Discontinuation of levothyroxine therapy for patients with subclinical hypothyroidism: a pilot randomized, double-blinded, placebo-controlled study

亚临床甲状腺功能减退症患者停止左旋甲状腺素治疗：一项随机、双盲、安慰剂对照试验研究

• 批准号: 10337077
• 负责人: Spyridoula Maraka
• 金额: --
• 依托单位: CENTRAL ARKANSAS VETERANS HLTHCARE SYS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337077
• 关键词: Address; Adult; Adverse event; Affect; American; Angina Pectoris; Area; Arkansas; Arrhythmia; Biochemical; Cardiovascular system; Caring; Clinic Visits; Clinical Practice Guideline; Clinical Trials; Computerized Medical Record; Controlled Clinical Trials; Data; Diagnosis; Dimensions; Double-Blind Method; Drug Prescriptions; Economics; Endocrine; Epidemic; Event; Foundations; Fracture; Guidelines; Habits; Healthcare Systems; Hyperthyroidism; Hypothyroidism; Iatrogenesis; Incidence; Informatics; Infrastructure; Interview; Investigator-Initiated Research; Knowledge; Laboratories; Measures; Methodology; Modification; Monitor; Names; National Health and Nutrition Examination Survey; Opioid; Patient Care; Patient Outcomes Assessments; Patient Self-Report; Patients; Persons; Pharmaceutical Preparations; Pilot Projects; Placebo Control; Placebos; Prevalence; Quality of life; Questionnaires; Randomized; Rare Diseases; Recommendation; Research; Rest; Retrospective cohort study; Risk; Safety; Societies; Structure; Symptoms; Synthroid; Testing; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyroxine; Veterans; Work; acceptability and feasibility; aged; base; blood lipid; bone loss; data warehouse; double-blind placebo controlled trial; evidence base; feasibility testing; improved; innovation; mortality; multi-site trial; novel; older patient; overtreatment; placebo controlled study; primary outcome; randomized trial; recruit; secondary outcome; therapy design; trend; willingness

Background: Subclinical hypothyroidism (SCH) is an increasingly common biochemical diagnosis made by finding mildly elevated thyroid stimulating hormone (TSH) yet normal thyroxine levels, affecting up to 200 in 1000 adults, of whom 135 will have nonspecific symptoms and the rest will have no symptoms at all. Following clinical practice guidelines from endocrine societies, SCH is often treated with levothyroxine (LT4). The prevalence of LT4-treated SCH has doubled from 1996 to 2006. More strikingly, LT4 has become the most prescribed drug in the U.S., surpassing opioids. However, no benefits of LT4 have been demonstrated on quality of life (QoL) or thyroid-related symptoms and little or no effect on cardiovascular events or mortality for patients with SCH. Yet, ~50% of patients older than 65 who take LT4 develop iatrogenic hyperthyroidism, increasing their risk for arrhythmias, angina pectoris, bone loss, and fractures. Based on this evidence, a guideline panel recently formulated a strong recommendation against routine LT4 use in most adults with SCH. Significance/Impact: There is clear evidence for overdiagnosis and overtreatment of patients with SCH, causing a substantial and unnecessary economic and treatment burden, and even harm. Once started, 9 in 10 patients with SCH continue LT4 therapy indefinitely. There is no evidence regarding the acceptability, feasibility, safety, and effects on QoL of discontinuing LT4 therapy among patients with SCH who have been previously started on LT4 therapy. Our study, consistent with the VA HSR&D priority area: Quality/Safety, will address these knowledge gaps and has the potential to improve the care delivered to thousands of Veterans. Innovation: This is the first study evaluating the acceptability and feasibility of discontinuing LT4 therapy among patients with treated SCH. This is also the first pilot randomized, double-blind, placebo-controlled trial to evaluate the safety and effects on QoL of discontinuing LT4 therapy in patients with SCH. Successful completion of this novel work will lay the foundation for the implementation of evidence-based care for Veterans with SCH and will contribute to addressing the national epidemic of LT4 overuse. Specific Aims: We propose a pilot study to address the following interrelated hypotheses: LT4-treated SCH is a highly prevalent condition among Veterans. Discontinuation of LT4 for Veterans with SCH will be feasible, acceptable, and safe, and will not negatively affect their QoL. In this proposal we aim to: 1) Identify the prevalence of LT4-treated SCH among Veterans. 2) Evaluate the feasibility of LT4 discontinuation among Veterans with SCH and determine the changes in QoL measures, blood lipids, and adverse events. 3) Assess the acceptability of LT4 discontinuation among Veterans with SCH and LT4-prescribing clinicians. Methodology: We will conduct a retrospective cohort study using the Corporate Data Warehouse through the VA Informatics and Computing Infrastructure and electronic medical records review to identify Veterans aged 18-89 years, diagnosed with SCH and treated with LT4 between January 1, 2009 and December 31, 2019 at CAVHS. We will then conduct a double-blind, placebo-controlled clinical trial where 50 Veterans receiving LT4 for SCH will be randomized 1:1 to continued LT4 or placebo. The primary outcome is feasibility (willingness to enter the trial, recruitment rate, and completion rate). Secondary outcomes are changes in QoL measures (Thyroid-specific QoL Patient-Reported Outcome-Hypothyroid Symptoms and Tiredness scores, EuroQoL 5- Dimension Self-Report Questionnaire) assessed at baseline, 6-8 weeks and 6 months after randomization, changes in blood lipids assessed at baseline and 6 months after randomization, and incidence of adverse events (overt hypothyroidism, hyperthyroidism, cardiovascular events, fractures, mortality). We will assess acceptability of LT4 discontinuation with semi-structured interviews of Veterans and 10 LT4 prescribers. Implementation/Next Steps: This study will test the feasibility, safety, and acceptability of discontinuing LT4 in patients with SCH and will pave the way to design an intervention to be tested in a large multi-site trial.

