A rational approach to liver toxicity monitoring in methotrexate users

甲氨蝶呤使用者肝脏毒性监测的合理方法

• 批准号: 8795166
• 负责人: Gabriela Schmajuk
• 金额: $ 13.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8795166
• 关键词: Address; Age; Alcohol consumption; Ambulatory Monitoring; Antidiabetic Drugs; Antihypertensive Agents; Area; Arthritis; Attitude; Benign; Biostatistical Methods; California; Caring; Caucasians; Chronic; Chronic Disease; Clinical; Clinical Data; Data; Detection; Diagnostic; Disease Management; Dose; Drug Utilization; Drug toxicity; Drug usage; Electronic Health Record; Enrollment; Environment; Faculty; Fellowship; Focus Groups; Frequencies; Geriatrics; Glucocorticoids; Goals; Health; Health Care Costs; Health Policy; Health Resources; Health Services Research; Hepatotoxicity; Incentives; Incidence; Inflammatory Arthritis; Institution; Intervention; K-Series Research Career Programs; Knowledge; Laboratories; Liver; Liver Cirrhosis; Liver Fibrosis; Liver Function Tests; Measures; Medical center; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Methods; Methotrexate; Mining; Modeling; Monitor; Oral; Outcome; Pain; Patient risk; Patients; Pattern; Perception; Performance; Pharmaceutical Preparations; Physicians; Play; Price; Provider; Quality of Care; Race; Reaction; Recording of previous events; Regimen; Reporting; Research; Research Personnel; Resources; Rheumatism; Rheumatoid Arthritis; Rheumatology; Rhubarb food; Risk; Role; San Francisco; Schedule; Science; Series; Specificity; Study models; Symptoms; System; Systemic Lupus Erythematosus; Techniques; Test Result; Testing; Toxic effect; Training; Uncertainty; Universities; Veterans; Work; autoimmune arthritis; career; cost; design; disability; evidence base; experience; high risk; improved; interest; liver injury; patient safety; programs; response; rheumatologist; screening; skills; tool

DESCRIPTION (provided by applicant): This is an application for a K23 award for Dr. Gabriela Schmajuk, a rheumatologist and health services research at the University of California, San Francisco (UCSF) and the San Francisco Veterans Affairs Medical Center (SFVAMC). Combined with a training plan focused on advanced biostatistical methods, qualitative techniques, and health policy, the goal of the current study is to use rich administrative and electronic health record data to develop a rational approach to drug toxicity monitoring using methotrexate, the first-line treatment for patients with inflammatory arthritis, as a model drug. Building upon her prior work which evaluated quality measures and patient safety in rheumatoid arthritis and systemic lupus erythematosus (JAMA 2011;305(5):480; Semin Arthritis Rheum 2011;40(6):559), the proposed series of projects will provide a framework to characterize the outcomes of current drug toxicity monitoring practices (including unintended harms) and individualize monitoring strategies that will improve patient outcomes and reduce health resource overuse. Although the National Quality Forum (NQF) recently endorsed several quality measures that address laboratory toxicity monitoring for outpatient drugs used in chronic rheumatic conditions, it is not known whether frequent toxicity monitoring in the absence of patient-reported symptoms leads to improved patient outcomes. On the contrary, stopping a drug due to benign or transient laboratory abnormalities can result in diagnostic and treatment interventions that are inappropriate, burdensome, and expensive. In the case of methotrexate, new NQF measures require testing of liver function tests (LFTs) every 12 weeks with the intent of reducing the incidence of hepatic fibrosis and cirrhosis. But frequent, untargeted monitoring, and the detection of potentially clinically insignificant LFT elevations, may have unintended consequences. For example, patients may have increased pain or disability if methotrexate is unnecessarily stopped, increased costs if they are switched to high-priced biologic agents, or increased harm if methotrexate is substituted by glucocorticoids, which have more long-term toxicities. The uncertainty around the effects of frequent, untargeted toxicity monitoring represents a critical gap in knowledge that hinders efforts to improve patient safety, reduce unintended harms, and maximize the quality of care for patients with rheumatic diseases. Aims 1 and 2 of this proposal will leverage administrative and clinical data from the Veterans Affairs system to (1) assess current practice patterns and downstream consequences of liver toxicity monitoring among methotrexate users with inflammatory arthritis and (2) develop and validate a prediction rule that identifies patients at low risk of developing LFTx > 2 x the upper limit of normal and thus may be candidates for less frequent monitoring. Aim 3 will convene focus groups of a diverse group of patients and clinicians to determine attitudes and identify barriers around using a potentially less intensive monitoring schedule for selected low- risk patients. The knowledge gained here will inform the next iteration of patient safety measures in this area, potentially reducing unnecessary testing while promoting screening that is effective. In addition, it will provide preliminary data for a R01 that will implement and test the value of a clinical decision support tool to guide medication toxicity monitoring for methotrexate users. The paradigm developed here can serve as a model for studying monitoring in other common clinical scenarios (for example, for users of anti-hypertensives, statins, or antidiabetic agents) where drug toxicity monitoring plays a key role in medication choice and disease management. Dr. Schmajuk has assembled an exceptional mentorship team with expertise in issues of medication monitoring, quality of care, and rheumatic diseases, as well as experience in using national VA data to address these questions. She will have access to a rich research environment, including the UCSF Arthritis Research Group and the San Francisco VA Geriatrics division, with their respective "work-in-progress" seminars, biostatisticians, and large faculties with similar research interests to mine. The resources of the SFVAMC and our academic affiliate will provide me with training opportunities, including a second year of VA Quality Scholars Fellowship and enrollment in the UCSF Training in Implementation and Dissemination Sciences Program. Dr. Schmajuk's long term goal is to become a rheumatologist at a leading academic institution where she can pursue an independent research career in health services research. Her research agenda will address the questions of quality of care, drug utilization, and drug safety for patients with rheumatic diseases. This mentored career development award will provide the skills, mentorship, and experience necessary to propel her to independence.

