Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers for Advanced Chronic Kidney Disease : A Systematic Review and Retrospective Individual Participant-Level Meta-analysis of Clinical Trials.

BACKGROUND: In patients with advanced chronic kidney disease (CKD), the effects of initiating treatment with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) on the risk for kidney failure with replacement therapy (KFRT) and death remain unclear. PURPOSE: To examine the association of ACEi or ARB treatment initiation, relative to a non-ACEi or ARB comparator, with rates of KFRT and death. DATA SOURCES: Ovid Medline and the Chronic Kidney Disease Epidemiology Collaboration Clinical Trials Consortium from 1946 through 31 December 2023. STUDY SELECTION: Completed randomized controlled trials testing either an ACEi or an ARB versus a comparator (placebo or antihypertensive drugs other than ACEi or ARB) that included patients with a baseline estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. DATA EXTRACTION: The primary outcome was KFRT, and the secondary outcome was death before KFRT. Analyses were done using Cox proportional hazards models according to the intention-to-treat principle. Prespecified subgroup analyses were done according to baseline age (<65 vs. ≥65 years), eGFR (<20 vs. ≥20 mL/min/1.73 m2), albuminuria (urine albumin-creatinine ratio <300 vs. ≥300 mg/g), and history of diabetes. DATA SYNTHESIS: A total of 1739 participants from 18 trials were included, with a mean age of 54.9 years and mean eGFR of 22.2 mL/min/1.73 m2, of whom 624 (35.9%) developed KFRT and 133 (7.6%) died during a median follow-up of 34 months (IQR, 19 to 40 months). Overall, ACEi or ARB treatment initiation led to lower risk for KFRT (adjusted hazard ratio, 0.66 [95% CI, 0.55 to 0.79]) but not death (hazard ratio, 0.86 [CI, 0.58 to 1.28]). There was no statistically significant interaction between ACEi or ARB treatment and age, eGFR, albuminuria, or diabetes (P for interaction > 0.05 for all). LIMITATION: Individual participant-level data for hyperkalemia or acute kidney injury were not available. CONCLUSION: Initiation of ACEi or ARB therapy protects against KFRT, but not death, in people with advanced CKD. PRIMARY FUNDING SOURCE: National Institutes of Health. (PROSPERO: CRD42022307589).

Role of Age and Competing Risk of Death in the Racial Disparity of Kidney Failure Incidence after Onset of CKD.

SIGNIFICANCE STATEMENT: Black adults in the United States have 2-4 times higher incidence of kidney failure than White adults. Yet, the reasons underlying this disparity remain poorly understood. Among 547,188 US veterans with new-onset CKD, according to a new race-free GFR equation, Black veterans had a 2.5-fold higher cumulative incidence of kidney failure, compared with White veterans, in any follow-up period from CKD onset. This disparity resulted from a combination of higher hazards of progression to kidney failure and lower hazards of competing-risk death in Black veterans. Both, in turn, were largely explained by the younger age at CKD onset in Black veterans, underscoring an urgent need to prevent early onset and slow progression of CKD in younger Black adults. BACKGROUND: The Black adult population is well known to have higher incidence of kidney failure than their White counterpart in the United States, but the reasons underlying this disparity are unclear. We assessed the racial differences in kidney failure and death from onset of CKD on the basis of the race-free 2021 CKD Epidemiology Collaboration equation and examined the extent to which these differences could be explained by factors at the time of CKD onset. METHODS: We analyzed a national cohort consisting of 547,188 US veterans (103,821 non-Hispanic Black and 443,367 non-Hispanic White), aged 18-85 years, with new-onset CKD between 2005 and 2016 who were followed through 10 years or May 2018 for incident kidney failure with replacement therapy (KFRT) and pre-KFRT death. RESULTS: At CKD onset, Black veterans were, on average, 7.8 years younger than White veterans. In any time period from CKD onset, the cumulative incidence of KFRT was 2.5-fold higher for Black versus White veterans. Meanwhile, Black veterans had persistently >2-fold higher hazards of KFRT throughout follow-up (overall hazard ratio [95% confidence interval], 2.38 [2.31 to 2.45]) and conversely had 17%-48% decreased hazards of pre-KFRT death. These differences were reduced after accounting for the racial difference in age at CKD onset. CONCLUSIONS: The 2.5-fold higher cumulative incidence of kidney failure in Black adults resulted from a combination of higher hazards of progression to kidney failure and lower hazards of the competing risk of death, both of which can be largely explained by the younger age at CKD onset in Black compared with White adults.

