MR1467 - The 65 Trial: Evaluating the clinical and cost-effectiveness of permissive hypotension in critically ill patients aged 65 years or over with vasodilatory hypotension

The 65 Trial is a pragmatic, multi-centre, parallel group randomised clinical trial (RCT) aiming to evaluate the clinical and cost-effectiveness of permissive hypotension (a mean arterial pressure (MAP) target range 60-65 mmHg whilst receiving vasopressors) in critically ill patients aged 65 years or over with vasodilatory hypotension.

This research is important to patients and the NHS because of emerging evidence from a meta-analysis suggesting that using a lower MAP target (permissive hypotension) to guide vasopressor treatment may increase survival in older critically ill patients. The prior research has involved too few patients to fully test this idea and therefore guide clinical decision-making, and a large clinical trial (this trial – the 65 Trial) is needed to provide robust evidence as to the effectiveness of using a lower MAP target to guide treatment in critical care.

The 65 Trial was funded by the National Institute for Health Research, Health Technology Assessment Programme (reference: 15/80/39, funding confirmed in year 2016), sponsored and managed by the Intensive Care National Audit & Research Centre (ICNARC) (reference: 01/05/17) and included 2,600 participants from approximately 65 NHS adult, general critical care units across England, Wales and Northern Ireland. Half of the participants were randomised to the intervention group (permissive hypotension) and the other half to the control group (usual care).

The primary objective for processing NHS Digital data requested under this agreement is to provide important outcome data for the 65 Trial. The outcomes for the trial are:

Primary outcomes:

• all-cause mortality at 90 days (clinical evaluation)

• incremental net monetary benefit (INB), evaluated at the NICE recommended threshold of £20,000 per quality-adjusted life year (QALY), at 90 days (economic evaluation)

Secondary outcomes:

• mortality at discharge from the critical care unit and acute hospital

• duration of survival to longest available follow-up

• duration of advanced respiratory and renal support (defined according to the Critical Care Minimum Dataset [CCMDS]) during the critical care unit stay

• days alive and free of advanced respiratory support and renal support

• duration of critical care unit and acute hospital stay

• cognitive function assessed using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE, short version) at 90 days and one year

• health-related quality of life, assessed using the EuroQol EQ-5D-5L questionnaire, at 90 days and one year

• resource use and costs at 90 days and one year

• estimated lifetime incremental cost-effectiveness

ICNARC are requesting patient status (i.e. dead, alive, unknown/unable to link) and date of death (if applicable) from NHS Digital to directly contribute to the clinical evaluation primary outcome data (all-cause mortality at 90 days post-randomisation) and the ‘duration of survival to longest available follow-up’ secondary outcome data. Fact of death (as opposed to date of death) would not be sufficient to address these outcomes, as a date is required to calculate the duration of survival.

In addition, participants are actively followed-up and sent questionnaires by the 65 Trial team at ICNARC at 90 days and then one year post-randomisation. Given the nature of critical illness, unfortunately some participants will pass away during the trial follow-up period. Participant status and date of death obtained from NHS Digital will therefore allow the researcher to ascertain whether contact at these follow-up time-points is appropriate. Where ICNARC finds out that a participant has passed away, no contact will be made - helping to ensure relatives are not caused undue distress by no longer appropriate contact. There are no other feasible ways of obtaining this data for all participants in a trial of this size.

The Intensive Care National Audit and Research Centre (ICNARC) are the sole Data Controller.

The Data Processors for the data being requested from NHS Digital are ICNARC, Babble Cloud (SUI) Limited and Exponential-E Ltd. Exponential-E Ltd manage ICNARC’s secure virtual data centre; and Babble Cloud (SUI) Limited provide ICNARC’s end user IT support.

Babble Cloud Limited will provide external desktop and network managed services, including end user and infrastructure support. Employees at Babble Cloud will not access the data held under this agreement, however, they will have remote access to ICNARC servers (which are hosted by Exponential-e). Babble Cloud Limited are registered under the DSP Toolkit (organisational reference: 8HP42) as ‘Standards Met’.

ICNARC is an independent health research charity which aims to help improve the quality of critical care through audit, research and education with, and in the interests of, patients and those who care for them. ICNARC requires data from NHS Digital for the purposes of these legitimate interests.

ICNARC process data for this study under the legitimate interest legal basis. This is because ICNARC is a registered charity and the data processing described here is to support scientific and statistical research. Specifically, data is processed under the following articles of the Data Protection Act 2018:

Article 6 (1) (f) Legitimate interests: the processing is necessary for your legitimate interests or the legitimate interests of a third party unless there is a good reason to protect the individual’s personal data which overrides those legitimate interests.

