Association of Kidney Function Measures With Signs of Neurodegeneration and Small Vessel Disease on Brain Magnetic Resonance Imaging: The Atherosclerosis Risk in Communities (ARIC) Study.

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD) is a risk factor for cognitive decline, but evidence is limited on its etiology and morphological manifestation in the brain. We evaluated the association of estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR) with structural brain abnormalities visible on magnetic resonance imaging (MRI). We also assessed whether this association was altered when different filtration markers were used to estimate GFR. STUDY DESIGN: Cross-sectional study nested in a cohort study. SETTING & PARTICIPANTS: 1,527 participants in the Atherosclerosis Risk in Communities (ARIC) Study. PREDICTORS: Log(UACR) and eGFR based on cystatin C, creatinine, cystatin C and creatinine in combination, or ß2-microglobulin (B2M). OUTCOMES: Brain volume reduction, infarcts, microhemorrhages, white matter lesions. ANALYTICAL APPROACH: Multivariable linear and logistic regression models fit separately for each predictor based on a 1-IQR difference in the predictor value. RESULTS: Each 1-IQR lower eGFR was associated with reduced cortex volume (regression coefficient: -0.07 [95% CI, -0.12 to-0.02]), greater white matter hyperintensity volume (logarithmically transformed; regression coefficient: 0.07 [95% CI, 0.01-0.15]), and lower white matter fractional anisotropy (regression coefficient: -0.08 [95% CI, -0.17 to-0.01]). The results were similar when eGFR was estimated with different equations based on cystatin C, creatinine, a combination of cystatin C and creatinine, or B2M. Higher log(UACR) was similarly associated with these outcomes as well as brain infarcts and microhemorrhages (odds ratios per 1-IQR-fold greater UACR of 1.31 [95% CI, 1.13-1.52] and 1.30 [95% CI, 1.12-1.51], respectively). The degree to which brain volume was lower in regions usually susceptible to Alzheimer disease and LATE (limbic-predominant age-related TDP-43 [Tar DNA binding protein 43] encephalopathy) was similar to that seen in the rest of the cortex. LIMITATIONS: No inference about longitudinal effects due to cross-sectional design. CONCLUSIONS: We found eGFR and UACR are associated with structural brain damage across different domains of etiology, and eGFR- and UACR-related brain atrophy is not selective for regions typically affected by Alzheimer disease and LATE. Hence, Alzheimer disease or LATE may not be leading contributors to neurodegeneration associated with CKD.

Associations of Vascular Risk and Amyloid Burden with Subsequent Dementia.

OBJECTIVE: Midlife vascular risk factors (MVRFs) are associated with incident dementia, as are amyloid ß (Aß) deposition and neurodegeneration. Whether vascular and Alzheimer disease-associated factors contribute to dementia independently or interact synergistically to reduce cognition is poorly understood. METHODS: Participants in the Atherosclerosis Risk in Communities-Positron Emission Tomography study were followed from 1987-1989 (45-64 years old) through 2016-2017 (74-94 years old), with repeat cognitive assessment and dementia adjudication. In 2011-2013, dementia-free participants underwent brain magnetic resonance imaging (with white matter hyperintensity [WMH] and brain volume measurement) and florbetapir (Aß) positron emission tomography. The relative contributions of vascular risk and injury (MVRFs, WMH volume), elevated Aß standardized uptake value ratio (SUVR), and neurodegeneration (smaller temporoparietal brain regions) to incident dementia were evaluated with adjusted Cox models. RESULTS: In 298 individuals, 36 developed dementia (median follow-up = 4.9 years). Midlife hypertension and Aß each independently predicted dementia risk (hypertension: hazard ratio [HR] = 2.57, 95% confidence interval [CI] = 1.16-5.67; Aß SUVR [per standard deviation (SD)]: HR = 2.57, 95% CI = 1.72-3.84), but did not interact significantly, whereas late life diabetes (HR = 2.50, 95% CI = 1.18-5.28) and Aß independently predicted dementia risk. WMHs (per SD: HR = 1.51, 95% CI = 1.03-2.20) and Aß SUVR (HR = 2.52, 95% CI = 1.83-3.47) independently contributed to incident dementia, but WMHs lost significance when MVRFs were included. Smaller temporoparietal brain regions were associated with incident dementia, independent of Aß and MVRFs (HR = 2.18, 95% CI = 1.18-4.01). INTERPRETATION: Midlife hypertension and late life Aß are independently associated with dementia risk, without evidence for synergy on a multiplicative scale. Given the independent contributions of vascular and amyloid mechanisms, multiple pathways should be considered when evaluating interventions to reduce the burden of dementia. ANN NEUROL 2022;92:607-619.

Accuracy assessment of implant placement with versus without a CAD/CAM surgical guide by novices versus specialists via the digital registration method: an in vitro randomized crossover study.

