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育， 功能障碍最终导致肺动脉高压，左心室舒张期心脏 疾病、心律失常、慢性肾脏疾病和猝死， SCD尚无获批或共识疗法。患肺动脉高压的风险， 舒张性心脏病可以通过实验室检查（NT-proBNP）和多普勒超声（Doppler）进行无创评估。 超声心动图（估计肺动脉收缩压）。最近的一项荟萃分析， 6000例SCD患者证实，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，估计肺动脉收缩压，步行 在6分钟步行试验中，与TRV未升高的患者相比， 与高死亡率相关（风险比为4.9）。在两个成人SCD患者的大型登记队列中，我们 发现大约20%的成人SCD人群具有两种生物标志物的高值，定义为 TRV ≥ 2.5米/秒且NT-proBNP ≥ 160 pg/mL，12个月死亡率为7.9%， 与TRV或NT-proBNP值正常的患者中0.5%相比，该组的风险比为 住院1.6。这表明TRV和NT-proBNP的简单筛查谱可以识别约 20%的SCD患者死亡和住院风险最高。鉴于死亡率的上升， 在SCD成人中，与心血管疾病相关的早期功能丧失，重要的是要测试 对这些患者进行有效的治疗。红细胞输注由以下两种方式进行： 简单输血或交换输血，后者将患者的血液取出，并用输注的红血代替 细胞交换输血已被证明对几乎所有SCD并发症的急性治疗有效， 包括严重急性胸部综合征、中风、脾或肝隔离症和多器官衰竭，以及 也长期用于预防中风和复发性急性胸部综合征。本研究 假设每月一次交换输血将限制疾病进展，提高运动能力， 预防血管闭塞性疼痛危象和急性胸部综合征的间歇发作， 造成右心衰竭我们建议进行一项临床试验来评估 与标准治疗相比，自动交换输血对患者发病率和死亡率的影响 150例成人高危SCD患者。该试验将利用现有的协调中心基础设施， 匹兹堡大学，将涉及22个经验丰富的临床研究中心。尽管安全性和广泛使用 红细胞分离术在成人SCD患者中的应用，目前还没有一致的或高质量的疗效数据， 改善我们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.