Phenotyping individuals with elevated mean pulmonary arterial pressure and elevated pulmonary vascular resistance in the United Kingdom

Pulmonary hypertension is when there is increased pressure in the blood vessels of the lungs. This increases the strain that is placed on the right side of the heart, ultimately leading to failure of the right side of the heart to pump against increased pressures. It is diagnosed by haemodynamics obtained by an invasive procedure known as a right heart catheterisation. This is where a catheter (a small hollow tube) is inserted through the vessels and directly measures the pressures in the right side of the heart and arteries in the lung, known as the pulmonary artery. Under the current guidelines a diagnosis of Pulmonary Hypertension is made when the mean pulmonary artery pressure of greater than 25mmHg. A diagnosis of pulmonary hypertension carries high mortality and morbidity. It is known that a mean pulmonary artery pressure of >20mmHg is abnormal, however this does not meet the criteria for Pulmonary Hypertension. These patients are often not formally followed up however, remain symptomatic. Some may even progress to pulmonary hypertension by its current definition. It is important to understand this group of patients who have a mean pulmonary artery pressure less than 25mmHg, however still have abnormal haemodynamics, looking specifically at their baseline characteristics, how the population behaves, progression and most importantly if they demonstrate increased attendances to hospital settings whilst still undiagnosed.

The primary objectives for this study are to look at mortality and admission to hospital for treatment in this population against a control population. This Data Sharing Agreement (DSA) with NHS England is a crucial component to meet the primary objectives of the study. Patients with suspected Pulmonary Hypertension will be reviewed in one of the seven specialist tertiary centres across the United Kingdom*: The Royal Free Hospital, The Hammersmith Hospital, The Freeman Hospital, The Royal Brompton, The Royal Papworth Hospital, The Golden Jubilee Hospital (Scotland) and The Royal Hallamshire Hospital. However, these sites may be a distance from their local hospitals. Therefore the capturing of admission to hospital for treatment across the UK will be a sensitive method to understand this population’s progression and if there is health-seeking behaviour. This could have significant implications upon the management of this population and if they should be monitored more closely. The aim of this study is to understand this population, with hope this will mean better surveillance/screening of patients and earlier interventions for patients who require it to promote better outcomes. This will provide a UK perspective on patients who are deemed to have “mild Pulmonary Hypertension” with a mean pulmonary artery pressure between 21-24mmHg. This may also influence guidelines on how to screen and manage this population.

*PLEASE NOTE that this DSA relates to only data from hospitals in England. The relevant Scottish data will be obtained in parallel Data Sharing Agreements with the Scottish equivalent data organisation.

This is a retrospective study looking at all right heart catheters done between 1 January 2009 - 31 December 2016 at the above-listed tertiary centres designated for Pulmonary Hypertension. Patients will be selected for the cohort according to their pulmonary artery pressure; less than 21mmHg, 21-24mmHg and greater 25mmHg; and by peripheral vascular resistance (i.e. the resistance in the pulmonary vessels against blood flow); less than 2 wood units [a], 2-3 wood units and greater than 3 wood units. The less than mean pulmonary artery pressure of 21mmHg with a pulmonary vascular resistance of less than 2 wood units will be considered a control group as this is theoretically considered within the realms of normal cardiovascular haemodynamics (i.e. the study of how blood flows through the cardiovascular system - the heart and blood vessels) . The mean pulmonary artery pressure of greater than 25mmHg will be considered controls for patients who have confirmed pulmonary hypertension by current definition as a comparator.

[a] Wood units. A simplified measurement of pulmonary vascular resistance that uses pressures instead of more complicated units measured by subtracting pulmonary capillary wedge pressure from the mean pulmonary arterial pressure and dividing by cardiac output in litres per minute.

Inclusion criteria includes patients aged over 18, having attended one of the Pulmonary Hypertension tertiary centres in the United Kingdom for assessment. The exclusion criteria include patients who have already had a confirmed diagnosis of Pulmonary hypertension or have been started on medication for pulmonary hypertension. The projected sample size is approximately 2,900 patients for the patients with a mean pulmonary artery pressure of < 25mmHg.

