Causal Inference for Better Understanding Clinical Trials Results: Reconciling Discrepant Comparative Evidence from Two Major Cardiovascular Safety Trials of Urate-Lowering Therapy
更好地理解临床试验结果的因果推断:调和两个主要降尿酸治疗心血管安全性试验的差异比较证据
基本信息
- 批准号:10507247
- 负责人:
- 金额:$ 8.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-15 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdherenceAffectAllopurinolArthritisCardiovascular systemCause of DeathCessation of lifeClinicalClinical ResearchClinical TrialsColchicineCollaborationsCommunitiesComplexDataDevelopmentEpidemiologistEpidemiologyEventFlareGlucocorticoidsGoalsGoldGoutInflammatory ArthritisInternationalLettersMediatingMediationMentorsMethodologyMethodsMorbidity - disease rateNon-Steroidal Anti-Inflammatory AgentsOutcomePatientsPharmaceutical PreparationsProbabilityProphylactic treatmentProtocols documentationResearchRheumatismRheumatologyRoleSafetySelection BiasStatistical MethodsTechniquesTimeTrainingUrateWeightadjudicatecardioprotectionclinical trial analysiscomparativecomparative effectiveness analysiscomparative effectiveness studydesignexperiencefebuxostatfollow-upimprovedinnovationinter-institutionalmultiple chronic conditionsprotective effect
项目摘要
Project Summary / Abstract
Clinical trials are the gold standard of causal inference. However, analyses typically employed in clinical trials
cannot answer nuanced questions involving mediating mechanisms. As a result, debate continues regarding the
cardiovascular implications of gout medications, such as urate-lowering therapy and, increasingly, colchicine,
despite the two major cardiovascular trials among gout patients: Cardiovascular Safety of Febuxostat and
Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) and Febuxostat versus Allopurinol
Streamlined Trial (FAST). CARES showed an increase in deaths among febuxostat users. However, it had a high
loss to follow-up rate. On the other hand, some of the effect estimates in FAST favored febuxostat. However, there
were differential discontinuation of urate-lowering therapy and differential use of colchicine in FAST. These
idiosyncrasies have led to lingering questions.
1. Did the increased use of colchicine (cardio-protective in non-gout trials) among the febuxostat group affect
FAST results in favor of febuxostat?
2. Did higher drug discontinuation in the febuxostat group in FAST and higher loss to follow-up in the allopurinol
group in CARES bias their results?
In this proposed study, we will use advanced causal inference methods to address these questions via parallel
analyses of FAST and CARES. In Aim 1, we will first conduct a comparative effectiveness study of colchicine
prophylaxis compared to no prophylaxis or non-steroidal anti-inflammatory drug prophylaxis in FAST and CARES.
We will then conduct causal mediation analysis to quantify the extent to which colchicine use explains the protective
point estimates favoring febuxostat in FAST. In Aim 2, We will estimate the "per-protocol effect" of febuxostat
compared to allopurinol on cardiovascular outcomes. This approach estimates the effect of these medications
under a causal scenario of full adherence and follow-up, reducing this significant interpretability difficulty of these
trials. Our methodologically innovative project is expected to help to reconcile the discrepant results from FAST
and CARES. PI will also develop a valuable collaboration network and preliminary data demonstrating the
usefulness of causal inference methods in clinical trial analysis. We will further disseminate these advanced
methods via online and offline methodology tutorials.
项目摘要/摘要
临床试验是因果推断的金标准。然而,通常在临床试验中使用的分析
无法回答涉及调解机制的微妙问题。因此,关于
痛风药物对心血管的影响,例如降低尿酸的治疗,以及越来越多的秋水仙碱,
尽管在痛风患者中进行了两项主要的心血管试验:非布索他汀的心血管安全性和
痛风和心血管疾病(CARE)患者的别嘌醇和非布索坦与别嘌醇的比较
简化了试用(快速)。CARE显示,非布索斯特使用者的死亡人数有所增加。然而,它有一个很高的
随访率损失。另一方面,FAST中的一些效果估计有利于非布索斯特。然而,在那里
在FAST中有区别地停止降尿酸治疗和不同程度地使用秋水仙碱。这些
个性导致了挥之不去的问题。
1.在非痛风试验中增加使用秋水仙碱(在非痛风试验中具有心脏保护作用)是否会影响
快速的结果有利于非布索斯特?
2.非布索他汀组停药次数多,停药时间快,失访次数多,对别嘌醇的影响较大
团体在关心他们的结果有偏差吗?
