BMJ OpenBSc (Hon), MBBS, MRCP, PhD, Dip, M.Ed, FESC. MSc National Institute for Health Research...

For peer review only

Cohort profile: Investigating variation in hospital acute coronary syndrome outcomes: Evaluation of the Methods

and Management of Acute Coronary Events (EMMACE)-3: a longitudinal study

Journal: BMJ Open

Manuscript ID: bmjopen-2014-006256

Article Type: Protocol

Date Submitted by the Author: 31-Jul-2014

Complete List of Authors: Alabas, Oras; University of Leeds, Division of Epidemiology and Biostatistics West, Robert; University of Leeds, Leeds Institute of Health Sciences Gillott, Richard; Leeds Teaching Hospitals NHS Trust, Leeds, UK, Department of Cardiology Khatib, Rani; Leeds Teaching Hospitals NHS Trust, Leeds, UK, Department of Cardiology Hall, Alistair; Leeds Teaching Hospitals NHS Trust, Leeds, UK, Department of Cardiology; Leeds General Infirmary, Institute for Cardiovascular Resaerch

Gale, Chris; University of Leeds, Divison of Epidemiology and Biostatistics; York Teaching Hospital NHS Foundation Trust, Cardiology

<b>Primary Subject Heading</b>:

Cardiovascular medicine

Secondary Subject Heading: Cardiovascular medicine, Epidemiology

Keywords: Cardiac Epidemiology < CARDIOLOGY, Coronary heart disease < CARDIOLOGY, Myocardial infarction < CARDIOLOGY

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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Title: Cohort profile: Investigating variation in hospital acute coronary syndrome

outcomes: Evaluation of the Methods and Management of Acute Coronary

Events (EMMACE)-3: a longitudinal study

Authors: Alabas OA1, West RM2, Gillott RG3, Khatib R3, Hall AS3, Gale CP1,4 on behalf

of the EMMACE-3 Investigators

1 Division of Epidemiology and Biostatistics, University of Leeds, Leeds, UK

2 Leeds Institute of Health Science, University of Leeds, UK

3 Department of Cardiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK

4 York Teaching Hospital NHS Foundation Trust, York, UK

Correspondence: Chris P. Gale

BSc (Hon), MBBS, MRCP, PhD, Dip, M.Ed, FESC. MSc

National Institute for Health Research Clinician Scientist Award Associate Professor of

Cardiovascular Health Research and Honorary Consultant Cardiologist

Division of Epidemiology and Biostatistics, Level 8, Worsley building, University of Leeds,

Clarendon Way, West Yorkshire, Leeds, LS2 9JT, UK

Key words: EMMACE-3, acute coronary syndrome, health related quality

of life, medications, outcomes

Word count: 2166

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Abstract

Purpose: Patients with cardiovascular disease are living longer and are more frequently

accessing healthcare resources. The Evaluation of the Methods and Management of Acute

Coronary Events (EMMACE-3) national registry is designed to investigate the long-term

trajectories of recovery from hosptialised acute coronary syndrome using multiple electronic

health records linked to prospective survey data.

Patients: Of the cohort, patients aged 18 years or older, who have been admitted with ACS

at one of the participating hospitals in England. The spectrum of ACS phenotypes includes

ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI) and troponin negative

ACS (unstable angina (UA)).

Findings to date: Prospective, longitudinal data are collected at four time points: in-hospital,

one month, six months and twelve months. These include repeated measures of: 1) health

related quality of, 2) General Practitioner and hospital specialists appointments, 3) physical

activity, 4) cardiac rehabilitation, 5) prescribed medications and 6) indices of medicines-

taking behaviour including the Morisky Medication Adherence, Adherence Estimator, A

modified version of the Single Question, Beliefs about Medicines Questionnaire and other

adherence probing questions.

Future plans: The complete data analysis of this cohort study will allow the evaluation of the

full pathway of care from hospital to community, providing data which other cardiovascular

studies lack. We also aimed to investigate the long-term trajectories of recovery from an

ACS (until death) as well as describing guideline recommended medicines and adherence

profiles.

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Key Messages

• EMMACE-3 is the largest contemporary national longitudinal study of detailed

trajectories of recovery after hospitalised acute coronary syndrome.

• Comprehensive patient-level and hospital-level data are collected using multiple

electronic health records linked to bespoke prospective repeated survey data.

• Together with EMMACE-3X and EMMACE-4, EMMACE-3 will collect repeated

measures data relating to around 12,000 patients admitted to hospitals across

England.

• Non-identifiable data will be made available to academic collaboratores upon

approval of applications.

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INTRODUCTION

Cardiovascular health and care

The last 10 years has seen a declince in mortality rates from cardiovascular disease.1,2 In

the United Kingdom (UK) from 2003 through 2010, the risk of in-hospital mortality from an

acute coronary syndrome (ACS) has fallen by half.3,4 Nevertheless, cardiovascular disease

is the leading cause of death in the UK and responsible for over 4 million deaths per year in

Europe.5,6

In addition, cardiovascular disease confers a substantial morbidity and finacial burden.7,8

Elderly patients with ACS account for more than half of all admissions to hospital.9,10 As a

result of a reduction in mortality rates patients are living longer and more frequently

accessing health care services. The forcasted impact of heart failure, cerebrovascular

disease and recurrent ACS as a result of improved survival is unpreceented.7,11,12 Moreover,

cardiovascular disease already costs the UK economy £29.1 billion in healthcare, informal

care and productivity losses.8 Consequently, there are new challenges for making the best

use of scarce healthcare resources. Future policies will require enhanced regulatory

apparatus to respond to the increasing demand.

Two important question facing healthcare decision-makers are: 1) how do patients recover

from an ACS, and 2) how does their initial presentation and hospital care impact on

subsequent healthcare resource use and health-related outcomes? Recently, a succession

of large-scale UK observational studies were funded in the UK aiming to improve

understanding of the variation in cardiovascular quality of care and outcomes.13 We also

have sought to anticipate and understand these challenges. In this paper we describe the

profile of the Evaluation of the Methods and Management of Acute Coronary Events

(EMMACE-3) study, a unique national collaborative research effort to collect repeated

measures for hospital readmissions, medicines and their adherence profiles, cardiac

rehabilitation, health related quality of life and cause-specific mortality in patients

hospitalised with ACS.

Evaluation of the Methods and Management of Acute Coronary Events (EMMACE)

EMMACE-3 is the third in a series of prospective studies. EMMACE-1 and EMMACE-2 were

regional, multi-centre, cross-sectional evaluations of around 2500 hospitalised ACS patients

each, undertaken in 1994 and 2003, respectively. That coincided with being five years

before and then also after the major national initiative in this area: the National Service

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Framework (NHS) for Coronary Heart Disease).14 The original study (commissioned by NHS

R&D) was tasked with assessing alternate methods of case ascertainment and their impact

on assessment of quality of care.15 To date, they have each reported variations in hospital

outcomes,16,17 temporal improvements in the adherence to guideline recommended

therapies and their association with a decline in mortality rates, 18 survival effectiveness of

cardiac rehabilitation,19 impact of clinical investigations and treatments on mortality 20-22 and

the relative impact of diabetes on early and late mortality by temporal changes in hospital

care.23, 24 EMMACE-3, undertaken between 1st November, 2009 and 17th September, 2013,

has an improved design over its predecessors being longitudinal and utilising multiple

electronic health record (EHR) linkages to offer previously unavailable scope for advanced

statistical techniques to infer causality from observation data.

