Charter will be developed. The sample size will not be adjusted to account 
for interim analyses; however stringent guidelines will be used for the stopping criteria for a benefit 
of the intervention.52  
The trial will be terminated if there is substantial or sufficient evidence of a benefit of the intervention 
or an increased mortality risk compared to control. The DSMC will also monitor recruitment and other 
trial progress. 
If the required number of patients is completed in advance of estimated recruitment time then the 
trial may be completed ahead of schedule depending on the event rates observed. Alternatively, if 
resources are available recruitment may continue in order to maximise the power of the trial. 
 Data handling and record keeping 
Data will be entered onto an online database and stored securely on Rackspace servers; 
http://www.rackspace.co.uk and managed by Sealed Envelope. Data will be kept for 15 years 
following completion of the trial. The data controller for the trial is the Chief Investigator (St Thomas’ 
Hospital is the data controller’s organisation) and the data processor is the LSHTM CTU. 
Personal data collected during the trial will be handled and stored in accordance with the 1998 Data 
protection act and LSHTM SOPs. 

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 Insurance 
All centres will be covered by NHS indemnity for negligent harm providing researchers hold a contract 
of employment with the NHS, including honorary contracts held by academic staff. Medical co-
investigators will also be covered by their own medical defence insurance for non-negligent harm. 
King's College London provides cover under its No Fault Compensation Insurance, which provides for 
payment of damages or compensation in respect of any claim made by a research subject for bodily 
injury arising out of participation in a clinical trial or healthy volunteer study (with certain restrictions). 
 Publications 
 
Policy 
Publications will follow the CONSORT guidelines. Authorship will follow international guidelines. 
 
Expected value of results 
There are no randomised control trial (RCT) data demonstrating that time critical delivery to a CAC for 
definitive care improves survival, and the management of patients without STE is controversial. 
Survival following OHCA remains extremely poor in this cohort at huge cost to the NHS. There is an 
urgent need for RCT data examining the benefits of urgent delivery of post-cardiac arrest care in 
specialist centres, specifically in the absence of STE. Post-arrest care is time-critical, requires a 
multidisciplinary approach and may be more optimally delivered in centres with greater provider 
experience. 
This trial would demonstrate if regionalisation of post-arrest care to specialist centres reduces 
mortality in the non-STE cohort, thus dramatically reshaping emergency care provision. Either 
supporting or refuting the current drive, in the lack of randomised data, to immediately transport all 
post-arrest patients with non-obvious cardiac cause to a CAC. 
 
Dissemination 
It is our intention to disseminate the results of the trial as widely as possible. This is likely to be through 
a publication in a peer-reviewed journal, and through presentations at National and International 
Cardiology conferences. 
 

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 Trial organisation 
 
Trial and logistics management 
The UK Clinical Research Collaboration accredited LSHTM CTU will be responsible for management for 
the trial, statistical analysis, database design, data collection and ensuring the trial is run to Good 
Clinical Practice (GCP) standard. 
 
Trial steering committee 
The Trial Steering Committee (TSC) is responsible for approving the trial protocol, monitoring trial 
progress and maintaining the scientific integrity of the trial through consultations and updates. 
Dr Mark De Belder (Chair) - Independent Cardiologist 
Prof Simon Redwood (Chief Investigator) - Cardiologist  
Prof Nick Curzen - Independent Cardiologist 
Dr Dawn Adamson - Independent Cardiologist 
Dr Lucy Blows - Independent Cardiologist 
Mr Garth Lane - Independent patient representative 
Mr Michael Connor - Independent patient representative 
Dr Tiffany Patterson – NIHR Academic Clinical Lecturer/ Specialist Registrar in Cardiology 
Prof Mamas Mamas – Independent Cardiologist 
Prof Martin Brown – Independent Neurologist 
Mr Mark Whitbread - Consultant Paramedic at LAS 
Observers: 
Mr Alexander Perkins - Trial Manager 
Mrs Karen Wilson - Cardiovascular Research Matron 
Dr Shannon Amoils - BHF representative 
Mr Tim Clayton - Associate Professor, LSHTM 
Mr Richard Evans - Senior Manager of the Clinical Trials Unit  
 
 
Project management group 
Prof Simon Redwood - Chief Investigator / Cardiologist 
Dr Tiffany Patterson - Specialist Registrar in Cardiology 
Mrs Karen Wilson - Cardiovascular Research Matron 

