Dataset Information

Impact of outcome adjudication in kidney disease trials: observations from the Study of Heart and Renal Protection (SHARP).

ABSTRACT:

Introduction

We aimed to assess opportunities for trial streamlining and the scientific impact of adjudication on kidney and cardiovascular outcomes in CKD.

Methods

We analysed the effects of adjudication of ~2100 maintenance kidney replacement therapy (KRT) and ~1300 major atherosclerotic events (MAEs) recorded in SHARP. We first compared outcome classification before versus after adjudication, and then re-ran randomised comparisons using pre-adjudicated follow-up data.

Results

For maintenance KRT, adjudication had little impact with only 1% of events being refuted (28/2115). Consequently, randomised comparisons using pre-adjudication reports found almost identical results (pre-adjudication: simvastatin/ezetimibe 1038 vs placebo 1077; risk ratio [RR] 0.95, 95%CI 0.88-1.04; post-adjudicated: 1057 vs 1084; RR=0.97, 95%CI 0.89-1.05). For MAEs, about one-quarter of patient reports were refuted (324/1275 [25%]), and reviewing 3538 other potential vascular events and death reports identified only 194 additional MAEs. Nevertheless, randomised analyses using SHARP's pre-adjudicated data alone found similar results to analyses based on adjudicated outcomes (pre-adjudication: 573 vs 702; RR=0.80, 95%CI 0.72-0.89; adjudicated: 526 vs 619; RR=0.83, 95%CI 0.74- 0.94), and also suggested refuted MAEs were likely to represent atherosclerotic disease (RR for refuted MAEs=0.80, 95%CI 0.65-1.00).

Conclusions

These analyses provide three key insights. First, they provide a rationale for nephrology trials not to adjudicate maintenance KRT. Secondly, when an event that mimics an atherosclerotic outcome is not expected to be influenced by the treatment under study (e.g. heart failure), the aim of adjudicating atherosclerotic outcomes should be to remove such events. Lastly, restrictive definitions for the remaining suspected atherosclerotic outcomes may reduce statistical power.

SUBMITTER: Herrington WG

PROVIDER: S-EPMC7614871 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Impact of outcome adjudication in kidney disease trials: observations from the Study of Heart and Renal Protection (SHARP).

Herrington William G WG Harper Charlie C Staplin Natalie N Haynes Richard R Emberson Jonathan J Reith Christina C Hooi Lai Seong LS Levin Adeera A Wanner Christoph C Baigent Colin C Landray Martin M

Kidney international reports 20230801 8

<h4>Introduction</h4>We aimed to assess opportunities for trial streamlining and the scientific impact of adjudication on kidney and cardiovascular outcomes in CKD.<h4>Methods</h4>We analysed the effects of adjudication of ~2100 maintenance kidney replacement therapy (KRT) and ~1300 major atherosclerotic events (MAEs) recorded in SHARP. We first compared outcome classification before versus after adjudication, and then re-ran randomised comparisons using pre-adjudicated follow-up data.<h4>Result ...[more]

PMID: 37538810

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Project description:BackgroundThe relevance of the cause of kidney disease to prognosis among patients with chronic kidney disease is uncertain.Study designObservational study.Settings & participants6,245 nondialysis participants in the Study of Heart and Renal Protection (SHARP).PredictorBaseline cause of kidney disease was categorized into 4 groups: cystic kidney disease, diabetic nephropathy, glomerulonephritis, and other recorded diagnoses.OutcomesEnd-stage renal disease (ESRD; dialysis or transplantation) and death.ResultsDuring an average 4.7 years' follow-up, 2,080 participants progressed to ESRD, including 454 with cystic kidney disease (23% per year), 378 with glomerulonephritis (10% per year), 309 with diabetic nephropathy (12% per year), and 939 with other recorded diagnoses (8% per year). By comparison with patients with cystic kidney disease, other disease groups had substantially lower adjusted risks of ESRD (relative risks of 0.28 [95% CI, 0.24-0.32], 0.40 [95% CI, 0.34-0.47], and 0.29 [95% CI, 0.25-0.32] for glomerulonephritis, diabetic nephropathy, and other recorded diagnoses, respectively). Albuminuria and baseline estimated glomerular filtration rate were associated more weakly with risk of ESRD in patients with cystic kidney disease than the 3 other diagnostic categories (P for interaction, <0.001 and 0.01, respectively). Death before ESRD was uncommon in patients with cystic kidney disease, but was a major competing risk for participants with diabetic nephropathy, whose adjusted risk of death was 2-fold higher than that of the cystic kidney disease group (relative risk, 2.35 [95% CI, 1.73-3.18]).LimitationsExclusion of patients with prior myocardial infarction or coronary revascularization.ConclusionsThe cause of kidney disease has substantial prognostic implications. Other things being equal, patients with cystic kidney disease are at much higher risk of ESRD (and much lower risk of death before ESRD) than other patients. Patients with diabetic nephropathy are at particularly high risk of death prior to reaching ESRD.