EMMACE-3

EMMACE-3 is a national, multi-centre, prospective, linked, longitudinal cohort study of

patients admitted with an ACS to National Health Service (NHS) hospitals in England. The

study has favourable ethical approval from the Leeds (West) Research Ethics Committee

(10/H1313/74). All patients were consented to enter the study and given the option for their

data to be used for the purposes of future research. EMMACE-3 has collected unique

longitudinal patient-level data enhanced by multiple linkages to cross-sectional electronic

health record data from both research and administrative sources including a survey of

hospital facilities, the Office for National Statistics (ONS) data and the national heart attack

register (Myocardial Ischaemia National Audit Project, MINAP).25 EMMACE-3, therefore,

provides a national registry of previously unrecorded data of the trajectories of recovery from

ACS.

EMMACE-3 was designed to improve our understanding of the effect of quality of care on

long-term health-related outcomes of patients hospitalised with ACS. The study aims to

quantify variation in health-related outcomes from ACS and to identify modifiable factors

which could lead to improved quality of care and health. It will allow the evaluation of the full

pathway of care from hospital to community, providing data which other cardiovascular

studies lack. We also aimed to investigate the long-term trajectories of recovery from an

ACS (until death) as well as describing guideline recommended medicines and adherence

profiles.

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COHORT DESCRIPTION

Study design

EMMACE-3 is a prospective longitudinal cohort study of ACS outcomes from time of

discharge over 1 year. The combined primary end point will be time to first occurrence of a

major adverse cardiovascular events (MACE), defined as one of the following: death, non-

fatal acute myocardial infarction and coronary revascularisation. The secondary end points

will be (i) quality of life assessed using EuroQol 5-dimension, EQ-5D26, (ii) readmission to

hospital with ACS, (iii) new diagnosis of or hospitalisation for heart failure, (iv) adherence to

medication, (v) cessation of smoking, (vi) completion of cardiac rehabilitation.

Study setting

EMMACE-3 is funded by the National Institute for Health Research (NIHR). The NIHR is

funded through the UK Department of Health to improve the health and wealth of the nation

through research. 27 EMMACE-3 is based at the University of Leeds who is its sponsor. Data

storage, linkage, sharing and other processing will be facilitated through the Medical

Research Council funded (MR/L01629X/1) Bioinformatics Centre at the University of Leeds

in partnerhsip with Leeds Teaching Hospitalis NHS Trust. EMMACE-3 forms part of a

portfolio of collaborative cardiovascular studies using EHRs working with a number of

partner organisations including the Farr Institute, University College London. The EMMACE-

3 investigators and collaborators are a multidisciplinary team of epidemiologists,

biostatisticians, health service researchers, health informaticians and clinical cardiologists.

Participants

EMMACE-3 cohort includes patients aged 18 years or older, who have been admitted with

ACS at one of the participating hospitals in England. The spectrum of ACS phenotypes

includes ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI) and troponin

negative ACS (unstable angina (UA))28. Figures 1 and 2 illustrate the spatial coverage and

rate at which 5375 participants with ACS from a total of 48 hospitals volunteered to be part

of this project. Each hospital provided their own recruitment support (Research Nurses)

funded through the NIHR-CLRN funding stream (5.2 Research Support Services Version 5).

This model encouraged an exponential rate of new centre participation as each hospital

acted as active stake-holders in the funding model. Moreover, the original study size

increased from less than 2000 to over 5000 ahead of time and target. We understand this to

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have been a fairly unique achievement as well as a fitting demonstration of the potential

strenghts of the new NHS R&D funding model. Consequently, EMMACE-3 has become an

important contributor to the NIHR Clinical Research Network cardiovascular research

portfolio.

Data collection

EMMACE-3 combines self-reported longitudinal data on numerous health parameters with

cross-sectional disease-specific clinical information (Figure 3). The cross-sectional data

includes: data from 1) the Myocardial Ischaemia National Audit Project (MINAP), 2) a survey

of hospital-level cardiovascular facilities and 3) patient-level deprivation indices (Index of

Multiple Deprivation score, Townsend score).29 Demographic data such as age, sex, place of

treatment and residency are recorded during the hospital admission.

Follow-up

Information is collected at four time points: in-hospital, one month, six months and twelve

months. This includes measures of: 1) health related quality of life (EQ-5D),26 2) General

Practitioner and hospital specialists appointments, 3) physical activity, 4) cardiac

rehabilitation, 5) prescribed medications and 6) indices of medicines-taking behaviour

including the Morisky Medication Adherence, Adherence Estimator, A modified version of the

Single Question, Beliefs about Medicines Questionnaire and other adherence probing

questions (Figure 3).30-34 Before each participant is sent a questionnaire their mortality status

is checked using the NHS Summary Care Record. Non-responders are issued a second and

third questionnaire, and contacted directly by telephone. The questionnaire data are linked to

cause-specific mortality and date of death (from linkage to the Office for National Statistics)

using each patient’s unique 10-digit NHS number, which is generated by the UK government

for every NHS user upon first entry into the healthcare system.

Statistical analysis

Shared frailty survival models (nesting patients within hosptials) will be used to estimate

factors associated with time to primary endpoint. Factors to be evaluated will include

medications, health related quality of life and hosptial facilities data, as well as baseline

clinical charactersitiscs. Sequential health related quality of life data will be studied both as a

measure of outcome (recovery pattern) and predictor of outcome (prognostic marker).

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Missing data will be multiply imputed, with values will be derived from an imputation model

based upon the observed values.35

FINIDINGS TO DATE

Cohort composition

Table 1 shows distrbution of EMMACE-3 hospitals’ facilities. Main baseline patient

characteristics were summarised in Table 2. There were 73.9% male, mean (SD) age 64.4

(11.9) years), the median (IQR) length of hospital stay was 4 (4-4) days. During

hospitalisation, mean (SD) of EQ-5D score was 0.74 (0.30) and mean (SD) EQ-5D visual

analogue score was 64.1 (20.0).

Attrition rate

Figure 4 shows a flow diagram of number of patients recruited at each stage. Of the

survivors, 5326 (99.1%) completed the in-hospital questionnaires and 4513 (84.0%), 4062

(75.6%) and 3512 (65.3%) subjects participated at one month, six months and 12 months,

respectively. At these latter time points 0.4%, 0.9%, 2.5% and 2.1% of the questionnaire

data attrition was due to deaths. The characteristics of patients by response to the

questionnaires are shown in Table 3.

