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）：该申请解决了一个被忽视的主要问题：在三重阴性（雌激素，孕酮，HER-2受体阴性）治疗期间和治疗期间和治疗期间遇到的基于蒽环类药物的化学治疗（ANTH-BC）心肌损伤没有有效的初级预防。如今，心血管（CV）事件，包括因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妇女死亡率的第二大主要原因。我们提供了初步数据，表明心肌损伤和LV功能障碍在收到Anth-BC（1至6个月）后发生，并且其他数据表明，用3-羟基-3-羟基-3-甲基甲基甲酰基核-A-A还原酶抑制剂（或Statins）治疗会导致心脏抑制剂（OR statians）预测心脏功能障碍。因此，我们建议在接受三重阴性乳腺癌的ANTH-BC的女性中进行双盲，随机，安慰剂对照试验，每天40毫克的阿托伐他汀。我们的主要结果是通过创新的磁共振成像（MRI）获得的，该形式识别启动Anth-BC后LV功能障碍。我们将收集这些MRI测量，以及其他调查表和血清测量，这些措施将提供对他汀类药物疗法影响LV功能的机制的理解。我们还将监测与毒素（包括糖尿病，认知能力下降，肌痛和肌酸激酶升高）有关的副作用的潜在发生。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个推荐地点，使用排名的块入学设计，重点是招募少数群体。我们召集了一组成熟的研究者，具有癌症患者的试验，他汀类药物的给药和评估与CV相关的结果的经验，以及使用创新的MRI和血清生物标志物的利用来鉴定心脏衰竭患者心脏失败患者的CV异常。独特的是，这项NHLBI提出的多中心研究将与国家癌症研究所支持Wake Forest研究基础临床肿瘤学计划的努力相结合。这种合作具有吸引力，因为它结合了NHLBI的调查强度，以确定CV疾病与NCI的现有资金，以进行乳腺癌女性进行随机临床试验。在整个文档中，颜色用于增强图和表的可读性，并且在表2的提案中索引了有关临床试验进行的许多其他细节 科学计划。这项研究代表了使用低成本，广泛可用的通用疗法治疗的乳腺癌女性AVOD CV损伤的初级预防临床试验。如果成功的话，该试验将建议使用主要预防乳腺癌患者的治疗范式来减轻ANTH-BC的心脏毒性作用，以改善乳腺癌女性的整体长期生存。