2/2 Sickle Cell Disease and CardiovAscular Risk - Red cell Exchange Trial (SCD-CARRE Trial)

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，所有主要心血管并发症 没有得到批准或共识的治疗方法的SCD。发生肺动脉高压的风险和 舒张性心脏病可通过实验室检测(NT-proBNP)和多普勒超声进行无创评估。 超声心动图(估计的肺动脉收缩压)。最近的一项荟萃分析，对大约 6000例SCD患者显示，三尖瓣返流速度(TRV)升高的患者 是一种多普勒超声心动图测量，用来估计肺动脉收缩压。 在6分钟步行试验中，估计比不升高TRV的人少30.4米，而TRV升高的人 与高死亡率(危险比为4.9)有关。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，定义为 Trv≥为2.5m/s，NT-ProBNP≥为160pg/mL，12个月死亡率为7.9%。 与TRV或NT-proBNP值正常的患者相比，这一组的风险比为0.5% 住院治疗1.6人。这表明，TRV和NT-proBNP的简单筛查图谱可以识别约 20%的SCD患者死亡和住院风险最高。考虑到死亡率的增加和 SCD成人与心血管疾病相关的早期功能丧失，检测很重要 对这类患者进行有效的治疗干预。红细胞输注是由以下两种方式之一实施的 单纯输血或交换输血，后者将患者的血液取出，代之以输入的红血。 细胞。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， 包括严重急性胸部综合征、中风、脾或肝隔离以及多器官衰竭，以及 也被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，以及 预防间歇性血管闭塞性疼痛危象和急剧增加的急性胸部综合征 并导致右心衰竭。我们建议进行一项临床试验以评估其疗效。 与护理标准相比，自动换血对患者发病率和死亡率的影响 在150例成人高危SCD患者中。试验将利用现有的协调中心基础设施， 匹兹堡大学，并将涉及22个经验丰富的临床站点。尽管安全，用途广泛 对于成人SCD患者的红细胞分离，尚无共识或高质量的疗效数据用于 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。

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 Doppler-echocardiographic 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.