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Table 1: Distrbution of EMMACE-3 hospitals’ facilities

Hospital Characteristics N (%)

Foundation Status 33 (68.8)

Primary PCI availability, 24 hours 7 days per week?

No 33 (71.7)

Yes 13 (28.26)

Number of Consultant Cardiologists

<5 21 (56.8)

≥5 16 (43.2)

Number of specialist ACS nurses

None 24 (55.8)

<5 13 (30.2)

≥5 6 (14.0)

Number of specialist heart failure nurses

None 9 (19.6)

<5 32 (69.6)

≥5 5 (10.9)

Number of specialist cardiac rehabilitation nurses

None 2 (4.8)

<5 30 (71.4)

≥5 10 (23.8)

Number of cardiology beds

None 4 (8.7)

<20 13 (28.3)

≥20 29 (63.0)

Number of Coronary Care Unit beds

<10 23 (51.1)

≥10 22 (48.9)

Distance to the nearest intervention centre, miles

Not applicable 15 (34.9)

<20 10 (23.3)

≥20 18 (41.9)

PCI: percutaneous coronary intervention

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Table 2: Baseline patient characteristics, from hospital admission data

Patient Characteristics N (%)

Demographics

Mean (SD) age, years 64.4 (11.9)

Men 3969 (73.8)

White 3138 (95.2)

Mean (SD) IMD score* 22.6 (15.5)

Current smoker 1142 (32.9)

Ex smoker 1215 (35.0)

Mean (SD) body mass index 28.8 (6.5)

Past medical history

Hypertension 1573 (45.3)

Diabetes mellitus 537 (15.5)

Previous angina 851 (24.5)

Previous myocardial infarction 709 (20.4)

Cerebrovascular disease 168 (4.8)

Asthma or COPD 434 (12.5)

Chronic renal failure 106 (3.1)

Chronic heart failure 68 (2.0)

Peripheral vascular disease 115 (3.3)

Acute coronary syndrome phenotype

STEMI 1,335 (38.6)

NSTEMI 2,008 (58.0)

Unstable angina 47 (1.4)

Medications prescribed at hospital discharge^

Aspirin 3,026 (89.3)

β blockers 2,781 (82.1)

Angiotensin converting enzyme (ACE) inhibitors 2,827 (83.5)

Statins (HMG Co-A reductase inhibitors) 3,025 (89.3)

Thienopyridine inhibitors 2,646 (78.4)

*IMD score: Index of Multiple Deprivation score for 2010

^ for survivors of the hospital stay, sample of medications given

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Table 3: Characteristics of participants by EMMACE-3 survey response

Follow-up Hospital stay One month Six months Twelve months

Patient characteristics Responder Non-responder Responder Non-responder Responder Non-responder Responder Non-responder

Denomenator N=5325 N=49 N=4454 N=862 N=3907 N=1313 N=3287 N=1863

Demographics

Mean age (SD), years 64.4 (11.9) 63.2 (14.2) 65.3 (11.4) 59.2 (12.8) 65.8 (11.2) 59.0 (12.1) 66.4 (10.9) 59.7 (12.0)

Men (%) 3919 (73.9) 36 (73.5) 3279 (73.7) 649 (75.4) 2871 (73.5) 993 (75.7) 2418 (73.6) 1394 (74.9)

White 3102 (95.2) 21 (91.3) 2643 (96.3) 460 (94.3) 2345 (95.8) 709 (92.9) 1982 (96.0) 1034 (93.2)

Median (IQR) IMD score 18.1 20.6 17.4 22.5 17.1 21.4 16.7 18.8

ACS phenotype

STEMI 1321 (38.7) 9 (34.6) 1113 (38.0) 212 (42.6) 985 (37.9) 330 (42.3) 827 (37.7) 482 (42.1)

NSTEMI 1982 (58.0) 17 (65.4) 1,717 (58.7) 269 (54.0) 1522 (58.6) 425 (54.4) 1287 (58.7) 627 (54.8)

UA 47 (1.4) 0 43 (1.5) 4(0.8) 42 (1.6) 5 (0.6) 37 (1.7) 10 (0.9)

ACS: acute coronary syndrome, STEMI: ST-elevation myocardial infarction, NSTEMI: non ST-elevation myocardial infarction, UA: unstable

angina.

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Electronic health records linkage

EMMACE-3 embraces the efficiency of contemporary observational research design. It

imports, pools and links EHR information derived from existing national clinical and

administrative data warehouses to the additional prospective and repeated relevant

healthcare measures. For mortality status the linkage success was 96.0%. Presently, for

MINAP and hospital facilities data, the import success is 66.2% and 100.0% respectively

(Table 4).

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Table 4: Data sources, types of data and collection system linked in the EMMACE-3 study

Parameter categories Data source Data type Linkage /recording

success

Clinical phenotype, characteristics and treatments MINAP Cross-sectional 66.2%

Date of death NHS Summary Care Record Longitudinal 96.0%

Cause of death ONS Longitudinal In process

Hospital facilities data EMMACE-3 survey Cross-sectional 100 %

Deprivation scores Department of community

and local government

Cross-sectional 94.5%

Survey data: hospital stay EMMACE-3 survey Longitudinal 99.1%

Survey data: one month from hospital discharge EMMACE-3 survey Longitudinal 83.0%

Survey data: six months from hospital discharge EMMACE-3 survey Longitudinal 72.7%

Survey data: twelve months from hospital discharge EMMACE-3 survey Longitudinal 61.2%

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International cardiovascular research platform

Each participant was asked if they would be willing to have their contact details and clinical

data securely stored on a database, and to be contacted for potential participation in future

observational studies and clinical trials. In total, 5375 consented to particate in EMMACE-3

and 3875 to have their data stored for the puposes of re-contact if necessary.

Data governace and collaboration

One of the goals of EMMACE-3 is to enable and facilitate national and international

collaborations with other research studies, researchers and industry. The rich patient-level

data will be an important resource for the identification of cardiovascular participants into

trials. Further information about the study is available at ClinicalTrial.gov (NCT01808027),

EMMACE.org. Collaborators are invited to contact the Chief Investigator, Chris Gale at

[email protected]. Data will be available to non-commercial research organisations

subject to approval by the CI. Only pseudonymised data will be released to collaborators.

EMMACE studies

EMMACE-3X

EMMACE-3X is an EMMACE-3 extension study with favourable ethical approval

(13/YH/0277). It is collecting health related quality of life data including EQ-5D, MacNew 36

and medications data for each participant annually until death or up to 10 years. Furthermore

it links EMMACE-3 data with Hospital Episode Statistics (HES) and primary care data

(Figure 3). Further information about EMMACE-3X is available at ClinicalTrial.gov

(NCT01955525), EMMACE.org.

