Mortality and HES data at 12 months for patients in the CHARIOT study (BMJ 2019;364:l729)

This agreement is to allow the University Hospital Southampton NHS Foundation Trust to hold and continue processing identifiable data that flowed under a previous iteration. There are no further flows of data under this agreement.

CHARIOT stands for the following: Is the [C]urrent T[h]reshold for Diagnosis of “[A]bnormality”, including Non ST Elevation Myocardial Infarction, using [R]aised H[i]ghly Sensitive Tr[o]ponin Appropriate for a Hospi[t]al Population?

A blood test called troponin forms a key part of the diagnosis of a heart attack (myocardial infarction). Troponin refers to a group of proteins that help regulate the contractions of the heart and skeletal muscles. High troponin levels can indicate a problem with the heart. The heart releases troponin into the blood following an injury, such as a heart attack. The upper limit of normal for this test is determined by the manufacturer of the test, based on the troponin levels in healthy individuals, generally aged between 18-40. Recently assays have been developed that provide a higher degree of sensitivity and as such allow rapid exclusion of a heart attack within a few hours. This benefit does however raise another issue; elevated levels of high sensitivity troponin are now frequently seen in patients who have not suffered a heart attack. In the absence of clinical features of a heart attack an elevated high-sensitivity troponin leaves clinicians uncertain as to how to interpret this result and whether it should result in changes to patient care.

The original CHARIOT study, which has been published in the BMJ (BMJ 2019;364:l729), collected high-sensitivity troponin results from 20,000 consecutive patients who had blood samples requested by clinicians at University Hospital Southampton (UHS). The aim was to provide a description of the distribution of high-sensitivity troponin in a hospital population.

The CHARIOT study has highlighted the potential flaws in the use of the high-sensitivity troponin assay in front line clinical practice: the concern that the test is used to diagnose Type 1 myocardial infarction and yet; a) the cut off provided by the manufacturer of the test as the upper limit of normal is not appropriate, so that 1 in 20 patients at a large UK hospital have a high sensitivity troponin above this level even when there is no clinical suspicion of a myocardial infarction; b) the cause of the elevated high-sensitivity troponin is likely to be due to myocardial injury, rather than a type 1 myocardial infarction in most cases.

Having established these important observations in CHARIOT, the Coronary Research Group (CRG) at UHS now wish to pursue a secondary question from this 20,000 patient population, which the CRG is in an unique position to do: release of troponin in these patients probably indicates myocardial injury and does this act as a surrogate for worse clinical outcome?

Recent data in other patient cohorts including diabetics (Circulation 2017; 135:1911-1921) and chronic lung disease (BMC Pulm Med. 2016; 16:164) have suggested high-sensitivity troponin levels are associated with cardiovascular risk.

This study will aim to assess whether there is an association between high-sensitivity troponin levels and 2.5 year outcomes (mortality status, cause of death and admission diagnoses). This work is of significant public interest for three reasons. Firstly, as demonstrated by the CHARIOT study, this issue is frequently encountered in clinical practice; secondly - clinicians are often unsure whether these results are of clinical significance. Finally, if this study does demonstrate an association between high-sensitivity troponin levels and outcomes then further studies will result to assess whether any medical interventions, (particularly proven cardiovascular therapies), could alter the prognosis in this group. This study therefore has significant potential implications for the healthcare of a large population of patients both in the UK and internationally.

As such the study meets the standards set out in section Article 6 (1)(E) of the General Data Protection Regulation for processing these data: "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". Furthermore for these reasons it also meets the expectations set out for processing data set out in Article 9(2)(J) of the General Data Protection Regulation: "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 key ethical question raised by this study is whether it is appropriate to process these data without consent. As already discussed the potential improvements that this study could offer to patient care both in the UK and internationally mean that this study is undoubtedly in the public interest. Furthermore this study will have minimal risk to the patients included in the study and their personal data will be kept pseudonymised. It is therefore clear that the study has an ethical mandate. This opinion is also held by both the Research Ethics Committee and the Confidentiality Advisory Group, as demonstrated by their support for this study.