For all cohorts, the baseline investigations will be collected, which are done routinely in clinical practice, to understand demographics of this population and changes in investigations over time, to understand how patients in this population progressed. This will be compared with outcomes. Primary outcome measures are mortality, cause of death and admissions to hospital for treatment. Data on mortality and admission to hospital for treatment will be required from 2009 onwards until March 2020 (though Civil Registration (Deaths) data automated product will be provided up to March 2021). The eligibility period for the study is between 1 January 2009 - 31 December 2016. The observation period is between 2009 and March 2021 however to avoid confounders, the observation period ends in March 2020 before the COVID-19 pandemic started. This will still allow for adequate follow up encounters to assess for progression in this population. The reason for this is that clinical practices throughout the United Kingdom for Pulmonary Hypertension were standardised and there was a drive to make patient data available electronically.

The primary objectives for this study are to understand hard endpoints of this population - in other words - mortality and admission to hospital for treatment. The civil registration (Deaths) data accessed through NHS England will allow assessment into if there is an increased mortality compared to the control groups. This will also identify cause of death and if Pulmonary Hypertension was a related or unrelated to cause of death.

Admission to hospital for treatment data analysis is a primary study objective. This data from NHS England is crucial in achieving our study objectives and will allow us to assess if there is increased admittance to hospital in this population compared to control groups. This will require reviewing attendances to hospital setting (Accident and Emergency, Admitted patient care and Outpatient services). The total number of hospital attendances and total number of bed days will be compared to the control groups. The hospital attendances will also be categorised into; “related to pulmonary hypertension”, “possibly related to pulmonary hypertension”, “unrelated to pulmonary hypertension” by reviewing diagnosis codes and reason for hospital attendances. The data that is required for admissions to hospital for treatment will provide an understanding of the natural progression of this patient group and to see if there is increased hospital attendance.

The record level NHS England data will be pseudonymised with patients being allocated a unique research ID. Any patient identifiers, including date of birth will be removed and the age of the patient at the time of encounter will be used as a surrogate.

Data Minimisation

To minimise the data that is being requested, the Chief Investigator has reviewed the data available in the datasets. This has been carefully selected to ensure only the fields that meet the objectives of this study are requested. Only the datasets that are required have been selected to achieve the outcome of the study. To achieve the objectives of the study, 4 databases have been requested: Civil registrations (Deaths) data, HES Accident and Emergency, HES – Admitted patient care and HES – Outpatient registry.

For admission to hospital for treatment data, patients in this population maybe discharged from tertiary services, however, continue to have ongoing symptoms and in some cases may progress to developing pulmonary hypertension by its current definition. These data sets will allow the study team to understand if patients who are discharged, continue to seek medical attention because of ongoing symptoms or progression and allow us to understand the cause. Hospital encounters will also be categorised into; “related to pulmonary hypertension”, “possibly related to pulmonary hypertension”, “unrelated to pulmonary hypertension” by reviewing diagnosis codes and reason for hospital attendances. The same process will occur with mortality data.

Cause of death will be identified and categorised into, "related to pulmonary hypertension, "possibly related to pulmonary hypertension" and "unrelated to pulmonary hypertension". Although date of death has been requested, this will be used to calculate years of survival from the "index right heart catheterisation", i.e. the time at which "mild pulmonary hypertension" was identified. The record-level pseudonymised NHS England data will be processed and only aggregated, suppressed data as per the HES analysis guide will be disseminated as outputs.

Patients are reviewed in the seven tertiary centres that specialise in Pulmonary Hypertension. As a result, there is a geographical spread of the patient population throughout the United Kingdom. Most patients are likely to have contact with local hospitals as opposed to a tertiary centre to seek medical attention. NHS England is the only option available to be able to collect this data on admission to hospital for treatment across England accurately. NHS England, through its safeguards and ability to use linkage with research identifiers as opposed to patient identifiers, allows the least intrusive way of collecting this data.

Legal aspects of data collection:

The Data Controller will process the data under GDPR Article 6 (1) (e). Processing is carried out by an NHS organisation in the public interest, in order to understand and help this patient population in the future.

This is a multi-centre retrospective study, looking at retrospective investigations that were done for clinical need. Relevant patient groups have been involved from the outset to provide input to the design of this study with the assistance of the Pulmonary Hypertension Association (PHA). The PHA ran a survey asking patient population, if there were any objections to the study. Working alongside the PHA a website page has been designed (RESEARCH: Is it possible to diagnose PH earlier? | PHA (phauk.org)) and a leaflet to act as a platform to share information about the study, updates and how to go about registering for the National Opt Out should the patient wish to. To keep patients informed, a newsletter has also been distributed through the Pulmonary Hypertension Association. National Data Opt-Outs will be upheld for this study.

