MR1172 - CE-MARC - Clinical Evaluation of Magnetic Resonance imaging in Coronary Heart Disease

This Data Sharing Agreement permits the retention of the data provided under previous iterations of this Agreement for an interim period. This is a pragmatic approach to provide an active Agreement whilst enabling University of Leeds to complete the necessary actions to enable a subsequent application to extend the Agreement meeting all applicable data sharing standards as published in NHS Digital’s website (see: https://digital.nhs.uk/services/data-access-request-service-dars/dars-guidance).

The following provides background information on the purpose of the original study:

The Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease (CEMARC) study is conducted by a multi-disciplinary group at the University of Leeds (UoL). Previously, UoL conducted a trial related to CEMARC, the results of which have been extensively cited since publication in the Lancet (2012).

752 Participants were recruited between 2006 and 2009 from cardiology clinics or following discharge from cardiology wards and requiring further investigation for chest pain thought to be coronary heart disease (CHD).

In patients with suspected CHD, an investigation called single-photon emission computed tomography (SPECT) was the most widely used test for the assessment of myocardial ischaemia, but its diagnostic accuracy is reported to be variable and it exposes patients to ionising radiation. CEMARC was the largest, prospective, real world evaluation of CMR and has established CMR’s high diagnostic accuracy in coronary heart disease and CMRs superiority over SPECT. CMR has since been adopted wider for the investigation of CHD.

The central aim of the CEMARC study was to establish the diagnostic accuracy of a cardiovascular magnetic resonance (CMR) protocol with x-ray coronary angiography as the reference standard, and to compare CMR with SPECT, in patients with suspected CHD.

The secondary objectives for the study were:

• To assess the prognostic value of CMR in predicting long-term outcomes.

• To compare the diagnostic accuracy of CMR with the current standard clinical investigations of exercise tolerance testing (ETT) and radionuclide perfusion imaging (SPECT).

• To evaluate the cost effectiveness of CMR in a diagnostic strategy for the systematic investigation of patients with suspected CHD.

• To assess patient preference of the different strategies for investigation of suspected CHD.

The purpose of this application is to obtain long term mortality data on the of the CEMARC study. UoL has already received and analysed 5 year mortality data from NHS digital on this group of participants and this application is to receive mortality data for these participants at the 10 year time point to support the secondary objective of assessing the prognostic value of CMR in predicting long term outcome.

Data relating to this project is backed up to the UoL Central Backup Service on UoL owned and managed servers, located within UoL managed data centres.

The lawful basis for processing this study is Article 6 1(e): task in the public interest and Article 9 2 (j): archiving in the public interest, scientific or historical research or statistical purposes as the outputs for this study are aimed at the entire medical community, hence the aim is to publish in a general medical journal rather than a specialist cardiovascular publication.

the cohort is alray held and flagged with NHS Digital from the earlier data dissemination previously therefore UoL provided identifiers already collected from participants as part of the trial dataset. These were:

• Name

• Address

• NHS number

• Date of birth

These identifiers ensure UoL minimise the chance of receiving data for anyone other than consenting trial participants. UoL are only requesting data on patients who have consented to being followed up as part of this study. As stated these Identifiers have previously been sent from the UoL to NHS digital and this data does not require updating.

NHS digital are required to return linked mortality data including Date of Birth and Supplied Member Number (Study ID) only, no other identifiers are required.

This work is wholly confined to England and Wales.

The original trial (prior to the 10 year follow up) was funded by the BHF. BHF have not had access to any of the data except in aggregate form (e.g. total number of participants recruited) as part of annual reports (to ensure that the trial is being run as per their funding requirements) and any publications. BHF do not have, have not had in the past, and will not have in the future, any access to study data including any data supplied by NHS Digital. BHF have no say in how the data is processed and this will not change.

The Chief Investigator is funding the application from University of Leeds departmental budget, however, this does not mean that there are additional parties who have rights to say how the data is to be processed or access to the data other than those on the original application.

