Use of NHS Digital datasets as trial data in the UK: a position paper

Background: Clinical trial teams increasingly want to make use of data from healthcare systems (“healthcare data”), particularly to enhance recruitment and follow-up of participants, to reduce time and cost, and to stop the duplication of effort. However, there is continued uncertainty of how regulators regard healthcare data used for trial purposes, in terms of provenance, quality and reliability. Objectives: There were two key objectives: First, to demonstrate the data integrity of two datasets held by NHS Digital (NHSD) that are most requested by trial teams; and second, to set out an approach by which any other healthcare systems datasets can be similarly evaluated. Method: The data lifecycles of the datasets were carefully documented, mapping the flow of data from the originating healthcare provider’s databases to NHSD warehouses and onwards to clinical trials teams. These were assessed for evidence of whether the datasets are accurate, reliable, complete, contemporaneous, and well-governed. Result: The assessment method was applied to (a) the Hospital Episode Statistics Admitted Patient Care (HES APC) dataset and (b) the Civil Registration of Deaths (CRD) dataset. This paper clearly demonstrates that their collection and management through NHSD systems ensure their integrity and reliability. The datasets are accurate representations of the data held by the originating providers (acute NHS trusts and local registrars). Conclusion: Based on these findings, the HES APC and CRD datasets satisfy the assessment criteria that demonstrate they are reliable transcribed copies of the original source data. Implications: First, these datasets can be used directly for clinical trial data, with trial teams focusing on the accuracy of algorithms and processes to identify particular outcomes rather than on the integrity of the data flow. Second, this assessment approach should be used to assess whether other healthcare systems datasets are ready to be used as transcribed copies of source data, and for data providers to take appropriate steps to redress this matter if they are not

Conventional and Genetic Evidence on the Association between Adiposity and CKD

Background The size of any causal contribution of central and general adiposity to CKD risk and the underlying mechanism of mediation are unknown. Methods Data from 281,228 UK Biobank participants were used to estimate the relevance of waist-to-hip ratio and body mass index (BMI) to CKD prevalence. Conventional approaches used logistic regression. Genetic analyses used Mendelian randomization (MR) and data from 394 waist-to-hip ratio and 773 BMI-associated loci. Models assessed the role of known mediators (diabetes mellitus and BP) by adjusting for measured values (conventional analyses) or genetic associations of the selected loci (multivariable MR). Results Evidence of CKD was found in 18,034 (6.4%) participants. Each 0.06 higher measured waist-to-hip ratio and each 5-kg/m2 increase in BMI were associated with 69% (odds ratio, 1.69; 95% CI, 1.64 to 1.74) and 58% (1.58; 1.55 to 1.62) higher odds of CKD, respectively. In analogous MR analyses, each 0.06–genetically-predicted higher waist-to-hip ratio was associated with a 29% (1.29; 1.20 to 1.38) increased odds of CKD, and each 5-kg/m2 genetically-predicted higher BMI was associated with a 49% (1.49; 1.39 to 1.59) increased odds. After adjusting for diabetes and measured BP, chi-squared values for associations for waist-to-hip ratio and BMI fell by 56%. In contrast, mediator adjustment using multivariable MR found 83% and 69% reductions in chi-squared values for genetically-predicted waist-to-hip ratio and BMI models, respectively. Conclusions Genetic analyses suggest that conventional associations between central and general adiposity with CKD are largely causal. However, conventional approaches underestimate mediating roles of diabetes, BP, and their correlates. Genetic approaches suggest these mediators explain most of adiposity-CKD–associated risk.</p

