Health related quality of life and clinical outcomes following acute myocardial infarction: linked EMMACE,HES and Civil Registration Mortality Data

The objective for processing of this data is to undertake research about health-related quality of life (HRQoL) in patients with myocardial infarction (MI; heart attack). Specifically, University of Leeds wish to investigate the relationship between HRQoL and clinical outcomes in this population. The study is entitled the EMMACE Study: (Evaluation of the Methods and Management of Acute Coronary Events). It is a national longitudinal consented cohort of patient reported outcomes of MI.

More people than ever are surviving their initial presentation with MI. Yet, many will have recurrent cardiovascular events, and some will die prematurely. Whilst HRQoL is an important patient-facing outcome after MI, there is a paucity of information about its association with subsequent clinical events. The overarching aim of this study is to enhance the EMMACE study consented cohort data using national healthcare data (Hospital Episode Statistics (HES) and Civil Registration Mortality data) to investigate the association of changes in HRQoL and subsequent clinical outcomes (fatal or non-fatal) following MI including stroke, recurrent MI, heart failure, atrial fibrillation, deaths following MI.

The University of Leeds is a public authority responsible for conducting scientific research for academic and public benefit. Data in the EMMACE Study is processed to enable the University of Leeds to perform its public task. University of Leeds rely on the following legal bases for processing data under the UK General Data Protection Regulation (GDPR):

Article 6(1)(e): Processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller. Few centres have sufficient patient through-put to provide this information.

Article 9(2)(j): Processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

The University of Leeds EMMACE study aims to investigate health related quality of life in patients with myocardial infarction. University of Leeds wish to investigate the relationship between health related quality of life and clinical outcomes in this population.

COHORT:

The trial has finished recruitment to participants. EMMACE 3 and EMMACE 4 are separate studies and not follow on studies.

The number in the cohort for EMMACE 3 is 5556 participants, recruited between 1st November 2011 and 17th September 2013.

The number in the cohort for EMMACE 4 is 9343 participants, recruited between October 2013 and 24th June 2015

For both trials the total is 14,899 participants.

The specific objectives of the research project are:

1. To describe MI patients according to their changes in HRQoL (from occurrence of MI to discharge, 30 days follow up, 6 months, and 12 months) and determine factors associated with these changes.

2. To summarise the incidence of fatal and non-fatal health outcomes amongst patients and determine if there are common patient clusters with respect to these outcomes.

3. To investigate whether changes in HRQoL have a differential impact on fatal and non-fatal clinical outcomes.

4. To investigate the association of quality of care, cardiac rehabilitation, medications, patient characteristics, socioeconomic status, changes in HRQoL with mortality.

The 4 objectives which will use the cohort are as follows;

Objectives 1, 3 and 4 will use 9566 patients from both the EMMACE 3 & EMMACE 4 studies who have:

- ST-Elevation Myocardial Infarction (STEMI), which is a very serious type of heart attack during which one of the heart's major arteries that supplies oxygen and nutrient-rich blood to the heart muscle is blocked. ST relates to a section on the electrocardiogram (ECG) test and may indicate whether a heart attack has taken place.

- Non-ST-elevation myocardial infarction (NSTEMI), which is less serious than an STEMI as the supply of blood to the heart may be only partially, rather than completely, blocked.

Please note that this is a subset from the total of 14,899 but only focusing on patients with STEMI and Non STEMI

Objective 2 will use all 14,899 patients from both studies EMMACE 3 & 4 including those without STEMI or NSTEMI

The EMMACE data cohort contains patient data on changes in HRQoL from MI to discharge, 30 days follow up, 6 months, 12 months measured using the EuroQol 5-dimension (EQ-5D-3L) questionnaire as well as information on cardiac rehabilitation, medications and patient characteristics - however - in order to meet the study objectives, the study team need to enhance the EMMACE dataset through linkage with HES and Civil Registration Mortality Data to determine the subsequent fatal and non-fatal outcomes following MI.

