Citations

6591 Background: BMT CTN 1101 was a Phase III randomized controlled trial evaluating the comparative effectiveness of unrelated umbilical cord blood (UCB) versus HLA-haploidentical related donor bone marrow (haplo-BM) cell sources for hematopoietic cell transplantation (HCT) in patients with high-risk hematologic malignancies (leukemias, lymphomas). We report results of an economic evaluation conducted as part of the clinical trial. Methods: 368 patients (90% of planned accrual) enrolled from 33 centers in the U.S. were randomly assigned to unrelated UCB (n=186) or haplo-BM (n=182) transplant. Healthcare utilization and costs were estimated using propensity-score matched cohorts of BMT patients in the OptumLabs Data Warehouse for trial participants <65 years, and Medicare claims for trial participants ≥65 years. Cost-effectiveness was calculated from payer perspectives (commercial, Medicare) over a 20-year time horizon from time of transplant. Weibull models (best fit based on AIC/BIC) were used to extrapolate survival from 5-year trial follow-up data. Trial participant surveys (EQ-5D) were used to derive health state utilities for estimating Quality-Adjusted Life Years (QALYs). One-way and probabilistic sensitivity analyses were conducted to assess uncertainty in results. Outcomes were discounted at 3% annually. Results: At 5-year follow-up, overall survival was 42% for haplo-BM versus 36% for UCB (P=.06). Over a 20-year time horizon, haplo-BM is expected to be more effective and more costly for <65 year-olds and in ≥65 year-olds it is expected to be more effective and less costly. In one-way uncertainty analyses, for persons <65, the cost/QALY result was most sensitive to life years and health state utilities. For persons ≥65, life years were more influential than costs and health state utilities. Using probabilistic sensitivity analysis, for persons <65 there was a 43% chance that haplo-BM was cost-effective using a willingness to pay threshold of $150k/QALY and 52% at a $200K/QALY threshold. Conclusions: Results from a large national clinical trial indicate that compared to UCB, haplo-BM was moderately cost-effective for patients aged <65 years, and less costly and more effective for persons ≥65 years. Haplo-BM is a fair value choice for commercially insured patients with high-risk leukemia and lymphoma who require HCT. For Medicare enrollees, haplo-BM is a preferred choice when considering costs and outcomes. [Table: see text]

Background: A composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data. Methods: We assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low–glucose and low-glucose hypoglycemia; very high–glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation. Results: The analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals. Conclusion: The GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments.

Introduction: Excessive bodyweight, often associated with dyslipidemia, may affect the pharmacology of drugs. Inclisiran, a small interfering RNA targeting PCSK9 hepatic mRNA, is an effective LDL-C lowering agent with twice-yearly subcutaneous dosing (after the initial and 3-month doses). Aim: To analyze the efficacy and safety of inclisiran in patients with heterozygous familial hypercholesterolemia, atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalent across body mass index (BMI) strata. Methods: In this post hoc analysis from ORION-9 (NCT03397121), ORION-10 (NCT03399370) and ORION-11 (NCT03400800), eligible patients were randomized 1:1 to receive 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) or placebo at baseline, Day 90 and 6-monthly thereafter. Analyses were stratified by baseline BMI: <25, 25-<30, 30-<35 or ≥35 kg/m 2 . Percentage change in atherogenic lipids from baseline at Day 510 was evaluated. Safety was assessed over 540 days. Results: Baseline demographic and clinical characteristics including atherogenic lipid levels were mostly balanced between the treatment arms and across the BMI strata ( Table ). Percentage change in atherogenic lipids from baseline at Day 510 was significantly greater with inclisiran vs placebo within each BMI stratum ( Table ). Treatment-emergent adverse events (TEAE) and treatment-emergent serious adverse events were generally similar between the treatment arms and were reported more frequently with increasing BMI strata (data not shown). Clinically relevant TEAEs at the injection site were reported more frequently with inclisiran vs placebo similarly across strata, but all were mild or moderate. Conclusions: Twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided effective and sustained lipid lowering in patients, irrespective of their baseline BMI, and was generally well tolerated.

