Dataset Information

Adverse Outcomes Associated With Off-Label Agents Used to Treat Dementia Patients With Psychosis: A Case-Control Medicare Database Study.

ABSTRACT:

Introduction

Currently, there are no Food and Drug Administration-approved therapies to treat dementia-related psychosis (DRP). This study investigated the association between using antipsychotics and the anticonvulsant divalproex (sodium valproate) to manage DRP and adverse outcomes.

Methods

A retrospective case/control matching study evaluated the risk of mortality, extrapyramidal symptoms (EPS), ischemic stroke, and cardiac arrest/ventricular arrhythmia (CA/VA) with ever-use of antipsychotics/divalproex in patients with DRP vs never-use.

Results

49 509 patients were included; 76.8% used an antipsychotic/divalproex. Treatment ever-use was associated with an increased risk of all-cause mortality (odds ratio, 1.14; 95% CI, 1.10-1.18) and a smaller increase in the risk of EPS (1.10; 1.00-1.19) relative to never-use (adjusted for matching demographic variables, comorbid conditions, and disability).

Conclusions

Current agents used for DRP were associated with increased risk of death and adverse outcomes. An increased risk of death was evident within 3 months of antipsychotic/divalproex initiation and persisted with long-term use.

SUBMITTER: Rashid N

PROVIDER: S-EPMC10623966 | biostudies-literature | 2022 Jan-Dec

REPOSITORIES: biostudies-literature

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Publications

Adverse Outcomes Associated With Off-Label Agents Used to Treat Dementia Patients With Psychosis: A Case-Control Medicare Database Study.

Rashid Nazia N Wetmore James B JB Irfan Muna M Abler Victor V

American journal of Alzheimer's disease and other dementias 20220101

<h4>Introduction</h4>Currently, there are no Food and Drug Administration-approved therapies to treat dementia-related psychosis (DRP). This study investigated the association between using antipsychotics and the anticonvulsant divalproex (sodium valproate) to manage DRP and adverse outcomes.<h4>Methods</h4>A retrospective case/control matching study evaluated the risk of mortality, extrapyramidal symptoms (EPS), ischemic stroke, and cardiac arrest/ventricular arrhythmia (CA/VA) with ever-use of ...[more]

PMID: 35331005

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Project description:IntroductionDementia-related psychosis (DRP) is characterized by hallucinations and delusions, which may increase the debilitating effects of underlying dementia. This network meta-analysis (NMA) evaluated the comparative efficacy, safety, and acceptability of atypical antipsychotics (AAPs) commonly used off label to treat DRP.MethodsWe included 22 eligible studies from a systematic literature review of AAPs (quetiapine, risperidone, olanzapine, aripiprazole, and brexpiprazole) used off label to treat DRP. Study outcomes were: (1) efficacy-neuropsychiatric inventory-nursing home (NPI-NH psychosis subscale), (2) safety-mortality, cerebrovascular events (CVAEs), and others (somnolence, falls, fractures, injuries, etc.), and (3) acceptability-discontinuations due to all causes, lack of efficacy, and adverse events (AEs). We used random-effects modeling to estimate pooled standardized mean differences (SMDs) for NPI-NH psychosis subscale scores and odds ratios (OR) for other dichotomous outcomes, with their respective 95% confidence intervals (CIs).ResultsCompared with placebo, aripiprazole (SMD - 0.12; 95% CI - 0.31, 0.06), and olanzapine (SMD - 0.17; 95% CI - 0.04; 0.02) demonstrated small, non-significant numerical improvements in NPI-NH psychosis scores (5 studies; n = 1891), while quetiapine (SMD 0.04; 95% CI - 0.23, 0.32) did not improve symptoms. The odds of mortality (15 studies, n = 4989) were higher for aripiprazole (OR 1.58; 95% CI 0.62, 4.04), brexpiprazole (OR 2.22; 95% CI 0.30, 16.56), olanzapine (OR 2.21; 95% CI 0.84, 5.85), quetiapine (OR 1.68; 95% CI 0.70, 4.03), and risperidone (OR 1.63; 95% CI 0.93, 2.85) than for placebo. Risperidone (OR 3.68; 95% CI 1.68, 8.95) and olanzapine (OR 4.47; 95% CI 1.36, 14.69) demonstrated significantly greater odds of CVAEs compared to placebo. Compared with placebo, odds of all-cause discontinuation were significantly lower for aripiprazole (OR 0.71; 95% CI 0.51, 0.98; 20 studies; 5744 patients) and higher for other AAPs. Aripiprazole (OR 0.5; 95% CI 0.31, 0.82) and olanzapine (OR 0.48; 95% CI 0.31, 0.74) had significantly lower odds of discontinuation due to lack of efficacy (OR 12 studies; n = 4382) compared to placebo, while results for quetiapine and risperidone were not significant. Compared with placebo, the odds of discontinuation due to AEs (19 studies, n = 5445) were higher for olanzapine (OR 2.62; 95% CI 1.75, 3.92), brexpiprazole (OR 1.80; 95% CI 0.80, 4.07), quetiapine (OR 1.25; 95% CI 0.82, 1.91), aripiprazole (OR 1.38; 95% CI 0.90, 2.13), and risperidone (OR 1.41; 95% CI 1.02, 1.94).ConclusionsOverall results demonstrate that, compared with placebo, quetiapine is not associated with improvement in psychosis in patients with dementia, while olanzapine and aripiprazole have non-significant small numerical improvements. These off-label AAPs (quetiapine, risperidone, olanzapine, aripiprazole, and brexpiprazole) are associated with greater odds of mortality, CVAEs, and discontinuations due to AEs than placebo. These results underscore the ongoing unmet need for newer pharmacological options with a more favorable benefit-risk profile for the treatment of DRP.