在这项拟议的研究中,我们将使用先进的因果推理方法通过并行方式来解决这些问题
对FAST和CARE的分析。在目标1中,我们将首先进行秋水仙碱的比较有效性研究。
在FAST和CARE中,预防与没有预防或非类固醇抗炎药物预防相比。
然后我们将进行因果调解分析,以量化秋水仙素的使用在多大程度上解释了
点数估计在FAST中支持非布索斯特。在目标2中,我们将评估非布索他汀的“按方案效应”
与别嘌醇相比,对心血管结果的影响。这种方法估计了这些药物的效果。
在完全遵守和跟进的因果情况下,降低这些
审判。我们的方法创新项目有望帮助协调来自FAST的不一致结果
并关心他们。PI还将开发一个有价值的合作网络和初步数据,展示
因果推断方法在临床试验分析中的有用性。我们将进一步传播这些先进的
方法通过线上和线下方法教程。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Sara K. Tedeschi其他文献
Core domain set for chronic and/or recurrent manifestations of calcium pyrophosphate deposition disease: OMERACT delphi survey to establish consensus
焦磷酸钙沉积病慢性和/或复发性表现的核心领域集:旨在达成共识的OMERACT德尔菲调查
- DOI:
10.1016/j.semarthrit.2025.152669 - 发表时间:
2025-06-01 - 期刊:
- 影响因子:4.400
- 作者:
Yiling Zhang;Sara K. Tedeschi;Abhishek Abhishek;Owen Hensey;David Grossberg;Ken Cai;Beverley Shea;Jasvinder A. Singh;Robin Christensen;Teodora Serban;Edoardo Cipolletta;Konstantinos Parperis;Cesar Diaz-Torne;Geraldine M McCarthy;Fabio Becce;Tamer A Gheita;Silvia Sirotti;Sara Nysom Christiansen;Luis Coronel;Lisa K Stamp;Nicola Dalbeth - 通讯作者:
Nicola Dalbeth
Core domain set for studies of acute calcium pyrophosphate crystal arthritis: OMERACT delphi survey to establish consensus
急性焦磷酸钙晶体性关节炎研究的核心领域集:基于国际骨关节炎研究学会(OMERACT)德尔菲调查达成的共识
- DOI:
10.1016/j.semarthrit.2025.152670 - 发表时间:
2025-06-01 - 期刊:
- 影响因子:4.400
- 作者:
Yiling Zhang;Sara K. Tedeschi;Abhishek Abhishek;Owen Hensey;David Grossberg;Ken Cai;Beverley Shea;Jasvinder A. Singh;Robin Christensen;Teodora Serban;Edoardo Cipolletta;Konstantinos Parperis;Cesar Diaz-Torne;Geraldine M McCarthy;Fabio Becce;Tamer A Gheita;Silvia Sirotti;Sara Nysom Christiansen;Luis Coronel;Lisa K Stamp;Nicola Dalbeth - 通讯作者:
Nicola Dalbeth
Genome-wide association study in chondrocalcinosis reveals emENPP1/em as a candidate therapeutic target in calcium pyrophosphate deposition disease
全基因组关联研究在软骨钙质沉着症中揭示了 emENPP1/em 作为焦磷酸钙沉积病的候选治疗靶点
- DOI:
10.1016/j.ard.2025.04.002 - 发表时间:
2025-06-01 - 期刊:
- 影响因子:20.600
- 作者:
Riku Takei;Ann Rosenthal;Tristan Pascart;Richard J. Reynolds;Tuhina Neogi;Robert Terkeltaub;Sara K. Tedeschi;Tony R. Merriman - 通讯作者:
Tony R. Merriman
Sara K. Tedeschi的其他文献
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{{ truncateString('Sara K. Tedeschi', 18)}}的其他基金
Causal Inference for Better Understanding Clinical Trials Results: Reconciling Discrepant Comparative Evidence from Two Major Cardiovascular Safety Trials of Urate-Lowering Therapy
更好地理解临床试验结果的因果推断:调和两个主要降尿酸治疗心血管安全性试验的差异比较证据
- 批准号:
10662563 - 财政年份:2022
- 资助金额:
$ 8.95万 - 项目类别:
Studying pseudogout using naturallanguage processing and novelimaging approaches
使用自然语言处理和新颖的成像方法研究假性痛风
- 批准号:
10359786 - 财政年份:2019
- 资助金额:
$ 8.95万 - 项目类别:
Studying pseudogout using naturallanguage processing and novelimaging approaches
使用自然语言处理和新颖的成像方法研究假性痛风
- 批准号:
10578683 - 财政年份:2019
- 资助金额:
$ 8.95万 - 项目类别:
Studying pseudogout using natural language processing and novel imaging approaches
使用自然语言处理和新颖的成像方法研究假性痛风
- 批准号:
10292824 - 财政年份:2019
- 资助金额:
$ 8.95万 - 项目类别:
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