Preventing Anthracycline Cardiovascular Toxicity with Statins

用他汀类药物预防蒽环类药物的心血管毒性

• 批准号: 8825555
• 负责人: William Gregory Hundley
• 金额: $ 2.34万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-14 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8825555
• 关键词: 3-hydroxy-3-methylglutaryl-coenzyme A; Address; Adjuvant; Adjuvant Chemotherapy; Adjuvant Therapy; Adverse effects; Aftercare; Animal Model; Anthracyclines; Attenuated; Binding; Biological Markers; Breast; Breast Cancer Treatment; Cancer Patient; Cancer Survivor; Cardiac; Cardiac Myocytes; Cardiovascular Abnormalities; Cardiovascular Diseases; Cardiovascular system; Clinical; Clinical Trials; Coenzyme A; Collaborations; Color; Community Clinical Oncology Program; Congestive Heart Failure; Creatine Kinase; DNA Double Strand Break; Data; Data Collection; Deterioration; Development; Dexrazoxane; Diabetes Mellitus; Double-Blind Method; ERBB2 gene; Enrollment; Enzymes; Estrogens; Event; Expenditure; Fibrosis; Florida; Free Radicals; Functional disorder; Funding; Future; Generations; Generic Drugs; Goals; Health; Healthcare; Heart failure; Hypotension; Imaging Techniques; Impaired cognition; Incidence; Inflammation; Inflammatory; Injury; Intervention; Intravenous; Iron; Left; Left Ventricular Dysfunction; Left Ventricular Ejection Fraction; Left Ventricular Function; Magnetic Resonance Imaging; Malignant Neoplasms; Measures; Mediating; Monitor; Morbidity - disease rate; Myalgia; Myocardial; National Cancer Institute; National Heart, Lung, and Blood Institute; Neurohormones; Nitrogen; North Carolina; Oral; Outcome; Oxidative Stress; Oxidoreductase; Oxygen; Patients; Performance; Pharmaceutical Preparations; Physicians; Physiologic pulse; Pilot Projects; Placebo Control; Prevention strategy; Primary Prevention; Production; Progesterone; Questionnaires; Randomized Clinical Trials; Readability; Recruitment Activity; Reducing Agents; Regimen; Research; Research Personnel; Rest; Schedule; Secondary Prevention; Serum; Site; South Carolina; Survivors; Testing; Thick; Time; Topoisomerase II; Toxic effect; Ventricular; Woman; advanced disease; atorvastatin; base; cancer recurrence; cardiovascular injury; chemotherapy; cost; cytokine; cytotoxic; design; early onset; experience; forest; hypercholesterolemia; improved; indexing; inhibitor/antagonist; innovation; malignant breast neoplasm; minority subjects; mortality; neglect; nitrosative stress; prevent; primary outcome; randomized placebo controlled trial; receptor; triple-negative invasive breast carcinoma; tumor

