Aspirin after hospitalisation with Pneumonia to prevent cardiovascular Events randomised Controlled Trial (ASPECT)

University of Bristol and North Bristol NHS Trust require access to NHS England data for the purpose of the following research project: Aspirin after hospitalisation with Pneumonia to prevent cardiovascular Events randomised Controlled Trial (ASPECT).

The following is a summary of the aims of the research project provided on behalf of the Controllers:

Pneumonia is an inflammation of one or both lungs, usually caused by infection. Pneumonia is very common with 270,000 patients admitted as an emergency to hospital in England every year (data from custom analysis of anonymised Hospital Episode Statistics (HES) data for the calendar year 2018). Most people recover completely but some have complications. Two of the most significant complications are heart attack or stroke. Around 1 in 13 patients (8%) who are admitted to hospital with pneumonia have a heart attack or stroke within three months. These events are thought to occur because the infection attacks blood vessels and causes clots, reducing the blood reaching the heart or brain. Patients who have a heart attack or stroke take longer to recover from pneumonia and are more likely to die. Aspirin has been used for decades to reduce the chance of having a heart attack or stroke in other patient groups. It works quickly with limited side effects in the vast majority of patients. Although aspirin has limited side effects in the vast majority of people, it carries a very small risk of significant bleeding, therefore it is not clear whether or not giving aspirin to everyone with pneumonia will be beneficial overall.

The ASPECT trial aims to test whether aspirin reduces the risk of a heart attack or stroke in patients who are admitted to hospital with pneumonia.

The following is a summary of the aims of the research programme:

- To evaluate the effectiveness of aspirin versus usual standard care in preventing major adverse cardiovascular events (MACE) in patients ≥ 50 years admitted to hospital with community-acquired pneumonia.

- To estimate the difference (risk difference and risk ratio) between randomised groups in:

1) MACE* up to 90 days following randomisation;

2) secondary outcomes, namely all-cause mortality, cardiovascular mortality and major bleeding events up to 90 days following randomisation.

*Composite outcome of any MI, stroke (ischaemic or stroke of unknown type) or cardiovascular mortality.

Adults aged 50 years and over admitted to hospital with pneumonia will be invited to take part in the study (potential participants).

This cohort comprises potential participants unable to provide written informed consent. Some potential participants may have capacity to verbally consent but are unable to physically complete a consent form, for example they may be too frail to hold a pen. In this instance, an independent witness (e.g. member of ward staff) can sign the form on their behalf. Some potential participants may lack capacity to consent, due to the severity of their condition or a prior condition. In this instance, consent may be obtained from a legally designated representative (relative, friend, or independent doctor), in personal or verbally via phone/video call. Should the patient regain capacity at a later time, confirmatory consent will be sought; this can be obtained in person, or verbally over the phone/video call. Confirmatory consent does not need to be sought once the patient has been discharged.

Participants will be split into two groups. Every person joining the study will have an equal chance of being in either group, so both groups will be made up of the same kinds of people.

- One group will be asked to take one tablet of low dose aspirin each day for 3 months, after taking a higher dose (2 tablets daily) for 7 days.

- The other group will be asked to refrain from taking aspirin for 3 months. In all other respects, both groups will have standard pneumonia treatment.

Recruitment started on 31 January 2023 and is estimated to continue until August 2026.

Participants will be followed up at 3 months (90 days) after randomisation without having to do anything, as data will be collected from routinely available sources held by NHS England. The study team will assess their recovery, specifically whether they have a heart attack or stroke, or any serious side effects of aspirin. Following up participants like this has been shown to be robust, reduces the burden on participants and makes the research much less expensive.

All final outcomes for the study will be ascertained from linked, routinely collected health Data from NHS England at 90 days post randomisation, and as such this application requests access to the following data sets for study analysis:

- Record-level HES Admitted Patient Care (APC) Data (including 5 years of historic data prior to Date of Randomisation)

- Record-level Civil Registrations Deaths Data

These datasets will provide the study primary outcome of any MACE defined using validated International classification of diseases 10 (ICD-10) codes for specified diagnoses in hospital or cardiovascular death (deaths with any of the specified ICD-10 codes) coded as the underlying cause up to 90 days after randomisation. This data will also aid the answering of secondary outcomes including Hospital length of stay, Bleeding events causing hospitalisation and Cardiovascular mortality. Five years of historic HES APC data has been requested on the recommendation of the study’s Trial Steering Committee (TSC) as it will enable to study to phenotype the trial cohort. For example, the study team will be able to estimate frailty score and the Charlson comorbidity index (a weighted index developed in 1984 to predict risk of death within 1 year of hospitalization for patients with specific comorbid conditions).