BACKGROUND: Many studies demonstrated that surgical guides might reduce discrepancies compared with freehand implant placement. This randomized crossover study aimed to assess the effects of approaches, practitioners' experience and learning sequences on the accuracy of single tooth implantation via digital registration method. No similar study was found. METHODS: This in vitro randomized crossover study enrolled 60 novice students (Group S) and 10 experienced instructors (Group I). Sixty students were randomly and evenly assigned to two groups (Group SA and SB). In Group SA, 30 students first performed single molar implant on a simulation model freehand (Group SAFH), and then with a CAD/CAM surgical guide (Group SASG). In Group SB, another 30 students first performed guided (Group SBSG) and then freehand (Group SBFH). Ten instructors were also divided into Group IAFH/IASG (n = 5) and IBSG/IBFH (n = 5) following the same rules. The accuracy of implant placement was assessed by the coronal and apical distance (mm) and angular (°) deviations using the digital registration method. T tests and nonparametric tests were used to compare the results among different groups of approaches, experience and sequences. RESULTS: For students, the coronal and apical distance and the angular deviations were significantly lower in surgical guide group than freehand group in total and in learning freehand first subgroup, but for learning surgical guide first subgroup the apical distance deviation showed no significant difference between two approaches. For students, the angular deviation of freehand group was significantly lower in learning surgical guide first group than learning freehand first group. For instructors, the coronal and apical distance and angular deviations showed no significant difference between two approaches and two sequences. For freehand approach, the coronal and apical distance and the angular deviations were significantly higher in student group than instructor group, while not significantly different between two groups for surgical guide approach. CONCLUSIONS: For novices, using a surgical guide for the first implant placement may reduce the potential deviations compared with freehand surgery, and may reach a comparable accuracy with that of specialists. For simple single molar implantation, the surgical guide may not be significantly helpful for experienced specialists.

Association between Circulating Protein C Levels and Incident Dementia: The Atherosclerosis Risk in Communities Study.

INTRODUCTION: Hemostasis depends on the delicate balance between coagulants and anticoagulants. Higher levels of circulating coagulants have been associated with higher risk of cerebral infarctions and dementia. In contrast, higher levels of circulating protein C, an endogenous anticoagulant, have been associated with lower risk of cerebral infarctions, and the association between protein C levels and the risk of dementia is unknown. The goal of this study was to evaluate the association of circulating protein C levels in midlife and late life with incident dementia. METHODS: Circulating protein C levels were measured using blood samples collected at the midlife baseline (1987-1989) and the late-life baseline (2011-2013) among 14,462 and 3,614 participants, respectively, in the Atherosclerosis Risk in Communities study. Protein C levels were measured using enzyme-linked immunosorbent assay at midlife and a modified aptamer-based assay at late life. Participants were followed up to 2013 from midlife and up to 2017 from late life. Incident dementia was ascertained during the follow-up periods using in-person cognitive and functional assessment, informant interviews, and International Classification of Diseases codes at hospitalization discharge and on death certificates. Cause-specific Cox regression models were used to evaluate the association between quintiles of circulating protein C and incident dementia. RESULTS: From midlife (mean age of 54), 1,389 incident dementia events were observed over a median follow-up of 23 years. From late life (mean age of 75), 353 incident dementia events were observed over a median follow-up of 4.9 years. At both midlife and late life, circulating protein C had an inverse association with incident dementia after adjusting for demographic, vascular, and hemostatic risk factors, incident stroke as time-dependent covariate, and incorporating stabilized weights based on propensity scores (quintile 5 vs. quintile 1 as the reference, midlife hazard ratio 0.80, 95% confidence interval 0.66-0.96, p value for trend 0.04; late-life hazard ratio 0.84, 95% confidence interval: 0.55-1.28, p value for trend 0.04). DISCUSSION/CONCLUSION: Circulating protein C has an inverse association with incident dementia independent of established risk factors, including stroke. Our results suggest studying anticoagulants in addition to coagulants can increase our understanding on the relationship between hemostasis and dementia.

Albuminuria and Estimated GFR as Risk Factors for Dementia in Midlife and Older Age: Findings From the ARIC Study.

RATIONALE & OBJECTIVE: Evidence is limited on how estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR) relate to dementia at different ages. We evaluated eGFR and UACR in midlife and older age as risk factors for dementia. Additionally, we assessed whether the association between eGFR and dementia is altered when cystatin C and ß2-microglobulin (B2M) levels are used for GFR estimation. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Two baselines from the Atherosclerosis Risk in Communities (ARIC) Study were used: visit 4 (1996-1998), including 9,967 participants 54 to 74 years old, and visit 5 (2011-2013), including 4,626 participants 70 to 90 years old. Participants were followed up until 2017. PREDICTORS: Log(UACR); eGFR based on creatinine, cystatin C, creatinine and cystatin C, or B2M levels (denoted as eGFRcr, eGFRcys, eGFRcr-cys, and eGFRB2M). OUTCOME: Incident dementia. ANALYTICAL APPROACH: Multivariable Cox proportional hazards regression models fit separately for each of the 5 predictors and based on a change in the predictor equivalent to the interquartile range for that predictor at visit 4 (IQRV4). eGFR models were adjusted for log(UACR) and log(UACR) models were adjusted for eGFRcys. RESULTS: We observed 1,821 dementia cases after visit 4 and 438 cases after visit 5. Dementia risk increased with higher albuminuria levels (HRs per IQRV4 [equivalent to 4.2-fold greater log albuminuria] of 1.15 [95% CI, 1.09-1.21] after visit 4 and 1.27 [95% CI, 1.13-1.42] after visit 5). An association with lower eGFR was seen for only eGFRcys (HRs per IQRV4 [equivalent to 24.3mL/min/1.73m2 lesser eGFRcys] of 1.12 [95% CI, 1.04-1.21] after visit 4 and 1.30 [95% CI, 1.12-1.52] after visit 5) and eGFRB2M (HRs per IQRV4 [equivalent to 18.3mL/min/1.73m2 lesser eGFRB2M] of 1.15 [95% CI, 1.07-1.23] after visit 4 and 1.34 [95% CI, 1.17-1.55] after visit 5). Differences between these associations in midlife and older age were not statistically significant. LIMITATIONS: Changes in potentially time-varying covariates were not measured. Dementia was not subclassified by cause. CONCLUSIONS: Albuminuria was consistently associated with dementia incidence. Lower eGFR based on cystatin C or B2M, but not creatinine, levels was also associated with dementia. Risk associations were similar when kidney measures were assessed at midlife and older age.

