Vertebral artery stenting to prevent recurrent stroke in symptomatic vertebral artery stenosis: the VIST RCT

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 11/129/16. The contractual start date was in March 2013. The draft report began editorial review in August 2017 and was accepted for publication in January 2019. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Hugh S Markus is supported by a National Institute for Health Research (NIHR) Senior Investigator award and his work is supported by the Cambridge University Hospitals Trust NIHR Comprehensive Biomedical Research Centre. He reports personal fees from AstraZeneca plc (Cambridge, UK) for teaching outside the submitted work. Peter M Rothwell is supported by Wellcome Trust and NIHR Senior Investigator awards and his work is supported by the NIHR Biomedical Research Centre, Oxford, UK. He reports personal fees from Bayer AG (Leverkusen, Germany) outside the submitted work.

Copyright statement

© Queen’s Printer and Controller of HMSO 2019. This work was produced by Markus et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

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Scientific background and rationale

Stroke in the posterior circulation accounts for 20% of all ischaemic stroke,1 and about 25% of cases of posterior circulation stroke are due to stenosis in the vertebral and/or the basilar arteries. 1 Despite the high proportion of posterior circulation stroke caused by vertebral and basilar stenosis, information about optimal management is lacking in comparison with that available for anterior circulation stroke. A similar proportion of anterior circulation stroke is caused by stenosis of the carotid arteries, associated with carotid artery stenosis. Large international trials in patients with symptomatic carotid stenosis [presenting with both transient ischaemic attack (TIA) and non-disabling stroke] have shown that carotid endarterectomy is associated with a reduced risk of recurrent stroke. 2 Carotid stenting has also been shown to be effective, although it is associated with a slightly higher risk of perioperative stroke than carotid endarterectomy. 3

It has been shown that patients with recently symptomatic vertebrobasilar stenosis have a similarly high risk of recurrent stroke to that in patients with symptomatic carotid stenosis, with the highest risk being in the first month. In a pooled analysis of two prospective studies, 90-day risk of stroke was 24.6%, with the risk higher with intracranial (33%) than with extracranial stenosis (16.2%). 4

Surgical access to the vertebral arteries is more difficult than that to the carotid artery, and, although vertebral stenosis can be treated surgically, such procedures have not been widely adopted worldwide. 1 By contrast, vertebral artery (VA) stenosis can more easily be treated with angioplasty and/or stenting. In early studies, proximal lesions were treated primarily with angioplasty; however, this was associated with a high restenosis rate, leading to the use of stenting for such lesions. 2 Several series have reported very low periprocedural complication rates for extracranial vertebral stenosis. Two systematic reviews were published in 2011 and 2012 with similar results. 5,6 Stayman et al. 5 identified 27 articles of series of cases of extracranial stenting meeting their inclusion criterion, with a total of 980 of 993 patients treated with stents. The majority of patients (56%) were noted to have contralateral VA stenosis or occlusion, and 92% were symptomatic at the time of treatment. A total of 11 patients (1.1%) experienced a stroke and eight (0.8%) experienced a TIA within 30 days of the procedure. Drug-eluting stents were associated with lower restenosis rates (11%) than bare metal stents (30%) at a mean of 24 months’ follow-up.

The VA comprises both an extracranial section (segments V1–V3) and an intracranial segment (V4). The complication rate following angioplasty and stenting is higher for intracranial than for extracranial vertebral stenosis. In a systematic review,7 perioperative stroke rates were 1.3% in 313 extracranial stents, 7.1% in intracranial vertebral angioplasties and 10.6% in intracranial vertebral stents. That review7 included data from the prospective multicentre Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries study,8 which included 61 vertebral and intracranial lesions. However, many of the studies included in previous reviews are now old and technology has significantly improved. Furthermore, as intracranial stenosis has a higher recurrent stroke rate if treated medically,4 it may still benefit from stenting.