Vascular Endothelial Growth Factor (VEGF)-B Blockade with CSL346 in Diabetic Kidney Disease: A Phase 2A Randomized Controlled Trial.

BACKGROUND: Increased vascular endothelial growth factor B (VEGF-B) expression in patients with diabetic kidney disease (DKD) is associated with increased lipid deposition in glomerular podocytes. Reducing VEGF-B activity in animal models of DKD using an anti-VEGF-B antibody improved histological evidence of glomerular injury and reduced albuminuria; effects attributed to prevention of ectopic lipid deposition in the kidney. CSL346 is a novel humanized monoclonal antibody that binds VEGF-B with high affinity. Targeting VEGF-B in patients with type 2 diabetes mellitus may improve DKD progression markers. METHODS: An international, randomized, double-blind, placebo-controlled, phase 2a study (NCT04419467) assessed CSL346 (8 mg/kg or 16 mg/kg subcutaneously every 4 weeks for 12 weeks) in participants with type 2 diabetes mellitus and a urinary albumin-to-creatinine ratio (UACR) ≥150 mg/g (17.0 mg/mmol), and eGFR >20 mL/min/1.73m2. Efficacy, safety/tolerability, pharmacokinetics, and pharmacodynamics of CSL346 were evaluated. The primary analysis compared the change from baseline in log-transformed UACR between the two CSL346 dose groups combined versus placebo at Week 16. RESULTS: In total, 114 participants were randomized. CSL346 did not significantly reduce UACR compared with placebo at Week 16 (combined CSL346 group difference from placebo 95% confidence interval]: 4.0% [-14.7, 26.8]). Furthermore, no effect was seen in participant subgroups (degree of kidney impairment or sodium-glucose cotransporter 2 [SGLT2] inhibitor use) or on urinary biomarkers reflecting proximal tubular injury. CSL346 was generally well tolerated; however, diastolic blood pressure was significantly higher with CSL346 16 mg/kg versus placebo from Week 2 onwards, with differences ranging from +3.8 to +5.3 mmHg (P = 0.002 at Week 16). CONCLUSIONS: CSL346 did not reduce UACR compared with placebo at 16 weeks in participants with type 2 diabetes mellitus and DKD, and was associated with an increase in diastolic blood pressure.

A meta-analysis of randomized controlled clinical trials for implications of acute treatment effects on glomerular filtration rate for long-term kidney protection.

Pharmacologic interventions to slow chronic kidney disease progression, such as ACE-inhibitors, angiotensin receptor blockers, or sodium glucose co-transporter 2 inhibitors, often produce acute treatment effects on glomerular filtration rate (GFR) that differ from their long-term chronic treatment effects. Observational studies assessing the implications of acute effects cannot distinguish acute effects from GFR changes unrelated to the treatment. Here, we performed meta-regression analysis of multiple trials to isolate acute effects to determine their long-term implications. In 64 randomized controlled trials (RCTs), enrolling 154,045 participants, we estimated acute effects as the mean between-group difference in GFR slope from baseline to three months, effects on chronic GFR slope (starting at three months after randomization), and effects on three composite kidney endpoints defined by kidney failure (GFR 15 ml/min/1.73m2 or less, chronic dialysis, or kidney transplantation) or sustained GFR declines of 30%, 40% or 57% decline, respectively. We used Bayesian meta-regression to relate acute effects with treatment effects on chronic slope and the composite kidney endpoints. Overall, acute effects were not associated with treatment effects on chronic slope. Acute effects were associated with the treatment effects on composite kidney outcomes such that larger negative acute effects were associated with lesser beneficial effects on the composite kidney endpoints. Associations were stronger when the kidney composite endpoints were defined by smaller thresholds of GFR decline (30% or 40%). Results were similar in a subgroup of interventions with supposedly hemodynamic effects that acutely reduce GFR. For studies with GFR 60 mL/min/1.73m2 or under, negative acute effects were associated with larger beneficial effects on chronic GFR slope. Thus, our data from a large and diverse set of RCTs suggests that acute effects of interventions may influence the treatment effect on clinical kidney outcomes.

