Impact of immunosuppression variability on outcomes after liver transplantation

免疫抑制变异性对肝移植术后结局的影响

基本信息

批准号：
10671218
负责人：
Therese Bittermann
金额：
$ 8.46万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10671218
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 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 organ transplant rejection post-transplant prevent retransplantation standardize guidelines stem transplant centers

项目摘要

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.

项目概要超过 95% 的肝移植 (LT) 接受者在其一生中只有一次机会接受新肝脏由于技术进步，患者的寿命和长期生存取决于移植物功能的延长。免疫抑制 (IS)，超过 70% 的受者在 LT 后存活超过 5 年，但存在很大的差异大多数 LT 后晚期死亡并非直接归因于肝功能衰竭，而是反映了肝功能衰竭。由于缺乏指导 IS 的国家建议，延长 IS 治疗的不良后果。 LT 后，不同中心的管理也不同。此外，IS 的疗效和安全性数据比较。治疗方案只能通过小型试验和荟萃分析获得，它们的解释和普遍性尚不明确。由于以下因素而受到限制：1）通常在不反映“现实世界”临床的环境中提供护理实践；2) 很少对 IS 方案进行比较，通常是在单个时间点进行比较；3) 错过了晚期或罕见的结果， 4）发表偏倚明显，因此需要进行人群水平的研究来综合评估。 LT 的 IS 方案的相对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，并进一步鼓励标准化的发展由于观察到的移植后结果的变异性中只有不到 10% 可以用以下方法来解释： LT 前因素，我们追求针对 LT 后管理的差异，例如 IS 方案选择，有可能利用新颖的联系在更广泛的范围内改变实践并改善结果。来自器官共享和医疗保险索赔联合网络的移植数据，其主要目标拟议的研究如下：目标 1 – 描述美国 IS 管理的中心变异性； – 评估 IS 方案与移植失败和死亡风险之间的关联以及目标 3 – 确定 IS 方案与急性排斥、严重感染和新发风险之间的关联癌症作为目标 2 中确定的关系的潜在机制。该提案还将促进 Dr. Bittermann 的职业发展成为一名完全独立、由 NIH 资助、专注于科学的临床研究者通过全面的指导计划促进 LT 药物流行病学和实践变异性。这将通过以下方式实现：1）通过中心提供有关高级方法的额外课程。宾夕法尼亚大学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是在精心挑选的具有广泛知识的教师团队的密切监督下获得的。药物流行病学、移植肝病学和结果研究方面的专业知识，以及长期的成功指导先前资助者的经验，3）参与中心 CCEB 的药物流行病学研究和培训，以及 4) 未来的开发和提交在资助期的后半段提供赠款，以进一步解决信息系统和相关的移植后管理问题 LT 收件人。