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

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, the investigators 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 the investigators 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.

The investigators 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.

Randomized to standard of care and automated exchange blood transfusion every 3-6 weeks for 12 months.

Biological: Red Blood Cell · Other: Standard of care

Randomized to standard of care

Other: Standard of care

Red blood cell exchange transfusions will be performed every 3-6 weeks to maintain a target post-transfusion hemoglobin S level of \<20% and a pre-transfusion hemoglobin S of \<30%.

NHLBI/ASH/ATS Expert Panel recommended guidelines

Plazo: 13 months

The efficacy of the intervention will be measured by comparing the total number of episodes of clinical worsening of SCD requiring acute health care encounters (non-elective infusion center/ER/Hospital visits) or resulting in death over 13 months between groups.

Plazo: 13 months

A 6-level prioritized rank-based outcome: 1.No death or SCD-related acute health care encounters (SCDAcuteE) within (w/in) 13 months (m) of randomization; 2. Had SCDAcuteE but NO major complications (acute kidney injury (AKI), acute chest syndrome (ACS), cor pulmonale, stroke, liver failure) associated with an SCDAcuteE nor death w/in 13 m of randomization; 3. Had 1 major complication (AKI, ACS, cor pulmonale, stroke, or liver failure) associated with an SCDAcuteE but not death w/in 13 m of randomization; 4. Had 2 major complications (AKI, ACS, cor pulmonale, stroke, or liver failure) associated with SCDAcuteE but not death w/in 13 m of randomization; 5. Had ≥ 3 major complications (AKI, ACS, cor pulmonale, stroke, or liver failure) associated with SCDAcuteE but not death w/in 13 m of randomization; 6.Death w/in 13 m of randomization. If the same complication reoccurs, occurrences will be counted as separate complications if the acute health care encounters are separated by ≥7 days.

Plazo: 13 months

Survival over thirteen-month period will be analyzed and compared between the group receiving the intervention and the group receiving care routinely provided for sickle cell patients based on the NHLBI guidelines.

Plazo: 13 months

Survival free of acute health care encounters over 13 months.

Plazo: 13 months

The total number of acute health care encounters (non-elective infusion center/ER/Hospital visits) with evidence of cor pulmonale (physical exam findings, NT-proBNP increase plus echocardiographic evidence of worsening right heart function).

Plazo: 4, 8, and 12 months

Measures of exercise capacity assessed at 4, 8 and 12 months by the distance walked in the six minute walk distance assessment

Plazo: 4, 8, and 12 months

Measures of exercise capacity assessed at 4, 8 and 12 months by the distance walked in a 7 day in the outpatient setting.

Plazo: 12 months

Established cardiovascular risk biomarkers and indices are combined to help the investigators form an opinion about cardiovascular risks. The following will be measured: NT-proBNP, QT prolongation, systemic pulse pressure, albuminuria, estimated GFR and CKD progression Kidney Disease Improving Global Outcomes (KDIGO) CKD Work Group criteria.

Plazo: 4, 8 and 12 months

Participants will be assessed for development of new leg ulcers at each physical exam.

Plazo: 4, 8 and 12 months

WHO functional status severity will be measured assessing by looking at limitation of usual physical activity from I (no limitation in usual physical activity) to Class IV (inability to perform any physical activity at rest)

Plazo: 4, 8 and 12 months

Nocturnal desaturation will measured using a wearable device to measure blood oxygen saturation for 7 nights at home.

Plazo: 4, 8 and 12 months

SCD specific patient reported outcomes as measured by self-reported pain

Plazo: 4, 8 and 12 months

SCD specific patient reported outcomes as measured by a modified version of health related quality of life questionnaire from PROMIS QoL measure

Plazo: 4, 8 and 12 months

SCD specific patient reported outcomes as measured by a modified version of health related quality of life questionnaire from ASCQ-Me QoL measure

Plazo: 4, 8 and 12 months

Cardiovascular function measures from echocardiography assessed at 4, 8 and 12 months: echocardiographic measures of tricuspid regurgitant jet velocity in m/s.

Plazo: 4, 8 and 12 months

Diastolic left heart function measured by E/A ratio, E/Em ratio, and deceleration times will be assessed by echocardiography.

Plazo: 4, 8 and 12 months

Systolic right heart health will be measured by assessing tricuspid annular plane systolic excursion (TAPSE), right ventricular size and contractility from echocardiography of the heart.

Plazo: 13 months

The number of acute health care encounters (non-elective infusion center/ER/Hospital visits) with at least one major complication.

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