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 new cardiovascular events on quality of life and hospital costs in people with cardiovascular disease in the United Kingdom and United States

Background Despite optimized risk factor control, people with prior cardiovascular disease remain at high cardiovascular disease risk. We assess the immediate‐ and longer‐term impacts of new vascular and nonvascular events on quality of life (QoL) and hospital costs among participants in the REVEAL (Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification) trial in secondary prevention. Methods and Results Data on demographic and clinical characteristics, health‐related quality of life (QoL: EuroQoL 5‐Dimension‐5‐Level), adverse events, and hospital admissions during the 4‐year follow‐up of the 21 820 participants recruited in Europe and North America informed assessments of the impacts of new adverse events on QoL and hospital costs from the UK and US health systems' perspectives using generalized linear regression models. Reductions in QoL were estimated in the years of event occurrence for nonhemorrhagic stroke (−0.067 [United Kingdom], −0.069 [US]), heart failure admission (−0.072 [United Kingdom], −0.103 [US]), incident cancer (−0.064 [United Kingdom], −0.068 [US]), and noncoronary revascularization (−0.071 [United Kingdom], −0.061 [US]), as well as in subsequent years following these events. Myocardial infarction and coronary revascularization (CRV) procedures were not found to affect QoL. All adverse events were associated with additional hospital costs in the years of events and in subsequent years, with the highest additional costs in the years of noncoronary revascularization (£5830 [United Kingdom], US dollars 14 133 [US Medicare]), of myocardial infarction with urgent CRV procedure (£5614, US dollars 24722), and of urgent/nonurgent CRV procedure without myocardial infarction (£4674/£4651 and US dollars 15 251/US dollars 17 539). Conclusions Stroke, heart failure, and noncoronary revascularization procedures substantially reduce QoL, and all cardiovascular disease events increase hospital costs. These estimates are useful in informing cost‐effectiveness of interventions to reduce cardiovascular disease risk in secondary prevention. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01252953; https://www.Isrctn.com. Unique identifier: ISRCTN48678192; https://www.clinicaltrialsregister.eu. Unique identifier: 2010‐023467‐18

Frailty, multimorbidity and polypharmacy: exploratory analyses of the effects of empagliflozin from the EMPA-KIDNEY trial

Background: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are recommended treatment for adults with chronic kidney disease (CKD), but uncertainty exists regarding their use in patients with frailty and/or multimorbidity, among whom polypharmacy is common. We derived a multivariable logistic regression model to predict hospitalization (reflecting frailty) and assessed empagliflozin’s risk-benefit profile in a post-hoc analysis of the double-blind, placebocontrolled EMPA-KIDNEY trial. Methods: The EMPA-KIDNEY trial randomized 6609 patients with CKD (estimated glomerular filtration rate [eGFR] ≥20<45 mL/min/1.73m2 , or ≥45<90 mL/min/1.73m2 with urinary albumin-to-creatinine ratio ≥200 mg/g) to receive either empagliflozin 10 mg daily or matching placebo and followed for two years (median). Additional characteristics analysed in subgroups were multimorbidity, polypharmacy and health-related quality of life (HRQoL) at baseline. Cox regression analyses were performed with subgroups defined by approximate thirds of each variable. Results: The strongest predictors of hospitalization were N-terminal prohormone of brain natriuretic peptide, poor mobility and diabetes; then eGFR and other comorbidities. Empagliflozin was generally well-tolerated independent of predicted risk of hospitalization. In relative terms, allocation to empagliflozin reduced the risk of the primary outcome of kidney disease progression or cardiovascular death by 28% (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.64-0.82); and all-cause hospitalization by 14% (HR 0.86, 95% CI 0.78-0.95); with broadly consistent effects across subgroups of predicted risk of hospitalization, multimorbidity, polypharmacy or HRQoL. In absolute terms, the estimated benefits of empagliflozin were greater in those at highest predicted risk of hospitalization (reflecting frailty) and outweighed potential serious harms. Conclusions: These findings support the use of SGLT2 inhibitors in CKD, irrespective of frailty, multimorbidity or polypharmacy

Effects of empagliflozin on fluid overload, weight and blood pressure in chronic kidney disease

BACKGROUND: Chronic kidney disease (CKD) is associated with fluid excess which can be estimated by bioimpedance spectroscopy. We aimed to assess effects of sodium glucose co-transporter 2 inhibition on bioimpedance-derived “Fluid Overload” and adiposity in a CKD population. METHODS: EMPA-KIDNEY was a 6609-participant double-blind placebo-controlled trial of empagliflozin 10 mg once daily in patients with CKD at risk of progression. In a 660-participant substudy, bioimpedance measurements were added to the main trial procedures at randomization, 2- and 18-month follow-up visits. The substudy’s primary outcome was the study-average difference in absolute “Fluid Overload” (an estimate of excess extracellular water) analyzed using a mixed-model repeated measures approach. RESULTS: The 660 substudy participants were broadly representative of the 6609- participant trial population. Substudy mean baseline absolute “Fluid Overload” was 0.4±1.7 L. Compared to placebo, the overall mean absolute “Fluid Overload” difference among those allocated empagliflozin was -0.24 L (95%CI -0.38, -0.11), with similar-sized differences at 2- and 18-months, and in pre-specified subgroups. Total body water differences comprised between-group differences in extracellular water of -0.49 L (95%CI -0.69, -0.30, including the -0.24 L “Fluid Overload” difference); and a -0.30 L (95%CI -0.57, -0.03) difference in intracellular water. There was no significant effect of empagliflozin on bioimpedance-derived adipose tissue mass (- 0.28 [95%CI -1.41, 0.85] kg). The between-group difference in weight was -0.7 kg (95%CI -1.3, -0.1). CONCLUSIONS: In a broad range of patients with CKD, empagliflozin resulted in a sustained reduction in a bioimpedance-derived estimate of fluid overload, with no statistically significant effect on fat mass

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