Relationships of change in Clinical Dementia Rating (CDR) on patient outcomes and probability of progression: observational analysis.

BACKGROUND: Understanding the relationship among changes in Clinical Dementia Rating (CDR), patient outcomes, and probability of progression is crucial for evaluating the long-term benefits of disease-modifying treatments. We examined associations among changes in Alzheimer's disease (AD) stages and outcomes that are important to patients and their care partners including activities of daily living (ADLs), geriatric depression, neuropsychiatric features, cognitive impairment, and the probabilities of being transitioned to a long-term care facility (i.e., institutionalization). We also estimated the total time spent at each stage and annual transition probabilities in AD. METHODS: The study included participants with unimpaired cognition, mild cognitive impairment (MCI) due to AD, and mild, moderate, and severe AD dementia in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) database. The associations among change in AD stages and change in relevant outcomes were estimated using linear mixed models with random intercepts. The probability of transitioning to long-term care facilities was modeled using generalized estimating equations. The total length of time spent at AD stages and annual transition probabilities were estimated with multistate Markov models. RESULTS: The estimated average time spent in each stage was 3.2 years in MCI due to AD and 2.2, 2.0, and 2.8 years for mild, moderate, and severe AD dementia, respectively. The annual probabilities of progressing from MCI to mild, moderate, and severe AD dementia were 20, 4, and 0.7%, respectively. The incremental change to the next stage of participants with unimpaired cognition, MCI, and mild, moderate, and severe AD dementia (to death) was 3.2, 20, 26.6, 31, and 25.3%, respectively. Changes in ADLs, neuropsychiatric features, and cognitive measures were greatest among participants who transitioned from MCI and mild AD dementia to more advanced stages. Participants with MCI and mild and moderate AD dementia had increasing odds of being transitioned to long-term care facilities over time during the follow-up period. CONCLUSIONS: The findings demonstrated that participants with early stages AD (MCI or mild dementia) were associated with the largest changes in clinical scale scores. Early detection, diagnosis, and intervention by disease-modifying therapies are required for delaying AD progression. Additionally, estimates of transition probabilities can inform future studies and health economic modeling.

Association between clinical dementia rating and clinical outcomes in Alzheimer's disease.

INTRODUCTION: We examined associations between the Clinical Dementia Rating Scale (CDR) and function (Functional Assessment Scale [FAS]), neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire [NPI-Q]), and cognitive impairment in Alzheimer's disease (AD). METHODS: We used data from the National Alzheimer's Coordinating Center Uniform Data Set and defined cognitively unimpaired and AD stages using CDR-global. RESULTS: Functional and neuropsychiatric symptoms occur as early as the mild cognitive impairment (MCI) phase. The adjusted lest square mean FAS (95% confidence interval [CI]) was lowest in cognitively unimpaired (3.88 [3.66, 4.11] to 5.01 [4.76, 5.26]) and higher with more advanced AD (MCI: 8.17 [6.92, 9.43] to 20.87 [19.53, 22.20]; mild: 18.54 [17.57, 19.50] to 28.13 [27.14, 29.12]; moderate: 26.01 [25.31, 26.70] to 29.42 [28.73, 30.10]). FAS and NPI-Q scores increased steeply with MCI (NPI-Q: 5.55 [4.89, 6.20] to 7.11 [6.43, 7.78]) and mild AD dementia (NPI-Q: 6.66 [5.72, 7.60] to 8.32 [7.32, 9.33]). DISCUSSION: CDR-global staged AD by capturing differences in relevant outcomes along AD progression. Highlights: There were strong associations among CDR and the various outcomes relevant to healthcare providers, patients, and their care givers, such as activities of daily living.Overall, activities of daily living, neuropsychiatric symptoms, and cognitive function outcomes deteriorated over time and can be observed in early stages of AD (MCI or mild dementia).Our findings directly inform the current understanding of AD progression and can aid in care planning and benefit assessments of early AD interventions to delay the progression of AD to more advanced stages.

Incremental net monetary benefit of herpes zoster vaccination: a systematic review and meta-analysis of cost-effectiveness evidence.