Association of Midlife to Late-Life Blood Pressure Patterns With Incident Dementia.

Importance: The association between late-life blood pressure (BP) and cognition may depend on the presence and chronicity of past hypertension. Late-life declines in blood pressure following prolonged hypertension may be associated with poor cognitive outcomes. Objective: To examine the association of midlife to late-life BP patterns with subsequent dementia, mild cognitive impairment, and cognitive decline. Design, Setting, and Participants: The Atherosclerosis Risk in Communities prospective population-based cohort study enrolled 4761 participants during midlife (visit 1, 1987-1989) and followed-up over 6 visits through 2016-2017 (visit 6). BP was examined over 24 years at 5 in-person visits between visits 1 and 5 (2011-2013). During visits 5 and 6, participants underwent detailed neurocognitive evaluation. The setting was 4 US communities: Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and Minneapolis, Minnesota. Follow-up ended on December 31, 2017. Exposures: Five groups based on longitudinal patterns of normotension, hypertension (>140/90 mm Hg), and hypotension (<90/60 mm Hg) at visits 1 to 5. Main Outcomes and Measures: Primary outcome was dementia onset after visit 5, based on Ascertain Dementia-8 informant questionnaires, Six-Item Screener telephone assessments, hospital discharge and death certificate codes, and the visit 6 neurocognitive evaluation. Secondary outcome was mild cognitive impairment at visit 6, based on the neurocognitive evaluation. Results: Among 4761 participants (2821 [59%] women; 979 [21%] black race; visit 5 mean [SD] age, 75 [5] years; visit 1 mean age range, 44-66 years; visit 5 mean age range, 66-90 years), there were 516 (11%) incident dementia cases between visits 5 and 6. The dementia incidence rate for participants with normotension in midlife (n = 833) and late life was 1.31 (95% CI, 1.00-1.72 per 100 person-years); for midlife normotension and late-life hypertension (n = 1559), 1.99 (95% CI, 1.69-2.32 per 100 person-years); for midlife and late-life hypertension (n = 1030), 2.83 (95% CI, 2.40-3.35 per 100 person-years); for midlife normotension and late-life hypotension (n = 927), 2.07 (95% CI, 1.68-2.54 per 100 person-years); and for midlife hypertension and late-life hypotension (n = 389), 4.26 (95% CI, 3.40-5.32 per 100 person-years). Participants in the midlife and late-life hypertension group (hazard ratio [HR], 1.49 [95% CI, 1.06-2.08]) and in the midlife hypertension and late-life hypotension group (HR, 1.62 [95% CI, 1.11-2.37]) had significantly increased risk of subsequent dementia compared with those who remained normotensive. Irrespective of late-life BP, sustained hypertension in midlife was associated with dementia risk (HR, 1.41 [95% CI, 1.17-1.71]). Compared with those who were normotensive in midlife and late life, only participants with midlife hypertension and late-life hypotension had higher risk of mild cognitive impairment (37 affected individuals (odds ratio, 1.65 [95% CI, 1.01-2.69]). There was no significant association of BP patterns with late-life cognitive change. Conclusions and Relevance: In this community-based cohort with long-term follow-up, sustained hypertension in midlife to late life and a pattern of midlife hypertension and late-life hypotension, compared with midlife and late-life normal BP, were associated with increased risk for subsequent dementia.

Association of NTproBNP and cTnI with outpatient sudden cardiac death in hemodialysis patients: the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) study.

BACKGROUND: Sudden cardiac death (SCD) is the most common etiology of death in hemodialysis patients but not much is known about its risk factors. The goal of our study was to determine the association and risk prediction of SCD by serum N-terminal prohormone of brain natriuretic peptide (NTproBNP) troponin I (cTnI) in hemodialysis patients. METHODS: We measured NTproBNP and cTnI in 503 hemodialysis patients of a national prospective cohort study. We determined their association with SCD using Cox regression, adjusting for demographics, co-morbidities, and clinical factors and risk prediction using C-statistic and Net Reclassification Improvement (NRI). RESULTS: Patients' mean age was 58 years and 54 % were male. During follow-up (median 3.5 years), there were 75 outpatient SCD events. In unadjusted and fully-adjusted models, NTproBNP had a significant association with the risk of SCD. Analyzed as a continuous variable, the risk of SCD increased 27 % with each 2-fold increase in NTproBNP (HR, 1.27 per doubling; 95 % CI, 1.13-1.43; p < 0.001). In categorical models, the risk of SCD was 3-fold higher in the highest tertile of NTproBNP (>7,350 pg/mL) compared with the lowest tertile (<1,710 pg/mL; HR for the highest tertile, 3.03; 95 % CI, 1.56-5.89; p = 0.001). Higher cTnI showed a trend towards increased risk of SCD in fully adjusted models, but was not statistically significant (HR, 1.17 per doubling; 95 % CI, 0.98-1.40; p = 0.08). Sensitivity analyses using competing risk models showed similar results. Improvement in risk prediction by adding cardiac biomarkers to conventional risk factors was greater with NTproBNP (C-statistic for 3-year risk: 0.810; 95 % CI, 0.757 to 0.864; and continuous NRI: 0.270; 95 % CI, 0.046 to 0.495) than with cTnI. CONCLUSIONS: NTproBNP is associated with the risk of SCD in hemodialysis patients. Further research is needed to determine if biomarkers measurement can guide SCD risk prevention strategies in dialysis patients.