In contrast to the considerable data from case series, there are far fewer data from randomised trials. The Carotid And Vertebral Artery Transluminal Angioplasty Study (CAVATAS)9 included both carotid and vertebral stenosis. However, only 16 patients were randomised between vertebral angioplasty or stenting and best medical treatment (BMT), and this used angioplasty as the trial was performed before the routine use of stents for treating arterial stenosis. The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial10 reported that outcomes among patients with stenosis in a variety of intracranial cerebral arteries were worse in the stent group than in the BMT group. Basilar artery stenting was associated with a particularly high complication rate, but few patients with VA stenosis were enrolled. However, a recent analysis suggested that outcomes after stenting are as poor in patients with VA stenosis as in patients with stenoses in other intracranial arteries. 11 Furthermore, the SAMMPRIS trial used the Wingspan stent system (Boston Scientific, Fremont, CA, USA), which has been associated with a higher complication rate. The Vertebral Artery Stenting Trial (VAST) included both patients with intracranial and those with extracranial VA stenosis and randomised them between stenting and BMT. It found no significant difference between the two groups. Although VAST was designed as a Phase II trial, it was terminated early owing to regulatory issues and because it was underpowered to detect a difference. 12

Specific objectives

The Vertebral artery Ischaemia Stenting Trial (VIST) was established to compare the risks and benefits of vertebral angioplasty and stenting plus BMT with those of BMT alone for recently symptomatic VA stenosis.

Trial design

VIST was a prospective, randomised, open, parallel, blinded end-point clinical trial performed at 14 hospitals, with both specialised stroke and interventional radiology services, in the UK. VIST sites and recruitment rates are shown in Appendix 1. It was planned to extend the study to other countries; however, after funding was ceased because of slower than anticipated recruitment, only 182 of the planned 540 patients, all from the UK, were recruited. VIST was initially established as a pilot (with a sample size of 100 participants), and was funded by the Stroke Association. The plan was to extend the pilot to a definitive Phase III trial if recruitment was feasible. After further funding from the National Institute for Health Research Health Technology Assessment programme, the pilot phase was extended to a Phase III trial.

Eligibility

Patients were identified from stroke and neurology services in secondary and tertiary care, with the following inclusion and exclusion criteria applied.

Settings and locations where the data were collected

The study was carried out at stroke centres in the UK. These centres had both a specialised stroke service and facilities for interventional radiology. It was planned to extend the study to centres outside the UK; however, only one overseas centre (Prince of Wales Hospital, Hong Kong) had opened to recruitment by the time recruitment was stopped and this had not recruited any patients by that time. To be allowed to participate, a centre had to have both a consultant neurologist or physician with an interest in stroke and a designated consultant interventional radiologist with experience in cerebral angioplasty/stenting. Interventionists were expected to have performed a minimum of 50 stenting procedures, of which at least 10 were on cerebral vessels. Centres with less than this level of experience joined for a probationary period, during which time procedures were proctored by an experienced interventionist until 10 procedures had been satisfactorily performed.

The study was approved by the Multicentre Ethics Committee in England (reference number 08/H0711/2) and all patients gave written informed consent.

Randomisation and masking

Patients were randomly assigned (1 : 1) to vertebral angioplasty/stenting plus BMT or BMT alone via an online randomisation service provided by the King’s College London Clinical Trials Unit. Authorised researchers at recruiting study sites who were delegated to request randomisation were provided with unique login details by the Clinical Trials Unit to access the system. Once the participant was confirmed as consenting and eligible to proceed into the study, the authorised researchers accessed the system and entered the relevant data, which included participant identifiers and stratifiers. The system then allocated the participant to treatment group using the method of block randomisation with randomly varying block sizes of two and four, stratified by site of VA stenosis (origin V1 vs. other extracranial V2 and V3 vs. intracranial V4). To account for the differing recurrent stroke risk associated with site of VA stenosis, randomisation was stratified by the site of VA stenosis (V1 vs. V2/V3 vs. V4). E-mails confirming the randomisation were automatically generated by the system and sent to relevant authorised researchers in the study site and central co-ordinating team; the e-mail revealed or concealed the treatment allocation depending on the recipient’s role in the study. Both patients and clinicians were aware of treatment allocation, but an independent adjudication committee, masked to treatment allocation, assessed all primary and secondary end points.

