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）是一种日益常见的生化诊断 发现轻度升高的甲状腺刺激激素（TSH）但正常的甲状腺素水平，影响多达200英寸 1000名成年人，其中135名将出现非特异性症状，其余的根本没有症状。下列的 内分泌社会的临床实践指南，SCH经常接受左甲状腺素（LT4）治疗。这 从1996年到2006年，LT4处理的SCH的患病率翻了一番。更令人惊讶的是，LT4已成为最大的 在美国开具的药物，超过阿片类药物。但是，没有证明LT4的好处 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 患有SCH的患者。然而，约有65名服用LT4的患者中约有50％出现医源性甲状腺功能亢进症， 增加其心律不齐，心绞痛，骨质流失和骨折的风险。基于这些证据， 指南小组最近提出了针对大多数SCH成年人的常规LT4使用的强烈建议。 显着性/影响：有明确的证据表明SCH患者过度诊断和过度治疗 造成巨大和不必要的经济和治疗负担，甚至造成伤害。一旦开始，十分之一 SCH患者继续LT4治疗无限期。没有关于可接受性的证据 在过去 以前开始从事LT4治疗。我们的研究与VA HSR＆D优先领域一致：质量/安全性，将 解决这些知识差距，并有可能改善提供给数千名退伍军人的护理。 创新：这是评估停用LT4治疗的可接受性和可行性的第一项研究 在接受治疗的患者中。这也是第一个随机的飞行员，双盲，安慰剂对照试验 评估SCH患者中停用LT4治疗QOL的安全性和影响。成功的 这项新工作的完成将为实施基于证据的护理奠定基础 拥有SCH的退伍军人，将有助于解决LT4过度使用的国家流行病。 具体目的：我们提出了一项试点研究，以解决以下相互关联的假设：LT4处理的SCH是 退伍军人中的状况极为普遍。与SCH的退伍军人的LT4停用将是可行的， 可以接受，安全，不会对其QoL产生负面影响。在此提案中，我们的目标是：1）确定 退伍军人中LT4处理的SCH的患病率。 2）评估LT4停用的可行性 具有SCH的退伍军人，并确定QOL测量，血脂和不良事件的变化。 3）评估 LT4与SCH和LT4处方临床医生中停药的可接受性。 方法论：我们将使用公司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识别老年退伍军人 18-89岁，被诊断为SCH，并在2019年1月1日至2019年12月31日之间使用LT4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名退伍军人接受LT4 因为SCH将被随机分为1：1，以续LT4或安慰剂。主要结果是可行性（愿意 输入试验，招聘率和完成率）。次要结果是QoL措施的变化 （甲状腺特异性QOL患者报告的结局 - 甲状腺功能障碍症状和疲劳得分，Euroqol 5-- 维度自我报告问卷）在基线，随机分组后的6-8周零6个月进行评估， 在基线和随机分组后6个月评估的血脂的变化以及不良的发生率 事件（明显的甲状腺功能减退症，甲状腺功能亢进，心血管事件，骨折，死亡率）。我们将评估 LT4停用的可接受性，对退伍军人和10个LT4处方者的半结构化访谈。 实施/下一步：本研究将测试中断LT4的可行性，安全性和可接受性 在患有SCH的患者中，将为设计干预措施铺平道路，以在一项大型多站点试验中进行测试。