Antihyperglycemic treatment patterns for chronic kidney disease and type 2 diabetes.

OBJECTIVE: Patients with type 2 diabetes (T2D) are at high risk for developing chronic kidney disease (CKD). The onset of incident CKD may complicate glycemic control among these patients. This study aimed to characterize antihyperglycemic medication use after incident CKD onset among patients with T2D to inform disease management. STUDY DESIGN: Retrospective cohort study. METHODS: Patients with incident CKD and prior T2D were identified from the Optum electronic health records database between March 2013 and September 2021. Patterns of antihyperglycemic use were assessed during the 1-year baseline period and after incident CKD diagnosis and described by baseline hemoglobin A1C (HbA1C) level (controlled [< 7%] vs elevated [≥ 7%]) and CKD severity. RESULTS: The study consisted of 262,395 patients, of whom 51% had elevated HbA1C. After CKD onset, 23.9% of patients initiated new antihyperglycemics within 1 year. Patients with elevated HbA1C had shorter time to new treatment initiation compared with those with controlled HbA1C (median, 28.7 vs 83.7 months). Patients with elevated urine albumin-to-creatinine ratio (uACR) had shorter median time to new treatment initiation (39.9-42.4 months) than those with normal uACR (59.8 months). Less than 7% of patients with stage 3 CKD and even smaller percentages of patients with higher stages of CKD utilized glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors. CONCLUSIONS: Treatment of T2D was considerably heterogenous by HbA1C level and CKD severity in patients with incident CKD. Current agents may not sufficiently fulfill the unmet need of T2D management in patients with CKD.

Comparison of 4- or 6-implant supported immediate full-arch fixed prostheses: A retrospective cohort study of 217 patients followed up for 3-13 years.

PURPOSE: Choosing four or six implants to support immediate full-arch fixed prostheses (FAFPs) is still controversial worldwide. This study aims to analyze and compare the long-term results of All-on-4 and All-on-6. MATERIALS AND METHODS: This retrospective cohort study enrolled 217 patients rehabilitated with 1222 implants supporting 271 FAFPs, including 202 prostheses supported by 4 implants (All-on-4 group) and 69 prostheses supported by 6 implants (All-on-6 group), and followed up for 3-13 years. Implant survival, prosthesis survival, complications, and implant marginal bone loss (MBL) were evaluated and compared between two groups. Patient characteristics including age, gender, jaw, opposite dentition condition, smoking habit, bruxism, bone quantity and quality, cantilever length (CL), prosthesis material, and oral hygiene were analyzed to assess their influence on the clinical results of the two groups. Six surgeons and three prosthodontists who performed FAFPs more than 5 years were invited for questionnaires, to assess patient- and clinician-related influences on implant number. RESULT: In general, All-on-4 group indicated no significant difference with All-on-6 group in the implant survival (implant-level: hazard ratio [HR] = 1.0 [95% confidence interval (CI): 0.8-1.2], P = 0.96; prosthesis-level: HR = 0.8 [95% CI: 0.3-1.8], P = 0.54), prosthesis survival (odds ratio [OR] = 0.8 [95% CI: 0.3-2.8], P = 0.56), biological complications (OR = 0.9 [95% CI: 0.5-1.8], P = 0.78), technical complications of provisional prosthesis (OR = 1.3 [95% CI: 0.7-2.3], P = 0.42), technical complications of definitive prosthesis (OR = 1.1 [95% CI: 0.6-2.2], P = 0.33) and the 1st, 5th, and 10th year MBL (P = 0.65, P = 0.28, P = 0.14). However, for specific covariates, including elderly patients, opposing natural/fixed dentition, smoking, bruxism, long CL, low bone density, and all acrylic provisional prostheses, All-on-6 was more predictable in some clinical measurements than All-on-4. The implant prosthodontists and the medium-experienced clinicians showed significant preference for All-on-6 (P < 0.05). CONCLUSION: Based on this study, the long-term clinical results showed no significant difference between All-on-4 and All-on-6 groups in general. However, for some specific characteristics, All-on-6 seemed to be more predictable in some clinical measurements than All-on-4. For the clinicians' decision-making, medium-experienced clinicians and the implant prosthodontists showed significant preference for All-on-6.

