Severe Painful Vaso-Occlusive Crises and Mortality in a Contemporary Adult Sickle Cell Anemia Cohort Study

<div><p>Background</p><p>Frequent painful vaso-occlusive crises (VOCs) were associated with mortality in the Cooperative Study of Sickle Cell Disease (CSSCD) over twenty years ago. Modern therapies for sickle cell anemia (SCA) like hydroxyurea are believed to have improved overall patient survival. The current study sought to determine the relevance of the association between more frequent VOCs and death and its relative impact upon overall mortality compared to other known risk factors in a contemporary adult SCA cohort.</p> <p>Methods</p><p>Two hundred sixty four SCA adults were assigned into two groups based on patient reported outcomes for emergency department (ED) visits or hospitalizations for painful VOC treatment during the 12 months prior to evaluation.</p> <p>Results</p><p>Higher baseline hematocrit (p = 0.0008), ferritin (p = 0.005), and HDL cholesterol (p = 0.01) were independently associated with 1 or more painful VOCs requiring an ED visit or hospitalization for acute pain. During a median follow-up of 5 years, mortality was higher in the ED visit/hospitalization group (relative risk [RR] 2.68, 95% CI 1.1-6.5, p = 0.03). Higher tricuspid regurgitatant jet velocity (TRV) (RR 2.41, 95% CI 1.5-3.9, p < 0.0001), elevated ferritin (RR 4.00, 95% CI 1.8-9.0, p = 0.001) and lower glomerular filtration rate (RR=2.73, 95% CI 1.6-4.6, p < 0.0001) were also independent risk factors for mortality. </p> <p>Conclusions</p><p>Severe painful VOCs remain a marker for SCA disease severity and premature mortality in a modern cohort along with other known risk factors for death including high TRV, high ferritin and lower renal function. The number of patient reported pain crises requiring healthcare utilization is an easily obtained outcome that could help to identify high risk patients for disease modifying therapies.</p> <p>Trial Registration</p><p>ClinicalTrials.gov NCT00011648 <a href="http://clinicaltrials.gov/" target="_blank"><u>http://clinicaltrials.gov/</u></a></p> </div

Kaplan Meier (KM) curve showing survival in sickle cell anemia by severe pain crises requiring an ED visit/ hospitalization in past year.

<p>Kaplan Meier (KM) curve showing survival in sickle cell anemia by severe pain crises requiring an ED visit/ hospitalization in past year.</p

Characteristics at Enrollment and Survival Status Based On Hydroxyurea Status and Fetal Hemoglobin Quartiles in Patients with HbSS.

<p>^at-test</p><p>^bChi-square test</p><p>^cCox regression with age as the time-scale</p><p>^dWilcoxon rank-sum test</p><p>^N/ANot applicable</p><p>^eHydroxyurea doses >35 mg/kg/d are not FDA-approved for the general management of patients with sickle cell anemia and were usually used in patients in preparation for hematopoietic stem cell transplantation.</p><p>^fMean maximum HbF and MCV are defined as the mean calculation of the highest values observed for each subject.</p><p>*p<0.001 when comparing HbF Lower 25% to HbF Upper 25% groups</p><p>**p<0.0001 when comparing HbF Lower 25% to HbF Upper 25% groups</p><p>^#p<0.001 when comparing No Hydroxyurea to Any Hydroxyurea groups</p><p>^##p<0.0001 when comparing No Hydroxyurea to Any Hydroxyurea groups</p><p>Characteristics at Enrollment and Survival Status Based On Hydroxyurea Status and Fetal Hemoglobin Quartiles in Patients with HbSS.</p

Comparison of Hematologic and Organ Function Parameters at Enrollment and Last visits in Patients with HbSS Based on Hydroxyurea Status and Fetal Hemoglobin Quartile.

<p>Abbreviations: HU, hydroxyurea; Low HbF, maximum fetal hemoglobin within the lowest quartile; High HbF, maximum fetal hemoglobin within the highest quartile; ANC, absolute neutrophil count; MCV, mean corpuscular volume; ARC, absolute reticulocyte count; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TRV, tricuspid regurgitant velocity; NT-ProBNP, brain natriuretic peptide</p><p>^aConversion factor from U/L to μkat/L is 0.017; conversion factor from mg/dL to μmoL/L is 17.1</p><p>^bWilcoxon rank-sum test, other p-values are from t-tests if not otherwise specified</p><p>^cEjection fraction and TRV were reported in 345 subjects at first visit and 261 subjects at last visit</p><p>^dNT-ProBNP levels are only reported in patients with a creatinine <1.0mg/dL, (N = 65 No HU, 165 any HU, 21 low HbF, 12 high HbF)</p><p>^#p<0.05 when comparing No Hydroxyurea to Any Hydroxyurea groups</p><p>^##p<0.001 when comparing No Hydroxyurea to Any Hydroxyurea groups</p><p>^###p<0.0001 when comparing No Hydroxyurea to Any Hydroxyurea groups</p><p>*p<0.05 when comparing HbF Lower 25% to HbF Upper 25% groups</p><p>**p<0.001 when comparing HbF Lower 25% to HbF Upper 25% groups</p><p>***p<0.0001 when comparing HbF Lower 25% to HbF Upper 25% groups</p><p>Comparison of Hematologic and Organ Function Parameters at Enrollment and Last visits in Patients with HbSS Based on Hydroxyurea Status and Fetal Hemoglobin Quartile.</p

Cox Regression Analysis of Variables Associated with Survival for Subjects with HbSS.

<p>^aInput variables: age, hydroxyurea exposure, hydroxyurea dose, dose group, maximum fetal hemoglobin, hemoglobin, white blood cell count, alkaline phosphatase, total bilirubin, albumin, creatinine, ejection fraction, and tricuspid regurgitant velocity. The input variables were selected based on univariate analysis results if they were associated either with mortality or hydroxyurea use. The final model is shown in the table and is obtained through backward stepwise model selection and includes variables associated with hydroxyurea use if they were significant at the 0.10 level. The hazard ratio units represent increase per one unit change of the factor. Hydroxyurea dose groups are compared to no hydroxyurea.</p><p>Cox Regression Analysis of Variables Associated with Survival for Subjects with HbSS.</p

Causes of Death in Patients with Homozygous Sickle Cell Disease.

<p>^aMore than one cause of death was assigned to 4 patients</p><p>^bOther: multi-organ failure (1); trauma (1); subglottic stenosis (1); acute myelogenous leukemia (1); hemolytic transfusion reaction (1); cocaine toxicity (1)</p><p>Causes of Death in Patients with Homozygous Sickle Cell Disease.</p