Comparing Bayesian hierarchical meta-regression methods and evaluating the influence of priors for evaluations of surrogate endpoints on heterogeneous collections of clinical trials.

BACKGROUND: Surrogate endpoints, such as those of interest in chronic kidney disease (CKD), are often evaluated using Bayesian meta-regression. Trials used for the analysis can evaluate a variety of interventions for different sub-classifications of disease, which can introduce two additional goals in the analysis. The first is to infer the quality of the surrogate within specific trial subgroups defined by disease or intervention classes. The second is to generate more targeted subgroup-specific predictions of treatment effects on the clinical endpoint. METHODS: Using real data from a collection of CKD trials and a simulation study, we contrasted surrogate endpoint evaluations under different hierarchical Bayesian approaches. Each approach we considered induces different assumptions regarding the relatedness (exchangeability) of trials within and between subgroups. These include partial-pooling approaches, which allow subgroup-specific meta-regressions and, yet, facilitate data adaptive information sharing across subgroups to potentially improve inferential precision. Because partial-pooling models come with additional parameters relative to a standard approach assuming one meta-regression for the entire set of studies, we performed analyses to understand the impact of the parameterization and priors with the overall goals of comparing precision in estimates of subgroup-specific meta-regression parameters and predictive performance. RESULTS: In the analyses considered, partial-pooling approaches to surrogate endpoint evaluation improved accuracy of estimation of subgroup-specific meta-regression parameters relative to fitting separate models within subgroups. A random rather than fixed effects approach led to reduced bias in estimation of meta-regression parameters and in prediction in subgroups where the surrogate was strong. Finally, we found that subgroup-specific meta-regression posteriors were robust to use of constrained priors under the partial-pooling approach, and that use of constrained priors could facilitate more precise prediction for clinical effects in trials of a subgroup not available for the initial surrogacy evaluation. CONCLUSION: Partial-pooling modeling strategies should be considered for surrogate endpoint evaluation on collections of heterogeneous studies. Fitting these models comes with additional complexity related to choosing priors. Constrained priors should be considered when using partial-pooling models when the goal is to predict the treatment effect on the clinical endpoint.

History of stroke as a predictor of high left atrial fibrosis in patients with persistent atrial fibrillation-insight from the DECAAF II randomized trial.

BACKGROUND: There is a strong relationship between left atrial (LA) remodeling and ischemic stroke (IS) risk in atrial fibrillation (AF) patients. The Efficacy of Delayed Enhancement MRI-Guided Ablation vs. Conventional Catheter Ablation of Atrial Fibrillation (DECAAF-II) is the biggest MRI-based, randomized, multicenter clinical trial performed on persistent AF patients. The aim of this study is to evaluate the relationship between history of stroke and atrial fibrosis in the DECAAF II population. METHODS: Persistent AF patients who underwent Late Gadolinium Enhancement Magnetic Resonance Imaging (LGE-MRI) were included in the study and divided into two different groups: those with a history of stroke and those without. Propensity score matching was performed to adjust for covariates. Atrial fibrosis was compared in both groups. Then, patients were divided into different fibrosis groups, using three different cut-offs of baseline atrial fibrosis: ≥ 15%, ≥ 20%, and ≥ 25%. Univariate logistic regression and adjusted multivariate analysis were performed to assess the effect of clinical characteristics and risk factors on baseline fibrosis. RESULTS: Eight-hundred forty-three patients were recruited in DECAAF II, of whom 70 (8.3%) had a history of stroke. Patients with history of stroke had a higher prevalence of hypertension (p = 0.043), diabetes (p = 0.014), and hyperlipidemia (p = 0.001). Seventy patients with no history of strokes were matched with patients with history of stroke to adjust for covariates using propensity score analysis. Patients in the stroke group had a significantly higher level of fibrosis than those without (20.2% vs. 8.1%, p = 0.017). Increased age was a significant predictor of all three baseline fibrosis classes (≥ 15%, ≥ 20%, and ≥ 25%). Additionally, history of stroke was found to be a predictor of baseline fibrosis ≥ 25% even after adjusting for other clinical characteristics and risk factors (OR = 1.98 [1.14-3.43], p = 0.01). CONCLUSIONS: Left atrial fibrosis level greater than 25% correlates with the history of previous stroke episodes in patients with persistent atrial fibrillation.