A detailed justification for the request of this level of data is outlined below:

The EMMACE study represents the largest contemporary national longitudinal study of patient reported outcomes and medications data for acute coronary syndrome. The study was designed to improve understanding of the effect of quality of care on health-related outcomes for patients hospitalised with acute coronary syndrome (ACS). The EMMACE studies, with consent for further linkage to electronic healthcare records, were given favourable ethical approval by Leeds (West) Research Ethics Committee (REC reference: 10/H131374, 13/YH/0277 and 12/WM/0431).

The EMMACE dataset contains patient reported data at admission, 1 month, 6 months and 1 year concerning patient related quality of life measured by the EQ-5D-3L questionnaire.

All patients were consented to enter the study and for their self-reported data to be linked to future electronic health record data.

EMMACE has already been successfully linked to data from the national heart attack registry (Myocardial Ischemia National Audit project, MINAP) thus providing information about hospital treatment for MI and comorbidities.

Further information in the form of a GDPR compliant transparency information leaflet was sent to all participants.

Whilst the EMMACE study provided information on determinants and trajectories of HRQoL following MI, questions remain on the association of changes in HRQoL and subsequent clinical patient outcomes for patients with MI.

The EMMACE data are limited to the extent that they do not capture the full range of quality of care, comorbidities, patient characteristics, clinical diagnosis, socioeconomic status, treatments and patient outcomes. Thus, the study team are not able to investigate the relationship between HRQoL, socio-economic status, quality of care, clinical diagnosis, treatments and fatal and non-fatal clinical outcomes.

This project has been funded by the British Heart Foundation (BHF) (PG/19/54/34511) to enhance the EMMACE data by linking it with existing electronic data on hospital episodes from HES and Civil Registration Mortality Data - facilitated by NHS England.

To summarise the incidence of fatal and non-fatal health outcomes amongst patients and determine if there are common patient clusters with respect to these outcomes and factors associated with these clusters, the EMMACE data will be linked electronically to HES and Civil Registration Mortality Data.

The HES data requested will include information on cause-specific hospital admissions, all HES records for the patients (i.e. their historical records and prospective ones after they entered EMMACE), any hospital diagnoses, clinical information and treatments.

These repeated cause-specific admissions, episodes and spells will be used to determine the longitudinal AMI patient phenotypes, patient transitions over time, and factors associated with these transitions. Non-fatal outcomes will include all hospital diagnoses such as heart failure, stroke, atrial fibrillation and acute coronary syndrome, with the fatal outcome being all-cause mortality. University of Leeds will investigate the effects of patient characteristics, socioeconomic status, diagnosis, changes in HRQoL, comorbidities, treatments on patient class membership and transition probabilities hence this data request from HES records.

To investigate the association of quality of care, cardiac rehabilitation, medications, treatments, patient characteristics, socioeconomic status, changes in HRQoL with mortality. EMMACE data will be linked electronically to Civil Registration Mortality data for information on cause specific mortality and date of death. Mortality data will be required at individual patient level about the occurrence, timing and causes of any death. The exact date of death will be required to calculate the survival time between date of entry into the EMMACE study and date of death. A survival time for those who have not die but are censored will be required.

To ensure comprehensive information on all confounders, University of Leeds are requesting individual patient level HES data on in-patient hospitalisations, patient demographic characteristics (age of patient, sex of patient, ethnicity), socio-economic factors (IMD indices, smoking status, employment status) information about diagnoses and operations, dates of admission and discharge, where patients were treated, comorbidities, revascularization procedures and treatments.

The research will be undertaken by the established Cardiovascular Epidemiology Research Group within the Leeds Institute of Cardiovascular and Metabolic Medicine, and physically located in the Leeds Institute for Data analytics at the University of Leeds.

The research group has a remit of using large scale routine data (HES) and clinical registries (MINAP registry) alongside advanced analytical epidemiological techniques to better understand and improve the quality of care of patients with cardiovascular disease.

Presently the EMMACE data are stored in two physically different secure locations.