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Mr Alexander Perkins - Trial Manager 
Mr Richard Evans - Senior Manager of the Clinical Trials Unit 
Mr Tim Clayton - Associate Professor, LSHTM 
Mr Mark Whitbread - Consultant Paramedic at LAS 
Dr Joanne Nevett - Clinical Advisor to the Medical Director of LAS 
Prof Rachael Fothergill - LAS Head of CARU 
Mr Adam Smith - LAS Paramedic Research Fellow 
 
Data and safety monitoring committee 
Dr Rod Stables (Chair) - Independent Cardiologist 
Mr Tim Morris - Independent Statistician 
 
 

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Appendix A: List of sites and Principal Investigators 
London Ambulance Service 
LAS is responsible for identification, randomisation and delivering the trial treatment. 
Site 
 
 
 
 
 
Principal Investigator 
London Ambulance Service 
 
 
Prof Rachael Fothergill 
CAC Sites 
Site 
 
 
 
 
 
Principal Investigator 
St Thomas Hospital 
 
 
 
Dr Tiffany Patterson 
St Barts’ Heart Centre  
 
 
Dr Ajay Jain 
King’s College Hospital  
 
 
Professor Philip MacCarthy 
Harefield Hospital 
 
 
 
Dr Miles Dalby 
St George’s Hospital 
 
 
 
Dr Sami Firoozi 
Royal Free Hospital 
 
 
 
Dr Roby Rakhit 
Hammersmith Hospital  
 
 
Dr Iqbal Malik 
Emergency Departments 
The following sites will receive patients randomised to control only.  
Site 
 
 
 
 
 
Principal Investigator 
St Thomas’ Hospital (ED only) 
 
 
Dr Tiffany Patterson 
King’s College Hospital (ED only) 
 
Professor Philip MacCarthy 
Harefield Hospital (ED only) 
 
 
Dr Miles Dalby 
St. George’s Hospital (ED only)  
 
Dr Sami Firoozi 
Royal Free Hospital (ED only) 
 
 
Dr Roby Rakhit 
Hammersmith Hospital (ED only) 
 
Dr Iqbal Malik 
Barnet Hospital  
 
 
 
Dr Roby Rakhit 
Northwick Park Hospital 
 
 
Dr Nigel Stephens 
Hillingdon Hospital 
 
 
 
Dr Gareth Rosser 
Queens Hospital, Romford 
 
 
Dr Darryl Wood 
University College Hospital 
 
 
Dr Robert Bell 
Homerton Hospital 
 
 
 
Dr Arvinder Kurbaan 
Ealing Hospital  
 
 
 
Dr Nigel Stephens 

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Queen Elizabeth Hospital 
 
 
Dr Antonis Pavlidis 
North Middlesex Hospital 
 
 
Dr Muhiddin Ozkor 
West Middlesex Hospital 
 
 
Dr Sukhjinder Nijjer 
Whittington Hospital 
 
 
 
Dr Rita Das 
Kingston Hospital 
 
 
 
Therese Sidney 
University Hospital Lewisham   
 
Dr Antonis Pavlidis 
St Helier Hospital 
 
 
 
Dr Richard Bogle 
Newham Hospital 
 
 
 
Dr Ajay Jain 
St Mary’s Hospital 
 
 
 
Dr Iqbal Malik 
King George Hospital 
 
 
 
Dr Darryl Wood 
Charing Cross Hospital  
 
 
Dr Iqbal Malik 
Chelsea and Westminster Hospital 
 
Dr Patrick Roberts 
Princess Royal Hospital  
 
 
Dr Ian Webb 
Croydon University Hospital 
 
 
Dr Oliver Spencer 
Darent Valley Hospital  
 
 
Dr Edward Petzer 
Watford Hospital 
 
 
 
Dr Masood Khan 
Royal London Hospital  
 
 
Dr Ajay Jain 
Whipps Cross Hospital  
 
 
Dr Ajay Jain 
Central Middlesex Hospital 
 
 
Dr Nigel Stephens 
Chase Farm Hospital 
 
 
 
Dr Roby Rakhit 
East Surrey Hospital 
 
 
 
Dr Maciej Marciniak 
 
 
 
 
 
 

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Appendix B: EQ-5D-5L 
 

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