OBJECTIVES: To perform a systematic review and meta-analysis to pool the incremental net benefit (INB) of each herpes zoster vaccine [i.e. Zoster Vaccine Live (ZVL) and Recombinant Zoster Vaccine (RZV)]. METHODS: We initially identified individual studies by hand-searching reference lists of the relevant systematic review articles. An updated comprehensive search was performed in Medline, Scopus, and Embase until June 2020 for additional studies. Studies were eligible if they assessed the cost-effectiveness/utility of any pair among ZVL and RZV, and no vaccine and reported economic outcomes. Details of the study characteristics, economic model inputs, costs, and outcomes were extracted. INB was calculated with monetary units adjusting for purchasing power parity for 2019 US dollars and pooled by meta-analysis. RESULTS: A total of 37 studies were pooled for meta-analysis stratified by perspectives [i.e. societal (SP) and third-party payer (TPP)] and vaccine types. In SP, ZVL was cost-effective compared to no vaccine when vaccinated at ages of 50-59 and 70-79 years with INBs (95% CI) of $0.61 (0.37, 0.85) and $9.67 (5.20, 14.14), respectively. RZV was cost-effective for those aged 60-69 and 70-79 years with INBs of $75.61 (17.98, 133.23) and $85.01 (30.02, 140.01), respectively. In TPP, ZVL was cost-effective compared to no vaccine when vaccinated at age 70-79 years with INB of $7.57 (0.27, 14.86) and RZV was cost-effective at 60-69 years with INB $220.87 (47.80, 393.93). The cost-effectiveness of RZV was robust across a series of sensitivity analyses, but ZVL differs on different vaccination ages. CONCLUSIONS: RZV may be cost-effective for vaccination in ages of 60-79 years for both SP and TPP perspectives, while ZVL might be cost-effective in some age groups, but results are not robust.

Meta-Analysis of NUDT15 Genetic Polymorphism on Thiopurine-Induced Myelosuppression in Asian Populations.

Backgound: The high incidence of thiopurine-induced myelosuppression in Asians is known to be attributable to genetic variation in thiopurine metabolism. A quantitative synthesis to summarize the genetic association with thiopurine-induced myelosuppression in Asians was therefore conducted. Methods: A Literature search was performed from January 2016 to May 2021 in the following databases: PubMed, Web of Science, and Embase and addition search included the studies from Zhang et al. Two reviewers independently extracted the following data: the author's name, year of publication, ethnicity, drugs, diseases, genetic polymorphisms, onset, type of myelosuppression and results of Hardy-Weinberg equilibrium. The Newcastle-Ottawa Scale was used to assess the quality of the studies. The pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the associations of NUDT15 and the risk of thiopurine-induced myelosuppression stratified by onset and type of myelosuppressive. Subgroup analysis by NUDT15 genetic polymorphisms was performed. Results: A total of 30 studies was included in this meta-analysis. The overall OR for the relationship between NUDT15 genetic polymorphisms and thiopurine-induced early onset of leukopenia and neutropenia in Asian populations were 11.43 (95% CI 7.11-18.35) and 16.35 (95% CI 10.20-26.22). Among NUDT15 polymorphisms, NUDT15*3 showed a significantly increased risk of early leukopenia (OR 15.31; 95% CI 9.65-24.27) and early neutropenia (OR 15.85; 95% CI 8.80-28.53). A significantly higher thiopurine-induced early neutropenic risk was also found for NUDT15*2 (OR 37.51; 95% CI 1.99-708.69). Whereas, NUDT15*5 and NUDT15*6 variants showed a lower risk of leukopenia. Conclusion: This study suggests that NUDT15*3 and NUDT15*2 are important genetic markers of thiopurine-induced early onset of myelotoxicity in Asians, therefore, early detection of these variants before initiating thiopurine therapy is necessary.

Opioid prescribing and health outcomes in opioid-naive patients: Analysis of a statewide health information exchange.