Additionally, under GDPR Article 9(2)(j) processing of Special Category Personal Data is necessary for archiving for research purposes. Data minimisation process is being followed and only data that is required specifically for the purposes of this study has been requested, to protect the rights of the data subjects.

The patient data will remain pseudonymised, with any patient identifiers removed by NHS England prior to dissemination. A unique research ID (Study ID) will be created for each data subject, which will be used for linkage to existing study data. Any outputs will be of aggregated data with small numbers suppressed according to the HES analysis guide, in order to safeguard patient data.

The Royal Free Hospital (a part of the legal entity which is Royal Free Hospital NHS Foundation Trust) will undertake the study and processing of NHS England data as data controller and data processor. The outputs will be measured by dissemination of the research outcomes, through scientific committees and publication in scientific journals. This will also be undertaken by the Royal Free Hospital, with support from the other National Pulmonary Hypertension centres in the United Kingdom. This will allow dissemination of research amongst healthcare professionals, scientific bodies, and health policy makers. This will help understand this population better and hopefully aid better outcomes in this population. Publication timelines are forecast for early 2022. The other sites, Statistician and Funders will only have access to aggregated and suppressed data, in accordance with the HES analysis guide.

The Royal Hallamshire Hospital will offer analysis support, having had previous experience with utilising and analysing NHS England HES data. However, this will be in an advisory capacity and they will have no access to the record-level pseudonymised NHS England data.

The other principle investigators will be involved in interpreting the outcomes of the aggregated and suppressed data only; however, this will involve no data processing.

NHS England is content that the purpose of this study is to better phenotype, define and understand a population diagnosed with pulmonary hypertension in the hope that this might lead to future projects to see if earlier intervention and treatment has a positive outcome, thus clearly demonstrating that the study purpose is research into public health and therefore providing benefit to health and social care in England.

However, in the interests of full transparency, it is noted here that the funder of the study, Actelion Pharmaceuticals Ltd (a part of the Janssen Pharmaceutical Companies of Johnston & Johnston), will obtain aggregated and suppressed (as per the HES analysis guide) outputs from study data. Thus results of this study may contribute towards commercial work that results in indirect financial benefit for the funder which, in turn, may provide further funding for research into the population.

The funder will have no access to record-level NHS England data, nor any involvement in the processing of data, and are not considered a Data Controller for this study. The funder has no ability to suppress the outcomes of this study, nor any say in the management of the outputs and their dissemination to the public and health professionals.

The UK phenotyping study for Mild Pulmonary Hypertension, will be collecting retrospective data from 7 sites (6 for England):

The Royal Free Hospital (Royal Free London NHS Foundation Trust - Data controller, Data Processor and study sponsor )

The Royal Brompton Hospital (Guy's and St Thomas' NHS Foundation Trust - previously Royal Brompton and Harefield NHS Foundation Trust)

The Hammersmith Hospital (Imperial College Healthcare NHS Trust)

The Royal Hallamshire Hospital (Sheffield Teaching Hospitals NHS Foundation Trust)

The Royal Papworth Hospital (Royal Papworth Hospital NHS Foundation Trust)

The Freeman Hospital (The Newcastle Upon Tyne Hospitals NHS Foundation Trust)

*** The Golden Jubilee Hospital - not relevant to this DSA as it is Scottish data ***

METHODOLOGY

1. Each site will search their local databases, to identify patients who potentially fulfil the criteria for the study (all patients who have undergone an invasive right heart catheterisations done between 1 January 2009 - 31 December 2016). The NHS numbers will then be sent securely over encrypted NHS email systems from the sites to the Royal Free Hospital. Patients will be allocated a unique study ID at each of the sites. Along with collecting baseline characteristics and investigations, a separate spreadsheet will be generated containing patient details required for the HES process – name, date of birth, NHS number and unique research ID. The unique research ID will be used for linkage. This spreadsheet containing patient identifiers, will be sent from each site to the Royal Free Hospital through secure encrypted NHS email.

The Royal Free Hospital will use the NHS England National Data Opt-Out extraction service to remove all cohort members who have registered a National Data Opt-Out.

