Clinical and Informatics Research on Large Clinical Databases

大型临床数据库的临床和信息学研究

• 批准号: 10487169
• 负责人: Clement McDonald
• 金额: $ 155.45万
• 依托单位: NATIONAL LIBRARY OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487169
• 关键词: Address; Admission activity; Adrenergic beta-Antagonists; Adverse drug effect; Adverse effects; Aging; Agreement; Ambulatory Care; Amoxicillin; Angiotensin-Converting Enzyme Inhibitors; Antibiotics; Anticoagulants; Antidiabetic Drugs; Antihypertensive Agents; Antiplatelet Drugs; Arrhythmia; Azithromycin; Big Data; Bone Density; Bone structure; Breast; COVID-19; COVID-19 severity; Calcium Channel Blockers; Cardiac; Cardiovascular Diseases; Cephalexin; Cessation of life; Characteristics; Chronic; Chronic Kidney Failure; Ciprofloxacin; Clavulanate; Clinical; Clinical Informatics; Clinical Trials; Cohort Studies; Collagen Type I; Complication; Data; Databases; Deterioration; Diabetes Mellitus; Diagnosis; Disease; Dissection; Diuretics; Drug Controls; Drug Exposure; Drug usage; Elderly woman; Enrollment; Epidemiology; Estrogens; Event; Exhibits; Female; Femoral Fractures; Fiber; Fluoroquinolones; Fracture; Glucose; Goals; Health; Hip region structure; Hormone replacement therapy; Hospitals; Hot flushes; Impaired cognition; Incidence; Infection; Influenza; Inpatients; Insulin; Intensive Care Units; Levaquin; Lipids; Long COVID; Long QT Syndrome; Longevity; Malignant Neoplasms; Marketing; Medicare; Medicare Part A; Menopause; Metformin; Methodology; Moxifloxacin; Night Sweating; Non-Insulin-Dependent Diabetes Mellitus; Observational Study; Oral; Osteoporosis; Outcome; Outpatients; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Pneumonia; Population; Postmenopausal Osteoporosis; Prevention; Progestins; Proton Pump Inhibitors; Publishing; Raloxifene; Regression Analysis; Reporting; Research; Rheumatism; Risk; Ruptured Aortic Aneurysms; SARS-CoV-2 infection; Serious Adverse Event; Signs and Symptoms; Stroke; Sulfonylurea Compounds; Symptoms; Syndrome; Tendon structure; Tensile Strength; Testing; Thiazolidinediones; Time; Torsades de Pointes; United States Department of Veterans Affairs; Withdrawal; Woman; analog; beneficiary; bisphosphonate; blood pressure medication; clinical database; clinical risk; diabetic; diabetic patient; drug development; drug maintenance; drug market; effective therapy; follow-up; fracture risk; glucagon-like peptide 1; hazard; human study; informatics infrastructure; inhibitor/antagonist; insight; interest; medication safety; mortality; mortality risk; pre-clinical; rituximab; sociodemographics; tendon rupture; tocilizumab; warning label

A. Possible Beneficial and Adverse Drug Effects on SARS-COV-2 Infections (COVID-19) We have identified one set of drugs used in ambulatory care that might reduce or increase incidence and/or severity of COVID-19. This combination is being tested in clinical trials, but the number of subjects has been small and observational data will likely be needed to support these studies. Some drugs that might reduce or aggravate COVID-19 include non-steroidals, anticoagulants, H2 blockers, anti-platelet agents, ACE inhibitors, and ARBs that treat rheumatologic disease (Tocilizumab, Rituximab, Sarilumab). We will study the association with the incidence and severity of COVID-19 infections. We