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.

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.

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.

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.