EMMACE-4

EMMACE-4 has favourable ethical approval (12/WM/0431) and is the latest active study in

the EMMACE series. It is adopted onto the NIHR CRN portfolio and will accrue 6000

participants across England. It, also, is a longitudinal study of ACS trajectories of recovery

after hospitalisation with ACS. EMMACE-4 will enhance its data collection using EHR data

from primary care (using databases such as; The Phoenix Partnership (TPP) Research One

and The Clinical Practice Research Datalink (CPRD)), pharmacy databases and from

linkage to HES data. In addition, it is collecting patient reported experience measures (The

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Picker Patient Experience Questionnaire PPE-15),37 repeated measures of EQ-5D (Brooks,

1996),28 Brief Illness Perception (IPQ), 38 the Satisfaction with Information about Medicines

Scale (SIMS), 39 Single Question,33 medications adherence and cause-specific mortality

(Figure 3). Further information about EMMACE-4 is available at ClinicalTrial.gov


STRENGTHS AND LIMITATIONS

EMMACE-3 is the largest contemporary longitudinal study of detailed trajectories of quality

of health care and outcomes for ACS. Other observational cardiovascular studies have been

instrumental in realising the research potential of linked EHRs, but have been limited by the

their lack of data for health related quality of life and medication adherence. 40 The study

strengths are:

• National and representative sample of contemporary ACS hospitalisations

• Multi-centre design allowing comparative analyses

• Repeated multi-dimensional validated measures of health related quality of life and

medication adherence profiles

• Efficiency of research data enhancement through bespoke linkages to clinical and

administrative electronic health care records

• Participant consent to enter future research studies

• Scalability through responsive funding from the NIHR

• Potential for health economic evaluations

There are, however, a number of limitations. Case ascertainment is not 100% and there is

evidence for survivorship bias. However, recruitment of all ACS was not the remit of

EMMACE-3. If necessary, more complete case ascertainment of ACS may be estimated

through the pooling of multiple secondary and primary care sources of EHRs. 34 For the

questionnaire data, missingness varied between 2% and 40%, and for MINAP data fields

varied between 1% and 10%. Our experience of handling missing data will be employed to

help mitigate the bias there is evidence for survivorship bias. 35

Author affiliations

1 Division of Epidemiology and Biostatistics, University of Leeds, Leeds, UK

2 Leeds Institute of Health Science, University of Leeds, UK

3 Department of Cardiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK

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4 York Teaching Hospital NHS Foundation Trust, York, UK

Acknowledgement

We gratefully acknowledge the participation of the EMMACE hospitals, their research staff,

principal investgators and the EMMACE study team.

EMMACE-3 investigators:

Basel Hanbali Airedale NHS Foundation Trust, John Davies Basildon and Thurrock

University Hospitals NHS Foundation Trust, Ranjit More Blackpool Teaching Hospitals NHS

Foundation Trust, Steve Lindsay Bradford Teaching Hospitals NHS Foundation Trust, Piers

Clifford Buckinghamshire Healthcare NHS Trust,Tim Reynolds Burton Hospitals NHS

Foundation Trust, S Grant Calderdale and Huddersfield NHS Foundation Trust, Justin

Cooke Chesterfield royal Hospital NHS Foundation Trust, Shahid Junejo and Samuel

McClure City Hospitals Sunderland NHS Foundation Trust, Mark Scoote Colchester Hospital

University NHS Foundation Trust, Mohammed Ahmed El-Harari County Durham and

Darlington NHS Foundation Trust, John McDonald East Lancashire Hospitals NHS Trust,

Matthew Faircloth Frimley Park Hospital NHS Foundation Trust, Mark Appleby Harrogate

and District NHS Foundation Trust, Mohammed AlObaidi Heatherwood and Wexham Park

Hospitals NHS Foundation Trust, Farqad Almagir Hull and East Yorkshire Hospitals NHS

Trust, Simon Hetherington Kettering General Hospital NHS Foundation Trust, Somnath

Kumar Lancashire Teaching Hospitals NHS Foundation Trust, Chris Gale Leeds Teaching

Hospitals NHS Trust &York Teaching Hospital NHS Foundation Trust, Nicola Brooks

Medway NHS Foundation Trust, Ted Lo Mid Staffordshire NHS Foundation Trust, Philip

Batin Mid Yorkshire Hospitals NHS Trust, Raj Khiani Milton Keynes Hospital NHS

Foundation Trust, Alan Bagnall Newcastle Hospitals NHS Foundation Trust, Roger Moore

North Cumbria University Hospitals NHS Trust, Christopher Gibbs Northern Devon

Healthcare NHS Trust, Sudipta Chattopadhyay Northern Lincounshire and Goole Hospitals

NHS Foundation Trust, Honey Thomas Northumbria Healthcare NHS Foundation Trust,

Jolanta Sobolewska Pennine Acute Hospitals NHS Trust, Dr Jo Porter Peterborough and

Stamford Hospitals Trust, Venkatesan Suresh Plymouth Hospitals NHS Trust, Paul Kalra

Portsmouth Hospitals NHS Trust, Usman El-Sheikh Royal Devon and Exeter NHS

Foundation Trust, Anwar Memon Scarborough and North East Yorkshire Health Care NHS

Trust, John Rowley Sherwood Forest Hospitals NHS Foundation Trust, Nigel Capps

Shrewsbury and Telford Hospitals NHS Trust, Philip Keeling South Devon Healthcare NHS

Foundation Trust, Mark De Belder South Tees Hospitals NHS Foundation Trust, Thuraia

Nageh Southend University Hospitals NHS Foundation Trust, Philip Lewis Stockport NHS

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Foundation Trust, Mark Dayer Taunton and Somerset NHS Foundation Trust, Alan Baonall

The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Adrian Brodison University

Hospital of Morecambe Bay NHS Foundation Trust, Ian Hudson University Hospitals of

Leicester NHS Trust, Francesco Lo Monaco West Middlesex University Hospital NHS Trust,

Telal Mudawi Wrightington Wigan and Leigh NHS Foundation Trust.

Contributors: CG participated in the development of the protocol, organization and funding.

OA and CG participated in writing the manuscript and analysing data. All authors have read

the draft critically to make contributions and also approved the final text.

Funding This work was supported by the National Institute for Health Research

(NIHR/CS/009/004)

Competing interests None

Patient consent Obtained

Ethics approval The EMMACE-3 study was given favourable ethical approval by Leeds

(West) Research Ethics committee (REC reference: 10/H131374).

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement Only pseudonymised data will be released to collaborators.

Legend

Figure 1: Regional map of English National Health Service hospitals and patients

participating in EMMACE-3

Figure 2: EMMACE-3 cumulative recruitment of participants

Figure 3: Flow chart of the EMMACE studies

Figure 4: Flow diagram showing number of EMMACE-3 participants at each phase of the

study

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17. West RM, Cattle BA, Bouyssie M, Squire I, de Belder M, Fox KA, et al. Impact of hospital

proportion and volume on primary percutaneous coronary intervention performance in

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18. Cubbon RM, Gale CP, Rajwani A, Abbas A, Morrell C, Das R, et al. Aspirin and mortality

in patients with diabetes sustaining acute coronary syndrome. Diabetes Care.

