Impact of immunosuppression variability on outcomes after liver transplantation

免疫抑制变异对肝移植术后结局的影响

• 批准号: 10215492
• 负责人: Therese Bittermann
• 金额: $ 16.92万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215492
• 关键词: Accounting; Acute; Address; Adverse event; Algorithms; American; Award; Back; Biometry; Biopsy; Calcineurin inhibitor; Caring; Cessation of life; Characteristics; Clinical; Clinical Investigator; Clinical Trials; Communities; Consensus; Data; Development; Donor person; Effectiveness; Equilibrium; Evaluation; Event; Faculty; Fostering; Funding; Future; Goals; Grant; Guidelines; Hepatology; Hospitalization; Immunosuppression; Infection; Knowledge; Life; Liver; Liver Failure; Liver diseases; Maintenance; Malignant Neoplasms; Medicare; Medicare claim; Mentors; Mentorship; Meta-Analysis; Methodology; Monitor; Organ; Organ Donor; Outcome; Outcomes Research; Patient-Focused Outcomes; Patients; Pennsylvania; Pharmaceutical Preparations; Pharmacoepidemiology; Physicians; Population; Population Research; Probability; Protocols documentation; Publication Bias; Quality of life; Recommendation; Regimen; Research; Research Training; Resources; Risk; Safety; Sample Size; Serious Adverse Event; Standardization; Supervision; Techniques; Therapeutic immunosuppression; Time; Transplant Recipients; Transplantation; United Network for Organ Sharing; United States National Institutes of Health; Universities; adverse outcome; career development; clinical center; clinical epidemiology; clinical practice; comparative effectiveness; comparative efficacy; comparative safety; dosage; evidence base; evidence based guidelines; experience; graft failure; graft function; high risk; improved; improved outcome; inclusion criteria; innovation; insight; liver transplantation; mortality; novel; post-transplant; prevent; retransplantation; standardize guidelines; stem; transplant centers

PROJECT SUMMARY Over 95% of liver transplant (LT) recipients have only one opportunity to receive a new liver during their lifetimes and long-term patient survival depends upon prolonged graft functioning. As a result of advances in immunosuppression (IS), over 70% of recipients survive more than 5 years after LT, yet wide variability exists in clinical outcomes at the center-level. Most late post-LT deaths are not directly due to liver failure, but reflect the adverse consequences of prolonged IS therapy. Due to the lack of national recommendations to guide IS after LT, its management differs across centers. Moreover, comparative efficacy and safety data for IS regimens are only available from small trials and meta-analyses. Their interpretation and generalizability are limited due to the following factors: 1) care is often provided in settings that do not reflect “real world” clinical practice; 2) few IS regimens are compared, often at a single time point; 3) late or rare outcomes are missed, and 4) publication bias is evident. Population-level research is therefore needed to evaluate comprehensively the comparative effectiveness and safety of IS regimens for LT. Understanding center differences in IS management will also identify suboptimal practices, and further encourage the development of standardized guidelines. Since fewer than 10% of the observed variability in post-transplant outcomes can be explained by pre-LT factors, we hypothesize that targeting differences in post-LT management, such as IS regimen selection, has the potential to change practice and improve outcomes on a wider scale. Using a novel linkage of transplant data from the United Network for Organ Sharing and Medicare claims, the primary aims of the proposed research are the following: Aim 1 – to describe center variability in IS management in the US; Aim 2 – to evaluate the association between IS regimen and the risks of graft failure and mortality; and Aim 3 – to determine the association between IS regimen and the risks of acute rejection, severe infection and de novo cancer as potential mechanisms for the relationships identified in Aim 2. This proposal will also foster Dr. Bittermann's career development into a fully independent NIH-funded clinical investigator with a scientific focus in LT pharmacoepidemiology and practice variability, facilitated through a comprehensive mentorship plan. This will be accomplished by: 1) additional coursework on advanced methodologies through the Center for Clinical Epidemiology and Biostatistics (CCEB) at the University of Pennsylvania, 2) direct implementation of these acquired techniques under the close supervision of a carefully selected team of faculty with extensive expertise in pharmacoepidemiology, transplant hepatology, and outcomes research, as well as longstanding experience with successfully mentoring prior grant recipients, 3) involvement in the Center for Pharmacoepidemiology Research and Training in the CCEB, and 4) development and submission of future grants during the latter part of the award period to further IS and related post-transplant management issues in LT recipients.

项目摘要 超过95%的肝移植（LT）接受者在其生命周期内只有一次机会接受新的肝脏。 寿命和长期患者存活取决于延长的移植物功能。由于以下方面的进展， 免疫抑制（IS），超过70%的受体在LT后存活超过5年，但存在很大的差异 在中心水平的临床结果。大多数晚期LT后死亡不是直接由于肝功能衰竭，而是反映了 长期IS治疗的不良后果。由于缺乏指导信息系统的国家建议， LT之后，其管理在各中心不同。此外，IS的疗效和安全性比较数据 治疗方案只能从小型试验和荟萃分析中获得。它们的解释和概括性是 由于以下因素而受到限制：1）通常在不反映“真实的世界”临床的环境中提供护理 实践; 2）很少比较IS方案，通常在单个时间点; 3）错过晚期或罕见结局， （4）发表偏倚明显。因此，需要进行人口一级的研究， IS方案治疗LT的比较有效性和安全性。了解IS的中心差异 管理层还将确定次优做法，并进一步鼓励制定标准化的 指南由于在移植后结果中观察到的变异性中只有不到10%可以解释为 LT前因素，我们假设，针对LT后管理的差异，如IS方案， 选择，有可能在更大范围内改变做法和改善成果。使用一种新颖的连接 来自器官共享联合网络和医疗保险索赔的移植数据， 拟议的研究如下：目的1 -描述美国IS管理中的中心变异性;目的2 - 评估IS方案与移植物衰竭和死亡风险之间的关系;目标3 - 确定IS方案与急性排斥反应、严重感染和新发 癌症作为目标2中确定的关系的潜在机制。这一建议也将促进博士。 Bittermann的职业发展成为一个完全独立的NIH资助的临床研究者，专注于科学 通过全面的导师计划促进LT药物流行病学和实践变异性。 这将通过以下方式实现：1）通过中心的高级方法学的额外课程， 宾夕法尼亚大学的临床流行病学和生物统计学（CCEB），2）直接实施 这些获得的技术在一个精心挑选的教师团队的密切监督下， 在药物流行病学、移植肝病学和结局研究方面的专业知识，以及长期以来 成功指导先前赠款接受者的经验，3）参与中心， CCEB的药物流行病学研究和培训，以及4）开发和提交未来的 在资助期的后期，我们会继续提供赠款，以进一步处理资讯科技及有关的移植后管理事宜， LT接受者。