描述(由申请人提供)：这是一份K23奖项的申请书，授予加布里埃拉·施马约克博士，她是加州大学旧金山分校(UCSF)和旧金山退伍军人事务医学中心(SFVAMC)的风湿病专家和医疗服务研究人员。结合以先进的生物统计学方法、定性技术和卫生政策为重点的培训计划，本研究的目标是利用丰富的行政和电子健康记录数据，开发一种合理的方法，使用炎性关节炎患者的一线治疗药物甲氨蝶呤作为模型药物进行药物毒性监测。在她之前评估类风湿性关节炎和系统性红斑狼疮的质量措施和患者安全性的工作(JAMA 2011；305(5)：480；Semin Artis Rheum 2011；40(6)：559)的基础上，拟议的一系列项目将提供一个框架，以表征当前药物毒性监测实践的结果(包括意外伤害)，并制定个性化监测策略，以改善患者结局，减少卫生资源过度使用。尽管国家质量论坛(NQF)最近批准了几项质量措施，解决了用于慢性风湿病的门诊药物的实验室毒性监测问题，但尚不清楚在没有患者报告的症状的情况下进行频繁的毒性监测是否会改善患者的预后。相反，由于良性或短暂的实验室异常而停药可能会导致不适当、负担沉重和昂贵的诊断和治疗干预。在甲氨蝶呤的情况下，新的NQF措施要求每12周进行一次肝功能测试(LFT)，目的是减少肝纤维化和肝硬变的发生率。但频繁的、无针对性的监测，以及检测到可能在临床上微不足道的LFT升高，可能会产生意想不到的后果。例如，如果不必要地停用甲氨蝶呤，患者可能会增加疼痛或残疾，如果改用高价生物制剂，可能会增加成本，如果用糖皮质激素取代甲氨蝶呤，可能会增加伤害，后者有更多的长期毒性。围绕频繁的、无针对性的毒性监测的影响的不确定性代表着知识中的一个严重差距，这阻碍了改善患者安全、减少意外伤害和最大限度地提高风湿病患者的护理质量的努力。该提案的目标1和2将利用退伍军人事务系统的管理和临床数据来(1)评估患有炎症性关节炎的甲氨蝶呤使用者的肝毒性监测的当前实践模式和下游后果，以及(2)开发和验证预测规则，该预测规则识别出患LFTx&GT；2的风险较低的患者是正常上限的2倍，因此可能是较少频繁监测的候选对象。AIM 3将召集不同患者和临床医生的焦点小组，以确定态度并确定障碍，对选定的低风险患者使用可能不那么密集的监测计划。在这里获得的知识将为这一领域的患者安全措施的下一次迭代提供信息，潜在地减少不必要的测试，同时促进有效的筛查。此外，它还将为R01提供初步数据，该R01将实施和测试临床决策支持工具的价值，以指导甲氨蝶呤使用者的药物毒性监测。这里开发的范例可以作为研究其他常见临床场景(例如，抗高血压药、他汀类药物或抗糖尿病药物的使用者)监测的模型，在这些情况下，药物毒性监测在药物选择和疾病管理中发挥关键作用。SchMajuk博士组建了一支卓越的指导团队，他们在药物监测、护理质量和风湿病问题上拥有专业知识，并在使用国家VA数据解决这些问题方面拥有经验。她将有机会接触到丰富的研究环境，包括加州大学旧金山分校的关节炎研究小组和旧金山退伍军人事务部，他们各自的“正在进行的”研讨会，生物统计学家，以及与我有相似研究兴趣的大型院系。SFVAMC和我们的学术分支机构的资源将为我提供培训机会，包括第二年的退伍军人管理局优质学者奖学金和加入加州大学旧金山分校的实施和传播科学培训计划。施马约克博士的长期目标是成为一家顶尖学术机构的风湿病专家，在那里她可以在卫生服务研究领域追求独立的研究生涯。她的研究议程将解决风湿病患者的护理质量、药物利用和药物安全性问题。这个辅导式职业发展奖将为她提供必要的技能、指导和经验，以推动她走向独立。