are also studying the phenomenon described as Long COVID to assess how distinct a syndrome it is by comparing it with what might be called Long Influenza. B. Metformin and longevity In the last decade, research on aging found that metformin use was associated with a reduction in cognitive decline and longer survival among diabetics compared to those treated with other oral agents. The FDA recently approved the first human study to see if an anti-diabetic medication, metformin, can protect diabetic patients from multiple diseases from aging. We identified about 300,000 Medicare beneficiaries diagnosed with type 2 diabetes post 12/31/2006 and followed them until death, switching to capitated plans, disenrollment from Medicare, or 12/31/2016, whichever comes first. During this follow-up, we also collected socio-demographic information, as well as, the use of common maintenance drugs used among diabetics, specifically: metformin, insulin, sulfonylureas, thiazolidinedione, GLP-1 analogues, DPP-4 inhibitors, SGLT-2 inhibitors, and other glucose lowering drugs), but also 5 antihypertensive medications (diuretics, beta-blockers, calcium-channel blockers, ACE inhibitors, and ARBs) and 1 lipid-lowering drug (statin). Controlling for other medication use and patients characteristics in time-varying manner, metformin was not strongly associated with longer survival (HR=0.95) and the association was not statistically significant. Rather, compared to the no use of each study medication, mortality risk declined with use of 3 diabetes drugs (SGLT-2 inhibitors, GLP-1 analogues, and DPP-4 Inhibitors), 3 blood pressure medications (diuretics, ARBs, and ACEI inhibitors) and statins. Statins exhibited the most consistent reduction in all-cause mortality risk but 20% of study patients never took a statin, suggesting missed prevention opportunities. C. Proton Pump Inhibitors (PPIs) and mortality PPIs have been associated with increases in the incidence of pneumonia, C Decile infection and osteoporosis/fractures, probable chronic renal failure, and cardiac events. Xie et al reported that PPIs could also increase the risk of death using Veterans Affairs (VA) data (HR of 1.15 1.25). From 2007-2016 Medicare Parts A, B and D data, we identified 1.2 million Medicare beneficiaries. We also defined a set of covariates: use of PPIs, use of H2 blockers as a control drug, admission to intensive care units or inpatient hospitals, socio-demographics, presence of 58 chronic conditions and treated them as time-dependent covariates in our main analysis of Cox proportion hazard regression. In addition to treating covariates in time-varying manner, we used the concept of lag-time to define drug exposure period in order to control for protopathic bias which occurs when the outcome of interest is associated with an exposure that actually results from early signs and symptoms of the outcome under study. With use of lag times, PPIs had no associations with death, in agreement with one RCT that showed no such association. D. Fluoroquinolones (FQ) and tendon complication FQs are among the most widely prescribed antibiotics in the outpatient setting. Several studies have reported the plausible associations between the use of FQs and tendon complications. The FDA issued black box warning labels to