Association Between Self-Reported Medication Adherence and Therapeutic Inertia in Hypertension: A Secondary Analysis of SPRINT (Systolic Blood Pressure Intervention Trial).

BACKGROUND: Therapeutic inertia (TI), failure to intensify antihypertensive medication when blood pressure (BP) is above goal, remains prevalent in hypertension management. The degree to which self-reported antihypertensive adherence is associated with TI with intensive BP goals remains unclear. METHODS AND RESULTS: Cross-sectional analysis was performed of the 12-month visit of participants in the intensive arm of SPRINT (Systolic Blood Pressure Intervention Trial), which randomized adults to intensive (<120 mm Hg) versus standard (<140 mm Hg) systolic BP goals. TI was defined as no increase in antihypertensive regimen intensity score, which incorporates medication number and dose, when systolic BP is ≥120 mm Hg. Self-reported adherence was assessed using the 8-Item Morisky Medication Adherence Scale (MMAS-8) and categorized as low (MMAS-8 score <6), medium (MMAS-8 score 6 to <8), and high (MMAS-8 score 8). Poisson regressions estimated prevalence ratios (PRs) and 95% CIs for TI associated with MMAS-8. Among 1009 intensive arm participants with systolic BP >120 mm Hg at the 12-month visit (mean age, 69.6 years; 35.2% female, 28.8% non-Hispanic Black), TI occurred in 50.8% of participants. Participants with low adherence (versus high) were younger and more likely to be non-Hispanic Black or smokers. The prevalence of TI among patients with low, medium, and high adherence was 45.0%, 53.5%, and 50.4%, respectively. After adjustment, neither low nor medium adherence (versus high) were associated with TI (PR, 1.11 [95% CI, 0.87-1.42]; PR, 1.08 [95% CI, 0.84-1.38], respectively). CONCLUSIONS: Although clinician uncertainty about adherence is often cited as a reason for why antihypertensive intensification is withheld when above BP goals, we observed no evidence of an association between self-reported adherence and TI.

A multicenter randomized trial to compare automatic versus as-needed follow-up for children hospitalized with common infections: The FAAN-C trial protocol.

INTRODUCTION: Physicians commonly recommend automatic primary care follow-up visits to children being discharged from the hospital. While automatic follow-up provides an opportunity to address postdischarge needs, the alternative is as-needed follow-up. With this strategy, families monitor their child's symptoms and decide if they need a follow-up visit in the days after discharge. In addition to being family centered, as-needed follow-up has the potential to reduce time and financial burdens on both families and the healthcare system. As-needed follow-up has been shown to be safe and effective for children hospitalized with bronchiolitis, but the extent to which hospitalized children with other common conditions might benefit from as-needed follow-up is unclear. METHODS: The Follow-up Automatically versus As-Needed Comparison (FAAN-C, or "fancy") trial is a multicenter randomized controlled trial. Children who are hospitalized for pneumonia, urinary tract infection, skin and soft tissue infection, or acute gastroenteritis are eligible to participate. Participants are randomized to an as-needed versus automatic posthospitalization follow-up recommendation. The sample size estimate is 2674 participants and the primary outcome is all-cause hospital readmission within 14 days of discharge. Secondary outcomes are medical interventions and child health-related quality of life. Analyses will be conducted in an intention-to-treat manner, testing noninferiority of as-needed follow-up compared with automatic follow-up. DISCUSSION: FAAN-C will elucidate the relative benefits of an as-needed versus automatic follow-up recommendation, informing one of the most common decisions faced by families of hospitalized children and their medical providers. Findings from FAAN-C will also have implications for national quality metrics and guidelines.

