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

项目摘要/摘要 痴呆症是老年人的一个主要公共卫生问题。阿尔茨海默病(AD)占50%到60% 痴呆症病例和近一半与痴呆症相关的死亡。胆碱酯酶抑制剂(ChEIs)形成了第一条线 阿尔茨海默病的药物治疗。然而，CHEIs的治疗效果被认为是适度的，它们的使用 会导致不良反应。尿失禁是CHEI治疗的一个突出的副作用，它是 通常与处方级联有关-这是一种临床现象，CHEI导致尿液 大小便失禁导致开出抗肌松药的处方。CHEIs和抗霉菌药物的相互作用往往会使 CHEIs的适度治疗益处，并可由于治疗相反的机制而加重AD 行为。阿尔茨海默病的这种恶化可能会导致更多的级联反应--开出美金刚治疗中度至... 严重的AD，和/或抗精神病药物来管理AD的行为症状，和/或可能导致严重的不良反应 事件(SAE)。我们的初步分析显示，6%的AD患者在CHEIs后开始使用抗霉菌药物 分别有30%和23%的AD患者在治疗后开始服用美金刚和抗精神病药物 最初的级联。尽管一些研究已经描述了阿尔茨海默病患者CHEI的最初处方级联反应，但没有一项研究 的研究评估了由于CHEIs和CHEIs的药物-药物相互作用而导致的处方级联的影响 抗血吸虫药物。因此，这项研究的总体目标是评估 在社区老年人中开出CHEI的级联及其相关相互作用的处方 广告。拟议研究的具体目标是：(1)检查开出连锁药方的程度 评估老年AD患者的CHEI；以及(2)评估与CHEI-抗心肌梗死相关的所有原因的SAEs 老年阿尔茨海默病患者的相互作用。这项研究将涉及倾向得分匹配队列设计，基于 65岁阿尔茨海默病患者的国家队列老年人。CHEIs的初始处方级联将包括启动 抗血吸虫药物。进一步的级联反应将包括启动美金刚(针对中到重度AD)和 抗精神病药物(治疗AD的行为症状)。全因SAE S将包括全因住院， 急诊科就诊、住院和死亡率。多年的多州医疗保险数据包括 A、B和D部分将用于检验以下假设：(I)CHEI-抗霉菌药物-药物相互作用 由于阿尔茨海默病的恶化导致进一步的级联反应，导致处方美金刚治疗中到重度 AD，以及处方抗精神病药物来管理AD的行为症状，以及(Ii)有更大的 由于CHEI-抗肌萎缩侧索硬化症相互作用而导致的全原因SAE的风险。随之而来的CHEI-抗蠕虫症用户将 与同时服用CHEIs和米拉贝格隆的患者相比，米拉贝格隆是一种非抗胆碱能替代品。这项研究将 在安德森行为模型的多变量背景下调整选择偏差。稳健的Cox比例 将使用危险模型来解释匹配的集合。这项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中处方级联的政策含义。

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.