Project description:ImportanceWhen making coverage determinations for off-label prescribing, Medicare Part D recognizes 2 compendia: the American Hospital Formulary Service (AHFS) Drug Information and the DRUGDEX Information System. Deficiencies in the accuracy and completeness of these compendia could result in coverage denials for necessary, effective, evidence-based treatments.ObjectiveTo evaluate these compendia for dermatologic conditions, with a focus on less common conditions that often require systemic treatment.Design, setting, and participantsThis cross-sectional study was conducted from July 1, 2018, through September 30, 2018. To identify diseases for which dermatologists may often need access to off-label systemic treatments, a list of 22 chronic, noninfectious, nonneoplastic diseases with at least 4 systemic therapies (including 1 in the first-line therapies and less than 25% approved by the US Food and Drug Administration) were selected for evaluation. With use of Treatment of Skin Disease, 5th Edition, a list of first-, second-, and third-line medications was created, including the level of evidence for each disease. A search of AHFS and DRUGDEX compendia was performed to evaluate for inclusion of the evidence-based therapies. In addition, the references cited in the compendia to justify inclusion of the therapy were examined qualitatively.Main outcomes and measuresPercentage of treatment options included in each compendium, stratified by level of evidence and position on the therapeutic ladder. Concordance between the 2 compendia was assessed using Cohen κ.ResultsOverall, 73 of 238 treatments (30.7%) evaluated were included in either compendium. Among individual diseases, 10 of 22 (45%) had 1 or fewer treatments included in the DRUGDEX compendium and 15 of 22 (68%) had 1 or fewer treatments included in the AHFS compendium. Discrepancies in which a medication was included in one compendium but not in the other compendium occurred for 53 of the 238 medications (22.3%) evaluated. Literature use did not follow a discernible pattern and was often based on decades-old sources.Conclusions and relevanceThe findings suggest that treatment options listed in these compendia are incomplete, outdated, idiosyncratic, and unpredictable. To ensure that patients can access treatments for their disease, it appears that policies to reduce the reliance on these compendia for coverage determinations should be developed.