Project description:BackgroundThe absolute and relative importance of smoking to vascular and nonvascular outcomes in people with chronic kidney disease (CKD), as well its relevance to kidney disease progression, is uncertain.Study designObservational study.Setting & participants9,270 participants with CKD enrolled in SHARP.PredictorBaseline smoking status (current, former, and never).OutcomesVascular events, site-specific cancer, ESRD, rate of change in estimated glomerular filtration rate (eGFR), and cause-specific mortality.ResultsAt baseline, 1,243 (13%) participants were current smokers (median consumption, 10 cigarettes/day); 3,272 (35%), former smokers; and 4,755 (51%), never smokers. Median follow-up was 4.9 years. Vascular event rates were 36% higher for current than never smokers (2,317 events; relative risk [RR], 1.36; 95% CI, 1.19-1.55), reflecting increases in both atherosclerotic (RR, 1.49; 95% CI, 1.26-1.76) and nonatherosclerotic (RR, 1.25; 95% CI, 1.05-1.50) events. Cancer was 37% higher among current smokers (632 events; RR, 1.37; 95% CI, 1.07-1.76), with the biggest RRs for lung (RR, 9.31; 95% CI, 4.37-19.83) and upper aerodigestive tract (RR, 4.87; 95% CI, 2.10-11.32) cancers. For 6,245 patients not receiving dialysis at baseline, ESRD incidence did not differ significantly between current and never smokers (2,141 events; RR, 1.02; 95% CI, 0.89-1.17), nor did estimated rate of change in eGFR (current smokers, -1.77±0.14 [SE]; never smokers, -1.70±0.07mL/min/1.73m(2) per year). All-cause mortality was 48% higher among current smokers (2,257 events; RR, 1.48; 95% CI, 1.30-1.70), with significant increases in vascular (RR, 1.35; 95% CI, 1.07-1.69) and nonvascular (RR, 1.60; 95% CI, 1.34-1.91) causes of death, especially cancer (RR, 2.32; 95% CI, 1.58-3.40) and respiratory (RR, 2.25; 95% CI, 1.51-3.35) mortality.LimitationsSmoking status not assessed during follow-up.ConclusionsIn this study of patients with CKD, smoking significantly increased the risks for vascular and nonvascular morbidity and mortality, but was not associated with kidney disease progression. The associations with vascular and neoplastic disease are in keeping with those observed in the general population and are likely modifiable by cessation.

Project description:BackgroundSimvastatin, 20mg, plus ezetimibe, 10mg, 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 designCost-effectiveness of simvastatin plus ezetimibe in SHARP, a randomized controlled trial.Setting & population9,270 patients with CKD randomly assigned to simvastatin plus ezetimibe versus placebo; participants in categories by 5-year cardiovascular risk (low, <10%; medium, 10%-<20%; or high, ≥20%) and CKD stage (3, 4, 5 not on dialysis, or on dialysis therapy).Model, perspective, & timelineAssessment during SHARP follow-up from the UK perspective; long-term projections.InterventionSimvastatin plus ezetimibe (2015 UK £1.19 per day) during 4.9 years' median follow-up in SHARP; scenario analyses with high-intensity statin regimens (2015 UK £0.05-£1.06 per day).OutcomesAdditional health care costs per major atherosclerotic event avoided and per quality-adjusted life-year (QALY) gained.ResultsIn SHARP, the proportional reductions per 1mmol/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 in patients at low risk to £15,230 in those at high risk (£30,500-£39,600 per QALY); and from £47,280 in CKD stage 3 to £28,180 in patients on dialysis therapy (£13,000-£43,300 per QALY). In scenario analyses, generic high-intensity statin regimens were estimated to yield similar benefits at substantially lower cost.LimitationsHigh-intensity statin-alone regimens were not studied in SHARP.ConclusionsSimvastatin 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.

Project description:BackgroundThere are limited studies on the effects of statins on outcomes in the moderate chronic kidney disease (CKD) population and their trajectory to end-stage kidney disease.ObjectiveTo examine the long-term effects of lipid-lowering therapy on all-cause mortality, cardiovascular morbidity, CKD progression, and socioeconomic well-being in Australian, New Zealand, and Malaysian SHARP (Study of Heart and Renal Protection) trial participants-a randomized controlled trial of a combination of simvastatin and ezetimibe, compared with placebo, for the reduction of cardiovascular events in moderate to severe CKD.DesignProtocol for an extended prospective observational follow-up.SettingAustralian, New Zealand, and Malaysian participating centers in patients with advanced CKD.PatientsAll SHARP trial participants alive at the final study visit.MeasurementsPrimary outcomes were measured by participant self-report and verified by hospital administrative data. In addition, secondary outcomes were measured using a validated study questionnaire of health-related quality of life, a 56-item economic survey.MethodsParticipants were followed up with alternating face-to-face visits and telephone calls on a 6-monthly basis until 5 years following their final SHARP Study visit. In addition, there were 6-monthly follow-up telephone calls in between these visits. Data linkage to health registries in Australia, New Zealand, and Malaysia was also performed.ResultsThe SHARP-Extended Review (SHARP-ER) cohort comprised 1136 SHARP participants with a median of 4.6 years of follow-up. Compared with all SHARP participants who originally participated in the Australian, New Zealand, and Malaysian regions, the SHARP-ER participants were younger (57.2 [48.3-66.4] vs 60.5 [50.3-70.7] years) with a lower proportion of men (61.5% vs 62.8%). There were a lower proportion of participants with hypertension (83.7% vs 85.0%) and diabetes (20.0% vs 23.5%).LimitationsAs a long-term follow-up study, the surviving cohort of SHARP-ER is a selected group of the original study participants, which may limit the generalizability of the findings.ConclusionThe SHARP-ER study will contribute important evidence on the long-term outcomes of cholesterol-lowering therapy in patients with advanced CKD with a total of 10 years of follow-up. Novel analyses of the socioeconomic impact of CKD over time will guide resource allocation.Trial registrationThe SHARP trial was registered at ClinicalTrials.gov NCT00125593 and ISRCTN 54137607.