All EMMACE 3 data, including identifiable data such as NHS number, sex and date of birth are stored at the University of Leeds. EMMACE 3 data at the University of Leeds is managed by Leeds Institute of Data Analytics (LIDA) who have control of the data, are responsible for supplying cohort information to NHS England and linking NHS England data to all non-identifiable data using study ID only. LIDA will supply pseudonymised data to the statisticians in the Cardiology Epidemiology group at the University of Leeds who will analyse the data. Statisticians in the Cardiology Epidemiology group do not have access to personal data but to study ID only.

EMMACE 4 data, including identifiable data such as NHS number, sex and date of birth are stored at the Leeds Teaching Hospitals NHS Trust (LTHT). This is for administrative purposes and for use in facilitating ongoing data linkages.

Access to this environment is controlled by two factor authentication and is granted a need only basis. All data received into this solution is via secure transfer and in accordance with all data sharing agreements. Data will be encrypted in transit and at rest. The data is transferred directly to the processing platform where any agreed processing will take place. Any data in this platform is deleted in accordance with any processing agreement.

All sites and data centres are protected by CCTV. Access control is limited via key fobs to office areas and safe rooms. All networks are segmented and where required for security prevent access, data flow, external access etc. All networks internally and externally are tested on a monthly basis for vulnerabilities.

DATA FLOW INTO NHS ENGLAND:

Leeds Institute of Data Analytics at University of Leeds will send the following identifiers to NHS England for the EMMACE 3 Cohort:

• NHS Number

• Sex

• Date of Birth

• Study ID

LTHT will send the following identifiers to NHS England for the EMMACE 4 Cohort:

• NHS Number

• Sex

• Date of Birth

• Study ID

All identifiers for participants who have withdrawn from further follow up from the EMMACE 3 and 4 studies will be removed from the data files prior to sending to NHS England.

The EMMACE data will be linked to HES and Civil Registration Mortality data for the period 2010/11 to 2020 by NHS England acting as the trusted third party. NHS England will return data to the University of Leeds that includes (for patients with prior and/or subsequent hospitalisations) corresponding HES records and corresponding cause of death and date of death for patients who have died. University of Leeds require only Study ID from NHS England as the identifier - NHS Number is not required to be returned..

University of Leeds requested data from 2010/11 to 2020 as the research study EMMACE recruited patients with Myocardial Infarction (MI) from 1st November 2011. In this current research one of the objectives is to summarise the incidence of fatal and non-fatal health outcomes amongst the patients and determine if there are common patient clusters with respect to these outcomes. To undertake this research work University of Leeds will require the episode and spells for periods of care of patients in the research study (EMMACE) who consented for their data to link to electronic health records, clinical information and diagnosis will be required to determine the fatal and non fatal outcomes and duration of outcomes. Geographical information from HES data is required to determine geographical variations in outcomes after Myocardial infarction.

One of the objectives is to investigate the association of cardiac rehabilitation, medications, treatments, patient characteristics, socio-economic status, and changes in HRQoL with mortality. In order to undertake this work, patient data, socioeconomic data, treatments from HES is required. IMD domain and overall ranks scores will be required to look at the relationship of specific domains with HRQoL.

The linked (EMMACE/HES/Civil Registration Mortality) data - the analytical cohort - will be stored separately from the EMMACE cohort that contains patient identifiers. That is, the analytical cohort (excluding NHS numbers) will be stored in a restricted directory within the University of Leeds password protected secure storage area network (SAN).

The University of Leeds Information Security Policy has been fully implemented and has been drawn up in line with ISO 27001 The University of Leeds are DSPT accredited. The data for this study is considered personal and its storage and sharing will abide by the University of Leeds data protection and sharing policies. The data will only be accessible to authorised individuals in the study team and will only be used for the purpose of this project. Data will not be used for commercial purposes or provided in record level form to any third party or used for any direct marketing.