背景：亚临床甲状腺功能减退症（SCH）是一种越来越常见的生化诊断， 发现轻度升高的促甲状腺激素（TSH），但甲状腺素水平正常， 1000名成年人，其中135人将有非特异性症状，其余的将没有任何症状。以下 根据内分泌学会的临床实践指南，SCH通常用左旋甲状腺素（LT 4）治疗。的 从1996年到2006年，接受LT 4治疗的SCH的患病率翻了一番。更引人注目的是，LT 4已成为最 在美国的处方药，超过了阿片类药物然而，LT 4的益处尚未在 生活质量（QoL）或甲状腺相关症状，对心血管事件或死亡率几乎没有影响， 然而，约50%的65岁以上服用LT 4的患者发生医源性甲状腺功能亢进， 增加心律失常、心绞痛、骨质流失和骨折的风险。根据这一证据，A 一个指南小组最近强烈建议大多数患有SCH的成年人不要常规使用LT 4。 意义/影响：有明确证据表明SCH患者存在过度诊断和过度治疗， 造成了巨大的和不必要的经济和治疗负担，甚至伤害。一旦开始，十分之九 患有SCH的患者无限期地继续LT 4治疗。没有关于可接受性的证据， 在已接受LT 4治疗的SCH患者中中止LT 4治疗的可行性、安全性和对QoL的影响 之前开始接受LT 4治疗。我们的研究与VA HSR&D优先领域：质量/安全一致，将 解决这些知识差距，并有可能改善向数千名退伍军人提供的护理。 创新：这是第一项评估停止LT 4治疗的可接受性和可行性的研究 这也是首个随机、双盲、安慰剂对照试验 评估SCH患者停止LT 4治疗的安全性和对生活质量的影响。 这项新工作的完成将为实施循证护理奠定基础， 退伍军人与SCH，并将有助于解决全国流行的LT 4过度使用。 具体目的：我们提出了一项初步研究，以解决以下相互关联的假设：LT 4治疗的SCH是 这是退伍军人中非常普遍的一种情况。对于患有SCH的退伍军人，停止LT 4治疗是可行的， 可接受的，安全的，不会对他们的QoL产生负面影响。在本提案中，我们的目标是：1）确定 退伍军人中LT 4治疗SCH的患病率。2)评价LT 4停药的可行性， SCH退伍军人，并确定QoL指标、血脂和不良事件的变化。3)评估 接受SCH治疗的退伍军人和LT 4处方临床医生对LT 4停药的可接受性。 方法：我们将通过使用企业数据仓库进行回顾性队列研究， VA信息学和计算基础设施和电子病历审查，以确定退伍军人年龄 18-89岁，在2009年1月1日至2019年12月31日期间诊断为SCH并接受LT 4治疗， CAVHS然后，我们将进行一项双盲、安慰剂对照的临床试验，其中50名接受LT 4的退伍军人 SCH的受试者将以1：1的比例随机分配至继续LT 4或安慰剂组。主要结果是可行性（愿意 进入试验、招募率和完成率）。次要结局是QoL指标的变化 （甲状腺特异性QoL患者报告结局-甲状腺功能减退症状和疲劳评分，EuroQoL 5- 维度自我报告问卷）在基线、随机化后6-8周和6个月进行评估， 基线和随机化后6个月评估的血脂变化，以及不良事件的发生率 事件（显性甲状腺功能减退、甲状腺功能亢进、心血管事件、骨折、死亡）。我们将评估 通过对退伍军人和10名LT 4处方者进行半结构化访谈，确定LT 4停药的可接受性。 实施/后续步骤：本研究将测试停用LT 4的可行性、安全性和可接受性 并将为设计一种在大型多中心试验中进行测试的干预措施铺平道路。