The data will be minimised as follows:

• Limited to a study cohort identified by University of Bristol. This portion of the cohort represents 4-5% of the total study cohort who have been entered into the trial under a legal representative having lost mental capacity.

• For each individual patient, NHS England Data will be provided from the Date of Randomisation and until 90 days post randomisation (first recruitment into the study started 31 January 2023) plus 5 years of historical HES APC data prior to the Date of Randomisation.

North Bristol NHS Trust is the research Sponsor and a joint Controller. The University of Bristol is also a joint Controller and both organisations are responsible for ensuring that the Data will only be processed for the purpose described above.

Virtus Datacentres provide back-up storage to the University of Bristol (via a third-party contract) by providing the building and rack-space, and provide IT assistance with the hardware, but have no access to the Data held on the systems. As a result, they are not considered a Processor in this Data Sharing Agreement.

The lawful basis for processing personal data under the UK GDPR is:

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;

The lawful basis for processing special category data under the UK GDPR is:

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.

This processing is in the public interest because the Controllers hope the study will identify if the use of aspirin can reduce the risk of MACE within 90 days for those people admitted to hospital with pneumonia by 15-20% per year (England alone) and therefore contribute to improvements in morbidity risk and the treatment of NHS patients in the UK (and beyond).

Additionally, under UK GDPR Article 9(2)(j) processing of Special Category Personal Data (of which Health data is one) is necessary for archiving for research purposes. Data minimisation processes are being followed and only data that is specifically required for the purposes of this study have been requested, to protect the rights of the data subjects. The data are required for research purposes in the public interest – meeting the conditions in the DPA 2018 Schedule 1 Part 1 (4) – which UK GDPR Recital 52(2) determines is an appropriate derogation from the prohibition on processing special categories of personal data.

The funding is provided by The National Institute for Health and Care Research (NIHR), the British government’s major funder of clinical, public health, social care and translational research. The NIHR have provided finding as part of their Health Technology Assessment Programme. The funder will have no access to record-level NHS England Data, nor have the ability to suppress or otherwise limit the publication of findings.

The cohort will be provided by University Hospitals Bristol and Weston NHS Foundation Trust, who are not a named processor in this DSA as they will not be receiving NHS England Data. However, a separate Data Processing Agreement is in place between University of Bristol, North Bristol NHS Trust, and University Hospitals Bristol and Weston NHS Foundation Trust for processing of the cohort for this DSA.

The Trial has a Public and Patient Involvement and Engagement (PPIE) group, which is consulted annually, and there are PPI representatives on the Trial Steering Committee (TSC) and Trial Management Group (TMG). The members of the TMG will have no access to record-level NHS England Data.

The ASPECT Trial Steering Group (TSC) and ASPECT Data Monitoring and Safety Committee (DMSC) may see record-level data from NHS England. The DMSC and TSC have members who are not substantively employed by the Data Controllers in this agreement. The role of DMSC members is to monitor the safety data from the ASPECT trial and make recommendations to the Trial Steering Committee on whether there are any ethical or safety reasons why the study should not continue. They may therefore need to disclose data in the DMSC report to aid the TSC decisions. This includes a line listing of events that the Chief Investigator (CI) has deemed to be potentially related to treatment and will include the ASPECT study identifier, reaction (ICD10 diagnosis code) and time from randomisation to diagnosis. The data will be at patient-level with patients identified using the unique ASPECT study identifier. NHS England acknowledges that there is a legal obligation relating to pharmacovigilance in CTIMPs and therefore NHS England record-level data may be shared to members of the ASPECT TSC and DMSC only for the specific purpose of safeguarding the safety and interests of trial participants and monitoring the overall conduct of the clinical trial as per the Adverse Event report described in the Study protocol.