Adverse event costs associated with first-line therapy for advanced non-small cell lung cancer in the United States: An analysis of clinical trials of immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors, such as pembrolizumab, nivolumab, and atezolizumab, have demonstrated substantial survival benefits in patients with advanced non-small cell lung cancer (NSCLC). However, there is limited evidence on their relative safety profiles and adverse event (AE)-related cost burden. OBJECTIVE: To compare the AE management costs of nivolumab plus ipilimumab with and without limited chemotherapy with those of chemotherapy, pembrolizumab plus chemotherapy, and atezolizumab plus chemotherapy in a first-line setting among patients with advanced NSCLC. METHODS: The mean per-patient AE costs were estimated using the incidence of all-cause grade 3/4 AEs with any-grade incidence greater than or equal to 15% and the corresponding costs of AE management in the inpatient setting. AE rates were obtained from individual patient data from the CheckMate 227 and CheckMate 9LA trials for nivolumab plus ipilimumab with/without limited chemotherapy and aggregated data from the KEYNOTE-189 and KEYNOTE-407 trials for pembrolizumab plus chemotherapy and the IMpower130 trial for atezolizumab plus chemotherapy. AE management costs from the third-party payer perspective were estimated based on inpatient medical costs from the 2016 United States Healthcare Cost and Utilization Project National Inpatient Sample. All costs were inflated to 2020 US dollars. RESULTS: Nivolumab plus ipilimumab and nivolumab plus ipilimumab plus limited chemotherapy were associated with lower per-patient grade 3/4 AE costs compared with chemotherapy ($1,708 and $624 lower over the treatment course, respectively). Compared with pembrolizumab plus chemotherapy, nivolumab plus ipilimumab was associated with lower grade 3/4 AE costs in patients with nonsquamous histology (difference: -$4,866) and squamous histology (difference: -$3,795), and nivolumab plus ipilimumab with limited chemotherapy also had lower AE costs for both nonsquamous (difference: -$2,800) and squamous (difference: -$2,753) disease. Similarly, nivolumab plus ipilimumab and nivolumab plus ipilimumab plus limited chemotherapy were also associated with lower AE costs ($11,400 and $8,809 lower, respectively) compared with atezolizumab plus chemotherapy among patients with nonsquamous disease. In particular, nivolumab plus ipilimumab without or with limited chemotherapy were associated with much lower AE costs of hematological AEs compared with chemotherapy and other immune checkpoint inhibitor-based treatments in combination with a full course of chemotherapy. CONCLUSIONS: Nivolumab plus ipilimumab with/without limited chemotherapy was associated with lower AE management costs compared with chemotherapy, pembrolizumab plus chemotherapy, and atezolizumab plus chemotherapy as first-line treatment for advanced NSCLC. The AE cost benefits were largely driven by the lower cost burden for hematological AEs for nivolumab plus ipilimumab with/without limited chemotherapy. DISCLOSURES This study was supported by Bristol-Myers Squibb. The sponsor was involved in all aspects of the work and in the decision to submit the manuscript for publication. Dr Stenehjem has received consulting fees from Bristol-Myers Squibb. Dr Lubinga was an employee of Bristol-Myers Squibb at the time of the study's conduct and holds stock/options. Drs Betts and Wu are employees of Analysis Group, Inc., a consulting company that has received funding from Bristol-Myers Squibb for this research.

Indirect treatment comparison (ITC) of the efficacy of vutrisiran and tafamidis for hereditary transthyretin-mediated amyloidosis with polyneuropathy.

BACKGROUND: Vutrisiran and tafamidis are approved therapies for treating hereditary transthyretin-mediated (ATTRv/hATTR) amyloidosis with polyneuropathy, a rapidly progressive and fatal disease. To assist healthcare decision-makers, an indirect treatment comparison (ITC) was undertaken to explore the comparative efficacy of vutrisiran and tafamidis. RESEARCH DESIGN AND METHODS: Individual patient data (vutrisiran vs. placebo) and published results (tafamidis vs. placebo) from phase 3 randomized controlled trials were used in a Bucher analysis to assess differences in treatment effects between vutrisiran and tafamidis on: Neuropathy Impairment Score-Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) score, NIS-LL Response, and modified Body Mass Index (mBMI). RESULTS: Greater treatment effects were observed at 18 months with vutrisiran vs. tafamidis for all endpoints, with statistically significant improvements in polyneuropathy (relative mean change in NIS-LL: -5.3 [95% confidence interval (CI): -9.4, -1.2; p = 0.011]), health-related quality of life (HRQOL, relative mean change in Norfolk QOL-DN: -18.3 [95% CI: -28.6, -8.0; p < 0.001]), and nutritional status (relative mean change in mBMI: 63.9 [95% CI: 10.1, 117.7; p = 0.020]). CONCLUSIONS: This analysis suggests vutrisiran has greater efficacy on multiple measures of polyneuropathy impairment and HRQOL compared to tafamidis in patients with ATTRv amyloidosis with polyneuropathy.

Hereditary transthyretin-mediated (ATTRv/hATTR) amyloidosis is a rare genetic disease that runs in families, affecting about 50,000 people worldwide. This condition results in abnormal protein deposits building up, causing damage to multiple nerves (polyneuropathy) and other organs, which can shorten lifespan and have other harmful effects. Polyneuropathy symptoms include weakness, numbness, pain, dizziness, and diarrhea. Over time, everyday activities become more difficult as patients become increasingly disabled and dependent on others. Several treatments have been approved for the polyneuropathy of ATTRv amyloidosis. Many of these work in different ways to impact the disease process. An indirect treatment comparison is a well-established statistical method used by healthcare decision-makers to compare treatments when head-to-head trials are unavailable. Indirect treatment comparisons using a common approach, the Bucher method, yield similar conclusions to head-to-head studies over 90% of the time. This method was used to compare clinical trial data for tafamidis and vutrisiran, two approved treatments for ATTRv amyloidosis with polyneuropathy. The findings show that vutrisiran is more effective than tafamidis at addressing the polyneuropathy of ATTRv amyloidosis as measured by changes to sensory or motor nervous system functioning and nutritional status. Also, vutrisiran showed greater maintenance of health-related quality of life compared to tafamidis. The expected benefits of vutrisiran over tafamidis are large enough to be noticeable and clinically meaningful to a patient or clinician. This highlights the potential advantages of vutrisiran compared to tafamidis with regard to preservation of physical function and quality of life when treating ATTRv amyloidosis with polyneuropathy.