2. Study data will be generated from medical records collecting baseline characteristics and investigations over a 10-year period.

3. The Royal Free Hospital will collate all separate cohorts together and send the complete cohort (approx. 2,900 records) to NHS England along with the Name, Date of Birth, NHS number and unique Study ID via the Secure Electronic File Transfer Service (SEFT).

4. NHS England will use the cohort identifiers and apply the National Opt Out preferences again to remove any cohort members who have opted out, and then link and extract all HES and Mortality data for the period April 2008 to March 2020.

5. NHS England will remove all identifiers (keeping the unique Study ID) and send the pseudonymised data extracts back to the Royal Free Hospital via SEFT.

The data will be returned to the Royal Free Hospital, without patient identifiers and with unique research ID alone. No identifiable fields have been requested from NHS England, to safeguard patient data. The data will be processed solely by the Royal Free Hospital by only substantive employees, who are bound by patient confidentially agreements. The record level pseudonymised data will be securely stored on Royal Free servers with password protection/restricted access drives. Statistical data analysis will be carried out via Trust owned remote devices connected to the Royal Free Hospital network either directly in person or remotely, using an appropriate statistical package. To remotely access the devices requires a secure 2-factor authenticator (VPN) and users are then able to securely access the secure server on the Trust’s IT framework. All data analysis will be conducted within the confines of the Trust’s secure server, and will not be downloaded to remote devices for storage or processing. There will be no linkage to data beyond that already described in this DSA. The original cohort identifiers (Patient Identifiable Data) is also stored separately and securely on Royal Free servers with password protection/restricted access drives.

The record level pseudonymised data will be interrogated to establish how many hospital attendances were required over a 10-year time scale. The data will also be further analysed to assess if these encounters were related, unrelated or possibly related to an underlying diagnosis of Pulmonary Hypertension. The data will remain pseudonymised using unique research IDs (Study ID) throughout this process to safeguard the subject’s identity. There will be no re-identification of the data subjects once the data has been collated.

The aggregated and suppressed data will be sent for analysis by a statistician who is a substantive employee of University College London. Only aggregated data and suppressed data (as per the HES analysis guide) will be sent onwards from the Royal Free Hospital. There will be no distribution of record level HES or mortality data, to mitigate the risk of re-identification of the patient. Aggregated and suppressed data files will be transferred via a secure and encrypted emailing system, using password protection.

The NHS England record-level data and original cohort identifiers will remain at the Royal Free Hospital, on an encrypted and password protected USB stick, for 5 years, in line with archiving practices for Research. Upon starting the archiving period, the USB will be issued to the Royal Free Hospital IT department who will store it securely at a secure off-site facility at Iron Mountain (UK) Limited together with the study documents. Only named members of the study team will have access to documents/USB archived off-site. The Royal Free Hospital will follow the guidelines of securely archiving the data as per this Data Sharing Agreement.

Iron Mountain (UK) Limited do not access data held under this agreement as they only supply the building and are therefore not listed as a Data Processor. Therefore, any access to the data held under this agreement would be considered a breach of the agreement. This includes granting of access to the database containing the data.

HES and ECDS DISCLOSURE CONTROL / SMALL NUMBER SUPPRESSION

In order to protect patient confidentiality, when presenting results calculated from HES record level data, outputs will contain only aggregate level data with small numbers suppressed in line with HES Analysis Guide. When publishing HES data, data analysts must make sure that:

· National-level figures only may be presented unrounded, without small number suppression

· cell values from 1 to 7 (inclusive) are suppressed at a local level to prevent possible identification of individuals from small counts within the table.

· Zeros (0) do not need to be suppressed.

· All other counts will be rounded to the nearest 5.

Data will not be made available to any third parties other than those specified except in the form of aggregated outputs with small numbers suppressed in line with the HES Analysis Guide.

The aim of this UK wide study will be to publish aggregated and suppressed data (as per the HES Analysis guide) in a peer reviewed journal, for instance the European Heart Journal and

Journal of the American College of Cardiology (JACC) and to present the findings at international conferences, including the European and British Society of Cardiology (ESC). A presentation of full baseline findings has already been held at ESC congress in 2024. The baseline findings will be presented at the Pulmonary Hypertension Forum (without the NHS England data as it won't be possible to analyse the data in the short timescale). The study team will be working closely with the Pulmonary Hypertension Association to publish update reports of the study for the patient association, to keep patient groups updated on the progress of the study. The seven UK pulmonary hypertension tertiary centres involved in the study also obtain a newsletter monthly to inform them of the progress of the study.