The data is required for a research project - and therefore ICNARC process the special category data (health data) under the following article of GDPR - 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.

Processing personal data is necessary for ICNARC's legitimate interests which are described in this agreement. The data to which access is requested are proportionate and necessary to achieve those interests. ICNARC have completed a legitimate interests assessment (LIA) and are satisfied that the interests of the data subjects do not override our legitimate interests; that they would reasonably expect the processing and it would not cause unjustified harm. The data subjects interests and fundamental rights are protected through appropriate minimisation of fields and patient records being processed; pseudonymisation to minimise any risk of identifying individuals; protection of the data in a secure environment, and guaranteeing secure destruction at any stage at the request of NHS Digital or after a defined period on completion of the project.

ICNARC have assessed this against the ICO’s checklist (https://ico.org.uk/for-organisations/guide-to-the-general-data-protection-regulation-gdpr/lawful-basis-for-processing/legitimate-interests/) and are content that the requirements are met.

Information collected during the 65 Trial is stored on secure servers at Exponential-E, who make regular back-ups of the data. This section of secure database can only be accessed by ICNARC staff, using a unique username and password, who have been given permission to carry out the required duties on the POPPI trial.

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

Previously, (and other previous iterations of this agreement) on a monthly basis, for accruing trial participants, an authorised member of the 65 Trial team at the ICNARC CTU would provide one excel spreadsheet, securely via SEFT, to NHS Digital.

NHS Digital then linked these data to create a list cleaning report to confirm each patients’ status (at that point in time), and, if relevant, date of death. NHS Digital will provide an excel spreadsheet to an authorised member of the 65 Trial team at the ICNARC CTU that contains the following: 65 Trial number, patient status, and death of death (if relevant). NHS Digital should also indicate where it has not been possible to complete linkage (e.g. unable to link). These data are pseudonymised, returned with a study id and provided at record level.

The data received from NHS Digital will be stored on secure servers at Exponential-E, who regularly back-up the data.

NOTE: For the purpose of this version of the agreement, no more list clean report will be provided. The total cohort size is 2,600 and linkage is complete.

The data will be analysed by authorised members of the 65 Trial team at the ICNARC CTU (substantive employees of ICNARC who have been appropriately trained in data protection and confidentiality). All outputs will be aggregated at a national level, with small numbers suppressed in line with HES analysis guide. It will not be possible to identify any individual participating patient in any reports, articles or presentations. Data will not be linked to any other external sources.

Once analysis and primary dissemination is complete, the data will be archived for five years. After five years, data will be anonymised, and identifiable data confidentially destroyed from all locations (ICNARC and DRS).

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

Only authorised, substantive ICNARC employees will access NHS Digital data. All ICNARC employees are trained in data protection and confidentiality and have signed a contract, which incorporates a confidentiality clause and the consequences of breaching confidentiality are covered by disciplinary procedures. Data received from NHS Digital is stored on secure servers at ICNARC, hosted by Exponential-e with regular back-ups of the data. Exponential-e are compliant with ISO 9001; ISO 27001; ISO 14001; ISO 22301; ISO 50001; ISO 20000 and also hold a Health & Social Care Network Complaint certificate of compliance. Employees of Exponential-e will not access the data held under this agreement, but will provide storage/back-up, and as such, are listed as processors.

Babble Cloud (SUI) Limited will provide external desktop and network managed services, including end user and infrastructure support. Employees at Babble Cloud (SUI) Limited have the ability to access NHS Digital data for logistical reasons but will not access the data held under this agreement, however, they will have remote access to ICNARC servers (which are hosted by Exponential-E Ltd).

The results of the 65 trial are being widely and actively disseminated. The data processing described in this application have contributed to the following outputs:

Reports

A comprehensive report has been submitted and published by the NIHR in March 2021 in the peer reviewed, open access Health Technology Assessment journal and will included recommendations for future policy, practice and research. REFERNCE: Mouncey PR, Richards-Belle A, Thomas K, Harrison DA, Sadique MZ, Grieve RD, Camsooksai J, Darnell R, Gordon AC, Henry D, Hudson N, Mason A J, Saull M, Whitman C, Young JD, Lamontagne F, Rowan KM. Reduced exposure to vasopressors through permissive hypotension to reduce mortality in critically ill people aged 65 and over: the 65 RCT. Health Technology Assessment 2021;25(14):1-90. DOI: 10.3310/hta25140

Submissions to peer reviewed journals

Ahead of the trial results, the trial protocol and statistical analysis plan were published in the Journal of the Intensive Care Society. These aimed to raise awareness of the 65 Trial amongst the critical care and trials community, ahead of the results.