Midlife Hemostasis Measures, 20-Year Cognitive Decline, and Incident Dementia.

BACKGROUND AND OBJECTIVES: Blood concentrations of hemostatic factors affect thrombosis and bleeding diathesis and may contribute to cognitive impairment through modifiable vascular pathologies. Whether hemostasis, assessed in middle age, is associated with late-life cognitive impairment remains largely unknown in a community-dwelling population. METHODS: Using data from 14,128 participants with cognitive function measurements in 1990-1992 from the Atherosclerosis Risk in Communities study, we assessed the associations of hemostasis measures with 20-year changes in cognitive performance and incident dementia. Activated partial thromboplastin time (aPTT) and level of fibrinogen, von Willebrand factor (VWF), factor VIII, factor VII, factor XI, d-dimer, and soluble thrombomodulin were measured in 1987-1989 or 1993-1995. Hemostasis measures were categorized into quintiles, with the lowest quintile indicating low coagulability. Cognitive performance was characterized using a combined z-score from 3 tests (that is, delayed word recall test [DWRT], digit symbol substitution [DSST], and word fluency test [WFT]), assessed in 1990-1992, 1996-1998, and 2011-2013. Dementia was determined either from in-person evaluations or using dementia surveillance through 2017. Mixed-effects models and Cox proportional hazards models were used to assess cognitive trajectories and risk of dementia, respectively. RESULTS: Among 12,765 participants with hemostasis measures in 1987-1989, who were aged 47-70 years at the first cognitive assessment, we observed significant trends of shorter aPTT (p for trend <0.001; difference in 20-year cognitive decline for fifth vs first quintile [Q5 vs Q1]: -0.104 [95% CI -0.160 to -0.048]) and higher levels of factor VII (p < 0.002; Q5 vs Q1: -0.085 [-0.142, -0.028]) and factor VIII (p = 0.033; Q4 vs Q1: -0.055 [-0.111, -0.000]) with greater 20-year cognitive declines. The associations with the decline in DSST were stronger than those with the decline in WFT or DWRT. Consistently, shorter aPTT and higher factor VIII levels were associated with higher dementia risk with HRs for Q5 vs Q1 of 1.23 (95% CI 1.07 to 1.42) and 1.17 (1.01-1.36), respectively, and p for trend of 0.008 and 0.024, respectively. DISCUSSION: Overall, our study found consistent trend associations of aPTT and factor VIII measured in midlife with cognitive decline and incident dementia over 20 years, likely driven by vascular pathologies.

A Matching-adjusted Indirect Comparison of Nivolumab Plus Cabozantinib Versus Pembrolizumab Plus Axitinib in Patients with Advanced Renal Cell Carcinoma.

BACKGROUND: The comparative efficacy and health-related quality of life (HRQoL) outcomes of nivolumab plus cabozantinib versus pembrolizumab plus axitinib as first-line treatments for advanced renal cell carcinoma (aRCC) have not been assessed in head-to-head trials. OBJECTIVE: To assess the efficacy and HRQoL outcomes of nivolumab plus cabozantinib versus pembrolizumab plus axitinib. DESIGN, SETTING, AND PARTICIPANTS: Patient-level data for nivolumab plus cabozantinib from the CheckMate 9ER trial and published data for pembrolizumab plus axitinib from the KEYNOTE-426 trial were used. CheckMate 9ER data were reweighted to match the key baseline characteristics as reported in KEYNOTE-426. INTERVENTION: Nivolumab (240 mg every 2 wk) plus cabozantinib (40 mg once daily) and pembrolizumab (200 mg every 3 wk) plus axitinib (5 mg twice daily, initially). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Hazard ratios (HRs) for progression-free survival (PFS), duration of response, overall survival (OS), and deterioration in HRQoL were assessed using weighted Cox proportional-hazard models, with sunitinib as a common anchor. Objective response rates (ORRs) and changes in HRQoL scores from baseline were assessed as difference-in-differences for the two treatments relative to sunitinib. RESULTS AND LIMITATIONS: After balancing patient characteristics between the trials, nivolumab plus cabozantinib was associated with significantly improved PFS (HR [95% confidence interval {CI}] 0.70 [0.53-0.93]; p = 0.01) and a significantly decreased risk of confirmed deterioration in HRQoL (Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease-related Symptoms: HR [95% CI] 0.48 [0.34-0.69]) versus pembrolizumab plus axitinib. OS was similar between treatments (HR [95% CI] 0.99 [0.67-1.44]; p = 0.94). Nivolumab plus cabozantinib was associated with numerically greater ORRs (difference-in-difference [95% CI] 8.4% [-1.7 to 18.4]; p = 0.10) and longer duration of response (HR [95% CI] 0.79 [0.47-1.31]; p = 0.36) than pembrolizumab plus axitinib. Comparative studies using data with a longer duration of follow-up are warranted. CONCLUSIONS: Nivolumab plus cabozantinib significantly improved PFS and HRQoL compared with pembrolizumab plus axitinib as first-line treatment for aRCC. PATIENT SUMMARY: This study was conducted to indirectly compare the results of two immunotherapy-based combinations-nivolumab plus cabozantinib versus pembrolizumab plus axitinib-for patients who have not received any treatment for advanced renal cell carcinoma. Patients who received nivolumab plus cabozantinib had a significant improvement in the length of time without worsening of their disease and in their perceived physical and mental health compared with pembrolizumab plus axitinib; patients remained alive for a similar length of time from the start of either treatment. This analysis further adds to our current knowledge of the relative benefits of these two treatment regimens and will help with physician and patient treatment decisions.