Three data drops are required on an ad-hoc basis based on a cumulative cohort which will be uploaded on each occasion. Data is limited to consented cohort members, recruited via legal representative. For each new cohort member, there will be one drop of 5 years of historic HES APC Data prior to the Date of Randomisation, and then latest available HES Data per drop for each cohort member between the Date of Randomisation and 90 days post randomisation.

University Hospitals Bristol and Weston NHS Foundation Trust will securely transfer data to NHS England. The data will consist of identifying details (specifically NHS Number, Date of Birth, Postcode, Gender and a unique person ID - also known as a Study ID) for the cohort to be linked with NHS England data. The cohort file will also contain the date of randomisation.

NHS England will then provide the University of Bristol with the relevant record-level Data from the HES APC and Civil Registrations Deaths datasets. The Data will contain no direct identifying data items but will contain a unique person ID which can be used to link the data with other record level data already held by the recipient.

NHS England Data will be stored on secure servers and a virtual backup datacentre hosted onsite at the premises of the University of Bristol and accessed via an Encapsulated Virtual Machine (eVM). Data from the University of Bristol will additionally be stored as a secondary back-up in geographically separate UK-situated datacentre owned by Virtus Datacentres on equipment owned by the University of Bristol. Virtus Datacentres provide the University of Bristol (via a third-party contract) with the building and rack-space, and provide IT assistance with the hardware, but have no access to the Data held on the systems.

NHS England Data will not be transferred to any other location, other than those stated above.

Direct access will be granted to substantive employees or agents of University of Bristol who are authorised by the ASPECT study team. Authorised personnel are prohibited from downloading or copying data to local devices.

All authorised personnel accessing the data have been appropriately trained in data protection and confidentiality. Identifying data items will be stored in a separate database to the linked dataset used for analysis on the secure server and access is limited to the ASPECT study team.

The data will not leave England at any time.

The data will be linked at person record level with data obtained from relevant local hospitals and study data via the pseudonymised Study ID.

The expected outputs of the processing hope to be as follows:

• A report of findings confirming the outcomes of the study

• A report of findings for the Data Monitoring and Safety Committee to confirm the safety of the study (annually)

• Submissions to peer reviewed journals at the end of the study

• Presentations to healthcare professions, research and participants

• Presentations at appropriate health- related conferences

• Publication of dashboards on Bristol Trial Centre’s website

• A database to be utilised as a resource for health research (under this DSA sublicensing and onward-sharing of NHS England Data is not permitted).

The outputs will contain only aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived.

The outputs hope to be communicated to relevant recipients through the following dissemination channels:

• Journals, such as Lancet and New England Journal of Medicine.

• Webinars open to healthcare professionals, researchers, participants

• Social media, such as X (formerly Twitter)

• Public reports

• Posters displayed at appropriate conferences

• Press/media engagement

• Public promotion of the research

• Participant newsletters - The study team aim to send the results of the study to participant by email or post if they have opted-in for this. This is information is collected on their baseline CRF.

The findings of this research study are expected to contribute to evidence-based decision-making for policy-makers, local decision-makers such as doctors, and patients to inform best practice to improve the care, treatment and experience of health care users relevant to the subject matter of the study.

If aspirin does indeed reduce the risk of MACE in patients admitted to hospital with pneumonia then with the high incidence of pneumonia, it means that there would be about 2,800-3,800 fewer MACE per year if aspirin were to reduce the risk by 15-20% (in England alone).

Aspirin is already known to be effective for other groups of patients with risk factors for MACE. Moreover, although the general risk of MACE has substantially reduced in the past two decades, cardiovascular disease still costs the NHS an estimated £9 billion per year in both acute and long-term costs. Given the widespread availability and familiarity of aspirin to patients and healthcare professionals any benefit would face few barriers to implementation in standard care for pneumonia treatment in acute care.

The use of the data could also:

• lead to the identification or improvement of treatments or interventions, or health and care system design to improve health and care outcomes or experience.

• advance understanding of the need for, or effectiveness of, preventative health and care measures for particular populations or conditions such as obesity and diabetes.

It is hoped that through publication of findings in appropriate media, the findings of this research will add to the body of evidence that is considered by the bodies, organisations and individual care practitioners charged with making policy decisions for or within the NHS or treatment decisions in relation to specific patients.

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