MR1455 - PARAMEDIC2 (Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug administration In Cardiac arrest) (s251 cohort)

This agreement is for the University of Warwick to receive and process Hospital Episode Statistics (HES) data and mortality data for inclusion in the PARAMEDIC2 trial. The PARAMEDIC 2 trial is a double-blind randomised placebo-controlled trial aiming to evaluate how safe and effective adrenaline is as a treatment for patients who suffer out of hospital cardiac arrest. The University of Warwick are the sole data controller who processes data under this agreement.

Over 50,000 people die each year following an out of hospital cardiac arrest (OHCA) in the UK. Although initial resuscitation efforts restart the heart in about 25-30% of resuscitation attempts, most of these patients die in the next few days in hospital from severe brain damage and overall survival (of attempted resuscitations) is less than 10%. Cardiac arrest causes a major burden on NHS resources (emergency treatment, post resuscitation care, rehabilitation) but treatment currently has a low chance of success. These dire outcomes have huge personal costs for patients and their families.

Adrenaline has been used as part of the treatment for cardiac arrest for many years. It works by increasing the blood supply to the heart. This makes it more likely that the heart will start beating again. There are, however, side effects of adrenaline treatment for cardiac arrest. Notably the heart may be overstimulated so it pumps inefficiently, reducing blood flow to the brain, which increases the risk of death over subsequent hours and days, and of survivors having serious brain damage.

Recently scientists have looked again at what is known about how adrenaline affects outcome after a cardiac arrest. There is a consistent pattern across research studies (including more than 450,000 patients in total), which suggests adrenaline improves initial survival but may lower overall survival and increases brain damage. The data are not strong enough to mandate a change in current practice but there are real concerns in the clinical and academic community that current practice may be harming patients. Whether the practice of giving adrenaline is effective or not therefore remains an important question that needs to be answered. Resolution of this uncertainty is urgent, as adrenaline is used widely to treat cardiac arrests, and if harmful, may be responsible for many avoidable deaths.

In light of these concerns, the International Liaison Committee on Resuscitation (ILCOR) has concluded there is an urgent need for a definitive randomised, placebo controlled trial that directly compares adrenaline with no adrenaline. An Randomized Controlled Trial (RCT) of adrenaline has the support of key stakeholders such as the College of Paramedics, Ambulance Medical Service Directors, Joint Royal College Ambulance Liaison Committee, Resuscitation Council (UK), and patient representatives.

The trial enrolled, and collected data on, 8000 patients who have been treated for cardiac arrest. All surviving patients were invited to take part in follow-up to find out about patients' health and quality of life after cardiac arrest. Recruitment to this study has finished and there will be no further recruitment.

The objective for processing data from NHS Digital is to collect data on survival, (mortality data) which form both the primary and secondary trial outcomes, as well as to collect data from Hospital Episode Statistics to tell the University of Warwick of a patient's length of stay in Intensive Care Unit (ICU) and hospital (trial secondary outcomes). Hospital Episode Statistics data will also be used in health economics analysis, alongside other data collected in patient questionnaires, to determine whether the use of adrenaline is cost-effective.

The lawful basis for holding personal data for this application is Article 6(1)(e) of the General Data Protection Regulation: 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 University of Warwick is a public authority and research institution. The lawful basis for holding and using special categories of personal data is Article 9(2)(j) of the General Data Protection Regulation as processing is necessary for archiving purposes in the public interest, and for scientific research purposes.

There are no moral or ethical issues raised by the dissemination of NHS Digital data. Ethics approval was granted by the South Central Oxford C Research Ethics Committee. There is minimal risk of harm to the public by the dissemination as the University of Warwick has appropriate security measures in place to protect the data.

Due to the timing of the receipt of data from NHS Digital, the primary and secondary outcomes of the trial were published without using NHS Digital data. The Hospital Episode Statistics data is being used in current ongoing health economics analysis, alongside other data collected in patient questionnaires, to determine whether the use of adrenaline is cost-effective.

The cohort submitted to NHS Digital for data linkage is restricted to only patients who were transported to hospital who did not decline consent/opt out of data collection (182 in the consent cohort, 3,056 in the s251 cohort). The data request was further minimised by only requesting data for specific years (2014-2018) which cover the trial recruitment and follow-up period. This agreement covers the cohort covered by s251 support.

The University of Warwick are the sole Data Controller and Data Processor. The trial is funded by the National Institute for Health Research Health Technology Assessment Programme. No NHS Digital data is transferred to the funder. There are no other commissioners involved.

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).

PARAMEDIC2 patients (or their legal representatives) were approached for consent for further data collection once they had reached the hospital ward. At that point they could consent to, or opt out of, further data collection. This agreement relates to individuals where they have given consent, and are covered further by the s251 support.

No identifiers will be submitted and no data will be requested for patients who have declined consent for further data collection.

Data was submitted to NHS Digital for the purposes of linkage. This included the following identififable data items: (Forename, Surname, NHS number, address, postcode, date of birth and gender). A file was submitted containing the details of those covered by s251 support only.