The data requested will help the research team to assess whether there is an association between high-sensitivity troponin levels and clinical outcomes. Specifically mortality status will allow the team to assess whether there is a link between high-sensitivity troponin levels and mortality. The cause of death is important because it would seem more likely that high-sensitivity troponin levels will predict cardiovascular mortality rather than all cause mortality. Without the cause of death the research team will be unable to evaluate this. Whilst mortality is a key aspect of health, future cardiovascular events are also of key importance . Therefore the discharge diagnoses from hospital admissions will allow the team to assess whether there is an association between high-sensitivity troponin levels and cardiovascular events.

The data returned from NHS England will need to be in a pseudonymised form (just with the unique study identifier that the CRG at UHS will send) to allow the CRG at UHS to link these data with the high-sensitivity troponin levels. If data were provided on an aggregate level it would not be possible to fully assess the association between high-sensitivity troponin levels and clinical/mortality outcomes. 2.5 year outcomes should provide the research teams with a clear picture of the relationship between high-sensitivity troponin levels and outcomes. This is the minimum time frame required to answer the primary objectives of this study. Is is likely that some patients will have moved or have been admitted to hospital whilst away from their permanent residence. Therefore the data will not be restricted to one particular geographical area, such as Southampton. It is not possible to achieve the aims of the study without processing these data. Furthermore the research team have specifically asked for the minimum data required to complete the objectives of this study, any less and it would not be possible to robustly evaluate the association between high-sensitivity troponin levels and clinical outcomes. The data required from the HES dataset relates to Diagnosis codes only.

The results from these analyses will result in improvements in the way clinicians interpret high-sensitivity troponin levels but may also precipitate further studies to assess whether any medical interventions could alter the outcomes in at risk groups identified by this study.

This study is a follow on from the CHARIOT study which recruited 20,000 consecutive patients (both in- and out-patients) in whom a biochemistry sample was performed at UHS between the 29th June 2017 and 24th August 2017. This request forms part of a separate study resulting from the original CHARIOT study. There are no additional phases. This particular study will be referred to as CHARIOT.

UHS will act as the sole Data Controller who also processes data.

The original CHARIOT study was funded by an unrestricted research grant from Beckman Coulter (BC). BC had no input in the study specifics. This sub-study requires no input from industry and specifically BC have no ongoing role. There are no other organisations involved. There are no funders/commissioners involved.

Under the previous iteration of this Agreement patient identifiers were sent to NHS England to link data to the cohort. NHS England sent identifiable data to the University Hospital Southampton NHS Foundation Trust. This extension agreement is to hold the data for processing purposes. There are no further flows of data under this agreement.

Only substantive employees of University Hospital Southampton NHS Foundation (who have been trained in data protection and confidentiality) will have access to the data and only for the purposes described in this document. The data will be stored on secured computers within each of the listed data processing organisations.

University Hospital Southampton NHS Foundation Trust (UHS) will provide NHS England with the following identifiers of the cohort for the linkage to the data requested

- NHS number,

- date of birth,

- gender

- Study ID.

NHS England will return clinical outcomes from the HES data and corresponding mortality data (date of death, cause of death and admission diagnoses) with each unique study ID. The CRG at UHS will then use the Study ID to link the data provided by NHS England to the high-sensitivity troponin levels. Re-identification of these patients will not be possible because the database will only contain the unique study identifier and gender of the patient - no other patient identifiers will be included. The patient identifiers are kept in a separate database.

No contact will be made with the patients selected. The data will only be used for this study.

The NHS England data is crucial to provide the most accurate information on the outcome of patients recruited to this study and will form the basis of a robust research study that will be submitted to peer reviewed journals.

The data from this study will not be used for commercial purposes, not provided in record level form to any other third party not mentioned in this agreement, and not used for direct marketing or commercial purposes.

All outputs will be aggregated with small numbers suppressed in line with the HES analysis guide.

There will be a multi-faceted approach to the dissemination of the results of this study. Firstly the results will be presented at respected medical conferences. Secondly the data will be published in respected peer review journals. These two activities will ensure that the key messages are available to the scientific community. The results will also be published (in a non-scientific format) on the UHS web pages. Like CHARIOT this study is also likely to generate significant press coverage which UHS will engage with to ensure that the results are widely disseminated to the general public. Finally the promotion of the published article through the use of social media will also widen the audience.