All organisations party to this agreement must comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract ie: employees, agents and contractors of the Data Recipient who may have access to that data). No new or further data will be provided under this version of the agreement.

Under this Agreement, the data may be securely stored but not otherwise processed. No new data will be provided by NHS Digital under this Agreement.

The study data, including data provided by NHS Digital under previous agreements, are currently held by University of Leeds.

The following provides background on the processing activities undertaken prior to this Agreement:

The flow of identifiers, which have already been sent to NHS Digital under a previous version are as follows:

• Surname/Forename Name

• Address

• Date of birth

• Gender

• NHS Number

• Study ID – the number a participant is allocated when they enter the study.

Data will be downloaded from the NHS Digital link and the data file saved in a secure folder on the P-Drive by a named member of the study team. Data will be entered into a secure password protected database held locally at the Clinical Trials research Unit (CTRU) at the UoL, by a data management assistant who will transcribe the data onto a case report form (CRF). Data will then be entered into a secure password protected database held locally at the UoL by a trained member of the data management team.

A copy of this CRF will then be sent to Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) at the UoL, to be securely filed with their copy of the participant file and the original filed in a secure tambour with other trial documentation at the CTRU. This will be securely filed with their copy of the participant file. Any electronic scanned versions will then be deleted. The original CRF will be filed in a secure tambour with the participant study files that include CRFs and any correspondence over data cleaning at the CTRU.

The data will then be processed by the trial statistician at the Clinical Trials Research Unit, Leeds Institute for Clinical Trials Research (LICTR) at the UoL.

All individuals with access to the data are substantive employees of the UoL, data will only be accessed by individuals with the CTRU who are directly involved with the NHS digital transfer and analysis of the data (Trial statisticians and data management assistant).

The UoL is both the Data controller and the Data Processor. Originally, British Heart Foundation funded this study - British Heart Foundation are no longer involved and have no say in how and what data is processed. The 10-year follow-up of the CEMARC study is being funded by the Chief Investigator at UoL. The Investigator has no say in how and what data is processed.

Data will be linked with existing CEMARC Trial data sets, which consist of patient demographics and results from diagnostic tests. Patients have given written informed consent to participate in the trial and the identifiers the UoL are collected as part of the trial. Data provided by participants and researchers is in accordance with the REC-approved trial protocol and participant consent.

The datasets contain the following information:

Date of clinic visit

• Patient name

• Patient gender

• Date of birth

• Confirmation and date of written consent

• Confirmation of eligibility

• Hospital

• Name of Consultant cardiologist

• Name of randomising CRN/clinician

• NHS number

• Hospital ID

• Ethnicity

• Patient address and telephone number

• GP address and telephone number

• Blood pressure

• Heart rate

• Past medical history including previous cardiovascular problems, diabetes mellitus (Type-1 or Type-2) hypertension and family history

• Smoking history

• Height and weight

• Blood test results

• Research blood sample for biochemical markers

• All drug treatment prior to clinic attendance.

• All drug treatment after clinic attendance.

• Tests clinically planned to include exercise test, SPECT, coronary angiography.

• Initial clinic diagnosis

The following details from the CMR investigation data:

• Date of investigation (If investigation not carried out, reason).

• Scan parameters and timing of protocol stages.

• The heart’s response to adenosine. (Adenosine is used to increase the blood flow in the heart as if the participant has been exercising)

• Comparison of rest/ stress blood flow scans

• Volumes of blood in the heart prior to contraction of the heart and after contraction.

• Evidence of scar tissue.

• Coronary anatomy.

• Cardiovascular complications.

• Exercise Tolerance Test (ETT) investigation data (using an exercise treadmill/bike testing): The CEMARC Clinicial Research Nurse (CRN) will record the following details from the ETT:

1. Date of investigation (If investigation not carried out, reason)

2. Heart rate prior to exercise and after,

3. Blood pressure

4. workload (Metabolic equivalents (METS) this represents the intensity of the exercise),

5. Exercise duration,

6. Any symptoms experienced during the tests,

7. Degree of ST segment shift which can indicate whether the participant has any heart disease,

8. Any irregular heartbeat (arrhythmia).

SPECT investigation data. A Cardiologist will record the following details from the SPECT:

• Date of investigation (If investigation not carried out, reason)

• Response to adenosine.