Impact of Local Tailoring on Acute Stroke Care in 21 Disparate Emergency Departments: A Prospective Stepped Wedge Type III Hybrid Effectiveness-Implementation Study.

BACKGROUND: Faster delivery of tPA (tissue-type plasminogen activator) results in better health outcomes for eligible patients with stroke. Standardization of stroke protocols in emergency departments (EDs) has been difficult, especially in nonstroke centers. We measured the effectiveness of a centrally led implementation strategy with local site tailoring to sustain adherence to an acute stroke protocol to improve door-to-needle (DTN) times across disparate EDs in a multihospital health system. METHODS: Prospective, type III hybrid effectiveness-implementation cohort study measuring performance at 21 EDs in Utah and Idaho (stroke centers [4]/nonstroke centers [17]) from January 2018 to February 2020 using a nonrandomized stepped-wedge design, monthly repeated site measures and multilevel hierarchical modeling. Each site received the implementation strategies in 1 of 6 steps providing control and intervention data. Co-primary outcomes were percentage of DTN times ≤60 minutes and median DTN time. Secondary outcomes included percentage of door-to-activation of neurological consult times ≤10 minutes and clinical effectiveness outcomes. Results were stratified between stroke and nonstroke centers. RESULTS: A total of 855 474 ED patient encounters occurred with 5325 code stroke activations (median age, 69 [IQR, 56-79] years; 51.8% female patients]. Percentage of door-to-activation times ≤10 minutes increased from 47.5% to 59.9% (adjusted odds ratio, 1.93 [95% CI, 1.40-2.67]). A total of 615 patients received tPA of ≤3 hours from symptom onset (median age, 71 [IQR, 58-80] years; 49.6% female patients). The percentage of DTN times ≤60 minutes increased from 72.5% to 86.1% (adjusted odds ratio, 3.38, [95% CI, 1.47-7.78]; stroke centers (77.4%-90.0%); nonstroke centers [59.3%-72.1%]). Median DTN time declined from 46 to 38 minutes (adjusted median difference, -9.68 [95% CI, -17.17 to -2.20]; stroke centers [41-35 minutes]; nonstroke centers [55-52 minutes]). No differences were observed in clinical effectiveness outcomes. CONCLUSIONS: A centrally led implementation strategy with local site tailoring led to faster delivery of tPA across disparate EDs in a multihospital system with no change in clinical effectiveness outcomes including rates of complication. Disparities in performance persisted between stroke and nonstroke centers.

Implementing weight maintenance with existing staff and electronic health record tools in a primary care setting: Baseline results from the MAINTAIN PRIME trial.

BACKGROUND: There is need for interventions that can assist with long-term maintenance of healthy body weight and be sustainably integrated into existing primary care teams. The goal of MAINTAIN PRIME (Promoting Real (World) IMplEmentation) is to evaluate whether a successful electronic health record (EHR)-based weight maintenance intervention can be adapted to a new clinical setting with primary care staff serving as coaches. METHODS: EHR tools include tracking tools, standardized surveys, and standardized "SmartPhrases" for coaching. Inclusion criteria were age 18-75 years, voluntary 5% weight loss in the past 2 years with prior BMI ≥ 25 kg/m2, and no bariatric procedures in past 2 years. Participants were randomized 1:1 to tailored online coaching with EHR tracking tools (coaching) or EHR tracking tools alone (tracking). RESULTS: We screened 405 individuals between September 2021 and April 2023; 269 participants enrolled (134 coaching; 135 tracking). The most common reason for not enrolling was ineligibility (55%). At baseline, participants were 50.3 (SD 15.02) years old, 66.4% female, and 84% White; 83.7% reported moderate physical activity. Average weight and BMI at baseline were 205.0 (SD 48.9) lbs. and 33.2 (6.8) kg/m2, respectively. Participants lost an average of 10.7% (SD 5.2) of their body weight before enrolling. We recruited 39 primary care coaches over the same period. Conclusion The study successfully identified and recruited primary care patients with recent intentional weight loss for participation in a weight maintenance program that uses EHR-based tools. We also successfully recruited and trained primary care staff as coaches.