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19. Lewinter C, Bland JM, Crouch S, Doherty P, Lewin RJ, Kober L, et al. The effect of

referral for cardiac rehabilitation on survival following acute myocardial infarction: a

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20. Lown MT, Munyombwe T, Harrison W, West RM, Hall CA, Morrell C, et al. Association of

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the concentration-related prognostic value of cardiac troponin I following acute coronary

syndrome. Am J Cardiol. 2011;108(9):1259-65. Epub 2011/08/30.

22. Manfrini O, Morrell C, Das R, Barth JH, Hall AS, Gale CP, et al. Effects of Angiotensin-

Converting Enzyme Inhibitors and Beta-Blockers on Clinical Outcomes in Patients with

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trends in mortality of patients with diabetes mellitus suffering acute myocardial infarction:

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29. Jordan H, Roderick P, Martin D. The Index of Multiple Deprivation 2000 and accessibility

effects on health. J Epidemiol Community Health. 2004;58(3):250-7. Epub 2004/02/18.

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35. Cattle BA, Baxter PD, Greenwood DC, Gale CP, West RM. Multiple imputation for

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(SIMS): a new measurement tool for audit and research. Quality in health care : QHC.

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Figure 1: Regional map of English National Health Service hospitals and patients participating in EMMACE-3 177x196mm (96 x 96 DPI)

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Figure 2: EMMACE-3 cumulative recruitment of participants 174x132mm (96 x 96 DPI)

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Figure 3: Flow chart of the EMMACE studies 251x157mm (96 x 96 DPI)

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Figure 4: Flow diagram showing number of EMMACE-3 participants at each phase of the study 157x177mm (96 x 96 DPI)

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Evaluation of the Methods and Management of Acute Coronary Events (EMMACE)-3: protocol for a longitudinal

study

Journal: BMJ Open

Manuscript ID: bmjopen-2014-006256.R1

Article Type: Protocol

Date Submitted by the Author: 22-Aug-2014

Complete List of Authors: Alabas, Oras; University of Leeds, Division of Epidemiology and Biostatistics West, Robert; University of Leeds, Leeds Institute of Health Sciences

Gillott, Richard; Leeds Teaching Hospitals NHS Trust, Leeds, UK, Department of Cardiology Khatib, Rani; Leeds Teaching Hospitals NHS Trust, Leeds, UK, Department of Cardiology Hall, Alistair; Leeds Teaching Hospitals NHS Trust, Leeds, UK, Department of Cardiology; Leeds General Infirmary, Institute for Cardiovascular Resaerch Gale, Chris; University of Leeds, Divison of Epidemiology and Biostatistics; York Teaching Hospital NHS Foundation Trust, Cardiology

<b>Primary Subject Heading</b>:

Cardiovascular medicine

Secondary Subject Heading: Cardiovascular medicine, Epidemiology

Keywords: Cardiac Epidemiology < CARDIOLOGY, Coronary heart disease < CARDIOLOGY, Myocardial infarction < CARDIOLOGY


BMJ Open on July 11, 2020 by guest. P

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1

Title: Evaluation of the Methods and Management of Acute Coronary Events

(EMMACE)-3: protocol for a longitudinal study

Authors: Alabas OA1, West RM2, Gillott RG3, Khatib R3, Hall AS3, Gale CP1,4 on

behalf of the EMMACE-3 Investigators

1 Division of Epidemiology and Biostatistics, University of Leeds, Leeds, UK.

2 Leeds Institute of Health Science, University of Leeds, UK.

3 Department of Cardiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

4 York Teaching Hospital NHS Foundation Trust, York, UK.

Correspondence: Chris P. Gale

BSc (Hon), MB;BS, PhD, Dip, M.Ed, FESC. MSc, FRCP

Associate Professor of Cardiovascular Health Research, Honorary Consultant

Cardiologist.

Division of Epidemiology and Biostatistics, Level 8, Worsley building, University of

Leeds, Clarendon Way, West Yorkshire, Leeds, LS2 9JT, UK.

Key words: EMMACE-3; acute coronary syndrome; health related quality of life;

medications; outcomes; electronic health records.

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Abstract

Introduction: Patients with cardiovascular disease are living longer and are more

frequently accessing healthcare resources. The Evaluation of the Methods and

Management of Acute Coronary Events (EMMACE)-3 national study is designed to

improve understanding of the effect of quality of care on health-related outcomes for

patients hospitalised with ACS.

Methods and analysis: EMMACE-3 is a longitudinal study of 5535 patients

hospitalised with an acute coronary syndrome in England. The study collects

repeated measures of health related quality of life, information about medications

and patient adherence profiles, a survey of hospital facilities, and morbidity and

mortality data from linkages to multiple electronic health records. Together with

EMMACE-3X and EMMACE-4, EMMACE-3 will assimilate detailed information for

about 13,000 patients across more than 60 hospitals in England.

Ethics and dissemination: EMMACE-3 was given a favourable ethical opinion by

Leeds (West) Research Ethics committee (REC reference: 10/H131374). Upon

successful application, study data will be shared with academic collaborators. The

findings from EMMACE-3 will be disseminated through peer reviewed publications,

at scientific conferences, the media, and through patient and public involvement.

Study registration number: ClinicalTrials.gov Identifier: NCT01808027. Information

about the study is also available at EMMACE.org.

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Key Messages

• EMMACE-3 is a contemporary longitudinal study of trajectories of recovery

after hospitalised acute coronary syndrome.

• Comprehensive patient-level and hospital-level data are being collected using

multiple electronic health records linked to bespoke survey data.

• Together with EMMACE-3X and EMMACE-4, EMMACE-3 aims to gather

repeated measures data for about 13,000 patients admitted to hospitals

across England.

• Non-identifiable data will be made available to academic collaborators upon

approval of application.

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INTRODUCTION

Cardiovascular health and care

The last 10 years has seen a decline in mortality rates from cardiovascular

disease.1,2 In the United Kingdom (UK) from 2003 through 2010, the risk of in-

hospital mortality from acute coronary syndrome (ACS) has fallen by half.3,4

Nevertheless, cardiovascular disease is the leading cause of death in the UK and is

responsible for over 4 million deaths per year in Europe.5,6

In addition, cardiovascular disease confers a substantial morbidity and financial

burden.7,8 Elderly patients with ACS account for more than half of all admissions to

hospital.9,10 As a result of a reduction in mortality rates, patients are living longer and

more frequently accessing health care services. The forecasted impact of heart

failure, cerebrovascular disease and recurrent ACS as a result of improved survival

is unpreceented.7,11,12 Moreover, cardiovascular disease already costs the UK

economy £29.1 billion in healthcare, informal care and productivity losses.8

Consequently, there are new challenges for making the best use of scarce

healthcare resources. Future policies will require enhanced regulatory apparatus to

respond to the increasing demand.

