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.可能对SARS-COV-2感染的有益和不利药物影响（Covid-19） 我们已经确定了一套用于门诊护理中的药物，这些药物可能会降低或增加COVID-19的发病率和/或严重性。这种组合正在临床试验中进行测试，但是受试者的数量很少，并且可能需要观察数据来支持这些研究。一些可能降低或加重COVID-19的药物包括非甾体类药物，抗凝剂，H2阻滞剂，抗植物药物，ACE抑制剂和治疗风湿病疾病的ARB（Tocilizumab，Rituximab，sarilumab）。我们将研究与Covid-19感染的发病率和严重程度的关联。我们还研究了描述为长期相互兴趣的现象，可以通过将其与所谓的长流感来评估综合征的不同。 B.二甲双胍和寿命 在过去的十年中，对衰老的研究发现，与其他口服药物相比，二甲双胍的使用量与糖尿病患者的认知能力下降和较长的生存率有关。 FDA最近批准了第一项人类研究，以查看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疾病的衰老。我们确定了大约300,000名医疗保险受益人，这些受益人被诊断出患有2型糖尿病，并在2006年12月31日之后，直到死亡，切换到投票计划，从Medicare撤消了Medicare或12/31/2016，以先到者为准。在此随访期间，我们还收集了社会人口统计学信息，以及使用糖尿病患者中使用的常见维持药物，特别是：二甲双胍，胰岛素，磺酰氟脲，硫代授予二酮，GLP-1类似物，DPP-1类似物，DPP-4抑制剂，SGLT-2抑制剂，SGLT-2抑制剂，以及其他Glucose Prististion，也是其他5个抑制剂，但也是5 5（DIBIS），但（指示），DIH-5（提示），提示（提示），dipipt，dipipt，diming timpict，dist niming（提示），抑制剂，该抑制剂，抑制剂，抑制剂。 β受体阻滞剂，钙通道阻滞剂，ACE抑制剂和ARB）和1种降低脂质的药物（Statin）。 控制其他药物使用和患者特征以时间变化的方式，二甲双胍与较长的生存期（HR = 0.95）并不密切相关，并且该关联在统计学上没有显着意义。相反，与不使用每种研究药物的使用相比，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抑制剂）和毒素。他汀类药物表现出最大的全因死亡率风险降低，但有20％的研究患者从未服用过汀类药物，这表明缺失了预防机会。 C.质子泵抑制剂（PPI）和死亡率 PPI与肺炎，C十分感染和骨质疏松/断裂，可能的慢性肾衰竭和心脏事件的发生率增加有关。 Xie等人报道说，PPI还可以使用退伍军人事务（VA）数据（HR为1.15 1.25）增加死亡的风险。从2007年至2016年，Medicare A部分A，B和D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阻滞剂作为控制药物，接受重症监护病房或住院医院，社会人口统计学，58种慢性病的存在，并将其作为时间依赖性协变量在我们对COX比例危害危害回归中的主要分析中。除了以时间变化的方式治疗协变量外，我们还使用了滞后时间的概念来定义药物暴露期，以控制原生病偏差，这在感兴趣的结果与暴露有关的结果实际上是由于所研究结果的早期体征和症状而导致的。使用滞后时间，PPI与未显示这种关联的RCT一致。 D.氟喹诺酮（FQ）和肌腱并发症 FQ是门诊环境中规定的抗生素之一。几项研究报道了使用FQS和肌腱并发症之间的合理关联。 FDA自2008年以来向FQS发出了黑匣子警告标签。几项观察性研究将FQ的使用与肌腱破裂，主动脉瘤或解剖（AA/AD）的风险增加。 I型和III型纤维为肌腱和主动脉壁提供了拉伸强度，并且在某些情况下可以破坏这些纤维，这一事实扩大了对这些报告的关联的关注。一些先前的研究将FQS与肌腱破裂之间的关系描述为类别的效应，并将阿莫西林作为对照药物，以确定这些并发症是否针对FQS。我们分别包括3种FQS（环丙沙星，左氧氟沙星，Moxifloxacin）和4种非FQ抗生素（阿莫西林，阿莫西林 - 克拉维烷酸酯，阿奇乳霉菌素或头甲霉素），其中5种是美国美国前5名抗生素药物。我们使用细灰竞争风险回归分析将死亡视为竞争风险，我们评估了120万Medicare人群中每种抗生素使用的肌腱破裂的独立风险。确切地说，我们通过研究抗生素（30天，31-60天，超过60天）内的时间暴露来评估风险，以避免使用过于简单（是/否）药物暴露可能发生的非差异错误分类。 E.女性激素替代疗法（HRT）与寿命，心血管疾病和癌症之间的关联 HRT是针对典型更年期相关症状的有效治疗方法（例如潮热，汗水，不规则时期等）和与绝经相关的长期健康问题（骨质疏松症，心血管疾病和中风的风险）。一些研究的报告吹嘘了人力资源管理对心血管疾病，癌症和全因死亡率等结果的负面影响。但是，它们背后的证据是薄弱的或已经逆转了。在这项研究中，我们从Medicare D部分进入了大约150万女性医疗保险受益人，到每个结果，死亡，改用转向计划的计划，撤销计划，Medicare的撤销或数据可用性的结束，然后我们将每种风险与未经治疗的hrt进行了对危险的治疗，并将各种hrt的每种风险都与您进行了分析，并将其用于危险分析。使用雌激素，但不使用雌激素+孕激素的使用，与乳腺癌和其他研究的癌症的风险较小有关，死亡风险显着降低。 F.表征常规规定QT繁殖药物的心脏风险 药物引起的长QT综合征是戒断或重新标记的最常见原因之一。在药物试验的临床前和临床阶段，都很难检测到与QT延长相关的严重不良事件。许多QT繁殖药物的临床风险仅通过市场后的监视发现。这项研究利用了大型CMS数据库（超过120万受试者），可以深入了解某些QT繁殖药物的心脏风险，这些药物患有严重心律不齐的严重风险（Torsades de Pointes），并表明某些药物宣称为长期QT风险确实显示出风险，而另一些药物则没有。 G.评估参加Medicare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降低而导致骨结构的逐渐恶化（BMD）与骨折密切相关。有几种可预防和治疗绝经后骨质疏松症的药物治疗，包括双膦酸盐，雌激素，raloxifene，denosumab等。但是，它们对骨折的有益和/或有害作用尚未得到很好的解决。我们正在对骨质疏松症患者进行全国范围的队列研究，以比较接受任何药物治疗的患者中任何，髋关节和非典型股骨骨折的风险