Project description:AimsDespite advances in heart failure (HF) treatment, HF with preserved ejection fraction (HFpEF) remains a health problem with a high mortality rate. HFpEF is composed of diverse phenogroups, of which patients with concomitant renal impairment have worse outcomes. Renal tubular damage (RTD) is associated with the development of HF and chronic kidney disease (CKD). However, the impact of RTD on HF progression in patients with HFpEF and CKD remains unclear. The aim of the present study was to examine whether RTD could predict HF-related events in patients with HFpEF and CKD.Methods and resultsWe measured RTD markers, such as urinary β2 -microglobulin to creatinine ratio (UBCR) and N-acetyl-β-d-glucosamidase (NAG) level, in 319 consecutive patients with HFpEF and CKD who were hospitalized for acute HF (49% females, mean age 76 ± 12). Based on previous reports, high UBCR and high NAG levels were defined as UBCR ≥300 μg/gCr and NAG >14.2 U/gCr, respectively. There were 91 HF-related events, defined as HF hospitalizations or HF deaths, during the median follow-up period of 5.2 years. The prevalence of high UBCR increased with advancing New York Heart Association functional class and albuminuria. Kaplan-Meier analysis demonstrated that patients with high UBCR had more HF-related events than those with normal or low UBCR. Multivariate Cox proportional hazards regression analyses demonstrated that high UBCR, but not high NAG level, was an independent predictor of HF-related events after adjusting for confounding risk factors in patients with HFpEF and CKD (hazard ratio, 2.60; 95% confidence interval, 1.52-4.72; P = 0.0009). UBCR significantly improved the C-statistic, with a significant net reclassification index and integrated discrimination improvement (0.738 vs. 0.684; P = 0.0244).ConclusionRTD, as assessed by a high UBCR, was associated with the severity and clinical outcomes of HFpEF and CKD, indicating that it could be a feasible marker for HF progression.

Project description:Blood pressure (BP) is a key modifiable risk factor for patients with CKD, with current guidelines recommending strict control to reduce the risk of both progression of CKD and cardiovascular disease. Trials of BP lowering require multiple visits to achieve target BP which increases the costs of such trials, and in routine care BP measured in clinic may not accurately reflect usual BP. We sought to assess whether a telemonitoring system for BP (using a Bluetooth-enable BP machine which could transmit BP measurements to a tablet device which had a bespoke app to guide measurement of BP and collect questionnaire data) was acceptable to patients with CKD, and whether patients would provide sufficient BP readings to assess variability and guide treatment. 25 participants with CKD were trained to use the telemonitoring equipment, asked to record BP daily for 30 days, attend a study visit, and then record BP on alternate days for the next 60 days. They were also offered a wrist-worn applanation tonometry device (BPro) which measures BP every 15 minutes over a 24 hour period.Participants were given questionnaires at the one-month and three-month time points, derived from the System Usability Scale and Technology Acceptance Model. All eligible participants completed the study. Mean age was 58 (SD 11) years and mean eGFR was 36 (SD 13) mL/min/1.73m2. 13 out of 25 (52%) participants provided >90% of expected data and 18 out of 25 (72%) provided >80% expected data. The usability of the telemonitoring system was rated highly with mean scores of 84.9/100 (SE 2.8) after 30 days and 84.2/100 (SE 4.1) after 90 days. The coefficient of variation (CV) for variability of telemonitoring systolic BP was 9.4% (95% confidence interval [CI] 7.8 to 10.9), compared to 7.9% (95% CI 6.4-9.5) for the BPro device (P=0.05) (and 9.0% over one year in a recently completed trial with identical eligibility criteria), indicating that most variation in BP is short-term. Telemonitoring is acceptable to patients with CKD and provides sufficient data to inform titration of antihypertensive therapies in either a randomized trial setting (comparing different targets BPs) or routine clinical practice. Such methods could be employed in both scenarios and reduce costs currently associated with such activities.Registration ISRCTN13725286.

Dataset Information

Impact of outcome adjudication in kidney disease trials: observations from the Study of Heart and Renal Protection (SHARP).

Introduction

Methods

Results

Conclusions

Publications

Impact of outcome adjudication in kidney disease trials: observations from the Study of Heart and Renal Protection (SHARP).

Similar Datasets

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