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: 8426050
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8426050
• 关键词: Address; Age; Alcohol consumption; Ambulatory Monitoring; Antidiabetic Drugs; Antihypertensive Agents; Area; Arthritis; Attitude; Benign; Biostatistical Methods; California; Caring; Caucasoid Race; 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 Care Costs; Health Policy; Health Resources; Health Services Research; Hepatotoxicity; Incentives; Incidence; 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; 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; Rheum; Rheumatism; Rheumatoid Arthritis; Rheumatology; 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; public health relevance; 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奖的申请，申请人是加州大学弗朗西斯科分校（UCSF）和弗朗西斯科退伍军人事务医疗中心（SFVAMC）的风湿病学家和卫生服务研究人员Gabriela Schmajuk博士。结合培训计划，重点是先进的生物统计方法，定性技术和卫生政策，目前的研究的目标是使用丰富的行政和电子健康记录数据，以制定一个合理的方法来监测药物毒性使用甲氨蝶呤，一线治疗炎症性关节炎患者，作为一种模型药物。基于她先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 Arthritis Rheum 2011;40（6）：559），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（包括非预期危害）的结果，并制定个性化的监测策略，以改善患者结局并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，这些措施涉及慢性风湿性疾病中使用的门诊药物的实验室毒性监测，但尚不清楚在没有患者报告症状的情况下频繁进行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止药物可能导致不适当的，负担沉重的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周进行一次肝功能检查（LFT），目的是降低肝纤维化和肝硬化的发生率。但是，频繁的、无针对性的监测，以及检测到潜在的临床上不显著的LFT升高，可能会产生意想不到的后果。例如，如果不必要地停止甲氨蝶呤，患者可能会增加疼痛或残疾，如果改用高价生物制剂，则会增加成本，或者如果甲氨蝶呤被糖皮质激素替代，则会增加伤害，糖皮质激素具有更长期的毒性。频繁、无针对性的毒性监测影响的不确定性代表了知识上的关键差距，阻碍了改善患者安全性、减少意外伤害和最大限度地提高风湿性疾病患者护理质量的努力。本提案的目的1和2将利用退伍军人事务系统的管理和临床数据，以（1）评估患有炎性关节炎的甲氨蝶呤使用者中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，该规则识别发展LFTx的低风险患者。2 x正常值上限，因此可能是不太频繁监测的候选值。目标3将召集不同群体的患者和临床医生的焦点小组，以确定态度，并确定周围的障碍，使用一个潜在的不太密集的监测时间表，为选定的低风险患者。在此获得的知识将为该领域的患者安全措施的下一次迭代提供信息，可能减少不必要的测试，同时促进有效的筛查。此外，它将为R 01提供初步数据，R 01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一个模型，用于研究监测在其他常见的临床情况下（例如，抗高血压药，他汀类药物，或抗糖尿病药物的用户），药物毒性监测在药物选择和疾病管理中起着关键作用。Schmajuk博士组建了一支出色的导师团队，他们在药物监测、护理质量和风湿性疾病方面具有专业知识，并在使用国家VA数据解决这些问题方面具有丰富的经验。她将有机会进入一个丰富的研究环境，包括加州大学旧金山分校关节炎研究小组和旧金山弗朗西斯科弗吉尼亚州老年医学部，与他们各自的“工作进展”研讨会，生物统计学家，和大型院系与我类似的研究兴趣。SFVAMC和我们的学术附属机构的资源将为我提供培训机会，包括VA质量学者奖学金的第二年和在执行和传播科学计划的UCSF培训招生。Schmajuk博士的长期目标是成为一家领先的学术机构的风湿病学家，在那里她可以从事卫生服务研究的独立研究事业。她的研究议程将解决风湿性疾病患者的护理质量，药物利用和药物安全性问题。这个指导职业发展奖将提供必要的技能，指导和经验，推动她独立。