Two important question facing healthcare decision-makers are: 1) how do patients

recover from ACS, and 2) how does their initial presentation and hospital care impact

on subsequent healthcare resource use and health-related outcomes? Recently, a

succession of large-scale UK observational studies were funded - aiming to improve

the understanding of variation in cardiovascular quality of care and outcomes.13 We

also have sought to anticipate and understand these challenges. In this paper we

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describe the profile of the Evaluation of the Methods and Management of Acute

Coronary Events (EMMACE)-3 study, a unique national collaborative research effort

collecting repeated measures for medicines and their adherence profiles, health

related quality of life, cardiac rehabilitation, hospital readmissions and cause-specific

mortality in patients who have been hospitalised with ACS.

Evaluation of the Methods and Management of Acute Coronary Events

(EMMACE)

EMMACE-3 is the third in a series of prospective studies. EMMACE-1 and

EMMACE-2 were regional, multi-centre, cross-sectional evaluations of around 2500

hospitalised ACS patients each, undertaken in 1994 and 2003, respectively. That

coincided with being five years before and then also after the major national initiative

in this area: the National Service Framework (NHS) for Coronary Heart Disease).14

The original study (commissioned by NHS R&D) was tasked with assessing alternate

methods of case ascertainment and their impact on assessment of quality of care.15

The studies have each reported variations in hospital outcomes,16,17 temporal

improvements in the adherence to guideline recommended therapies and their

association with a decline in mortality rates, 18 impact of cardiac rehabilitation on

survival,19 impact of clinical investigations and treatments on mortality 20-22 and the

relative impact of diabetes on early and late mortality by temporal changes in

hospital care.23, 24

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Aims and objectives

The objective of EMMACE-3 is to improve the understanding of the effect of quality

of care on health-related outcomes for patients hospitalised with ACS. The study

aims to 1) quantify variation in health-related outcomes from ACS, 2) identify

modifiable factors which could lead to improve quality of care and health, 3)

investigate the longer-term trajectories of recovery from ACS, and 4) describe the

use of guideline recommended medicines. Upon completion, the study will allow the

evaluation of the full pathway of care from hospital to community, providing data

which other cardiovascular studies lack.

METHODS AND ANALYSIS

Study design

EMMACE-3 is a multi-centre longitudinal cohort study of ACS outcomes from time of

hospital discharge over 1 year. The combined primary end point is time to first

occurrence of a major adverse cardiovascular events (MACCE), defined as one of

the following: death, non-fatal acute myocardial infarction and coronary

revascularisation. The secondary end points are (i) quality of life assessed using

EuroQol 5-dimension, EQ-5D25, (ii) readmission to hospital with ACS, (iii) new

diagnosis of, or hospitalisation, for heart failure, (iv) medication use and patient

adherence profiles, (v) cessation of smoking, (vi) completion of cardiac rehabilitation.

Study setting

EMMACE-3 is based at the University of Leeds who is its sponsor. Data storage,

linkage, sharing and other processing will be undertaken at the University of Leeds in

partnership with Leeds Teaching Hospitals NHS Trust. EMMACE-3 forms part of a

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portfolio of collaborative cardiovascular studies using EHRs working with a number

of partner organisations including the Farr Institute, University College London and

the National Institute for Cardiovascular Outcomes Research, University College

London. The EMMACE-3 investigators and collaborators are a multidisciplinary team

of epidemiologists, biostatisticians, health service researchers, health informaticians

and clinical cardiologists.

Study timeline

EMMACE-3 began on 1st November, 2011 and completed recruitment of 5555

patients on 17th September, 2013. For up to 10 years data will be gathered on these

patients using surveys and EHRs as part of EMMACE-3X study.

Inclusion criteria

The study includes patients aged 18 years or older, who have been admitted with

ACS at one of the participating hospitals in England. The spectrum of ACS

phenotypes includes ST-elevation myocardial infarction (STEMI), non-STEMI

(NSTEMI) and troponin negative ACS (unstable angina (UA)) 26.

Exclusion criteria

Patients at a terminal stage of any illness, and those in whom follow up would be

inappropriate or impractical were excluded from the study.

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Recruitment

Figures 1 and 2 illustrate the spatial coverage and rate at which 5375 participants

(excluding multiple entry records) with ACS from a total of 48 hospitals volunteered

to be part of this project. Each hospital provided their own recruitment support

(Research Nurses) funded through the NIHR-CLRN funding stream (5.2 Research

Support Services Version 5). This model encouraged an exponential rate of new

centre participation as each hospital acted as active stake-holders in the funding

model.

Data collection

Routine clinical information are being gathered from hospital records and clinical

databases and supplemented with data from questionnaires at 3 time points over the

first year after hospital discharge.

EMMACE-3 combines self-reported longitudinal data on numerous health

parameters with cross-sectional disease-specific clinical information (Figure 3). The

cross-sectional data, which is summarised in Tables 1 and 2, includes: 1)

demographic data such as age, sex, place of treatment and residency, 2) information

from the national heart attack registry Myocardial Ischaemia National Audit Project,

MINAP)27, 3) a survey of hospital-level cardiovascular facilities and 4) patient-level

deprivation indices (Index of Multiple Deprivation score, Townsend score28.

Longitudinal data is being collected at four time points: in-hospital, 1 month, 6

months and 12 months post discharge (Figure 3). These include measures of: 1)

health related quality of life (EQ-5D),25 2) General Practitioner and hospital

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specialists appointments, 3) physical activity, 4) cardiac rehabilitation, 5) prescribed

medications and 6) indices of medicines-taking behaviour including the Morisky

Medication Adherence, Adherence Estimator, A modified version of the Single

Question Questionnaire, Beliefs about Medicines Questionnaire and other

adherence probing questions.29-33

Before each participant is sent a questionnaire their mortality status is checked using

the NHS Summary Care Record. Non-responders are issued a second and third

questionnaire, and/or contacted directly by telephone. Each patients data are tracked

for cause-specific mortality and date of death (from linkage to the Office for National

Statistics).

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Table 1: Baseline patient characteristics.

Patient characteristics N (%)

Demographics

Mean (SD) age, years 64.4 (11.9)

Men 3969 (73.8)

White 3138 (95.2)

Mean (SD) IMD score* 22.6 (15.5)

Current smoker 1142 (32.9)

Ex smoker 1215 (35.0)

Mean (SD) body mass index 28.8 (6.5)

Past medical history

Hypertension 1573 (45.3)

Diabetes mellitus 537 (15.5)

Previous angina 851 (24.5)

Previous myocardial infarction 709 (20.4)

Cerebrovascular disease 168 (4.8)

Asthma or COPD 434 (12.5)

Chronic renal failure 106 (3.1)

Chronic heart failure 68 (2.0)

Peripheral vascular disease 115 (3.3)

Acute coronary syndrome phenotype

STEMI 1,335 (38.6)

NSTEMI 2,008 (58.0)

Unstable angina 47 (1.4)

Medications prescribed at hospital discharge^

Aspirin 3,026 (89.3)

β blockers 2,781 (82.1)

Angiotensin converting enzyme (ACE) inhibitors 2,827 (83.5)

Statins (HMG Co-A reductase inhibitors) 3,025 (89.3)

Thienopyridine inhibitors 2,646 (78.4)

*IMD score: Index of Multiple Deprivation score for 2010.

