Comparison of chronic kidney disease trial designs and analysis strategies.
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ABSTRACT: Background
Despite the large burden of chronic kidney disease (CKD), it is challenging to conduct adequately powered clinical trials in this setting. Sound and efficient trials are needed to advance treatment. Various analysis strategies can be used to compare the efficacy of a parallel trial design with that of three two period trial designs.Methods
The type 1 error rates and powers of various trial designs were calculated using simulated data from models fit to two recent CKD trials. In addition, we assessed the influences of a variety of analysis strategies and of the presence of a carryover effect.Results
The parallel and crossover designs (with analysis of change from baseline to the off treatment value) maintained the target type 1 error rate in all scenarios. In some scenarios, an open label design yielded inflated type 1 error rates. In many scenarios, the open label and delayed start designs had unacceptably low power and high type 1 error rates. Overall, the crossover design had the highest power by far, and always controlled the type 1 error rate.Conclusion
The recommended approach to a CKD trial is a two period design with an endpoint that is the rate of change in estimated glomerular filtration rate from pretreatment to off treatment. As compared to a parallel trial, a crossover study involves a considerably smaller sample size and shorter total follow-up duration. A crossover design may also be preferable for patients, and facilitates recruitment of a sufficient number of subjects.
SUBMITTER: Lawrence J
PROVIDER: S-EPMC8041635 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundReadmission following hospital discharge is common and is a major financial burden on healthcare systems.ObjectivesOur objectives were to 1) identify studies describing post-discharge interventions and their efficacy with respect to reducing risk of mortality and rate of hospital readmission; and 2) identify intervention characteristics associated with efficacy.MethodsA systematic review of the literature was performed. We searched MEDLINE, PubMed, Cochrane, EMBASE and CINAHL. Our selection criteria included randomized controlled trials comparing post-discharge interventions with usual care on rates of hospital readmission and mortality in high-risk chronic disease patient populations. We used random effects meta-analyses to estimate pooled risk ratios for all-cause and cause-specific mortality as well as all-cause and cause-specific hospitalization.ResultsWe included 31 randomized controlled trials encompassing 9654 patients (24 studies in CHF, 4 in COPD, 1 in both CHF and COPD, 1 in CKD and 1 in an undifferentiated population). Meta-analysis showed post-discharge interventions reduced cause-specific (RR = 0.71, 95% CI = 0.63-0.80) and all cause (RR = 0.90, 95% CI = 0.81-0.99) hospitalization, all-cause (RR = 0.73, 95% CI = 0.65-0.83) and cause-specific mortality (RR = 0.68, 95% CI = 0.54-0.84) in CHF studies, and all-cause hospitalization (RR = 0.52, 95% CI = 0.32-0.83) in COPD studies. The inclusion of a cardiac nurse in the multidisciplinary team was associated with greater efficacy in reducing all-cause mortality among patients discharged after heart failure admission (HR = 0.64, 95% CI = 0.54-0.75 vs. HR = 0.87, 95% CI = 0.73-1.03).ConclusionsPost-discharge interventions reduced all-cause mortality, cause-specific mortality, and cause-specific hospitalization in CHF patients and all-cause hospitalization in COPD patients. The presence of a cardiac nurse was associated with greater efficacy in included studies. Additional research is needed on the impact of post-discharge intervention strategies in COPD and CKD patients.
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Project description:BackgroundIn chronic kidney disease, intensive systolic blood pressure (SBP) control reduces mortality at a cost of greater acute kidney injury risk. Kidney transplantation involves implantation of denervated kidneys and immunosuppressive medications that increase acute kidney injury risk. The optimal blood pressure (BP) target in kidney transplant recipients (KTRs) is uncertain. Prior observational studies from the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial demonstrate associations of lower SBP levels and reduced mortality risk, but the relationship of BP with kidney allograft function remains unknown. Thus, in FAVORIT, we investigated the relationship of SBP and diastolic blood pressure (DBP) with risk of kidney allograft failure and estimated glomerular filtration rate (eGFR) slope among stable KTRs.MethodsCox proportional hazards and multivariable linear regression models adjusted for demographics, transplant characteristics, comorbidities, baseline eGFR, and urine albumin-to-creatinine ratio were used to determine associations of SBP and DBP with time to a composite kidney outcome of ≥50% eGFR decline or dialysis dependence, and with annualized eGFR change, respectively. Multivariable restricted cubic spline plots were developed to evaluate the functional form of the relationships.ResultsAmong 3,598 KTRs, mean age was 52 ± 9 years, SBP was 136 ± 20 mm Hg, DBP was 79 ± 12 mm Hg, and eGFR was 49 ± 18 ml/minute/1.73 m2. There were 369 events of ≥50% eGFR decline or dialysis dependence during a mean follow-up of 4.0 ± 1.5 years. There was no association of either SBP (compared with SBP 120 to <130 mm Hg, hazard ratio (HR) for the SBP < 110 was 1.01 (95% confidence interval (CI) 0.60 to 1.70) and 130 to <140 was 0.89 (0.64 to 1.24)) or DBP (compared with DBP 70 to <80 mm Hg, HR for the DBP 60 to <70 was 1.00 (95% CI 0.74 to 1.34) and 80 to <90 was 0.90 (0.68 to 1.18)) with the kidney failure outcome or annualized eGFR slope, and, when examined using restricted cubic splines, there was no evidence of "J"- or "U"-shaped relationships.ConclusionsIn a large sample of stable KTRs, we found no evidence of thresholds at which lower BPs were related to higher risk of allograft failure or eGFR decline. In light of prior findings of mortality benefit at low SBP, these observational findings suggest lower BP may be beneficial in KTRs. This important question requires confirmation in future randomized trials in KTRs.
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