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

项目总结/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%至60%， 痴呆病例和近一半的痴呆相关死亡。胆碱酯酶抑制剂（ChEI）形成第一线 AD的药物治疗。然而，ChEI的治疗效果被认为是适度的， 导致不良影响。尿失禁是ChEI治疗的一个突出的不良反应， 通常涉及处方级联-一种临床现象，其中ChEI诱导的尿 尿失禁导致开抗毒蕈碱药的处方。ChEI和抗毒蕈碱药物的相互作用往往会使 ChEI的治疗益处不大，并且由于ChEI的治疗相反机制， 行动AD的这种恶化可以沉淀额外的级联反应-美金刚用于中度至中度AD。 重度AD，和/或抗精神病药物治疗AD的行为症状，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后开始使用抗毒蕈碱药物， 开始，美金刚和抗精神病药分别由30%和23%的AD患者开始， 初始级联。虽然一些研究已经描述了AD中ChEI的初始处方级联，但没有一项研究表明， 的研究评估了由于ChEI的药物相互作用而导致的处方级联的影响， 抗毒蕈碱药因此，本研究的总体目标是评估 ChEI的处方级联及其在社区老年人中的相关相互作用， AD.本研究的具体目标是：（1）检查处方级联的程度 老年AD患者中ChEI的比例;（2）评估与ChEI-抗毒蕈碱相关的全因SAE 老年人与AD的相互作用。该研究将涉及基于以下因素的倾向评分匹配队列设计： 全国年龄> 65岁的AD患者队列。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开始美金刚（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将包括全因住院， 急诊就诊、住院和死亡率。多年的多州医疗保险数据， A、B和D部分将用于检验以下假设：（i）ChEI-抗毒蕈碱药物-药物相互作用 由于AD恶化导致进一步级联，导致美金刚胺处方用于中度至重度AD AD，以及抗精神病药的处方，以管理AD的行为症状，和（ii）有更大的 ChEI-抗毒蕈碱相互作用引起的全因SAE风险。伴随ChEI-抗毒蕈碱药物使用者将 与ChEI和米拉贝隆（一种非抗胆碱能替代药物）的伴随使用者相比。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倚。稳健考克斯比例 将使用危险模型来说明匹配的集合。这项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.