BACKGROUND: Widespread use of prescription opioids is associated with adverse outcomes. OBJECTIVE: To identify factors associated with adverse health outcomes and health care use using a statewide health information exchange. METHODS: This is a retrospective cohort study using the Indiana Network for Patient Care. Adult opioid-naive patients who received an opioid prescription between January 2012 and December 2017 were included. The outcomes included (1) a composite outcome of any combination of opioid abuse, dependence, or overdose, (2) all-cause mortality, and (3) health care use. Independent variables included opioid dosage, dispensed amount, days supply, concurrent use of short-acting (SA) and long-acting (LA) opioids, and concurrent use with benzodiazepine or gabapentinoids. Additional variables included patients' age, sex, race, modified Charlson Comorbidity Index score, mental health conditions, and medications for opioid use disorders. Factors associated with composite outcome and mortality were identified using Cox proportional hazards and reported as adjusted hazard ratio (aHR) and 95% CI. Factors associated with health care use were identified using Poisson regression and reported as adjusted incidence rate ratio (aIRR) and 95% CI. RESULTS: 1,328,287 opioid prescriptions were identified for 341,722 patients. Opioid-related factors associated with the composite outcome, mortality, and hospitalizations, respectively, included opioid dosage (aHR 1.003 [95% CI 1.001-1.006]; aHR not applicable; aIRR 1.07 [1.06-1.08]), opioid days supply (aHR 1.03 [1.02-1.03]; aHR 1.009 [1.005-1.014]; aIRR 0.94 [0.92-0.96]), concurrent SA/LA opioids (aHR 2.12 [1.78-2.54]; aHR 1.40 [1.14-1.70]; aIRR 1.40 [1.37-1.42]), and use of benzodiazepines/gabapentinoids (aHR 1.68 [1.38-2.04]; aHR 1.23 [1.01-1.51]; aIRR 1.25 [1.23-1.27]). CONCLUSION: Many factors are associated with poor health outcomes, especially concurrent use of SA and LA opioids and overlapping prescriptions of opioids with benzodiazepines or gabapentinoids. Identification of factors associated with adverse outcomes may help identify patients at risk for poor outcomes and could inform possible interventions.

The Reversal of Bleeding Caused by New Oral Anticoagulants (NOACs): A Systematic Review and Meta-Analysis.

New oral anticoagulants (NOACs; ie, direct thrombin inhibitor [DTI] and factor Xa [FXa] inhibitors) were used as alternatives to warfarin. Specific antidotes (idarucizumab for dabigatran and andexanet alfa for FXa inhibitors) and hemostatic reversal agents were used for lowering bleeding, but their efficacies were still uncertain. The objectives of this study were to estimate and compare the efficacy of NOAC antidotes on bleeding reversal and death. Studies were identified from MEDLINE and Scopus databases until May 2018. Case reports/series and cohorts were selected if they assessed reversal or death rates. Data were independently extracted by 2 reviewers. Individual patient data and aggregated data of outcomes were extracted from case reports/series and cohorts. Binary regression was used to estimate outcome rates, risk ratio (RR) along with 95% confidence interval (CI). Interventions were NOACs and reversal agents (ie, DTI-specific, DTI-standard, FXa-specific, and FXa-standard). Among 220 patients of 93 case reports/series, reversal rates were 95.9%, 77.6%, and 71.5% for DTI-specific, FXa-standard, and DTI-standard. Pooled RRs for DTI-specific and FXa-standard versus DTI-standard, respectively, were 1.34 (CI: 1.13-1.60) and 1.09 (CI: 0.84-1.40). Death rate was 0.18 (CI: 0.06-0.57) times lower in DTI-specific versus DTI-standard. For pooling 10 subcohorts, pooled RRs were 1.08 (CI: 1.00-1.16), 1.29 (CI: 1.20-1.39), and 1.13 (CI: 1.01-1.25) for DTI-specific, FXa-specific, and FXa-standard versus DTI-standard. In conclusion, specific reversal agents might be useful for reversal of bleeding and lowering the risk of death than standard reversal agents. Our findings were based on case reports/series and selected cohorts, further comparative studies are thus needed.