The results of this study are likely to be of immediate clinical relevance to clinicians by providing them with a better understanding of the clinical significance of the high-sensitivity troponin levels. Furthermore, if these data demonstrate that the high-sensitivity troponin levels are associated with cardiovascular outcomes then this is likely to stimulate further research to evaluate whether medical interventions can alter the outcomes seen in this group of patients. Whilst the aggregate results will be published to allow clinicians, scientists and the public to understand the implications of raised high-sensitivity troponin levels, the data themselves will not be released and will be stored and then destroyed following the standards set out by NHS England.

The patients included in the original CHARIOT study have not been directly informed of their participation in the study (apart from via the privacy notice) and as such UHS will not be sending any outputs directly to the patients included. The study therefore has no immediate direct benefit to the patients involved and is purely designed to guide future care of similar patients. However once the study has completed UHS plan to ensure that the results are available widely both to the medical community and the public. The outputs to the medical community will take the form of peer reviewed publications and presentations at medical conferences. The main output to the public will be through the updates and explanation of the results in the trusts patient facing research website. Furthermore, as was the case with the original CHARIOT study, it is likely that there will be some interest from the national press and so this will also provide a specific way of providing the outputs to the cohort involved and the general public.

All outputs will contain only aggregate level data with small numbers suppressed in line with the HES analysis guide.

The outcome data have been presented at the British Society of Cardiology, European Society of Cardiology and published in the American Journal of Cardiology.

Analysis of data provided by NHS England has provided further insights of important scientific value. These were presented at both the British Society of Cardiology and European Society of Cardiology. The results sparked much interest. The manuscript is currently being prepared for publication in a prestigious medical journal.

Results presented at a Cardiovascular conference in Barcelona. ESC.

The expected measurable benefit of the data access and the study will be an important contribution to the optimal use and interpretation of high sensitivity troponin assays in front line clinical practice. Use of high sensitivity troponin assays in front line practice is flawed in two ways. Firstly, there is widespread misunderstanding about the meaning of a raised high-sensitivity troponin; such a result is often incorrectly labelled as implying type 1 myocardial infarction, due to low awareness of myocardial injury. Secondly the upper limit of normal supplied by the manufacturer of the blood test is based upon a predominantly healthy population and UHS have shown in CHARIOT that this is not the 99th centile for 20,000 consecutive hospital patients.

Thus, whilst the current application of high-sensitivity troponin is largely flawed, data are accumulating that the assay (determining the quality) may have a clinically valuable alternative role as a biomarker of cardiovascular risk (Lancet 2018: 391; 10138: 2398).

The proposed study represents a unique opportunity to assess whether the high-sensitivity troponin levels in the 20,000 consecutive patients are indeed associated with mortality and future (HES derived) events. If so, the "never means nothing" hypothesis of high-sensitivity troponin should lead UHS to change the way that clinicians interpret the assay in front line hospital practice. It would no longer be an assay mistakenly used to "rule in" type 1 myocardial infarction, but rather a biomarker for patient risk prognosis.

The dissemination of this data is in the public interests because it has the potential to change the way that large groups of patients are managed.

The data are likely to result in changes in the way that high-sensitivity troponins are requested and also interpreted by clinicians. Furthermore as already discussed it is likely that these data will precipitate further study to assess whether cardiovascular interventions could change the outcomes in this group. This study will have wide implications, because, as demonstrated by the original CHARIOT study these patients are frequently seen in clinical practice. The benefit will be achieved by potential changes in clinical practice. It is expected that the dissemination of these data will occur within six months of NHS England releasing that data and then changes in clinical care will follow afterwards.

This Agreement is required to support the peer review of the medium term mortality of this cohort. The medium term mortality provides increased statistical power which has allowed the team to conduct further analyses that are of benefit in demonstrating the potential prognostic value of these assays. These data demonstrate that the assay is closely associated with mortality. These data are likely to lead to further studies to assess whether any medical interventions can alter this increased risk which may well lead to new treatments for these patients

These data support the concept that high sensitivity troponin is associated with adverse outcomes and as such these data are likely to stimulate further research to ascertain whether these adverse outcomes could be adjusted.

The study will allow clinicians a better understanding of how to interpret the high sensitivity troponin assays tests.