Interventions

Follow-up

Both entry and follow-up data were collected via an online electronic case report form hosted by King’s College London. Participants were seen at the time of the procedure (if allocated to stenting) and at 1 month and 1 year post randomisation by the local neurologist/stroke physician. In addition, telephone follow-up was performed at 6 months and 2 years, and after that on a yearly basis, at the co-ordinating centre by a designated stroke physician or neurologist using a standard pro forma. If patients experienced possible outcome events during follow-up, an end-point form was completed, the results of imaging were obtained and the data were reviewed by the adjudication committee. Members of the adjudication committee reviewed cases independently and were blinded to subject identity. Repeat imaging with either MRA or CTA at 1 year to check for vessel patency was encouraged but not mandated.

Angiographic imaging at baseline and at 12 months was assessed by central reading of the images by an experienced interventional neuroradiologist (AC). Restenosis was defined as any residual or recurrent stenosis of at least 50% or occlusion of the VA on CTA or MRA during follow-up.

Outcomes

The primary end point was fatal or non-fatal stroke in any arterial territory (including periprocedural stroke) during trial follow-up.

The secondary end points were:

• fatal or non-fatal stroke in any arterial territory (including periprocedural stroke) within 3 months post randomisation

• posterior circulation stroke (including periprocedural stroke) during follow-up

• periprocedural stroke or death (within 30 days of the procedure)

• posterior circulation stroke or TIA during follow-up

• death from any cause during follow-up

• restenosis in treated artery during follow-up.

An additional exploratory end point of fatal or non-fatal stroke and TIA was added. There were two reasons for this. First, as the trial was to be terminated early, we wanted an end point that would include the maximum number of ischaemic events. Second, it proved difficult to determine unequivocally whether or not some strokes were posterior circulation.

Stroke was defined as a rapid-onset focal disturbance of cerebral function, lasting > 24 hours or leading to death, with no apparent cause other than that of vascular origin. The diagnosis did not mandate imaging confirmation of a cerebral infarct.

It was intended that data would be collected and analysed on cost-effectiveness, and the following additional secondary end points were included in the statistical analysis plan:

• NHS and Personal Social Services costs

• quality-adjusted life-years

• within-trial and long-run incremental cost-effectiveness.

However, owing to the early termination of recruitment and the withdrawal of funding for this analysis, data were not available for these secondary analyses.

Adverse events were collected on a dedicated form and reviewed by the co-ordinating centre prior to unbinding of the treatment group.

Patient and public involvement in study design

The trial design was reviewed by the St George’s Patient and Carer Stroke Group. The group felt that it was an important topic to investigate further. The group helped to ensure that the design was feasible. In particular, there was significant input from one member (Mr John Dennis), who had experience of vertebral stenting and played a key role throughout the trial. He commented on study design and patient materials, assisted with preparation of the grant application, on which he was a co-applicant, and was a member of the Trial Steering Committee.

Sample size

For sample size estimates the following figures were used: a stroke risk in the medically treated group of 24% over a 3-year period; and a risk reduction in the stented group of 45% (including periprocedural rate).

Statistical methods

The main analyses performed were on an intention-to-treat basis. Per-protocol analyses including patients who received the assigned treatment and had at least 50% VA stenosis confirmed by angiography were also conducted. HRs with 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models. Each patient accrued follow-up time from the date of randomisation until the time of first event of each type, death or 1 March 2016 (the time by which follow-up of at least 1 year was available for all patients). The proportional hazards assumption was tested using scaled Schoenfeld residuals and was found to be satisfactory. Kaplan–Meier survival analysis was used to construct time-to-event curves and the log-rank test was used to compare the cumulative events between groups.

All statistical tests were two-sided and a p-value of < 0.05 was considered statistically significant. The statistical analyses were performed using Stata^® version 14.1 (StataCorp LP, College Station, TX, USA).