Data from NHS Digital was downloaded via the secure web portal (SEFT) and stored in a PGP-encrypted file by a member of the trial team at University of Warwick. Only approved users who are members of the research team and substantive employees of the University of Warwick continue to have access to this folder.

Fact of death and date of death will be used to determine whether patients enrolled in the trial survived up to 30 days (the primary outcome measure) and up to 12 months post cardiac arrest (secondary outcome measures). This will be combined with other data on the cardiac arrest e.g. treatments, neurological outcome and health status for the purposes of analysis, in order to answer the key trial question on the effectiveness of adrenaline. Data will be analysed using an anonymous Trial Identification number. Data will also be used to make sure a patient is alive before writing to them or their legal representative, to avoid causing any distress to relatives.

Hospital Episode Statistics data will be used be used as part of the health economic analysis. The HES data will be combined with other data collected during the trial (for example cardiac arrest data, patient questionnaire data) to determine the clinical and cost-effectiveness of adrenaline.

Data from NHS Digital will not be stored, processed or be in any other way accessible to any organisation except for the University of Warwick, as described in this agreement. No flow of data from NHS Digital is permitted to NICOR, ICNARC or any organisation other than the University of Warwick, and no flow of data into NHS Digital is permitted other than from the University of Warwick.

Warwick Clinical Trials Unit will also be requesting data from other hospital datasets (ICNARC and NICOR). Data from HES, ICNARC and NICOR will be combined via a 4-digit trial identification number. Patient identifiable details are already collected as part of the PARAMEDIC2 trial. However, the University of Warwick required identifiable data to be flowed back to them following the ‘list clean’ to ensure they had a complete and accurate set of patient identifiers for further data linkage with other datasets (ICNARC and NICOR), as per the approved data flow diagram. It cannot be pseudo-anonymised data as this would result in sub-optimal data linkage with other hospital datasets. The University of Warwick will not link the data further, as only the data linkages described are permitted under this agreement.

Hospital Episode Statistics data, mortality data and list clean data has already been disseminated from NHS Digital. No further data will be flowed, this request is for a Data Sharing Agreement extension only. In line with the conditions of the data sharing agreement, no NHS Digital data has been flowed to other organisations e.g. ICNARC and NICOR. The NHS Digital data has been combined with the PARAMEDIC2 trial data set for the purposes of health economics analysis as stated in the processing activities above. The NHS Digital data will not be linked with any other datasets.

There will be no attempt to re-identify or re-contact patients. Date of birth and date of death are still being retained by the University of Warwick while analysis is still ongoing. University of Warwick will commit to destroying the identifiers (date of birth) when they are no longer needed for analysis.

The results of the PARAMEDIC2 trial have the potential to influence resuscitation guidelines worldwide, therefore trial results will be submitted for publication and disseminated as quickly as possible.

The University will submit the final trial results for publication in a high impact, open access peer reviewed journal such as The New England Journal of Medicine or The Lancet once data analysis is complete. Outputs will contain aggregate data only. Small numbers will be suppressed in line with the HES analysis guide. In addition, the University will present the results at scientific conferences, and to key stakeholders such as ambulance services (National Ambulance Service Medical Directors and Joint Royal College Ambulance Liaison Committee, (JRCALC)).

The trial will be reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines. The main publications will be the report to the funding body (NIHR Health Technology Assessment (HTA) Monograph) and a NIHR journal publication. In addition, the results will be presented at international conferences. This will ensure that the results are communicated rapidly to those who will put them into practice. The University will inform the ILCOR to ensure the results will be incorporated into national and international resuscitation guidelines via existing guideline development groups, which include several of the trial co-investigators.

The University will incorporate the findings of the trial into relevant review articles and ensure the findings of the trial are available through NHS Evidence. The University will work with their Marketing and Communication team to develop a strategy for communication with the media (television, radio, newspaper etc) to enhance communication of the trial results to patients / participants.

The University will produce a lay summary of the trial results with their public and patient involvement partners that include the trials management group (monthly meeting), the independent trial steering committee that meets on a bi-annual basis and the University Patient and Public Involvement (PPI) Group (UNTRAP) that meets annually. All groups have lay representation and participants from variety of backgrounds. This will be disseminated through their press officer, user groups, websites and INVOLVE database (an NIHR PPI network) to participants of the trial who indicated they wanted to know the results.

The following additional outputs are planned:

Data supplied by NHS Digital will be used in the Health Economics analysis and will be published in paper 4 and paper 12. Paper 4 is currently being prepared by the Health Economics team prior to review by co-authors. We anticipate the paper will be submitted for publication to a high impact journal before end of 2019. This paper will be essential enable the NHS, patients and clinicians to understand the overall cost and benefits of adrenaline use in cardiac arrest.

