Sickle Cell Disease and Cardiovascular Risk- Red Cell Exchange SCD-CARRE

镰状细胞病和心血管风险 - 红细胞交换 SCD-CARRE

• 批准号: 10653703
• 负责人: Mark T Gladwin
• 金额: $ 335万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653703
• 关键词: Accelerometer; Accident and Emergency department; Activities of Daily Living; Acute; Adult; Adverse effects; Age; Alloimmunization; Antigens; Biological Markers; Blood; Blood capillaries; Cardiac Catheterization Procedures; Cardiopulmonary; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cephalic; Cessation of life; Childhood stroke; Chronic; Chronic Kidney Failure; Clinical; Clinical Trials; Cohort Studies; Consensus; Deceleration; Development; Diagnosis; Disease; Disease Progression; Doppler Echocardiography; Echocardiography; Elderly; Erythrocytes; Event; Failure; Functional disorder; Genes; Healthcare; Heart Diseases; Heart Injuries; Hemoglobin; Hemoglobin SS; Hemolytic Anemia; Heterozygote; Home; Hospitals; Infusion procedures; Injury to Kidney; Iron; Left; Measures; Meta-Analysis; Microalbuminuria; Morbidity - disease rate; Multivariate Analysis; Myocardial dysfunction; Organ; P-Selectin; Pain; Pathogenesis; Patients; Pattern; Pharmaceutical Preparations; Physiological; Plasma; Point Mutation; Polymers; Premature Mortality; Prevention; Probability; Proteinuria; Pulmonary Hypertension; Pulse Pressure; Reaction; Risk; Risk Reduction; Safety; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Stroke; Sudden Death; Testing; Therapeutic Intervention; Transfusion; Treatment Efficacy; Ventricular; Visit; Walking; acute chest syndrome; autosome; beta Globin; beta Thalassemia; cardiovascular risk factor; chronic pain; disorder risk; exercise capacity; functional loss; hazard; health related quality of life; high risk; improved; inhibitor; intervention effect; lung injury; lung pressure; meter; mortality; mortality risk; mutant; organ injury; prevent; pro-brain natriuretic peptide (1-76); pulmonary arterial pressure; right ventricular failure; sildenafil; standard of care; therapeutic evaluation; therapeutically effective; vaso-occlusive crisis

As patients with sickle cell disease (SCD) live to adulthood, the chronic impact of sustained hemolytic anemia and episodic vaso-occlusive events take their toll, with the progressive development of cardiopulmonary organ dysfunction. This culminates in the development of pulmonary hypertension, left ventricular diastolic heart disease, dysrhythmia, chronic kidney disease and sudden death, all major cardiovascular complications of SCD for which there are no approved or consensus therapies. The risk of having pulmonary hypertension and diastolic heart disease can be non-invasively assessed by laboratory tests (NT-proBNP) and Doppler-echocardiography (estimated pulmonary artery systolic pressure). A recent meta-analysis of approximately 6000 patients with SCD demonstrated that patients with elevated tricuspid regurgitant jet velocity (TRV), which is an Dopplerechocardiographic measurement that estimates the pulmonary artery systolic pressure, walked an estimated 30.4 meters less in a 6 minute walk test than those without elevated TRV, and elevated TRV was associated with high mortality (hazard ratio of 4.9). In two large registry cohorts of adult patients with SCD, we found that approximately 20% of the adult SCD population have high values for both biomarkers, defined as a TRV ≥ 2.5 meters per second AND a NT-proBNP ≥ 160 pg/mL, and that the 12-month mortality rate is 7.9% in this group as compared to 0.5% in patients with normal TRV or NT-proBNP values, with a risk ratio for hospitalization of 1.6. This suggests that a simple screening profile of TRV and NT-proBNP can identify about 20% of patients with SCD at the highest risk of death and hospitalization. Given the increased mortality and early loss of functional capacity associated with cardiovascular disease in SCD adults, it is important to test effective therapeutic interventions in such patients. Red blood cell transfusions are administered by either simple or exchange transfusion, the latter removes the patients blood and replaces it with transfused red blood cells. Exchange transfusions have proven effective for acute treatment of almost all SCD complications, including severe acute chest syndrome, stroke, splenic or hepatic sequestration, and multi-organ failure, and are also used chronically for stroke prevention and recurrent acute chest syndrome. In this study we hypothesize that monthly exchange transfusion will limit disease progression, improve exercise capacity, and prevent interval episodes of vaso-occlusive painful crisis and the acute chest syndrome that acutely increases pulmonary pressures and cause right heart failure. We propose to perform a clinical trial to evaluate the effects of automated exchange blood transfusion on patient morbidity and mortality, compared to standard of care among 150 adult high risk SCD patients. The trial will leverage existing coordinating center infrastructure at the University of Pittsburgh and will involve 22 experienced clinical sites. Despite the safety and wide utilization of erythrocytapheresis in adult patients with SCD, there is no consensus or quality efficacy data on its use to improve outcomes in our aging high-risk SCD patients with progressive end-organ dysfunction.

随着镰状细胞病(SCD)患者活到成年，持续性溶血性贫血的慢性影响 随着心肺器官的逐渐发展，间歇性血管闭塞事件也会造成损失 功能障碍。最终发展为肺动脉高压，左心室舒张性心脏 疾病、心律失常、慢性肾脏疾病和猝死，都是SCD的主要心血管并发症 目前还没有得到批准或一致认可的治疗方法。发生肺动脉高压和舒张压的风险 心脏病可通过实验室检测(NT-proBNP)和多普勒超声心动图进行无创性评估 (估计的肺动脉收缩压)。最近一项对约6000例SCD患者的荟萃分析 结果显示，三尖瓣返流速度(TRV)升高的患者行走的速度估计为 在6分钟步行试验中比无TRV升高的人少30.4米，且TRV升高与 死亡率高(危险比为4.9)。在两个成年SCD患者的大型登记队列中，我们发现 大约20%的成年SCD人群这两个生物标志物的值都很高，被定义为TRV≥2.5 M/s和NT-ProBNP≥160pg/ml，该组12个月死亡率为7.9% 相比之下，TRV或NT-proBNP值正常的患者的住院风险比为0.5% 1.6.这表明，简单的TRV和NT-proBNP筛查资料可以识别约20%的患者 SCD的死亡和住院风险最高。鉴于死亡率的增加和早期的损失 与SCD成人心血管疾病相关的功能能力，重要的是测试有效性 对这类患者的治疗干预。红细胞输注是通过简单的或 换血，后者去除患者的血液，并用输入的红细胞取而代之。 交换输血已被证明对几乎所有SCD并发症的急性治疗都有效，包括 严重的急性胸部综合征，中风，脾或肝隔离，以及多器官衰竭，也是 长期用于预防中风和复发的急性胸部综合征。在这项研究中，我们假设 每月交换输血将限制疾病进展，提高运动能力，防止间歇 血管闭塞性疼痛危象和急性增加肺功能的急性胸部综合征的发作 并导致右心衰竭。我们建议进行一项临床试验，以评估自动化的效果 换血与150名成人护理标准对患者发病率和死亡率的影响 高危SCD患者。该试验将利用加州大学现有的协调中心基础设施 匹兹堡，并将涉及22个经验丰富的临床站点。尽管它的安全性和广泛用途 在成人SCD患者中，关于其用于治疗SCD的疗效尚无共识或质量数据 改善患有进行性终末器官功能障碍的老年高危SCD患者的预后。