Meta-analysis of results with those of other randomised controlled trials

The results of VIST were meta-analysed with those of previous randomised controlled trials (RCTs) of stenting for vertebral stenosis. Randomised trials investigating the effect of stenting and/or angioplasty on recurrent stroke or TIA in symptomatic VA stenosis patients were identified by searching PubMed (including MEDLINE) until 9 June 2017. Abstracts were reviewed by one author (SL). The search terms used were ‘stenting’ or ‘angioplasty’ or ‘stent’; ‘VA stenosis’ or ‘extracranial stenosis’ or ‘intracranial stenosis’; ‘stroke’ or ‘transient ischemic attack’; and ‘randomized trial’ or ‘randomized controlled trial’ or ‘clinical trial’. No language or other restrictions were imposed. The primary end point was any stroke. Analyses were performed separately for extra- and intracranial stenosis. Data were extracted by one author (SL) and included the name of the trial, number of outcome events, total number of patients in the stenting/angioplasty and medical groups, and the relative risk estimate (HR or odds ratio), comparing stenting/angioplasty with BMT. Relative risk estimates were combined using a random-effects model, and heterogeneity among estimates was evaluated using the Q-test and I²-statistic.

Recruitment

Owing to slow recruitment, support for continued recruitment by the funder was withdrawn after 182 patients were recruited, and, at that point, analysis was planned after every patient had been followed up for at least 1 year. Each patient accrued follow-up time from the date of randomisation until the time of first event of each type, death or 1 March 2016.

The trial profile is shown in Figure 1. Between 23 October 2008 and 4 February 2015, 182 patients were enrolled. Three patients (two who withdrew after randomisation and one who did not attend after the initial randomisation visit) did not contribute any follow-up data and were excluded. None of these three patients had outcome events. Of the 179 remaining patients, 88 were assigned to BMT alone (‘medical’ group) and 91 were assigned to stenting or angioplasty plus BMT (‘stent’ group). Follow-up data until March 2016 were available for all 179 patients.

FIGURE 1.

Patient flow in the two groups of the study.

Baseline characteristics

At baseline patients were well matched for age, sex and cardiovascular risk factors (Table 2). Similar proportions in both groups had stroke and TIA as the qualifying event, and the location of the vertebral stenosis was similar in both groups. The location of the VA target stenosis was extracranial in 83% and intracranial in 17%; most extracranial stenosis affected the V1 segment.

However, the time from last symptoms to randomisation was shorter in the stenting group by a mean of 12.8 days, and this could introduce a potentially important imbalance as a result of the previously noted association between time from symptoms and risk of recurrent stroke. 4 This implies that patients in the medical group were exposed to the highest stroke risk for 13 days fewer than those in the stent group. The percentage of patients randomised within 14 days of last symptoms was 47% in the stent group and 30% in the medical group. To account for this imbalance, two exploratory analyses were performed: first, controlling for time from symptoms; and, second, controlling for time in those subjects randomised within 2 weeks of symptoms. The 2-week cut-off point was chosen as this had been identified as the high-risk period for symptomatic carotid stenosis during which patients with moderate (50–70% stenosis) benefit from intervention (with carotid revascularisation), and after which there is no significant benefit. 15

Details of intervention

Ninety-one patients were randomised to stenting; however, stenting was not performed in 30 of those patients (33.0%) (see Figure 1). The most common reason, applying to 23 (76.7%) participants, was the finding of stenosis < 50% on intra-arterial angiography carried out at the time of the planned stenting. Of the 61 patients in the stent group, the stenosis was extracranial in 48 (78.7%) and intracranial in 13 (21.3%). Fifty-eight (63.7%) patients had a stent placed (56 balloon-expandable and two self-expanding) and three patients had angioplasty alone (no distal protection devices were used). Mean stenosis in the treated VA of stented patients was 78.7 [standard deviation (SD) 1.6%] pre stent and 9.6 (SD 1.8%) post stent.

Follow-up and characteristics of the two groups during follow-up

The median follow-up was 3.5 (interquartile range 2.1–4.7) years. Medical treatment and risk factors were recorded at each follow-up visit and were similar between groups, except for slightly higher dual antiplatelet use in the stent group in the first year, particularly at month 1 (57% vs. 33%) (Table 3).