• Comparison of rest/ stress blood flow-scan

• Cardiovascular complications

A Cardiologist will record the following details from the x-ray angiography investigation data:

• Date of investigation (If investigation not carried out, reason)

• Narrowing in each of the main coronary arteries (blood vessels which transport oxygen to the heart).

• Coronary artery dominance- this has important implications in the imaging of the coronary arteries and any planning for coronary artery bypass grafting

• Any abnormalities to the walls or pumping action of the heart.

• Cardiovascular Complications.

Details of any serious adverse events relating to the investigations were reported to and recorded by the CEMARC CRN or CEMARC Research Fellow. Serious Adverse Events (SAE) and Serious Adverse Reactions (SAR) are defined as an untoward (unfavourable) event or reaction, which is fatal or life-threatening, requires or prolongs hospitalisation, is significantly or permanently disabling or incapacitating, or may jeopardise the patient and may require medical or surgical intervention to prevent a major cardiovascular event. The following details will be provided by the CEMARC CRN or CEMARC Research Fellow:

• Full details in medical terms with a diagnosis, if possible

• Duration (start and end dates; times, if applicable)

• Action taken

• Outcome

The data will be used to determine safety endpoints in terms of cardiovascular event rates, which include cardiovascular cause of death.

Data will not be used for any other purposes: it will not be used for commercial purposes, nor for direct marketing purposes. Data will not be accessed by any third parties, nor will it be accessible across multiple organisations.

Aside from the main CEMARC trial data sets – arising from the CEMARC trial described above (along with the consent provided) the data will not be linked with any other data sets (publicly-available or otherwise), and so this data will not be used to perform any kind of “trend analysis”. There will also be no bench marking against peer groups. The sole purpose of the data is to determine the safety endpoints for the trial, as described above.

There will be no data linkage undertaken with NHS Digital data provided under this agreement that is not already noted in the agreement.

Data will only be accessed and processed by substantive employees of UoL and will not be accessed or processed by any other third parties not mentioned in this agreement.

Any Research Fellows and Cardiologists are employed by the NHS sites, their roles on the study are to interpret and collect data from participants’ s investigation and to transcribe onto paper CRFs and to send to the CTRU for data entry. Research Fellows will not have any access to NHS Digital data or to the secure locked tambours where the paper CRFs are kept.

No new or further data will be provided under this version of the agreement. A short term extension is in place as a pragmatic approach to enable legal retention of already disseminated data. This agreement allows retention of data, but not permission to otherwise process it.

These outputs will include an analysis of time until first major adverse cardiovascular event (MACE), and the incidence of at least one of these events, as well as the individual components: cardiac death, arrhythmia, myocardial infarction, heart failure, unplanned revascularisation, stroke/TIA, Acute Coronary Syndrome.

The CEMARC trial team will aim to submit these findings to a high impact general medical journal (e.g. New England Journal of Medicine, Lancet, Journal of the American Medical Association) in the first instance. Conference and scientific meeting presentations will follow, as was the case with earlier outputs (see 5d iii. Yielded benefits).

The outputs are aimed at the entire medical community, hence the trial team aim to publish in a general medical journal rather than a specialist cardiovascular publication. CEMARC have an excellent track record of achieving this with the main CEMARC papers having been published in the Lancet and Annals of Internal Medicine (see 5d iii. Yielded benefits).

All outputs will contain only data that is aggregated with small numbers suppressed in line with the HES Analysis Guide.

No new or further data will be provided under this version of the agreement. A short term extension is in place as a pragmatic approach to enable legal retention of already disseminated data. This agreement allows retention of data, but not permission to otherwise process it.