Impact of Educational Attainment on Health Outcomes in Moderate to Severe CKD

BackgroundThe inverse association between educational attainment and mortality is well established, but its relevance to vascular events and renal progression in a population with chronic kidney disease (CKD) is less clear. This study aims to determine the association between highest educational attainment and risk of vascular events, cause-specific mortality, and CKD progression.Study DesignProspective epidemiologic analysis among participants in the Study of Heart and Renal Protection (SHARP), a randomized controlled trial.Setting & Participants9,270 adults with moderate to severe CKD (6,245 not receiving dialysis at baseline) and no history of myocardial infarction or coronary revascularization recruited in Europe, North America, Asia, Australia, and New Zealand.PredictorHighest educational attainment measured at study entry using 6 levels that ranged from “no formal education” to “tertiary education.”OutcomesAny vascular event (any fatal or nonfatal cardiac, cerebrovascular, or peripheral vascular event), cause-specific mortality, and CKD progression during 4.9 years’ median follow-up.ResultsThere was a significant trend (P<0.001) toward increased vascular risk with decreasing levels of education. Participants with no formal education were at a 46% higher risk of vascular events (relative risk [RR], 1.46; 95% CI, 1.14-1.86) compared with participants with tertiary education. The trend for mortality across education levels was also significant (P<0.001): all-cause mortality was twice as high among those with no formal education compared with tertiary-educated individuals (RR, 2.05; 95% CI, 1.62-2.58), and significant increases were seen for both vascular (RR, 1.84; 95% CI, 1.21-2.81) and nonvascular (RR, 2.15; 95% CI, 1.60-2.89) deaths. Lifestyle factors and prior disease explain most of the excess mortality risk. Among 6,245 participants not receiving dialysis at baseline, education level was not significantly associated with progression to end-stage renal disease or doubling of creatinine level (P for trend = 0.4).LimitationsNo data for employment or health insurance coverage.ConclusionsLower educational attainment is associated with increased risk of adverse health outcomes in individuals with CKD

Cost-effectiveness of Simvastatin plus Ezetimibe for Cardiovascular Prevention in CKD:Results of the Study of Heart and Renal Protection (SHARP)

Background Simvastatin, 20 mg, plus ezetimibe, 10 mg, daily (simvastatin plus ezetimibe) reduced major atherosclerotic events in patients with moderate to severe chronic kidney disease (CKD) in the Study of Heart and Renal Protection (SHARP), but its cost-effectiveness is unknown. Study Design Cost-effectiveness of simvastatin plus ezetimibe in SHARP, a randomized controlled trial. Setting & Population 9,270 patients with CKD randomly assigned to simvastatin plus ezetimibe versus placebo; participants in categories by 5-year cardiovascular risk (low, = 20%) and CKD stage (3, 4, 5 not on dialysis, or on dialysis therapy). Model, Perspective, & Timeline Assessment during SHARP follow-up from the UK perspective; long-term projections. Intervention Simvastatin plus ezetimibe (2015 UK 1.19 pound per day) during 4.9 years median follow-up in SHARP; scenario analyses with high-intensity statin regimens (2015 UK 0.05- pound 1.06 pound per day). Outcomes Additional health care costs per major atherosclerotic event avoided and per quality-adjusted life-year (QALY) gained. Results In SHARP, the proportional reductions per 1 mmol/L of low-density lipoprotein (LDL) cholesterol reduction with simvastatin plus ezetimibe in all major atherosclerotic events of 20% (95% CI, 6%-32%) and in the costs of vascular hospital episodes of 17% (95% CI, 4%-28%) were similar across participant categories by cardiovascular risk and CKD stage. The 5-year reduction in major atherosclerotic events per 1,000 participants ranged from 10 in low-risk to 58 in high-risk patients and from 28 in CKD stage 3 to 36 in patients on dialysis therapy. The net cost per major atherosclerotic event avoided with simvastatin plus ezetimibe compared to no LDL-lowering regimen ranged from 157,060 pound in patients at low risk to 15,230 pound in those at high risk (30,500- pound 39,600 pound per QALY); and from 47,280 pound in CKD stage 3 to 28,180 pound in patients on dialysis therapy (13,000- pound 43,300 pound per QALY). In scenario analyses, generic high-intensity statin regimens were estimated to yield similar benefits at substantially lower cost. Limitations High-intensity statin-alone regimens were not studied in SHARP. Conclusions Simvastatin plus ezetimibe prevented atherosclerotic events in SHARP, but other less costly statin regimens are likely to be more cost-effective for reducing cardiovascular risk in CKD. (C) 2016 The Authors. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc

Impact of CKD on Household Income

Introduction The impact of chronic kidney disease (CKD) on income is unclear. We sought to determine whether CKD severity, serious adverse events, and CKD progression affected household income. Methods Analyses were undertaken in a prospective cohort of adults with moderate-to-severe CKD in the Study of Heart and Renal Protection (SHARP), with household income information available at baseline screening and study end. Logistic regressions, adjusted for sociodemographic characteristics, smoking, and prior diseases at baseline, estimated associations during the 5-year follow-up, among (i) baseline CKD severity, (ii) incident nonfatal serious adverse events (vascular or cancer), and (iii) CKD treatment modality (predialysis, dialysis, or transplanted) at study end and the outcome “fall into relative poverty.” This was defined as household income <50% of country median income. Results A total of 2914 SHARP participants from 14 countries were included in the main analysis. Of these, 933 (32%) were in relative poverty at screening; of the remaining 1981, 436 (22%) fell into relative poverty by study end. Compared with participants with stage 3 CKD at baseline, the odds of falling into poverty were 51% higher for those with stage 4 (odds ratio [OR]: 1.51; 95% confidence interval [CI]: 1.09–2.10), 66% higher for those with stage 5 (OR: 1.66; 95% CI: 1.11–2.47), and 78% higher for those on dialysis at baseline (OR: 1.78, 95% CI: 1.22–2.60). Participants with kidney transplant at study end had approximately half the risk of those on dialysis or those with CKD stages 3 to 5. Conclusion More advanced CKD is associated with increased odds of falling into poverty. Kidney transplantation may have a role in reducing this risk

Development and evaluation of rapid data-enabled access to routine clinical information to enhance early recruitment to the national clinical platform trial of COVID-19 community treatments.

BACKGROUND: The COVID-19 pandemic has presented unique challenges for rapidly designing, initiating, and delivering therapeutic clinical trials. PRINCIPLE (Platform Randomised Trial of Treatments in the Community for Epidemic and Pandemic Illnesses) is the UK national platform investigating repurposed therapies for COVID-19 treatment of older people in the community at high risk of complications. Standard methods of patient recruitment were failing to meet the required pace and scale of enrolment. This paper describes the development and appraisal of a near real-time, data-driven, ethical approach for enhancing recruitment in community care by contacting people with a recent COVID-19 positive test result from the central NHS Test and Trace service within approximately 24-48 h of their test result. METHODS: A multi-disciplinary team was formed to solve the technical, ethical, public perception, logistical and information governance issues required to provide a near-real time (approximately within 24-48 h of receiving a positive test) feed of potential trial participants from test result data to the research team. PRINCIPLE was also given unique access to the Summary Care Record (SCR) to ensure safe prescribing, and to enable the trial team to quickly and safely bring consented patients into the trial. A survey of the public was used to understand public perceptions of the use of test data for this proposed methodology. RESULTS: Prior to establishing the data service, PRINCIPLE registered on average 87 participants per week. This increased by up to 87 additional people registered per week from the test data, contributing to an increase from 1013 recruits to PRINCIPLE at the start of October 2020 to 2802 recruits by 20 December 2020. Whilst procedural caveats were identified by the public consultation, out of 2639 people contacted by PRINCIPLE following a positive test result, no one raised a concern about being approached. CONCLUSIONS: This paper describes a novel approach to using near-real time NHS operational data to recruit community-based patients within a few days of presentation with acute illness. This approach increased recruitment and reduced time between positive test and randomisation, allowing more rapid evaluation of treatments and increased safety for participants. End-to-end public and patient involvement in the design of the approach provided evidence to inform information governance decisions. TRIAL REGISTRATION: PRINCIPLE is funded by UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research. EudraCT number: 2020-001209-22 . 26/03/2020 ISRCTN registry: ISRCTN86534580 . 20/03/2020 REC number: 20/SC/058 IRAS number: 281958

Potential health and economic impacts of dexamethasone treatment for patients with COVID-19

Dexamethasone can reduce mortality in hospitalised COVID-19 patients needing oxygen and ventilation by 18% and 36%, respectively. Here, we estimate the potential number of lives saved and life years gained if this treatment were to be rolled out in the UK and globally, as well as the cost-effectiveness of implementing this intervention. Assuming SARS-CoV-2 exposure levels of 5% to 15%, we estimate that, for the UK, approximately 12,000 (4,250 - 27,000) lives could be saved between July and December 2020. Assuming that dexamethasone has a similar effect size in settings where access to oxygen therapies is limited, this would translate into approximately 650,000 (240,000 - 1,400,000) lives saved globally over the same time period. If dexamethasone acts differently in these settings, the impact could be less than half of this value. To estimate the full potential of dexamethasone in the global fight against COVID-19, it is essential to perform clinical research in settings with limited access to oxygen and/or ventilators, for example in low- and middle-income countries