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

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

The planned analysis of the EMMACE study will be disseminated nationally and internationally in peer-reviewed open access research journals (such as European Heart Journal, Heart, BMJ); national and international research conferences, departmental seminars, through the media and stakeholder meetings with patients. The EMMACE researchers have established relations with the International Quality of Life Society (ISOQOL) through which study findings will be disseminated. Furthermore the Cardiovascular Epidemiology research team has established connections with numerous relevant groups through which findings will be disseminated to the NHS as well as patients, including the European Society of Cardiology, the British Cardiovascular Society and National Instititute for Health and Care Excellence (NICE). The EMMACE study dissemination strategy will be as follows:

Peer-reviewed publications published 2020-2022:

- Hurdus et al., 2020. Association of cardiac rehabilitation and health-related quality of life following acute myocardial infarction. Heart, 106(22), pp.1726-1731.

- Munyombwe et al., 2021. Association of multimorbidity and changes in health-related quality of life following myocardial infarction: a UK multicentre longitudinal patient-reported outcomes study. BMC medicine, 19(1), pp.1-14.

- Dondo et al., 2022. Sex differences in health-related quality of life trajectories following myocardial infarction: national longitudinal cohort study. BMJ open, 12(11), p.e062508.

Planned publications for 2023-2030:

- Association of Health related quality of life and mortality in survivors of myocardial infarction. Target journal BMJ

- Association of Health related quality of life and major adverse cardiovascular events (MACE) in survivors of myocardial infarction. Target journal Lancet

- Associations of medication adherence, health related quality of life and patient outcomes in survivors of myocardial infarction. Target journal Heart

- Joint modelling of changes in health-related quality of life and survival or major adverse cardiovascular events in survivors of myocardial infarction. Target Journal Quality of life research journal. This paper will look at the association between time to event (mortality) and longitudinal HRQoL through joint modelling. University of Leeds will generate individualized patient-level predictions of survival probability based on the individual’s available HRQoL information.

- Determinants of health-related quality of life in survivors of heart attacks: A structural equation modelling approach. Target Journal BMC Quality of life research. This paper will use the HRQoL conceptual model developed by Wilson and Clearly to look at associations of individual characteristics, environmental characteristics, biological and physiological variables, symptoms status, physical function, general health perceptions and HRQoL.

-Identification of myocardial infarction subgroups through phenotyping of fatal and non-fatal outcomes. Target journal BMC medicine. This paper will determine MI patient phenotypes based on fatal and non-fatal outcomes using machine learning approaches. University of Leeds will investigate the effects of patient demographic, socioeconomic characteristics, treatments, changes in HRQoL and co-morbidities on phenotype groups.

Conference presentations undertaken 2020-2021:

- 28th ISOQoL conference, 2020. Association of multimorbidity and changes in health-related quality of life following myocardial infarction: a UK multicentre longitudinal patient-reported outcomes study.

- European Society of Cardiology, digital conference, 2021. Sex differences in health related quality of life among myocardial infarction survivors: An inverse weighted propensity score analysis. Digital poster presentation.

- Cardiac surgery consortium monthly meetings, NIHR Yorkshire and Humber meeting, 2022.

Planned conference presentations for 2023-2030:

- European Society of Cardiology, August 2023. Association of health related quality of life and mortality: EMMACE population based cohort study: Accepted poster presentation.

- ISOQoL 30th Annual annual conference, October 2023. Association of health related quality of life and major adverse cardiovascular events (MACE): EMMACE population based cohort study: Accepted poster presentation.

- ISOQoL 30th Annual annual conference, October 2023. Association of health related quality of life and major adverse cardiovascular events (MACE): Systematic review, meta-analysis and evidence mapping: Accepted poster presentation

- ISOQoL conferences (2024 to 2030).

- British Society of Cardiology conference (2024 to 2030).

- European Society of Cardiology Congress (August 2024 to 2030).

Patient and Public Involvement

The research outputs as described will be published in peer-reviewed journals and presented at conferences and will be reported through press release through national media. A lay person friendly summary of the study results will be disseminated to the West Yorkshire Patient and Public involvement group.