^ for survivors of the hospital stay, sample of medications given.

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Table 2: Distribution of EMMACE-3 hospital cardiovascular facilities Hospital characteristics N (%)

Foundation Status 33 (68.8)

Primary PCI availability, 24 hours 7 days per week?

No 33 (71.7)

Yes 13 (28.26)

Number of Consultant Cardiologists

<5 21 (56.8)

≥5 16 (43.2)

Number of specialist ACS nurses

None 24 (55.8)

<5 13 (30.2)

≥5 6 (14.0)

Number of specialist heart failure nurses

None 9 (19.6)

<5 32 (69.6)

≥5 5 (10.9)

Number of specialist cardiac rehabilitation nurses

None 2 (4.8)

<5 30 (71.4)

≥5 10 (23.8)

Number of cardiology beds

None 4 (8.7)

<20 13 (28.3)

≥20 29 (63.0)

Number of Coronary Care Unit beds

<10 23 (51.1)

≥10 22 (48.9)

Distance to the nearest intervention centre, miles

Not applicable 15 (34.9)

<20 10 (23.3)

≥20 18 (41.9)

PCI: percutaneous coronary intervention

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Attrition rate

Figure 4 shows that of the survivors, 5326 (99.1%) completed an in-hospital

questionnaire and 4513 (84.0%), 4062 (75.6%) and 3512 (65.3%) subjects

participated at 1 month, 6 months and 12 months, respectively. At these latter time

points 0.4%, 0.9%, 2.5% and 2.1% of the questionnaire data attrition was due to

deaths. The characteristics of patients by return or not of their questionnaires are

shown in Table 3.

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Table 3: Patient characteristics by response to questionnaire.

Follow-up Hospital stay 1 month 6 months 12 months

Patient characteristics Responder Non-responder Responder Non-responder Responder Non-responder Responder Non-responder

Denominator N=5325 N=49 N=4454 N=862 N=3907 N=1313 N=3287 N=1863

Demographics

Mean age (SD), years 64.4 (11.9) 63.2 (14.2) 65.3 (11.4) 59.2 (12.8) 65.8 (11.2) 59.0 (12.1) 66.4 (10.9) 59.7 (12.0)

Men (%) 3919 (73.9) 36 (73.5) 3279 (73.7) 649 (75.4) 2871 (73.5) 993 (75.7) 2418 (73.6) 1394 (74.9)

White 3102 (95.2) 21 (91.3) 2643 (96.3) 460 (94.3) 2345 (95.8) 709 (92.9) 1982 (96.0) 1034 (93.2)

Median (IQR) IMD score 18.1 20.6 17.4 22.5 17.1 21.4 16.7 18.8

ACS phenotype

STEMI 1321 (38.7) 9 (34.6) 1113 (38.0) 212 (42.6) 985 (37.9) 330 (42.3) 827 (37.7) 482 (42.1)

NSTEMI 1982 (58.0) 17 (65.4) 1,717 (58.7) 269 (54.0) 1522 (58.6) 425 (54.4) 1287 (58.7) 627 (54.8)

UA 47 (1.4) 0 43 (1.5) 4(0.8) 42 (1.6) 5 (0.6) 37 (1.7) 10 (0.9)

ACS: acute coronary syndrome, STEMI: ST-elevation myocardial infarction, NSTEMI: non ST-elevation myocardial infarction, UA: unstable

angina.

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Electronic health records linkage

EMMACE-3 embraces the efficiency of contemporary observational research design.

It imports, pools and links EHR information derived from existing national clinical and

administrative data warehouses to patient-level repeated measures survey data. For

mortality status the linkage success was 96.0%. Presently, for MINAP and hospital

cardiovascular facilities data, the import success is 66.2% and 100.0% respectively.

(Table 4).

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Table 4: Data sources, types of data and collection system linked in the EMMACE-3 study

Parameter categories Data source Data type Linkage /recording

success

Clinical phenotype, characteristics and treatments MINAP Cross-sectional 66.2%

Date of death NHS Summary Care Record Longitudinal 96.0%

Cause of death ONS Longitudinal In process

Hospital facilities data EMMACE-3 survey Cross-sectional 100 %

Deprivation scores Department of community

and local government

Cross-sectional 94.5%

Survey data: hospital stay EMMACE-3 survey Longitudinal 99.1%

Survey data:one month from hospital discharge EMMACE-3 survey Longitudinal 83.0%

Survey data:six months from hospital discharge EMMACE-3 survey Longitudinal 72.7%

Survey data: twelve months from hospital discharge EMMACE-3 survey Longitudinal 61.2%

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International cardiovascular research platform

Each participant was asked if they would be willing to have their contact details and

clinical data securely stored on a database, and to be contacted for potential

participation in future observational studies and clinical trials. In total, 5375

consented to participate in EMMACE-3 and 3875 to have their data stored for the

purposes of re-contact for future research.

Statistical analysis

Shared frailty survival models (nesting patients within hospitals) will be used to

estimate factors associated with time to primary endpoint. Factors to be evaluated

will include medications, health related quality of life and hospital facilities data and

baseline clinical characteristics using a significance level of 0.05. Sequential health

related quality of life data will be studied both as a measure of outcome (recovery

pattern) and predictor of outcome (prognostic marker). Missing data will be multiply

imputed, with values will be derived from an imputation model based upon the

observed values.34 Statistical analyses will be performed using Stata version 12.1

(StataCorp)

Collaboration

One of the goals of EMMACE-3 is to enable and facilitate national and international

collaborations. The rich patient-level data will be an important resource for the

identification of cardiovascular participants into trials. Further information about the

study is available at ClinicalTrial.gov (NCT01808027), EMMACE.org. Collaborators

are invited to contact the Chief Investigator, Chris Gale at [email protected].

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Data will be available to non-commercial research organisations subject to approval

by the CI. Only pseudonymised data will be released to collaborators.