REFERENCES: Richards-Belle A, Mouncey PR, Grieve RD, Harrison DA, Sadique MZ, Henry D, Whitman C, Camsooksai J, Gordon AC, Young JD, Rowan KM, Lamontagne F. Evaluating the clinical and cost-effectiveness of permissive hypotension in critically ill patients aged 65 years or over with vasodilatory hypotension: Protocol for the 65 randomised clinical trial. Journal of the Intensive Care Society 2020;21(4):281-2. DOI:10.1177/1751143720971433

Thomas K, Patel A, Sadique Z, Grieve RD, Mason AJ, Moler S, Gordon AC, Rowan KM, Mouncey PR, Lamontagne F, Harrison DA; on behalf of the 65 trial investigators. Evaluating the clinical and cost-effectiveness of permissive hypotension in critically ill patients aged 65 years or over with vasodilatory hypotension: Statistical and Health Economic Analysis Plan for the 65 trial. Journal of the Intensive Care Society 2019. DOI: 10.1177/1751143719860387 [Epub ahead of print]

The results of the 65 Trial have also been published in the Journal of the American Medical Association (JAMA) - a high-impact, widely read, general medical journal. This was published in March 2020. Reference: Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension: A Randomized Clinical Trial. - 2020 - https://doi.org/10.1001/jama.2020.0930.

Presentations/conferences

The primary results of the 65 trial have been formally presented at the following conferences:

- Critical Care Reviews 2021, by Francois Lamontagne and Paul Mouncey

- Society of Intensive Care of the West of England, Paul Mouncey

We continue to disseminate the results of the 65 trial, and work on future publications, for example understanding the treatment effect across subgroups, where the effectiveness of the intervention may have been different.

All data presented/reported will be aggregated at a national level, with small numbers suppressed in line with HES analysis guide. It will not be possible to identify any individual participating patient in any reports, articles or presentations.

Dissemination activities are led by ICNARC. The funder will not be involved in decisions to submit articles for publication or present the results at conferences. Further dissemination is ongoing focussing on secondary analysis of the dataset.

The 65 Trial is a pragmatic, multi-centre, randomised clinical trial to evaluate the clinical and cost-effectiveness of permissive hypotension (mean arterial pressure (MAP) target range 60-65 mmHg whilst receiving vasopressors) in critically ill patients aged 65 years or over with vasodilatory hypotension. There is genuine uncertainty as to which MAP target should be used to guide vasopressor therapy in critically ill patients in critical care units.

It is not yet known whether permissive hypotension is clinically and cost-effective (this is what the 65 Trial will provide information on) but - it is anticipated that if the strategy of permissive hypotension is found to be clinically and cost-effective, that implementation of these outputs into national and international clinical guidelines and subsequently into the NHS will lead to improvements in monitoring and titration of vasopressors in the critical care unit, ensuring a reduction in the potentially unnecessary exposure to vasopressors in elderly patients.

This will improve health and reduce the health burden on patients and their carers and to the NHS. This dissemination will directly meet ICNARC’s legitimate interest, for the processing of data in this application, of improving the quality of critical care.

The magnitude of the impact of this dissemination is likely to be very large, given that United Kingdom (UK) national clinical audit data indicates that close to half (44%) of all patient admissions to adult, general critical care units (around 170,000 admissions annually) have hypotension and receive vasopressor therapy and it is estimated that 40-50% of these cases will represent vasodilatory hypotension.

This will need an effective implementation strategy. Active and wide dissemination of the results of the 65 trial will be an important part of this strategy – and will begin upon publication of the primary trial results (estimated to be published before summer 2020). A number of approaches have been identified, including: involving stakeholders; providing evidence in an integrated and graded way; taking account of the context and identifying the elements relevant to decision making, e.g. benefits, harms and costs; making recommendations as specific as possible; and using a multifaceted approach.

This study is not in support of a PhD/post graduate research study.

The 65Trial database is now locked and primary dissemination of the trial results has completed. As indicated in the ‘Outputs’ section, yielded benefits to date have included:

Publication of the clinical and cost-effectiveness results in the Journal of the American Medical Association (JAMA)

Publication of the Final Report to the National Institute for Health Research (NIHR) Health Technology Assessment Programme

The Trial Protocol and Statistical and Health Economic Analysis Plan have been published for public benefit.

Presentations at national and international conferences have been given to present the research and preliminary results.

As the results showed that that there was no statistically significant benefit, but it was deemed safe and potentially clinically effective, in reducing exposure to vasopressors by targeting a blood pressure of 60-65mmHg in patients over , the intervention has been included in guidelines. This may mean that older patients are being treated with less intensive drugs within a ICU, reducing their potential adverse effects.