Geographical variation in kidney function testing and associations with health care costs among patients with chronic kidney disease and type 2 diabetes.

OBJECTIVES: Clinical practice guidelines recommend at least annual testing of estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (uACR) for patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). This study assessed the adequacy of eGFR and uACR testing in this patient population across the United States. STUDY DESIGN: Observational real-world study. METHODS: Adults with CKD and T2D were identified from the Optum Clinformatics database (2015-2019). The eGFR and uACR tests were assessed nationally and by state. The proportions of tested patients and patients receiving adequate monitoring per clinical practice guidelines were analyzed during the 1-year period after T2D and CKD diagnosis, along with all-cause health care costs. RESULTS: Among 101,057 adults with CKD and T2D, 94.1% had at least 1 eGFR test and 38.7% had at least 1 uACR test over 1 year. Only 20.3% of patients had adequate uACR monitoring; this was much lower than observed for adequate eGFR monitoring (86.6%). The eGFR testing rates were high across states (range, 79.5% [Colorado] to 97.3% [Alabama]); conversely, uACR testing rates were uniformly lower and showed wider variation (range, 14.0% [Maine] to 58.9% [Hawaii]). Mean annual all-cause health care costs were $28,636 and increased with CKD GFR stage. Lower uACR testing rates were associated with higher health care costs at the state level (Pearson r = -0.55; P < .01). CONCLUSIONS: In the United States, uACR testing is underutilized, with large geographical variations in testing rates noted between states. Lower uACR testing rates were associated with higher health care costs. The lack of sufficient uACR testing raises concerns about CKD management in patients with T2D.

Value of Remission in Patients with Rheumatoid Arthritis: A Targeted Review.

The treat-to-target strategy, which defines clinical remission as the primary therapeutic goal for rheumatoid arthritis (RA), is a widely recommended treatment approach in clinical guidelines. Achieving remission has been associated with improved clinical outcomes, quality of life, and productivity. These benefits are likely to translate to reduced economic burden in terms of lower healthcare costs and resource utilization. As such, a literature review was conducted to better understand the economic value of remission. Despite the large heterogeneity found in RA-related economic outcomes across studies, patients in remission consistently had lower direct medical and indirect costs, less healthcare resource utilization, and greater productivity compared to those without remission. Remission was associated with 19-52% savings in direct medical costs and 37-75% savings in indirect costs. The economic value of remission should thus be considered in economic analyses of RA therapies to inform treatment and reimbursement decisions.

CKD Progression and Economic Burden in Individuals With CKD Associated With Type 2 Diabetes.

Rationale & Objective: To evaluate progression patterns and associated economic outcomes, using estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) based on the Kidney Disease: Improving Global Outcomes (KDIGO) risk categories, among patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). Study Design: Patients with T2D and moderate- or high-risk CKD were selected from the Optum electronic health records database (January 2007-December 2019). Progression patterns and post-progression economic outcomes were assessed. Setting & Participants: Adults with T2D and CKD in clinical settings. Predictor: Baseline KDIGO risk categories. Outcomes: Progression to a more severe KDIGO risk category; healthcare resource utilization and medical costs. Analytical Approach: Progression probability was estimated using cumulative incidence. Healthcare resource utilization and costs were compared across progression groups. Results: Of 269,187 patients (mean age 65.6 years) with T2D and CKD of moderate or high baseline risk, 18.9% progressed to the very high-risk category within 5 years. Among moderate-risk patients, 17.8% of CKD stage G1-A2, 44.0% of stage G2-A2, and 61.3% of stage G3a-A1 patients progressed to a higher KDIGO risk category. Among high-risk patients, 63.9% of stage G3b-A1/G3a-A2 and 56.0% of stage G2-A3 patients progressed to very high risk. Within the same eGFR stage, a higher UACR stage was associated with 4- to 7-times higher risk of progressing to very high risk and faster eGFR decline. Nonprogressors had lower annual medical costs ($16,924) than patients who progressed from moderate risk to high risk ($22,117, P < 0.05), from high risk to very high risk ($32,204, P < 0.05), and from moderate risk to very high risk ($35,092, P < 0.05). Limitations: Infrequent lab testing might have caused lags in identifying progression; medical costs were calculated using unit costs. Conclusions: Patients with T2D and CKD of moderate or high risk per KDIGO risk categories had high probabilities of progression, incurring a substantial economic burden. The results highlight the value of UACR in CKD management.

Common Medications and Intracerebral Hemorrhage: The ARIC Study.

