REstart or STop Antithrombotics Randomised Trial (RESTART)

The University of Edinburgh will use the data for the 'REstart or STop Antithrombotics Randomised Trial'.

RESTART is studying the potentially beneficial effects of starting antiplatelet drugs (one or more of aspirin, clopidogrel or dipyridamole, chosen by the patients physician), on the risks of a heart attack, stroke and other clotting problems as well as their effect on the risk of a brain haemorrhage happening again, for adults surviving a stroke due to bleeding in the brain and who were taking a prescribed antithrombotic (i.e., anticoagulant or antiplatelet) drug for the prevention of illnesses such as angina, heart attack or stroke before their bleed.

A magnetic resonance imaging (MRI) sub-study will also study whether the presence of brain microbleeds modify the effects of antiplatelet drugs.

537 consented participants were recruited from 103 recruiting sites in NHS hospitals throughout the UK and randomly allocated to take an antiplatelet or avoid taking antiplatelets. All participants are followed up for at least 6 months after randomisation either by postal or telephone questionnaire to check for the occurrence of any relevant events or outcomes and their medications. In addition, participants GPs, and the hospital which recruited them, provide information on any relevant adverse events which occur during the follow up period including hospital admissions and deaths. These events will be compared in those taking an antiplatelet and those avoiding it to compare the event rate.

Recruitment commenced on the 22nd May 2013 and closed at midday on the 31st May 2018 with 537 participants (97 from Scotland). Follow-up will be completed for events that occur by the end of November 2018. Data has therefore only been requested to cover this period of participation.

This proposal for NHS Digital data along with the data from NHS Scotland will enable RESTART to more accurately determine the number of outcome events which occur after the date of a patient’s randomisation, until the time of this data extract or the last period of data available. It is already known that the primary source of ascertainment of these outcome events (annual postal questionnaires to participants’ general practitioners) misses some events that participants have reported. Therefore, RESTART seeks secondary data to improve the accuracy of its data on the occurrence of the trial’s major outcomes, which will improve the scientific validity of the trial’s findings. The primary objective of the trial is to estimate, when all participants have completed at least 6 months of follow-up, the relative and absolute effects of antiplatelet drugs on the risk of brain haemorrhage happening again associated with a policy of starting antiplatelet drugs after the acute phase of brain haemorrhage. Ultimately, RESTART intends to determine whether antiplatelet drugs are beneficial for patients after brain haemorrhage because the gains from prevention of clotting problems outweigh the risks of bleeding at any site.

A brain MRI sub-study is incorporated into the trial protocol to determine whether patients with tiny deposits of blood in the brain called 'microbleeds' on an MRI brain scan have an increased risk of having a recurrent brain haemorrhage if prescribed antiplatelet drugs following a brain haemorrhage.

This specific proposal will allow RESTART to identify any missing primary and secondary outcome events in the trial which were not reported using the primary sources of follow-up (patient and GP follow-up, ad hoc reports from patients or research staff at participating sites) and determine the long-term survival of participants. This will enable RESTART to determine whether antiplatelet drugs are a safe and effective treatment.

To carry out the work described above, the University of Edinburgh require HES Admitted Patient Care (APC) data linked to Civil Registration (Deaths) data. To ensure the accuracy of the patient reported data and to pick up any deaths or hospital episodes that were not reported to the trial, hospital episodes and deaths of the study cohort were provided by NHS Digital. The cohort came from various locations within the UK, and therefore a UK-wide request was required. This was the only method that could confirm the events that could prove vital to the results of the study. The data provided were the minimum required to fulfil the objectives of the study, namely details of any hospital admissions and reason for admission for each participant from the time of recruitment to the most recent data available, and date and cause of death for patients in the study cohort, to enable the research team to accurately characterise outcomes and cross-check with outcomes reported by investigators.

University of Edinburgh rely on Article 6(1)e (processing is necessary for the performance of a task carried out in the public interest) and Article 9(2)j (processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes) as their legal bases for processing the HES APC data disseminated under this Agreement. GDPR does not apply to the data solely relating to deceased individuals. This work is in the public interest as the results of the randomised controlled trial are the only reliable data about the effects of antiplatelet therapy after stroke due to intracerebral haemorrhage, which directly informs the care of patients.