Outcome events during stenting

There were two major complications during the stenting procedure, both in patients with intracranial stenosis. One died from subarachnoid haemorrhage during stenting due to vessel rupture. A second had a non-fatal periprocedural brainstem stroke. Among patients with extracranial stenosis, one stented patient had a non-fatal stroke within 30 days of intervention.

Primary outcome

The primary end point was fatal or non-fatal stroke, which occurred in five patients (including one fatal stroke) in the stent group and in 12 patients (including two fatal strokes) in the medical group (HR 0.40, 95% CI 0.14 to 1.13; p = 0.08) (Table 4 and Figure 2). For the primary end point there were 41 strokes per 1000 person-years in the medical group compared with 16 strokes per 1000 person-years in the stent group. Therefore, the absolute risk benefit was 25 strokes per 1000 person-years.

FIGURE 2.

Kaplan–Meier curves for the cumulative probability of (a) fatal or non-fatal stroke in any arterial territory (primary end point), (b) fatal or non-fatal stroke in any arterial territory or TIA and (c) death from any cause during follow-up, according to treatment group (intention-to-treat population). A log-rank test was used to test the hypothesis that stroke incidence, stroke or TIA incidence, or mortality rate between groups was the same.

Key secondary outcomes

The HR in patients with extracranial and intracranial VA stenosis was 0.37 (95% CI 0.10 to 1.36) and 0.47 (95% CI 0.08 to 2.60), respectively (see Table 4). Other secondary end points, fatal or non-fatal stroke within 90 days and death from any cause (see Figure 2), did not differ between the groups (see Table 4). The per-protocol analyses yielded similar results (see Table 4).

We were unable to accurately classify stroke severity at 3 months to allow division of stroke into disabling and non-disabling according to the predefined modified Rankin Scale score. This is because a number of strokes were picked up some months after they occurred. For this reason we have not included the secondary end point of disabling stroke.

Adverse events

Adverse events are listed in Table 5. There was no difference between the two treatment groups.

Follow-up angiographic imaging

Follow-up angiographic imaging with CTA or MRA was carried out in 47 of the 61 the patients undergoing stenting. This showed three stent occlusions: two in V1 and one in V2. Because the stent obscured the lumen on CTA and MRA, it was not possible to accurately measure the degree of stenosis on the follow-up imaging and, therefore, only report on whether or not the artery was occluded, which we were able to reliably determine.

Meta-analysis of VIST results with those of other published randomised controlled trials

The systematic review identified four other trials: CAVATAS,9 the SAMMPRIS trial,10,11 VAST12 and the Vitesse Intracranial Stent Study for Ischemic Stroke Therapy (VISSIT). 16 CAVATAS9 randomised 16 patients with vertebral stenosis: eight to angioplasty and eight to medical therapy alone. There were no outcome events during follow-up and, therefore, this study did not contribute data to the meta-analysis. The SAMMPRIS trial10,11 randomised patients with a stenosis in a variety of intracranial vessels, but only data for vertebral stenosis were included in the meta-analysis. VAST12 recruited only patients with vertebral stenosis and therefore all of its data were included in the meta-analysis. VISSIT,16 like the SAMMPRIS trial,10,11 randomised patients with a stenosis in a variety of intracranial arteries. We were unable to separate data for vertebral stenosis and the corresponding author did not respond to a request for additional data. Therefore, VISSIT16 could not be included in the meta-analysis.

The results of the meta-analysis are shown in Figure 3. For any vertebral stenosis there was no benefit of stenting, with a relative risk (RR) of 0.89 (95% CI 0.36 to 2.21). There was no evidence of any benefit when analysis was limited to intracranial stenosis (RR 1.14, 95% CI 0.44 to 2.91). Likewise, there was no significant benefit when analysis was limited to extracranial stenosis, although there was a possible trend towards benefit (RR 0.66, 95% CI 0.25 to 1.72).

FIGURE 3.

Relative risk of stroke among patients randomised to stenting/angioplasty vs. BMT alone in randomised trials of VA stenosis. Note that the results of CAVATAS9 are not included because there were no end points in either group of the trial. Squares represent trial-specific RRs (the size of the square reflects the trial-specific statistical weight); horizontal lines represent 95% CIs; and diamonds represent the combined RR with its 95% CI from a random-effects meta-analysis. a, The RR estimates are odds ratios in the SAMMPRIS trial10,11 and in VAST,12 and HRs in VIST.