Project description:Purpose: Voriconazole (VOR) is combined with atorvastatin (ATO) to treat fungal infections in patients with dyslipidemia in clinical practice. However, the pharmacokinetic interactions and potential mechanisms between them are unknown. Therefore, this study aimed to investigate the pharmacokinetic interactions and potential mechanisms between ATO and VOR. Patients and methods: We collected plasma samples from three patients using ATO and VOR. Rats were administered either VOR or normal saline for 6 days, followed by a single dose of 2 mg/kg ATO, and then plasma samples were collected at different time points. The incubation models of human liver microsomes or HepG2 cells were constructed in vitro. A high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) system was developed to determine the concentration of ATO, 2-hydroxy-ATO, 4-hydroxy-ATO, and VOR. Results: In patients, VOR significantly reduced the metabolism of ATO and slowed the formation of 2-hydroxy- and 4-hydroxy-ATO. In rats pretreated with orally administered VOR for 6 days or normal saline given a single dose of 2 mg/kg ATO administered orally on Day 6, the t1/2 of ATO was significantly prolonged from 3.61 to 6.43 h, and the area under the concentration-time curve (AUC0-24h) values of ATO increased from 53.86 to 176.84 h μg.L-1. However, the pharmacokinetic parameters of VOR (20 mg/kg) with or without pretreatment with ATO (2 mg/kg) only slightly changed. In vitro studies indicated that VOR inhibited the metabolism of ATO and testosterone, and the IC50 values were 45.94 and 49.81 μM. However, no significant change in transporter behaviors of ATO was observed when VOR or transporter inhibitors were co-administered. Conclusion: Our study demonstrated that VOR has significant interactions with ATO, probably due to VOR's inhibition of the CYP3A4-mediated metabolism of ATO. Based on the clinical cases and potential interactions, the basic data obtained in our study are expected to help adjust the dose of ATO and promote the design of rational dosage regimens for pharmacotherapy for fungal infections in patients with dyslipidemia.

Project description:Background/objectivesNo data exist regarding the validity of International Classification of Disease (ICD)-10 dementia diagnoses against a clinician-adjudicated reference standard within Medicare claims data. We examined the accuracy of claims-based diagnoses with respect to expert clinician adjudication using a novel database with individual-level linkages between electronic health record (EHR) and claims.DesignIn this retrospective observational study, two neurologists and two psychiatrists performed a standardized review of patients' medical records from January 2016 to December 2018 and adjudicated dementia status. We measured the accuracy of three claims-based definitions of dementia against the reference standard.SettingMass-General-Brigham Healthcare (MGB), Massachusetts, USA.ParticipantsFrom an eligible population of 40,690 fee-for-service (FFS) Medicare beneficiaries, aged 65 years and older, within the MGB Accountable Care Organization (ACO), we generated a random sample of 1002 patients, stratified by the pretest likelihood of dementia using administrative surrogates.InterventionNone.MeasurementsWe evaluated the accuracy (area under receiver operating curve [AUROC]) and calibration (calibration-in-the-large [CITL] and calibration slope) of three ICD-10 claims-based definitions of dementia against clinician-adjudicated standards. We applied inverse probability weighting to reconstruct the eligible population and reported the mean and 95% confidence interval (95% CI) for all performance characteristics, using 10-fold cross-validation (CV).ResultsBeneficiaries had an average age of 75.3 years and were predominately female (59%) and non-Hispanic whites (93%). The adjudicated prevalence of dementia in the eligible population was 7%. The best-performing definition demonstrated excellent accuracy (CV-AUC 0.94; 95% CI 0.92-0.96) and was well-calibrated to the reference standard of clinician-adjudicated dementia (CV-CITL <0.001, CV-slope 0.97).ConclusionThis study is the first to validate ICD-10 diagnostic codes against a robust and replicable approach to dementia ascertainment, using a real-world clinical reference standard. The best performing definition includes diagnostic codes with strong face validity and outperforms an updated version of a previously validated ICD-9 definition of dementia.

Dataset Information

Adverse Outcomes Associated With Off-Label Agents Used to Treat Dementia Patients With Psychosis: A Case-Control Medicare Database Study.

Introduction

Methods

Results

Conclusions

Publications

Adverse Outcomes Associated With Off-Label Agents Used to Treat Dementia Patients With Psychosis: A Case-Control Medicare Database Study.

Similar Datasets

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