FQs since 2008. Several observational studies associate the use of FQ with an increased risk for tendon rupture, aortic aneurysms or dissections (AA/AD). The fact that collagen type I and III fibers provide tensile strength to both tendons and aortic walls, and that FQs can disrupt these fibers in some circumstances, magnify concerns about these reported associations. Some prior studies described the relationship between FQs and tendon rupture as a class effect and included amoxicillin as a control drug to determine whether these complications are specific to FQs. We separately included 3 FQs (ciprofloxacin, levofloxacin, moxifloxacin) and 4 non-FQ antibiotics (amoxicillin, amoxicillin-clavulanate, azithromycin or cephalexin), 5 of which were the top 5 antibiotic agents in the US. Using Fine-Gray competing risk regression analyses treating death as a competing risk, we assessed the independent risk of tendon rupture for each antibiotic use in a 1.2 million Medicare population. Precisely, we assessed the risk by temporal exposure within study antibiotics (within 30 days, 31-60 days, more than 60 days) to avoid non-differential misclassification that can occur with too simple (yes/no) drug exposure. E. Association between Female Hormone replacement therapy (HRT) and longevity, cardiovascular diseases and cancers HRT is an effective treatment for the typical menopause-related symptoms (such as hot flashes, night sweats, irregular periods etc.) and long-term health problems associated with menopause (the risk of osteoporosis, cardiovascular disease and stroke). Reports of some studies have trumpeted negative effects of HRT on outcomes such as cardiovascular diseases, cancers, and all-cause mortality. However, the evidence behind them is weak or has been reversed. In this study, we traced about 1.5 million female Medicare beneficiaries from Medicare Part D entry to the onset of each outcome, death, switching to capitated plan, disenrollment from Medicare, or end of data availability whichever comes first and then we compared each risk among women treated with HRT of various kinds with to those not treated, and we treated almost all covariates as time time-dependent in a Cox proportional hazard regression analysis. Estrogen use, but not combined estrogen+progestin use, was associated with less risk of breast and other studied cancers and a significant reduction in mortality risk. F. Characterizing the cardiac risks of commonly prescribed QT-prolonging drugs Drug-induced long QT syndrome is one of the most frequent cause of withdrawal or relabeling of marketed drugs. It is difficult to detect serious adverse events associated with QT prolongation during drug development, both in the preclinical and clinical phases of drug trials. The clinical risks of many QT-prolonging drugs are only discovered by post-marketing surveillance. This study leverages the large CMS database (over 1.2 million subjects) to provide insight into the cardiac risks of some QT-prolonging drugs with known risk of severe cardiac arrhythmia (Torsades de pointes) and showed that some medications declared to be long QT risks did exhibit risk and others did not. G. Evaluating the risk of fractures among elderly women enrolled in Medicare Osteoporosis characterized by progressive deterioration of bone