DESCRIPTION (provided by applicant): This application addresses a neglected major problem: no effective primary prevention for anthracycline- based chemotherapeutic (Anth-bC) myocardial injury experienced during and after treatment for triple negative (estrogen, progesterone, HER-2 receptor negative) breast cancer. Today, cardiovascular (CV) events including heart failure due to myocardial injury and left ventricular (LV) dysfunction are the second leading cause of mortality in women receiving adjuvant therapy for breast cancer. We provide preliminary data indicating that myocardial injury and LV dysfunction occur early upon receipt of Anth-bC (1 to 6 months), and additional data suggesting that treatment with 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors (or statins) prevents cardiac dysfunction during receipt of Anth-bC. Accordingly, we propose to conduct a double blind, randomized, placebo controlled trial of 40 mg per day of atorvastatin in women receiving Anth-bC for triple negative breast cancer. Our primary outcomes are acquired with an innovative form of magnetic resonance imaging (MRI) that identifies LV dysfunction after initiation of Anth-bC. We will collect these MRI measures along with other questionnaire derived and serum measures that will provide understanding of the mechanisms by which statin therapy influences LV function. We will also monitor for the potential occurrence of side effects related to the administration of statins including diabetes, cognitive decline, myalgias and creatine kinase elevations. The study will be conducted at 6 referral sites within North Carolina, South Carolina, and Florida using a permuted block enrollment design with emphasis on recruiting minority subjects. We have assembled an accomplished group of investigators with experience in the conduct of trials of patients with cancer, the administration of statins and assessing CV-related outcomes, and the utilization of innovative MRI and serum biomarkers to identify CV abnormalities in heart failure patients. Uniquely, this NHLBI proposed multi-center study will combine with efforts from the National Cancer Institute supported Wake Forest Research Base Clinical Community Oncology Program. This collaboration is attractive as it combines the investigative strengths of the NHLBI to ascertain CV disease with the existing funding from the NCI to conduct randomized clinical trials in women with breast cancer. Throughout the document, color is used to enhance the readability of Figures and Tables, and many of the additional details regarding conduct of a clinical trial are indexed within the proposal in Table 2 of the scientific plan. This study represents the first clinical trial of primary prevention to avod CV injury in women treated for breast cancer using a low-cost, widely available generic therapy. If successful, this trial will suggest a new paradigm in the management of breast cancer patients using primary prevention to attenuate the cardiotoxic effects from Anth-bC for the purpose of improving the overall long-term survival of women with breast cancer.

描述（由申请人提供）：本申请解决了一个被忽视的主要问题：对于三阴性（雌激素、孕激素、HER-2受体阴性）乳腺癌治疗期间和治疗后经历的基于蒽环类化疗（Anth-bC）的心肌损伤，没有有效的一级预防。如今，心血管（CV）事件，包括心肌损伤引起的心力衰竭和左心室（LV）功能障碍，是接受乳腺癌辅助治疗的女性死亡的第二大原因。我们提供的初步数据表明，心肌损伤和左心室功能障碍在接受 Anth-bC 后早期（1 至 6 个月）发生，另外的数据表明，使用 3-羟基-3-甲基戊二酰辅酶-A 还原酶抑制剂（或他汀类药物）治疗可预防接受 Anth-bC 期间的心功能障碍。因此，我们建议对接受 Anth-bC 治疗三阴性乳腺癌的女性进行一项双盲、随机、安慰剂对照试验，每天服用 40 毫克阿托伐他汀。我们的主要结果是通过一种创新形式的磁共振成像 (MRI) 获得的，该磁共振成像 (MRI) 可以识别 Anth-bC 启动后的左心室功能障碍。我们将收集这些 MRI 测量值以及其他问卷调查和血清测量值，以帮助了解他汀类药物治疗影响左室功能的机制。我们还将监测与服用他汀类药物相关的潜在副作用，包括糖尿病、认知能力下降、肌痛和肌酸激酶升高。该研究将在北卡罗来纳州、南卡罗来纳州和佛罗里达州的 6 个转诊地点进行，采用排列分组招生设计，重点是招募少数族裔受试者。我们组建了一支经验丰富的研究人员团队，他们在对癌症患者进行试验、服用他汀类药物和评估心血管相关结果以及利用创新的 MRI 和血清生物标志物来识别心力衰竭患者的心血管异常方面拥有丰富的经验。独特的是，这项 NHLBI 提议的多中心研究将与国家癌症研究所支持的维克森林研究基地临床社区肿瘤学计划的努力相结合。这项合作很有吸引力，因为它结合了 NHLBI 查明 CV 疾病的研究优势和 NCI 现有的资金，用于对乳腺癌女性进行随机临床试验。在整个文件中，颜色用于增强图形和表格的可读性，并且有关临床试验进行的许多其他细节都在表 2 的提案中索引 的科学计划。这项研究代表了第一个针对接受乳腺癌治疗的女性使用低成本、广泛使用的非专利疗法进行一级预防以避免心血管损伤的临床试验。如果成功，该试验将为乳腺癌患者的管理提供一种新的范例，利用一级预防来减轻 Anth-bC 的心脏毒性作用，从而提高乳腺癌女性患者的总体长期生存率。