EMMACE-3X

EMMACE-3X is an EMMACE-3 extension study with favourable ethical opinion

(13/YH/0277) and is adopted onto the NIHR CRN portfolio. Patients recruited to the

EMMACE-3 study are being re-contacted and invited to participate in the EMMACE-

3X study. EMMACE-3X aims to collect health related quality of life data using the

EQ-5D25 and MacNew35 questionnaires as well as medications data for each

participant annually until death or up to 10 years. Furthermore, EMMACE-3X will link

EMMACE-3 data with Hospital Episode Statistics (HES) and primary care data

(Figure 3). Further information about EMMACE-3X is available at ClinicalTrial.gov


EMMACE-4

EMMACE-4 has favourable ethical opinion (12/WM/0431) and is the latest active

study in the EMMACE series. It is adopted onto the NIHR CRN portfolio and will

accrue 8000 participants across England. It, also, is a longitudinal study of ACS

trajectories of recovery after hospitalisation with ACS. EMMACE-4 will enhance its

data collection using EHR data from primary care (using databases such as; The

Phoenix Partnership (TPP) Research One and The Clinical Practice Research

Datalink (CPRD)), pharmacy databases and from linkage to HES data. In addition, it

is collecting patient reported experience measures (The Picker Patient Experience

Questionnaire PPE-15),36 repeated measures of EQ-5D,25 Brief Illness Perception

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(IPQ), 37 the Satisfaction with Information about Medicines Scale (SIMS), 38 a

modified version of the Single Question Questionnaire,32 medications adherence and

cause-specific mortality (Figure 3). Further information about EMMACE-4 is available

at ClinicalTrial.gov (NCT01819103), EMMACE.org.

STRENGTHS AND LIMITATIONS

EMMACE-3 is a contemporary longitudinal study of detailed trajectories of quality of

health care and outcomes for ACS. Other observational cardiovascular studies have

been instrumental in realising the research potential of linked EHRs, but have been

limited by their lack of data for health related quality of life and medication

adherence. 39 The study strengths are:

• National and representative sample of contemporary ACS hospitalisations

• Multi-centre design allowing comparative analyses

• Repeated multi-dimensional validated measures of health related quality of

life and medication adherence profiles

• Efficiency of research data enhancement through bespoke linkages to clinical

and administrative electronic health care records

• Participant consent to enter future research studies

• Scalability through responsive funding from the NIHR

• Potential for health economic evaluations

There are, however, a number of limitations. Case ascertainment is not 100% and

there is evidence for survivorship bias. However, recruitment of all ACS was not the

remit of EMMACE-3. If necessary, more complete case ascertainment of ACS may

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be estimated through the pooling of multiple secondary and primary care sources of

EHRs.39 For the questionnaire data, missingness varied between 2% and 40%, and

for MINAP data fields varied between 1% and 10%.

Ethics and Dissemination

EMMACE-3 was given a favourable ethical opinion by Leeds (West) Research Ethics

committee (REC reference: 10/H131374). Upon successful application, study data

will be shared with academic collaborators. The findings from EMMACE-3 will be

disseminated through peer reviewed publications, at scientific conferences, the

media, and through patient and public involvement.

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Contributors: CG is the Chief Investigator of EMMACE-3, 3X and 4 and led the

development of the protocol, organization and funding. OA and CG participated in

writing the manuscript and analysing data. All authors have read the draft critically to

make contributions and also approved the final text.

Funding This work was supported by the National Institute for Health Research

grant number (NIHR/CS/009/004).

Competing interests None

Patient consent Obtained

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement Only pseudonymised data will be released to collaborators.

Acknowledgement

We gratefully acknowledge the participation of the EMMACE hospitals, their

research staff, principal investigators and the EMMACE study team.

EMMACE-3 investigators:

Basel Hanbali Airedale NHS Foundation Trust, John Davies Basildon and Thurrock

University Hospitals NHS Foundation Trust, Ranjit More Blackpool Teaching

Hospitals NHS Foundation Trust, Steve Lindsay Bradford Teaching Hospitals NHS

Foundation Trust, Piers Clifford Buckinghamshire Healthcare NHS Trust,Tim

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Reynolds Burton Hospitals NHS Foundation Trust, S Grant Calderdale and

Huddersfield NHS Foundation Trust, Justin Cooke Chesterfield royal Hospital NHS

Foundation Trust, Shahid Junejo and Samuel McClure City Hospitals Sunderland

NHS Foundation Trust, Mark Scoote Colchester Hospital University NHS Foundation

Trust, Mohammed Ahmed El-Harari County Durham and Darlington NHS Foundation

Trust, John McDonald East Lancashire Hospitals NHS Trust, Matthew Faircloth

Frimley Park Hospital NHS Foundation Trust, Mark Appleby Harrogate and District

NHS Foundation Trust, Mohammed AlObaidi Heatherwood and Wexham Park

Hospitals NHS Foundation Trust, Farqad Almagir Hull and East Yorkshire Hospitals

NHS Trust, Simon Hetherington Kettering General Hospital NHS Foundation Trust,

Somnath Kumar Lancashire Teaching Hospitals NHS Foundation Trust, Chris Gale

Leeds Teaching Hospitals NHS Trust &York Teaching Hospital NHS Foundation

Trust, Nicola Brooks Medway NHS Foundation Trust, Ted Lo Mid Staffordshire NHS

Foundation Trust, Philip Batin Mid Yorkshire Hospitals NHS Trust, Raj Khiani Milton

Keynes Hospital NHS Foundation Trust, Alan Bagnall Newcastle Hospitals NHS

Foundation Trust, Roger Moore North Cumbria University Hospitals NHS Trust,

Christopher Gibbs Northern Devon Healthcare NHS Trust, Sudipta Chattopadhyay

Northern Lincounshire and Goole Hospitals NHS Foundation Trust, Honey Thomas

Northumbria Healthcare NHS Foundation Trust, Jolanta Sobolewska Pennine Acute

Hospitals NHS Trust, Dr Jo Porter Peterborough and Stamford Hospitals Trust,

Venkatesan Suresh Plymouth Hospitals NHS Trust, Paul Kalra Portsmouth Hospitals

NHS Trust, Usman El-Sheikh Royal Devon and Exeter NHS Foundation Trust,

Anwar Memon Scarborough and North East Yorkshire Health Care NHS Trust, John

Rowley Sherwood Forest Hospitals NHS Foundation Trust, Nigel Capps Shrewsbury

and Telford Hospitals NHS Trust, Philip Keeling South Devon Healthcare NHS

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Foundation Trust, Mark De Belder South Tees Hospitals NHS Foundation Trust,

Thuraia Nageh Southend University Hospitals NHS Foundation Trust, Philip Lewis

Stockport NHS Foundation Trust, Mark Dayer Taunton and Somerset NHS

Foundation Trust, Alan Baonall The Newcastle Upon Tyne Hospitals NHS

Foundation Trust, Adrian Brodison University Hospital of Morecambe Bay NHS

Foundation Trust, Ian Hudson University Hospitals of Leicester NHS Trust,

Francesco Lo Monaco West Middlesex University Hospital NHS Trust, Telal Mudawi

Wrightington Wigan and Leigh NHS Foundation Trust.

Legend

Figure 1: Regional map of English National Health Service hospitals and patients

participating in EMMACE-3

Figure 2: EMMACE-3 cumulative recruitment of participants

Figure 3: Flow chart of the EMMACE studies

Figure 4: Flow diagram showing number of EMMACE-3 participants at each phase of

the study

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BMJ OpenBSc (Hon), MBBS, MRCP, PhD, Dip, M.Ed, FESC. MSc National Institute for Health Research...

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