The University of Edinburgh is the sole Data Controller under this Agreement, who also process the data. No other organisations have any role in determining the purpose for which the data is used or have any access to the data.

The processing of NHS Digital data will be carried out within the University of Edinburgh Safe Haven. A similar application has been made to the Public Benefit and Privacy Panel for Health and Social Care for data relating to patients recruited in Scotland.

RESTART supplied NHS Digital with patients’ identifiers (forename, surname, date of birth, NHS No., postcode, and RESTART study id (i.e., pseudonymous identifier) to facilitate the linkage and the participant’s date of randomisation to limit the data extraction from this date to the end of the available follow up period. One patient withdrew from the trial immediately following recruitment, and their data was not requested from NHS Digital. Two patients withdrew from continuing the trial after the data was received from NHS Digital, and their data is included, in line with the participant information leaflet v4.0 21st Dec 2015, p12 which stated, “If you do decide to withdraw, RESTART will retain information collected about you before the time you withdrew.”

The data received back from NHS Digital included the RESTART trial ID (as provided) and any dates of admission to NHS hospitals and the primary diagnosis leading to these admissions from HES Admitted Patient Care, as well as Mortality data (including Date of Death and Cause of Death). The data was then securely transferred to the University of Edinburgh Safe Haven.

A copy of the RESTART trial dataset was transferred to the Safe Haven. The Data manager linked these dataset with the data provided by NHS Digital, using the RESTART study number. The two datasets were then be compared in order to find the Outcome Events (Intracranial events, Extracranial Cardiovascular events, and Death of any cause) which were present in the NHS data but not in the RESTART trial dataset. If the record-level data provided by NHS Digital indicate that any of these outcomes might have occurred, University of Edinburgh will obtain source data from participating sites to verify or refute the occurrence of these outcomes. For any outcomes that are verified, two fields will be manually populated in the trial database for relevant participants after characterising the outcome (outcome event type and date); this will not involve importing record-level data provided by NHS Digital. This will be the only linkage with the NHS Digital data.

RESTART has a study-specific database that is password protected and held securely on University Datastore. Access is routinely reviewed and revoked when any team member leaves RESTART.

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

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 i.e. employees, agents and contractors of the Data Recipient who may have access to that data).

1. A trial database which will be kept securely in the University of Edinburgh Safe Haven - patient level data identifiable.

2. A completely aggregated version of the patient-level data with small numbers supressed, used for the primary analysis, has been made available behind access controls that require approval by the Trial Steering Committee, for use by the wider research community upon reasonable request. No NHS Digital data other than aggregated data with small numbers suppressed is made available to researchers not substantively employed by the University of Edinburgh. These outputs are primarily for health professionals to guide their patient care and for those developing evidence based guidelines. This output does not include record level data provided by NHS Digital; NHS Digital data processing is detailed in section 5b. The data are provided via https://datashare.ed.ac.uk/handle/10283/3265.

3. Pseudonymised data are for use solely for the RESTART trial by the University of Edinburgh (and includes NHS Digital data).

4. Presentations for healthcare staff and lay audiences - aggregated data only with small numbers suppressed.

5. Open access papers in peer reviewed journals - aggregated data only with small numbers suppressed. Publications and presentations to date:

a. RESTART Collaboration. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial. Lancet. 2019 Jun 29;393(10191):2613-2623. doi: 10.1016/S0140-6736(19)30840-2. Epub 2019 May 22. Presented at the European Stroke Organisation Conference in 2019.

b. Al-Shahi Salman R, Minks DP, Mitra D, Rodrigues MA, Bhatnagar P, du Plessis JC, Joshi Y, Dennis MS, Murray GD, Newby DE, Sandercock PAG, Sprigg N, Stephen J, Sudlow CLM, Werring DJ, Whiteley WN, Wardlaw JM, White PM; RESTART Collaboration. Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial. Lancet Neurol. 2019 Jul;18(7):643-652. doi: 10.1016/S1474-4422(19)30184-X. Epub 2019 May 22. Presented at the European Stroke Organisation Conference in 2019.

