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

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.

Grant Number: 5U24HL143217-07
NIH Institute/Center: NIH
Principal Investigator: Maria Brooks