structure due to decreased bone mineral density (BMD) has been found to be closely associated with fractures. There are several pharmacotherapies available for prevention and treatment of postmenopausal osteoporosis including bisphosphonate, estrogen, raloxifene, denosumab and more. However, their beneficial and/or detrimental effect on fractures is not well addressed. We are conducting a nationwide cohort study of patients with osteoporosis to compare risks of any, hip and atypical femur fractures among patients treated with any of the drugs

A. 药物对 SARS-COV-2 感染 (COVID-19) 可能产生的有益和不利影响 我们已经确定了一组用于门诊护理的药物，可能会减少或增加 COVID-19 的发病率和/或严重程度。这种组合正在临床试验中进行测试，但受试者数量很少，可能需要观察数据来支持这些研究。一些可能减少或加重 COVID-19 的药物包括非甾体类药物、抗凝剂、H2 阻滞剂、抗血小板药物、ACE 抑制剂和治疗风湿病的 ARB（托珠单抗、利妥昔单抗、Sarilumab）。我们将研究与 COVID-19 感染的发生率和严重程度的关联。我们还在研究被描述为“长新冠病毒”的现象，通过将其与所谓的“长流感”进行比较来评估其综合征的独特性。 B. 二甲双胍与长寿 在过去的十年中，关于衰老的研究发现，与接受其他口服药物治疗的患者相比，二甲双胍的使用与糖尿病患者认知能力下降的减少和更长的生存期有关。 FDA 最近批准了第一项人体研究，以确定抗糖尿病药物二甲双胍是否可以保护糖尿病患者免受多种衰老疾病的影响。我们确定了约 300,000 名 Medicare 受益人在 2006 年 12 月 31 日后被诊断患有 2 型糖尿病，并对他们进行跟踪直至死亡、转为人头计划、退出 Medicare 或 2016 年 12 月 31 日（以先到者为准）。在此随访期间，我们还收集了社会人口统计信息，以及糖尿病患者常用维持药物的使用情况，特别是：二甲双胍、胰岛素、磺酰脲类、噻唑烷二酮、GLP-1类似物、DPP-4抑制剂、SGLT- 2 种抑制剂和其他降血糖药物），还有 5 种抗高血压药物（利尿剂、β 受体阻滞剂、钙通道阻滞剂、ACE 抑制剂和ARB）和 1 种降脂药（他汀类药物）。 以随时间变化的方式控制其他药物使用和患者特征后，二甲双胍与较长生存期没有很强的相关性（HR=0.95），并且这种相关性不具有统计学意义。相反，与不使用每种研究药物相比，使用 3 种糖尿病药物（SGLT-2 抑制剂、GLP-1 类似物和 DPP-4 抑制剂）、3 种血压药物（利尿剂、ARB 和 ACEI）可降低死亡风险抑制剂）和他汀类药物。他汀类药物在全因死亡风险方面表现出最一致的降低作用，但 20% 的研究患者从未服用过他汀类药物，这表明他们错过了预防机会。 C. 质子泵抑制剂 (PPI) 和死亡率 PPI 与肺炎、C Decile 感染和骨质疏松/骨折、可能的慢性肾功能衰竭和心脏事件的发生率增加有关。 Xie 等人使用退伍军人事务部 (VA) 数据报告称，PPIs 还可能增加死亡风险（HR 为 1.15 1.25）。根据 2007 年至 2016 年 Medicare A、B 和 D 部分的数据，我们确定了 120 万 Medicare 受益人。我们还定义了一组协变量：使用 PPI、使用 H2 阻滞剂作为对照药物、入住重症监护病房或住院医院、社会人口统计、58 种慢性病的存在，并将它们视为时间依赖性协变量。 Cox比例风险回归分析。除了以随时间变化的方式处理协变量之外，我们还使用滞后时间的概念来定义药物暴露期，以控制原病性偏差，当感兴趣的结果与实际由早期体征和实际结果引起的暴露相关时，就会发生原病性偏差。研究结果的症状。通过使用滞后时间，PPIs 与死亡没有关联，这与一项显示没有这种关联的随机对照试验一致。 D. 氟喹诺酮类药物 (FQ) 和肌腱并发症 FQ 是门诊中最广泛使用的抗生素之一。几项研究报告了 FQ 的使用与肌腱并发症之间的合理关联。自 2008 年起，FDA 就对 FQ 发布了黑框警告标签。多项观察性研究表明，使用 FQ 会增加肌腱断裂、主动脉瘤或夹层 (AA/AD) 的风险。 I 型和 III 型胶原蛋白纤维为肌腱和主动脉壁提供抗拉强度，并且 FQ 在某些情况下会破坏这些纤维，这一事实加剧了人们对这些已报道的关联的担忧。之前的一些研究将 FQ 与肌腱断裂之间的关系描述为类效应，并使用阿莫西林作为对照药物，以确定这些并发症是否是 FQ 特有的。我们分别纳入了 3 种 FQ 抗生素（环丙沙星、左氧氟沙星、莫西沙星）和 4 种非 FQ 抗生素（阿莫西林、阿莫西林克拉维酸、阿奇霉素或头孢氨苄），其中 5 种是美国排名前 5 的抗生素药物。使用 Fine-Gray 竞争风险回归分析，将死亡视为竞争风险，我们评估了 120 万医疗保险人群中每种抗生素使用情况下肌腱断裂的独立风险。准确地说，我们通过研究抗生素的时间暴露（30 天、31-60 天、60 天以上）来评估风险，以避免因过于简单（是/否）药物暴露而可能发生的非差异性错误分类。 E. 女性激素替代疗法 (HRT) 与长寿、心血管疾病和癌症之间的关联 HRT 是治疗典型的更年期相关症状（如潮热、盗汗、月经不规律等）和与更年期相关的长期健康问题（骨质疏松、心血管疾病和中风的风险）的有效治疗方法。一些研究报告宣扬激素替代疗法对心血管疾病、癌症和全因死亡率等结果的负面影响。然而，它们背后的证据薄弱或已被推翻。在这项研究中，我们追踪了大约 150 万女性 Medicare 受益人，从加入 Medicare D 部分到每种结果（死亡、转为按人头计划、从 Medicare 退出或数据可用性终止，以先到者为准）的发生，然后我们比较了各个风险接受各种 HRT 治疗的女性与未接受治疗的女性相比，我们在 Cox 比例风险回归分析中将几乎所有协变量视为时间依赖性。雌激素的使用，而不是雌激素+孕激素的联合使用，与乳腺癌和其他研究的癌症的风险降低以及死亡风险的显着降低相关。 F. 描述常用 QT 延长药物的心脏风险特征 药物引起的长 QT 综合征是上市药物撤回或重新标签的最常见原因之一。无论是在药物试验的临床前阶段还是临床阶段，在药物开发过程中都很难检测到与 QT 延长相关的严重不良事件。许多 QT 延长药物的临床风险只能通过上市后监测来发现。这项研究利用大型 CMS 数据库（超过 120 万名受试者）深入了解一些具有已知严重心律失常（尖端扭转型室性心动过速）风险的延长 QT 间期的药物的心脏风险，并表明一些声称具有长 QT 风险的药物确实会增加心脏风险。表现出风险，而其他人则没有。 G. 评估参加医疗保险的老年妇女的骨折风险 骨质疏松症的特征是由于骨矿物质密度（BMD）降低而导致骨结构逐渐恶化，已发现与骨折密切相关。有多种药物疗法可用于预防和治疗绝经后骨质疏松症，包括双膦酸盐、雌激素、雷洛昔芬、狄诺塞麦等。然而，它们对骨折的有益和/或有害影响尚未得到很好的解决。我们正在对骨质疏松症患者进行一项全国性队列研究，以比较接受任何药物治疗的患者发生髋部骨折和非典型股骨骨折的风险