Phenotyping Depression After Mild Traumatic Brain Injury: Evaluating the Impact of Multiple Injury, Gender, and Injury Context.

The chronic mental health consequences of mild traumatic brain injury (TBI) are a leading cause of disability. This is surprising given the expectation of significant recovery after mild TBI, which suggests that other injury-related factors may contribute to long-term adverse outcomes. The objective of this study was to determine how number of prior injuries, gender, and environment/context of injury may contribute to depressive symptoms after mild TBI among deployed United States service members and veterans (SMVs). Data from the Long-term Impact of Military-Relevant Brain Injury Consortium Prospective Longitudinal Study was used to assess TBI injury characteristics and depression scores previously measured on the Patient Health Questionnaire-9 (PHQ-9) among a sample of 1456 deployed SMVs. Clinical diagnosis of mild TBI was defined via a multi-step process centered on a structured face-to-face interview. Logistical and linear regressions stratified by gender and environment of injury were used to model depressive symptoms controlling for sociodemographic and combat deployment covariates. Relative to controls with no history of mild TBI (n = 280), the odds ratios (OR) for moderate/severe depression (PHQ-9 ≥ 10) were higher for SMVs with one mild TBI (n = 358) OR: 1.62 (95% confidence interval [CI] 1.09-2.40, p = 0.016) and two or more mild TBIs (n = 818) OR: 1.84 (95% CI 1.31-2.59, p < 0.001). Risk differences across groups were assessed in stratified linear models, which found that depression symptoms were elevated in those with a history of multiple mild TBIs compared with those who had a single mild TBI (p < 0.001). Combat deployment-related injuries were also associated with higher depression scores than injuries occurring in non-combat or civilian settings (p < 0.001). Increased rates of depression after mild TBI persisted in the absence of post-traumatic stress disorder. Both men and women SMVs separately exhibited significantly increased depressive symptom scores if they had had combat-related mild TBI. These results suggest that contextual information, gender, and prior injury history may influence long-term mental health outcomes among SMVs with mild TBI exposure.

SCALE-UP II: protocol for a pragmatic randomised trial examining population health management interventions to increase the uptake of at-home COVID-19 testing in community health centres.

INTRODUCTION: SCALE-UP II aims to investigate the effectiveness of population health management interventions using text messaging (TM), chatbots and patient navigation (PN) in increasing the uptake of at-home COVID-19 testing among patients in historically marginalised communities, specifically, those receiving care at community health centres (CHCs). METHODS AND ANALYSIS: The trial is a multisite, randomised pragmatic clinical trial. Eligible patients are >18 years old with a primary care visit in the last 3 years at one of the participating CHCs. Demographic data will be obtained from CHC electronic health records. Patients will be randomised to one of two factorial designs based on smartphone ownership. Patients who self-report replying to a text message that they have a smartphone will be randomised in a 2×2×2 factorial fashion to receive (1) chatbot or TM; (2) PN (yes or no); and (3) repeated offers to interact with the interventions every 10 or 30 days. Participants who do not self-report as having a smartphone will be randomised in a 2×2 factorial fashion to receive (1) TM with or without PN; and (2) repeated offers every 10 or 30 days. The interventions will be sent in English or Spanish, with an option to request at-home COVID-19 test kits. The primary outcome is the proportion of participants using at-home COVID-19 tests during a 90-day follow-up. The study will evaluate the main effects and interactions among interventions, implementation outcomes and predictors and moderators of study outcomes. Statistical analyses will include logistic regression, stratified subgroup analyses and adjustment for stratification factors. ETHICS AND DISSEMINATION: The protocol was approved by the University of Utah Institutional Review Board. On completion, study data will be made available in compliance with National Institutes of Health data sharing policies. Results will be disseminated through study partners and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT05533918 and NCT05533359.