Introduction: Disorders of glucose metabolism increase in prevalence globally and contribute to excess risk of ASCVD, necessitating intensive lipid lowering. Aim: To analyze efficacy and safety of inclisiran (small interfering RNA targeting hepatic PCSK9 mRNA) across the strata of glycemic disorders. Methods: In this post hoc, pooled analysis of ORION-10 and ORION-11, 3174 patients (pts) with ASCVD/ASCVD risk equivalent (including diabetes mellitus [DM]) were randomized 1:1 to receive 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) or placebo (pbo) at baseline (BL), Day (D) 90, and 6-monthly thereafter. Analyses were stratified by BL glycemic status (normoglycemia, pre-DM or DM). LDL-C percentage (%) change from BL to D510 and time-adjusted % change from D90 to D540 were evaluated. Safety was assessed over 540 days. Results: BL characteristics were generally balanced between the treatment arms across the glycemic strata ( Table 1 ). LDL-C % change and time-adjusted % change were greater with inclisiran vs pbo and were similar across all strata ( Table 2 ). Treatment-emergent adverse events (TEAE) and treatment-emergent serious adverse events were generally similar between the treatment arms; TEAEs were reported more frequently in pts with vs without glycemic disorders (not shown). Clinically relevant TEAEs at the injection site were reported more frequently with inclisiran vs pbo across the strata but all were mild or moderate ( Table 2 ). Conclusions: Twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided effective and sustained LDL-C lowering irrespective of BL glycemic status, and was generally well tolerated.

Introduction: Accelerated cognitive decline is influenced by vascular aging. Arterial stiffness and pressure amplification, measures of vascular aging, are associated with lower cognitive performance though their association with cognitive domains has been understudied. Hypothesis: Arterial stiffness and pressure amplification are associated with lower global and domain-specific cognition among a sample of Caucasian and African American (AA) older adults. Methods: In a cross-sectional study of 4618 members from visit 5 (2011-2013) of ARIC (mean age: 75 years, 41% men, 20% AA), we measured arterial stiffness (carotid-femoral pulse wave velocity (cfPWV)) and pressure amplification (pulse pressure amplification (PPA), central pulse pressure (cPP) and carotid systolic blood pressure (cSBP)) using the Omron VP-1000 Plus device. Race-specific 25th percentile cut points were estimated for each measure. Domain-specific cognitive function was examined using the Delayed Word Recall Test (memory), Digit Symbol Substitution Test (executive function/processing speed), and Word Fluency Test (language). Test-specific z scores were calculated from sample means and standard deviations. A global cognition z score was generated by averaging the test-specific z scores. Linear regression was used to estimate the associations between race-specific 25th percentile dichotomies for arterial stiffness and pressure amplification measures with test-specific and global cognition z scores, adjusted for age, sex, education, ApoE4, heart rate, smoking and body mass index. Results: Among AAs, there was no significant association between measures of arterial stiffness and pressure amplification with either global or the domain-specific measures of cognition. Among Caucasians, all measures of arterial stiffness and pressure amplification were associated with lower global cognitive z scores (cfPWV: Beta (β) =-0.11, 95% Confidence Interval (CI): -0.19, -0.04; PPA: β=-0.11, 95% CI: -0.19, -0.03; cPP: β=-0.11, 95% CI: -0.18, -0.04; cSBP: β=-0.12, 95% CI: -0.20, -0.05). All measures of arterial stiffness and pressure amplification also were associated with lower executive function/processing speed (cfPWV: β=-0.09, 95% CI: -0.16, -0.03; PPA: β=-0.15, 95% CI: -0.22, -0.08; cPP: β=-0.14, 95% CI: -0.21, -0.07; cSBP: β=-0.13, 95% CI: -0.20, -0.07). High cfPWV was associated with lower memory (β=-0.12, 95% CI: -0.20, -0.04); and high cSBP was associated with lower language (β=-0.12, 95% CI: -0.20, -0.04). Conclusions: Arterial stiffness and measures of pressure amplification are inversely associated with global and domain-specific cognition in Caucasian older adults, but not in a smaller sample of AAs. Further study of the role of modifiable components of arterial aging on the preservation of cognition, particularly executive function/psychomotor speed, in older adulthood is warranted.

Background: As a high-flow, low-impedance organ, the brain is sensitive to excessive pressure and flow pulsatility. Increased pulsatility and arterial stiffness are hypothesized to contribute to cerebral microvascular damage linked to cognitive impairment. The association of arterial stiffness with mild cognitive impairment (MCI) and dementia in a biethnic population is not well characterized, and the association of pressure amplification with MCI and dementia is relatively unexplored. Objectives: To quantify the cross-sectional association of arterial stiffness, measured by aortic pulse wave velocity (PWV), and pressure amplification with MCI and dementia in a biethnic population of older adults. Methods: We included 4,945 adults (2,903 females; 1,069 African Americans; mean age 75 years) from the population-based ARIC-NCS. The Omron VP-1000 plus system was used to measure arterial stiffness (carotid-femoral PWV (cfPWV)) and pressure amplification measures (central systolic blood pressure (cSBP), central pulse pressure (cPP), and pulse pressure amplification (PPA)). A neurologist and neuropsychologist classified MCI and dementia using psychometric assessments, medical history, cerebral magnetic resonance imaging, and physical examinations, with adjudication by a third reviewer. We used multinomial logistic regression to evaluate associations of race-specific 25th percentile cut points of PWV and pressure amplification with normal cognition (reference), MCI and dementia. We stratified by race and adjusted for age, sex, and heart rate, ApoE4, education, smoking status, and study center. Results: There were 760 Caucasians with MCI and 110 with dementia, and 201 African Americans with MCI and 47 with dementia. Among Caucasians, those with lower PPA had a higher prevalence of dementia, odds ratio (OR)=1.84 (95% confidence interval (CI): 1.15, 2.97), comparing participants below the 25th percentile to those above it, and those with higher cSBP had a higher prevalence of MCI, OR=1.33 (95% CI: 1.09, 1.63), comparing participants above the 75th percentile to those below it. Also among Caucasians, those with higher cPP had a higher prevalence of MCI, OR=1.25 (95%CI: 1.01, 1.55), and dementia, OR=1.66 (95% CI: 1.00, 2.73), comparing participants above the 75th percentile to those below it. There were no statistically significant associations with cfPWV, among African Americans, and no evidence for effect modification by hypertension or diabetes. Conclusion: Arterial stiffness and components of pressure amplification were associated with MCI and dementia in Caucasians but not in African Americans, possibly due to the limited sample size. Longitudinal characterization of the observed associations is warranted to determine whether these measures are independent predictors of MCI and dementia among Caucasian and African American older adults.