University of Leeds have an active, well-rehearsed and effective relationship with the BHF and University of Leeds press offices, whereby the research findings may be disseminated to the wider regional, national, and international audience. The BHF will publish the results of the study in their free e-newsletter.

University of Leeds will provide an update on the study findings on the Leeds Institute of Cardiovascular and Metabolic Medicine study website which is available to the public.

Additionally:

• A lay person summary will be disseminated to the West Yorkshire Patient and Public involvement group. This group is run by the Leeds Clinical Research Facility Operations Manager at Leeds General Infirmary. There are 40+ members of the group. University of Leeds will contact the Manager when the results are ready and ask to distribute the lay person summary to the group by email. University of Leeds have previously discussed with the Manager about presentations to the group however due to COVID 19 the group no longer has regular meetings. This option would be discussed with the Manager when the results are available.

• The University of Leeds will make a press release for any significant findings from the study. This press release is available to all, articles are on the University of Leeds website thus can be looked at by anybody, including the press, this may result in the increase of knowledge.

• Any findings from the study will be discussed with the BHF, who will disseminate as they see appropriate. This will be in form of a patient newsletter. The BHF assigns a Case Officer to the grant, University of Leeds will direct all discussions about dissemination through the Case Officer.

• A lay person summary will be made available on the University of Leeds website.

• Twitter will be used to signpost the public and experts to the layperson summary and all study publications (@UoLCardioEpi).

Whilst planned analyses have the potential to achieve high impact peer reviewed publications, it is the clinical implications of the results for healthcare professionals, patients and regulators that are of greater virtue.

The results from the proposed study will help answer major gaps in the knowledge base on the associations between changes in HRQoL and subsequent health outcomes. Identifying precisely in whom worse (or better) outcomes may occur will permit the design and testing of novel interventions targeted specifically at common, and potentially previously unknown, consequences of a heart attack for patients with specific health related quality of life trajectories.

The aim of the EMMACE study is to improve the quality of life and clinical outcomes of patients with MI. The planned research will provide a unique and comprehensive insight into the relationship between changes in HRQoL and clinical outcomes among patients with MI. HRQoL is a patient reported outcome measure (PROM) which can detect change in risk of events for patients, and potentially serve as a predictor of future risk (using patient-facing data capture tools). Understanding the association between changes in HRQoL and health outcomes, and precisely in whom worse (or better) outcomes may occur will permit the design and testing of novel intervention to reduce premature death from MI.

Results from this research will help design interventions to improve quality of life and cardiovascular outcomes in survivors of heart attacks. The results will be used to inform the UK Integrated Care Boards (ICBs) who work in partnerships with hospitals and are responsible for the commissioning of specialist services including acute cardiac care.

In this study, through linkage to HES and Civil Registration Mortality data, University of Leeds will be able to classify patients into particular phenotypes (or disease risk patterns) using fatal (deaths) and non-fatal outcomes (stroke, heart failure, atrial fibrillation, re-infarction and any other hospitalisations). This will allow University of Leeds to determine the types of patients who may benefit from more intensive care, to improve their quality of life and survival.

The research work that has been conducted to date has identified characteristics of patients who are likely to have poor outcomes after having a heart attack and health related quality of life domains that are problematic. Prediction models have been developed for use in clinical practice to identify patients at high risk of poor outcomes following myocardial infarction. However, more research work is in progress to externally validate these models, so these models cannot yet be used in clinical practice for patient decision making. It is hoped that the findings will enable targeted interventions by designing and testing novel interventions to reduce poor patient outcomes and improve health related quality of life.

The research findings have been disseminated in high impact peer reviewed journals and presentations at international conferences which are sources of information for patients, clinicians, and other researchers. As a result of the recommendations in these publications, clinicians who provide care to patients post MI are likely to pay greater attention to patients at high risk identified in our research who need targeted interventions to improve their quality of life and survival.