c. Al-Shahi Salman R, Dennis MS, Sandercock PAG, Sudlow CLM, Wardlaw JM, Whiteley WN, Murray GD, Stephen J, Rodriguez A, Lewis S, Werring DJ, White PM; RESTART Collaboration. Effects of Antiplatelet Therapy After Stroke Caused by Intracerebral Hemorrhage: Extended Follow-up of the RESTART Randomized Clinical Trial. JAMA Neurol. 2021 Sep 3:e212956. doi: 10.1001/jamaneurol.2021.2956. Epub ahead of print. Presented at the European Stroke Organisation Conference in 2021.

d. Wiegertjes K, Dinsmore L, Drever J, Hutchison A, Stephen J, Valdés Hernández MC, Bhatnagar P, Minks DP, Rodrigues MA, Werring DJ, de Leeuw FE, Klijn CJ, Al-Shahi Salman R, White PM, Wardlaw JM. Diffusion-weighted imaging lesions and risk of recurrent stroke after intracerebral haemorrhage. J Neurol Neurosurg Psychiatry. 2021 Sep;92(9):950-955. doi: 10.1136/jnnp-2021-326116. Epub 2021 Jun 8. Presented at the European Stroke Organisation Conference in 2021.

Pending output:

The linked data received from NHS Digital have been processed, compared to the RESTART dataset, and outcomes identified. However, the trial statistician started maternity leave unexpectedly early in February 2021, and they will not be returning to work until 2022. Therefore, University of Edinburgh need to retain the data to allow completion of the analyses of outcomes reported in RESTART vs. outcomes detected by linked data. This will result in a further journal publication, reporting aggregated data with small numbers suppressed only, as above.

The University of Edinburgh expects the completion of analyses comparing outcomes reported in RESTART vs. outcomes detected by linked data to determine the accuracy of both methods of outcome ascertainment. These analyses will be submitted for publication.

The results are expected to determine whether linked secondary data alone could be used as a source of outcome ascertainment in a definitive main phase trial. This is expected to benefit Health and Social Care by determining the accuracy of a cost-efficient method for assessing outcomes to determine the clinical effectiveness of the intervention (antiplatelet therapy) in a main phase trial. A trial, designed in this way, is consistent with the UK vision to unleash the full potential of clinical research delivery to tackle health inequalities, bolster economic recovery and to improve the lives of people across the UK, as described in the recent policy paper, “The Future of UK Clinical Research Delivery” (https://www.gov.uk/government/publications/the-future-of-uk-clinical-research-delivery).

The chief investigator at the University of Edinburgh has submitted an outline proposal for such a definitive main phase trial (designed to use linked data as the primary source of outcome ascertainment) to the NIHR Health Technology Assessment funding committee on 12 November where they learnt that a full application has been invited by NIHR HTA. The completion of the analyses of the RESTART dataset will inform the full application for the definitive main phase trial, which is designed to deliver clinical practice-changing results and improve the lives for survivors of brain haemorrhage.

More than one third of the adults with a stroke due to bleeding into the brain – known as brain haemorrhage – are taking drugs to prevent clotting when they have a brain haemorrhage. These patients had previously suffered illnesses like angina, heart attack, or stroke due to blood vessel blockage, which is why they are treated with drugs to prevent further clots occurring. These drugs are usually stopped when the brain haemorrhage occurs. But when patients recover from brain haemorrhage, they and their doctors are often uncertain about whether to restart these drugs to prevent further clots occurring, or whether to avoid them in case they increase the risk of brain haemorrhage happening again.

RESTART studied the potentially beneficial effects of antiplatelet drugs such as aspirin on the risks of heart attack, stroke and other clotting problems as well as their effect on the risk of a brain haemorrhage happening again. The results show that antiplatelet therapy is very unlikely to increase the risk of another brain haemorrhage, which is likely to be outweighed by the reduction in other major vascular events. This is useful information for prescribers and has already influenced guidelines in Canada, China and the USA.