AbstractThe efficacy of COVID‐19 convalescent plasma (CCP) as a treatment for hospitalized patients with COVID‐19 remains somewhat controversial; however, many studies have not evaluated CCP documented to have high neutralizing antibody titer by a highly accurate assay. To evaluate the correlation of the administration of CCP with titer determined by a live viral neutralization assay with 7‐ and 28‐day death rates during hospitalization, a total of 23 118 patients receiving a single unit of CCP were stratified into two groups: those receiving high titer CCP (>250 50% inhibitory dilution, ID50; n = 13 636) or low titer CCP (≤250 ID50; n = 9482). Multivariable Cox regression was performed to assess risk factors. Non‐intubated patients who were transfused with high titer CCP showed 1.1% and 1.7% absolute reductions in overall 7‐ and 28‐day death rates, respectively, compared to those non‐intubated patients receiving low titer CCP. No benefit of CCP was observed in intubated patients. The relative benefit of high titer CCP was confirmed in multivariable Cox regression. Administration of CCP with high titer antibody content determined by live viral neutralization assay to non‐intubated patients is associated with modest clinical efficacy. Although shown to be only of modest clinical benefit, CCP may play a role in the future should viral variants develop that are not neutralized by other available therapeutics.

Background Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling. Patients and methods In this phase II trial (ClinicalTrials.gov NCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 2:1 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was Response Evaluation Criteria in Solid Tumors-defined progression-free survival (PFS). Patients with carcinosarcoma or prior immune checkpoint inhibitor received combination treatment (Arm C). Baseline biopsy and serial peripheral blood mononuclear cell (PBMC) samples were analyzed and associations between patient outcome and immune data from cytometry by time of flight (CyTOF) and PBMCs were explored. Results Median PFS was 5.3 (90% CI 3.5 to 9.2) months in Arm A (n=36) and 1.9 (90% CI 1.6 to 3.4) months in Arm B (n=18) (HR=0.59, 90% CI 0.35 to 0.98; log-rank p=0.09, meeting the prespecified statistical significance criteria). The most common treatment-related adverse events in Arm A were diarrhea (50%) and elevated liver enzymes (aspartate aminotransferase 47%, alanine aminotransferase 42%). In-depth baseline CyTOF analysis across treatment arms (n=40) identified 35 immune-cell subsets. Among immunotherapy-pretreated patients in Arm C, non-progressors had significantly higher proportions of activated tissue-resident (CD103+CD69+) ɣδ T cells than progressors (adjusted p=0.009). Conclusions Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation.

Abstract Electroconvulsive therapy (ECT) is a highly therapeutic and cost-effective treatment for severe and/or treatment-resistant major depression. However, because of the varied clinical practices, there is a great deal of heterogeneity in how ECT is delivered and documented. This represents both an opportunity to study how differences in implementation influence clinical outcomes and a challenge for carrying out coordinated quality improvement and research efforts across multiple ECT centers. The National Network of Depression Centers, a consortium of 26+ US academic medical centers of excellence providing care for patients with mood disorders, formed a task group with the goals of promoting best clinical practices for the delivery of ECT and to facilitate large-scale, multisite quality improvement and research to advance more effective and safe use of this treatment modality. The National Network of Depression Centers Task Group on ECT set out to define best practices for harmonizing the clinical documentation of ECT across treatment centers to promote clinical interoperability and facilitate a nationwide collaboration that would enable multisite quality improvement and longitudinal research in real-world settings. This article reports on the work of this effort. It focuses on the use of ECT for major depressive disorder, which accounts for the majority of ECT referrals in most countries. However, most of the recommendations on clinical documentation proposed herein will be applicable to the use of ECT for any of its indications.