Impact of Prescribing Cascade and Associated Drug Interaction in Alzheimer's Disease

级联处方和相关药物相互作用对阿尔茨海默病的影响

• 批准号: 10212709
• 负责人: Rajender R Aparasu
• 金额: $ 44.99万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212709
• 关键词: Accounting; Acetylcholine; Acetylcholinesterase; Adverse effects; Adverse event; Age; Alzheimer' s Disease; Alzheimer' s disease patient; American; Anti-Cholinergics; Antipsychotic Agents; Behavioral Model; Behavioral Symptoms; Brain; Cause of Death; Cessation of life; Cholinesterase Inhibitors; Chronic Disease; Clinical; Cognition; Cognitive; Communities; Cox Proportional Hazards Models; Data; Dementia; Drug Interactions; Elderly; Emergency department visit; Enzymes; Expenditure; Galantamine; Goals; Healthcare; Hospitalization; Institutionalization; Lead; Medical; Medicare; Medicare claim; Memantine; Memory impairment; Methods; Neurobehavioral Manifestations; Neurotransmitters; Patients; Pharmaceutical Preparations; Pharmacotherapy; Population; Prevalence; Problem behavior; Prosencephalon; Public Health; Quality of life; Research; Risk; Safety; Sampling; Selection Bias; Serious Adverse Event; Specificity; Testing; Therapeutic; Therapeutic Effect; Treatment Effectiveness; Urinary Incontinence; Variant; aged; base; care costs; cholinergic; cholinergic neuron; cohort; design; donepezil; evidence base; functional decline; hazard; human old age (65+); improved; mortality; neurotransmission; policy implication; prevent; rivastigmine; systematic review

PROJECT SUMMARY/ABSTRACT Dementia is a major public health concern in older adults. Alzheimer’s disease (AD) accounts for 50% to 60% of dementia cases and nearly half of dementia-related deaths. Cholinesterase inhibitors (ChEIs) form the first line of pharmacotherapy for AD. However, the treatment effectiveness of ChEIs is considered modest and their use leads to adverse effects. Urinary incontinence is a prominent adverse effect of ChEI treatment, which is commonly implicated in prescribing cascade - a clinical phenomenon where the ChEI-induced urinary incontinence leads to prescribing of antimuscarinics. ChEIs and antimuscarinics interaction tends to nullify the modest treatment benefit of ChEIs and can worsen AD due to the therapeutically opposing mechanism of actions. This worsening of AD can precipitate additional cascades - prescribing of memantine for moderate-to- severe AD, and/or antipsychotics to manage behavioral symptoms of AD, and/or may lead to Serious Adverse Events (SAEs). Our preliminary analyses revealed that 6% of AD patients initiated antimuscarinics after ChEIs initiation, and memantine and antipsychotics were initiated by 30% and 23% AD patients, respectively, after the initial cascade. Although some studies have described the initial prescribing cascade of ChEIs in AD, none of the studies have evaluated the impact of prescribing cascades due to the drug-drug interaction of ChEIs and antimuscarinics. Therefore, the overall goal of this research is to evaluate the healthcare impact of the prescribing cascades of ChEIs and their associated interactions among community-dwelling older adults with AD. The specific aims of the proposed research are to: (1) examine the extent of prescribing cascades of ChEIs in older adults with AD; and (2) assess all-cause SAEs associated with ChEI-antimuscarinic interaction in older adults with AD. The study will involve propensity score-matched cohort design based on a national cohort of older adults > 65 years with AD. The initial prescribing cascade of ChEIs will include initiation of antimuscarinics. Further cascades will include initiation of memantine (for moderate-to-severe AD) and antipsychotics (for behavioral symptoms of AD). All-cause SAEs s will include all-cause hospitalization, emergency department visits, institutionalization, and mortality. Multi-year multistate Medicare data involving Parts A, B, and D will be used to test the following hypotheses: (i) ChEI-antimuscarinic drug-drug interaction leads to further cascades due to worsening of AD leading to prescribing of memantine for moderate-to-severe AD, as well as prescription of antipsychotics to manage behavioral symptoms of AD, and (ii) there is a greater risk for all-cause SAEs due to ChEI-antimuscarinic interaction. Concomitant ChEI-antimuscarinic users will be compared with concomitant users of ChEIs and mirabegron, a non-anticholinergic alternative. The study will adjust for selection bias within the multivariable context of Anderson Behavioral Model. Robust Cox proportional hazards models will be used to account for the matched sets. The proposed study will have significant clinical and policy implications for preventing, detecting, and reversing prescribing cascades in AD.

项目概要/摘要 痴呆症是老年人的一个主要公共卫生问题。阿尔茨海默氏病（AD）占 50% 至 60% 痴呆症病例和近一半的痴呆症相关死亡。胆碱酯酶抑制剂 (ChEI) 构成第一线 AD 的药物治疗。然而，ChEI 的治疗效果被认为是有限的，并且它们的使用 导致不良影响。尿失禁是 ChEI 治疗的一个突出不良反应， 通常与处方级联有关 - 一种临床现象，其中 ChEI 诱导的尿 失禁导致服用抗毒蕈碱药物。 ChEI 和抗毒蕈碱药物的相互作用往往会抵消 ChEI 的治疗效果有限，但由于与治疗相反的机制，可能会使 AD 恶化 行动。 AD 的恶化可能会引发额外的级联反应——为中度至中度患者开出美金刚处方 严重 AD，和/或抗精神病药物来控制 AD 行为症状，和/或可能导致严重不良反应 事件 (SAE)。我们的初步分析显示，6% 的 AD 患者在 ChEI 后开始服用抗毒蕈碱药物 开始治疗后，分别有 30% 和 23% 的 AD 患者开始使用美金刚和抗精神病药物 初始级联。尽管一些研究描述了 ChEI 在 AD 中的初始处方级联，但没有一项研究 的研究评估了由于 ChEI 的药物-药物相互作用引起的处方级联的影响， 抗毒蕈碱药。因此，本研究的总体目标是评估医疗保健的影响 社区居住的老年人之间的 ChEI 级联处方及其相关相互作用 广告。拟议研究的具体目标是：（1）检查处方级联的程度 患有 AD 的老年人中 ChEI 的含量； (2) 评估与 ChEI 抗毒蕈碱药物相关的全因 SAE 老年人与 AD 的相互作用。该研究将涉及基于倾向得分匹配的队列设计 全国 65 岁以上患有 AD 的老年人队列。 ChEI 的初始处方级联将包括启动 抗毒蕈碱药。进一步的级联反应将包括启动美金刚（用于中度至重度 AD）和 抗精神病药（用于 AD 的行为症状）。全因 SAE 包括全因住院治疗、 急诊科就诊、住院治疗和死亡率。多年多州医疗保险数据涉及 A、B 和 D 部分将用于检验以下假设： (i) ChEI-抗毒蕈碱药物间相互作用 由于 AD 恶化，导致进一步级联反应，导致中度至重度患者需要使用美金刚 AD 以及抗精神病药处方来控制 AD 的行为症状，并且 (ii) 存在更大的影响 ChEI-抗毒蕈碱相互作用导致全因 SAE 的风险。伴随 ChEI 抗毒蕈碱使用者将 与同时服用 ChEI 和米拉贝隆（一种非抗胆碱能替代品）的患者相比。该研究将 在安德森行为模型的多变量背景下调整选择偏差。鲁棒 Cox 比例 危险模型将用于解释匹配的集合。拟议的研究将具有重要的临床意义 以及预防、检测和逆转 AD 处方级联的政策影响。