Background Antiplatelets, anticoagulants, and statins are commonly prescribed for various indications. The associations between these medications and the risk of intracerebral hemorrhage (ICH) and cerebral microbleeds (CMBs) are unclear. Methods and Results We performed a retrospective study of the ARIC (Atherosclerosis Risk in Communities) study cohort, recruited from 4 US communities in 1987 to 1989 with follow-up. In 2011 to 2013, a subset (N=1942) underwent brain magnetic resonance imaging with CMB evaluation. Time-varying and any antiplatelet, anticoagulant, or statin use was evaluated at subsequent study visits in participants not on each medication at baseline. To determine the hazard of ICH and odds of CMB by medication use, logistic and Cox proportional hazard models were built, respectively, adjusting for the propensity to take the medication, concomitant use of other medications, and cognitive, genetic, and radiographic data. Of 15 719 individuals during up to 20 years of follow-up, 130 participants experienced an ICH. The adjusted hazard of ICH was significantly lower among participants taking an antiplatelet at the most recent study visit before ICH versus nonusers (hazard ratio [HR], 0.53; 95% CI, 0.30-0.92). Statin users had a significantly lower hazard of an ICH compared with nonusers (adjusted HR, 0.13; 95% CI, 0.05-0.34). There was no association of CMB and antiplatelet, anticoagulant, or statin use in adjusted models. Conclusions In this US community-based study, antiplatelet and statin use were associated with lower ICH hazard, whereas no association was noted between CMBs and antiplatelets, anticoagulants, and statins. Further study is needed to understand the differential roles of these medications in cerebral microhemorrhages and macrohemorrhages.

Characteristics and treatment patterns of relapsed/refractory diffuse large B-cell lymphoma in patients receiving ≥3 therapy lines in post-CAR-T era.

OBJECTIVE: Several novel treatments have been approved for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) since chimeric antigen receptor T-cell (CAR-T) therapy became available. The objective of this study was to describe characteristics and treatment patterns in patients with R/R DLBCL post-CAR-T approval. METHODS: Adult patients with R/R DLBCL who initiated third-line treatment or later (3 L+) since 18 October 2017 were identified using administrative claims from IQVIA PharMetrics Plus (1 January 2014-31 March 2020). Treatments were categorized as chemotherapy/chemoimmunotherapy (CT/CIT), targeted therapies, CAR-T and stem cell transplant (SCT). Treatment distribution, treatment duration of CT/CIT and targeted therapies, and initiation of next-line therapy were described for patients receiving 3 L; analyses were repeated for 4 L. RESULTS: A total of 145 patients received 3 L between 18 October 2017 and 31 March 2020. Mean age was 57 years, and 34% were female. CT/CIT (44.9%), targeted therapies (26.9%), CAR-T (17.2%) and SCT (11.0%) were administered in 3 L. The median treatment duration was 2.9 months for CT/CIT and targeted therapies combined. 31% of patients initiated 4 L within a median follow-up of 5.8 months. Among patients who received 4 L (N = 55), targeted therapies were most commonly used (36.4%), and the median treatment duration was 2.5 months. CONCLUSIONS: Post-CAR-T approval, the majority of patients were treated with CT/CIT or targeted therapies in 3 L and 4 L, though most of the targeted therapies prescribed are not indicated for DLBCL. Treatment duration was short. A high proportion of patients moved to the next line of therapy (LOT) during a short follow-up period. This study highlights the unmet need for more effective treatments for patients with R/R DLBCL in 3 L+.

Network meta-analysis of nivolumab plus ipilimumab in the second-line setting for advanced hepatocellular carcinoma.

Aims: To compare the efficacy of nivolumab 1 mg/kg + ipilimumab 3 mg/kg with regorafenib 160 mg, cabozantinib 60 mg and nivolumab 3 mg/kg monotherapy for second-line treatment of advanced hepatocellular carcinoma. Materials & methods: Indirect comparison using network meta-analysis and propensity score weighting. Results: Nivolumab 1 mg/kg + ipilimumab 3 mg/kg had significantly higher objective response rate (median 31.2% [95% credible interval: 19.6-44.5%]) than cabozantinib (4.2% [2.0-6.5%]) and regorafenib (4.8% [1.1-8.3%]), and significantly longer overall survival (cabozantinib: hazard ratio: 0.46 [95% credible interval: 0.27-0.79]; regorafenib: 0.56 [0.32-0.97]). Nivolumab 1 mg/kg + ipilimumab 3 mg/kg had significantly better objective response rate (difference 21.0% [4.5-37.5%]) and overall survival (hazard ratio: 0.58 [0.35-0.96]) than nivolumab monotherapy. Conclusion: Nivolumab 1 mg/kg + ipilimumab 3 mg/kg had a superior efficacy versus cabozantinib 60 mg, regorafenib 160 mg and nivolumab 3 mg/kg monotherapy as second-line therapy for advanced hepatocellular carcinoma.

Large-scale plasma proteomic analysis identifies proteins and pathways associated with dementia risk.

The plasma proteomic changes that precede the onset of dementia could yield insights into disease biology and highlight new biomarkers and avenues for intervention. We quantified 4,877 plasma proteins in nondemented older adults in the Atherosclerosis Risk in Communities cohort and performed a proteome-wide association study of dementia risk over five years (n = 4,110; 428 incident cases). Thirty-eight proteins were associated with incident dementia after Bonferroni correction. Of these, 16 were also associated with late-life dementia risk when measured in plasma collected nearly 20 years earlier, during mid-life. Two-sample Mendelian randomization causally implicated two dementia-associated proteins (SVEP1 and angiostatin) in Alzheimer's disease. SVEP1, an immunologically relevant cellular adhesion protein, was found to be part of larger dementia-associated protein networks, and circulating levels were associated with atrophy in brain regions vulnerable to Alzheimer's pathology. Pathway analyses for the broader set of dementia-associated proteins implicated immune, lipid, metabolic signaling and hemostasis pathways in dementia pathogenesis.