Paper 12 is the end of trial report to the funder which will be submitted to the funder for review on 14th August 2019. The typical time from submission to publication in the HTA journal is around 12 months. All outputs and publications will contain only aggregated data with small numbers suppressed in line with the HES Analysis Guide.

1. Time to administration of adrenaline, submitted to Intensive Care Medicine July 2019

2. Long-term outcomes (modified Rankin Scale, questionnaire data), draft paper written, awaiting review by co-authors

3. Intravenous vs intraosseous access, draft paper written, awaiting review by co-authors

4. Health economics main cost-effectiveness analysis, under development

5. Airway management and quality of CPR, in development

6. Long-term outcomes methodology, in development

7. Measurement properties of PROMs, in development

8. Drug dosing errors, under review by co-authors,

9. Public communication and opt-out requests related to the PARAMEDIC2 trial, in development

10. Long-term outcomes after cardiac arrest (pooled data), awaiting confirmation of funding

11. Ordinal outcomes analysis, draft paper written, awaiting review by co-authors

12. NIHR HTA monograph

The trial is due to be completed by late Summer 2019 (NIHR have extended their support to this date) and the University expects the output from this trial will impact international resuscitation guidelines. There are established pathways through which advances in resuscitation science can be rapidly implemented into practice.

The University will ensure that the results of this trial are fed into the ILCOR evidence assessment and guideline process. ILCOR run a 5 yearly review of resuscitation science from which international CPR guidelines are created. There is good evidence of penetration of these guidelines into clinical practice within 1-2 years of their publication. In addition, ILCOR run an on-going evidence evaluation process whereby new studies are identified and incorporated in to systematic reviews. The outputs from these reviews are shared with national resuscitation councils such as Resuscitation Council (UK) and from the basis for the development and revision of national guidelines.

Guidelines used by the NHS are based on recommendations from the Resuscitation Council UK (RCUK) and are implemented within NHS Ambulance Trusts through the JRCALC. Key investigators on the trial also hold senior positions within the Resuscitation Council so they will be aware of the work and the results. It is likely that the trial findings will be presented at a RCUK national conference.

The applicant anticipates that the impact of this trial will be sufficient to determine future policy on whether adrenaline is continued to be used as a treatment for out-of-hospital cardiac arrest.

As per the outputs section, the health economics trial analysis is due to be submitted for publication in a high impact journal later this year. This analysis uses data from Hospital Episode Statistics to determine whether adrenaline is a cost-effective treatment for out-of-hospital cardiac arrest (OHCA). The effect of adrenaline on clinical outcomes reported by the trial is small (0.8% improvement in survival to 30 days), no improvement in survival with a favourable neurological outcome. The cost effectiveness analysis will allow policy makers to assess the overall costs and benefits of treatment with adrenaline. Given the uncertainty about interpretation of the clinical results, we anticipate the health economic analysis will be of high importance to decision makers.

The study does not contribute to a PhD project. The magnitude of the impact on policy, patients and NHS efficiency will be fully known once the health economics cost-effectiveness results are published.

The main results of the PARAMEDIC2 trial were published in the New England Journal of Medicine in July 2018. Results were reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines and outputs within this publication contain aggregated data only. The main results paper has received one of the highest attention scores (10th out of nearly 25,000 articles) ever published by the New England Journal of Medicine and was listed at #27 in the Altmetric Top 100 articles of 2018. The results are expected to influence resuscitation guidelines worldwide and are prompting discussions around the world about what the priorities and most important outcomes for patients are. The results have been presented at conferences e.g. European Resuscitation Council Congress in October 2018 as well as to key stakeholders to ensure that results are communicated rapidly to those who will put them into practice.

The main results were presented to the International Liaison Committee on Resuscitation who have developed a draft Consensus on Science with Treatment Recommendations (CoSTR). https://costr.ilcor.org/document/vasopressors-in-adult-cardiac-arrest. The final CoSTR will be published in October 2019 which will inform resuscitation guidelines around the world.

There is good evidence of penetration of these recommendations into clinical practice within 1-2 years of their publication. In addition, ILCOR run an on-going evidence evaluation process whereby new studies are identified and incorporated in to systematic reviews. The outputs from these reviews are shared with national resuscitation councils such as Resuscitation Council (UK) and from the basis for the development and revision of national guidelines.

Results of the trial have also been communicated to the public via news articles. An infographic lay summary of the results has been sent to clinicians, participants and their legal representatives, and has been made available for download on the trial website. https://warwick.ac.uk/fac/sci/med/research/ctu/trials/critical/paramedic2/results/leaflet_patients.pdf

A synthesis of current evidence on adrenaline, including the trial results has been published in Cochrane Library “Adrenaline and vasopressin for cardiac arrest (Review). (doi: 10.1002/14651858.CD003179.pub2)

In addition “The effects of adrenaline in out of hospital cardiac arrest with shockable and non-shockable rhythms: Findings from the PACA and PARAMEDIC-2 randomised controlled trials” has been published in Resuscitation. (doi: 10.1016/j.resuscitation.2019.05.007)