In the UK, there are an estimated 1.98 million people suffering with symptoms of angina, which costs the UK economy £9.0 billion/year (British Heart Foundation Statistics Database. 2008. www.heartstats.org). From a patient perspective Coronary Heart Disease is associated with either premature loss of life or a significant reduction in quality of life. The disease tends to run in families and exemplifies inequalities in health: lower socio-economic classes and ethnic minorities are particularly affected. Despite the continued high disease prevalence in the UK, over 10 years ago the National Service Framework on CHD recognised that ‘research findings were incompletely and variably applied in clinical practice and that there was an urgent need to correct this in the prevention, diagnosis and treatment of CHD’ (Department of Health. 2000. National Service Framework for Coronary Heart Disease. Modern Standards and Service Models. DH, London).

In the ‘fight against cardiovascular disease’ a key step is making the right diagnosis, so every patient gets the right treatment. CE-MARC has shown that using CMR rather than SPECT, fewer patients with significant coronary artery disease will be misdiagnosed, and as an additional benefit, fewer unnecessary angiograms will be performed in those patients without significant disease. This is important for patients and healthcare funders. CE-MARC has shown CMR is a cost-effective investigation compared to the current NHS standard of SPECT. Across the UK and Europe there is a shift away from nuclear perfusion imaging (SPECT) towards CMR. Some UK hospitals have stopped SPECT completely and developed CMR services instead. There are now over 50 hospitals providing CMR in the UK, compared to ~ 20 hospitals 5 years ago.

At the 5 year follow up CEMARC showed MRI was a better predictor of patients having heart attacks or emergency admissions than Nuclear SPECT - the CEMARC trial team wishes to investigate whether this continues during 10 years of follow up to August 2019.

As the use of cardiac MRI as an investigational tool in the setting of stable chest pain grows, it is essential to properly measure and evaluate the long-term outcomes. The measurable benefits of a robust evaluation will include:

• better diagnosis for patients with suspected coronary heart disease

• better prediction of longer-term outcomes

• fewer unnecessary angiograms

• cost savings to the NHS, all of which are patently in the public interest

Outputs from the CEMARC trial have included journal articles and conference presentations. The main CEMARC papers have been published in the Lancet and the Annals of Internal Medicine.

The primary outcome analysis was presented orally at the American Heart Association Scientific Conference (Chicago 2010).

Study data has been presented at scientific meetings:

• British Cardiac Society (BCS) 2007, 2012 and 2013

• Society of Cardiovascular Magnetic Resonance (SCMR) 2010, 2011, 2012, 2013

• International Conference of Nuclear Cardiology (ICNC) 2007

keynote lectures have been presented at:

• SCMR (San Francisco, 2013)

• EuroCMR (Florence 2013)

• EuroCMR (Vienna 2012)

• Nordic Cardiac Imaging (Copenhagen 2012)

• BSCMR (Glasgow 2013); as well as numerous invited lectures at academic institutions across the UK.

In addition to outputs in academic journals and scientific conference presentations, CE-MARC has received a lot of publicity in the lay press. It was featured on the BBC and ITV news broadcasts, on the BBC news website, on local radio and in newspapers.

CE-MARC was the largest prospective evaluation of the diagnostic accuracy of cardiovascular magnetic resonance (CMR) compared to invasive X-ray coronary angiography for the investigation of suspected angina (cardiac chest pain). In addition, it was the first large scale clinical trial to compare a multi-parametric CMR test to the current ‘reference standard’ myocardial perfusion imaging test (SPECT – single photon emission computed tomography).

CE-MARC has been described as a landmark trial that is changing the way patients with suspected angina are investigated across the UK and Europe. In brief, the study has shown:

1) CMR has superior diagnostic accuracy compared to SPECT (the current NHS standard) (i.e. CMR is more accurate)

2) CMR is more cost effective than SPECT (i.e. cheaper for the NHS)

3) CMR is a better test than SPECT for determining prognosis (i.e. identifying high risk patients).

These findings support the much wider use of CMR for the diagnosis and management of patients with ischaemic heart disease.