VIST investigators

VIST centres (and numbers of patients recruited)

St George’s University Hospitals NHS Foundation Trust (Barry Moynihan, Hugh Markus, Andrew Clifton and Jeremy Madigan), n = 77; Oxford University Hospitals NHS Foundation Trust (Peter Rothwell, Ursula Schulz and Wilhelm Kuker), n = 38; University Hospitals of North Midlands NHS Trust (Christine Roffe and Sanjeev Nayak), n = 14; Sheffield Teaching Hospitals NHS Foundation Trust (Ralf-Bjoern Lindert and Peter Gaines), n = 11; The Walton Centre NHS Foundation Trust, Liverpool (Alakendu Sekhar and Hans Nahser), n = 8; King’s College Hospital NHS Foundation Trust (Bartlomiej Piechowski-Jozwiak and Timothy Hampton), n = 8; Newcastle upon Tyne Hospitals NHS Foundation Trust (Anand Dixit and Anil Gholkhar), n = 7; University College Hospitals NHS Foundation Trust (David Werring and Stefan Brew), n = 6; Imperial College Healthcare NHS Trust (Pankaj Sharma and Maneesh Patel), n = 4; Cambridge University Hospitals NHS Foundation Trust (Hugh Markus and Nick Higgins), n = 2; Leeds Teaching Hospitals NHS Trust (Ahamad Hassan and Anthony Goddard), n = 2; North Bristol NHS Trust (Neil Baldwin and Marcus Bradley), n = 2; Nottingham University Hospital NHS Trust (Senthil Raghunathan and Robert Crossley), n =2; and Royal Preston Hospital (Hedley Emsley and Siddhartha Wuppalapati), n = 1.

Contributions of authors

Hugh S Markus (Professor of Stroke Medicine and Honorary Consultant Neurologist) contributed to the study design, obtaining funding, study organisation, patient recruitment, data interpretation and writing the first draft of the paper.

Susanna C Larsson (Postdoctoral Research Associate) contributed to developing the statistical analysis, data analysis and writing the first draft of the paper.

John Dennis (patient and public involvement representative Trial and Steering Committee member) contributed to study design, study materials, presentation of results and revising the manuscript.

Wilhelm Kuker (Consultant Neuroradiologist) contributed to obtaining funding, study design and neuroradiological oversight.

Ursula G Schulz (Consultant Neurologist) contributed to obtaining funding, patient recruitment and follow-up, and revising the manuscript.

Ian Ford (Professor of Statistics) contributed to study design, advised on the statistical analysis and critically reviewed the paper.

Andrew Clifton (Consultant Neuroradiologist) contributed to study design, obtaining funding, neuroradiological analysis and oversight, and revising the manuscript.

Peter M Rothwell (Professor of Neurology) contributed to study design, obtaining funding, patient recruitment and revising the manuscript.

Publications

Markus HS, van der Worp HB, Rothwell PM. Posterior circulation ischaemic stroke and transient ischaemic attack: diagnosis, investigation, and secondary prevention. Lancet Neurol 2013;12:989–98.

Rothwell P, Markus HS. Improved medical treatment in secondary prevention of stroke. Lancet 2014;383:290–1.

Markus HS, Larsson SC, Kuker W, Schultz U, Ford I, Rothwell PM, Clifton A; VIST Investigators. Stenting for symptomatic vertebral artery stenosis: the Vertebral Artery Ischaemia Stenting Trial. Neurology 2017;89:1229–36.

Data-sharing statement

All data requests should be submitted to the corresponding author for consideration. Access to available anonymised data may be granted following review.

Patient data

This work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people’s patient records, to understand more about disease, develop new treatments, monitor safety, and plan NHS services. Patient data should be kept safe and secure, to protect everyone’s privacy, and it’s important that there are safeguards to make sure that it is stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation.

Disclaimers

This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care.