All data outputs will be aggregated and suppressed as per the HES Analysis guide. Data will be tabulated and depicted in a graphical format to ease interpretation of the analysis.

The aggregated and suppressed output results and report will be disseminated to all the principle investigators involved in the study for review and approval prior to publication. Publication target audience will be researchers, scientist and clinicians involved directly in patient care.

The study team have been working closely with the Pulmonary Hypertension Association UK (a charity providing a National information network for patients with Pulmonary Hypertension and their carers) from the outset of the study design. The study team informed the patient forum of their intent and the study purpose, and surveyed their patient population and acted upon their feedback. The study team have provided contact details to offer more information and a point of contact at all points during the study.

The study has a dedicated webpage hosted by Pulmonary Hypertension Association UK. The PHA have no affiliation with the study or this DSA. The PHA have been providing progress notes via this webpage on the study for patients and their carers, and hope to also publish frequent updates on outcomes from the study data analysis.

The study aims to provide an insight into patients with “mild pulmonary hypertension” in the United Kingdom. This is a population that does not currently meet the criteria for formal diagnosis, however, still demonstrates higher mortality and morbidity. It will give an insight into progression and which patient groups need to be monitored more closely. This will hopefully translate into guidance to ensure better outcomes in this population and influence national guidance on Pulmonary Hypertension (European Society of Cardiology – Guidance on Pulmonary Hypertension).

The study is supporting one part-time postgraduate research degree (Doctor of Medicine by Research) at University College London, who is a substantive employee of the Royal Free Hospital. Outputs from the postgraduate research degree will only contain data which is aggregated and suppressed as per the HES Analysis Guide.

Analysis of the Data and subsequent publication in journals will continue until 2027.

There is no formal pathway currently for patients identified with “mild pulmonary hypertension” in the current guidance. Dissemination of data aims to benefit the provision of health care and adult social care by offering identification and early access to specialist commissioned NHS service to reduce morbidity and mortality to a group of normally healthy, able and socioeconomically productive patients. The evidence gathered would seek to enable revision of Pulmonary Hypertension guidance at the regional tertiary centres, and it is hoped also ESC guidelines as well which would support the promotion of health by improved recognition of this disease by a larger audience. This processing is therefore in the public interest that this study accesses such valuable NHS England data to understand this population in greater detail.

Analysis of registry patients has identified circa 2,900 patients between 1 January 2009 - 31 December 2016 inclusive that have a ‘mean pulmonary artery pressure’ (mPAP) of less than 25mmHg, which does not meet the current definition of Pulmonary Hypertension, globally defined as a mean pulmonary artery pressure of >25mmHg. These patients are later clinically referred to Pulmonary Hypertension Services because they remain symptomatic or have an abnormality that has been incidentally identified by another investigation. This figure likely vastly underestimates the ‘real’ number of patients who have abnormal pulmonary circulation and cardiovascular haemodynamics. These individuals would not come to the attention of specialist services as they are not classified by current guidance. There is an increased mortality associated with this group of patients, who do not formally meet the criteria, however, still demonstrate abnormal cardiovascular haemodynamics. It is therefore very important to investigate this population to understand them better and to understand the progression in this disease pathology and factors that predict this. This could benefit patients in the future and is anticipated that it could be fundamental to changing guidelines and identifying patients early in the disease process to allow patients to be appropriately followed up, screened and to intervene earlier to try and limit the progress of the disease before changes to the pulmonary vasculature become irreversible. Understanding “Mild Pulmonary Hypertension” better, will hopefully impact the overall mortality and morbidity and health burden placed on NHS services.

The information provided by NHS England is important in achieving the study’s primary end point question: 'Is mortality and admission to hospital for treatment greater in this population?'

Combined with HES and Civil Registrations (Deaths) data, this study offers the potential to determine causation. Untreated, Pulmonary Hypertension does negatively impact on the patient population, the qualitative and quantitative analysis of this data will hopefully allow an insight into silent disease progression, it may also provide information towards understanding which factors influence why some patients do not progress to Pulmonary Hypertension. This is particularly important given the implications of having the diagnosis, including starting unnecessary medications, lifestyle and psychological impact.

Not stated in the register.