A further major impact of CEMARC has been the CEMARC2 trial, which demonstrated that adherence to the prevailing NICE Guidelines (CG95 2010) resulted in a high excess of unnecessary invasive procedures (angiography), without the benefit of reduced coronary events (Walker et al., 2013).

The Chief Investigator has presented the results of the study at numerous conferences including:

• European Society of Cardiology,

• American College of Cardiology,

• Society for Cardiovascular Magnetic Resonance,

• European (Society of Cardiology) Cardiovascular Magnetic Resonance,

• Australian Cardiac Society,

• Danish Cardiac Society,

• US Grand Rounds

REFERENCES:

Greenwood, J. P., Herzog, B. A., Brown, J. M., Everett, C. C., Nixon, J., Bijsterveld, P., ... & Plein, S. (2016). Prognostic value of cardiovascular magnetic resonance and single-photon emission computed tomography in suspected coronary heart disease: long-term follow-up of a prospective, diagnostic accuracy cohort study. Annals of internal medicine, 165(1), 1-9.

Greenwood, J. P., Maredia, N., Radjenovic, A., Brown, J. M., Nixon, J., Farrin, A. J., ... & Ball, S. G. (2009). Clinical e valuation of magnetic resonance imaging in coronary heart disease: The CE-MARC study. Trials, 10(1), 62.

Younger, J. F., Plein, S., Crean, A., Ball, S. G., & Greenwood, J. P. (2009). Visualization of coronary venous anatomy by cardiovascular magnetic resonance. Journal of Cardiovascular Magnetic Resonance, 11(1), 26.

Greenwood, J. P., Motwani, M., Maredia, N., Brown, J. M., Everett, C. C., Nixon, J., ... & Plein, S. (2014). Comparison of cardiovascular magnetic resonance and single-photon emission computed tomography in women with suspected coronary artery disease from the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease (CE-MARC) Trial. Circulation, 129(10), 1129-1138.

Greenwood, J. P., Ripley, D. P., Berry, C., McCann, G. P., Plein, S., Bucciarelli-Ducci, C., ... & Mangion, K. (2016). Effect of care guided by cardiovascular magnetic resonance, myocardial perfusion scintigraphy, or NICE guidelines on subsequent unnecessary angiography rates: the CE-MARC 2 randomized clinical trial. Jama, 316(10), 1051-1060.

Maredia, N., Kozerke, S., Larghat, A., Abidin, N., Greenwood, J. P., Boesiger, P., & Plein, S. (2008). Measurement of left ventricular dimensions with contrast-enhanced three-dimensional cine imaging facilitated by kt SENSE. Journal of Cardiovascular Magnetic Resonance, 10(1), 27.

Maredia, N., Radjenovic, A., Kozerke, S., Larghat, A., Greenwood, J. P., & Plein, S. (2010). Effect of improving spatial or temporal resolution on image quality and quantitative perfusion assessment with k‐t SENSE acceleration in first‐pass CMR myocardial perfusion imaging. Magnetic resonance in medicine, 64(6), 1616-1624.

Greenwood, J. P., Maredia, N., Younger, J. F., Brown, J. M., Nixon, J., Everett, C. C., ... & Ball, S. G. (2012). Cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary heart disease (CE-MARC): a prospective trial. The Lancet, 379(9814), 453-460.

Walker, S., Girardin, F., McKenna, C., Ball, S. G., Nixon, J., Plein, S., ... & Sculpher, M. (2013). Cost-effectiveness of cardiovascular magnetic resonance in the diagnosis of coronary heart disease: an economic evaluation using data from the CE-MARC study. Heart, 99(12), 873-881.

Walker, S., Girardin, F., McKenna, C., Ball, S. G., Nixon, J., Plein, S., ... & Sculpher, M. (2013). Cost-effectiveness of cardiovascular magnetic resonance in the diagnosis of coronary heart disease: an economic evaluation using data from the CE-MARC study. Heart, 99(12), 873-881.