Utilization and outcomes of erythropoietin stimulating agents in sickle cell disease patient: A real world data analysis

Abstract Background: Sickle cell disease (SCD) is hereditary blood disorder leading to anemia, vaco-occlusive crises, organ damage. Its treatment remains challenging. There are various reports of utilization of Erythropoietin Stimulating Agents (ESAs) in sickle cell patients along with hydroxyurea showing some benefit in decreasing sickle cell crisis.[1-3] Here, using global research network dataset, we evaluate outcomes of using ESAs in SCD. Methods: Trinetx, a global federated research network that provides a dataset of electronic medical records from different healthcare organizations (HCOs), was utilized. Initial query was made to isolate patients with age >18 years, who had SCD without crisis or sickle cell/thalassemia disease or sickle cell/Hb-C disease (ICD 10 codes D57.1, D57.2, D57.4, D57.80) and Hemoglobin levels between 7 and 10 gm/dl. The population was divided into two cohorts based on receipt of ESAs (EPO, Epoietin alfa, Darbepoetin alfa). Propensity Score matching (PSM) was carried to match age, sex, race, chronic heart failure, chronic lung disease, neoplasms, chronic kidney disease stages 4 and 5, use of hydroxyurea and crizanlizumab. Outcomes of all-cause mortality (ACM), sickle cell crisis, ischemic stroke, cardiac ischemia and other arterio-venous thrombosis were evaluated. Results: 19,143 patients with SCD were identified, of whom 9.14% (n=1750) patients received EPO. The patients who received EPO were older (49 ± 18.2 vs 32.2 ± 17.4 years, p<0.0001), with more males receiving EPO (10.01% vs 8.81%, p=0.019). Use of hydroxyurea was found to be more in EPO group (37% (n=629) vs 16% (n=1568), p<0.0001). The median follow- up period was 887.5 days in EPO group and 1078 days in non-EPO group. All-cause mortality was high for patients receiving EPO (31.94% (544) vs 8.94% (1499), p<0.0001, OR = 4.78 (4.26, 5.36) with Hazard ratio 4.21 (3.82, 4.65; log-rank test = p<0.0001)). Sickle cell crisis risk was less in patients receiving EPO (14.86% (129) vs 36.34% (3521), p<0.001, OR=0.31 (0.25,0.37) with HR 0.34 (0.28,0.41)). The risk of developing stroke (11.56% vs 6.52%, p<0.0001), cardiac ischemia (17.91% vs 5.15%, p<0.0001), and other arterio-venous thrombosis (19.62% vs 9.36%, p<0.0001) was high in EPO group. After PSM, the all-cause mortality was still high in EPO group (29.22% vs 20.21%, p<0.0001, OR=1.63 (1.33,1.99), HR=1.3 (1.09,1.55)) with no significant difference in sickle cell crisis (20.25% vs 19.19%, p=0.6607, OR=1.07 (0.79,1.44)). The risk of cardiac ischemia (15.03% vs 9.16%, p<0.0001), and other arterio-venous thrombosis (18.86% vs 11.58%, p<0.001) remained higher in EPO group, while there was no significant difference in risk of stroke (10.71% vs 8.59%, p=0.1233). Conclusion: This real-world data shows that ESAs use does increase the utilization of hydroxyurea, but its significance in improving survival and sickle cell crisis still needs to be evaluated with prognostic studies. The study also highlights potential risks of arterio-venous thrombosis with the use of ESAs. Reference:Obeagu EI. Maximizing longevity: erythropoietin's impact on sickle cell anaemia survival rates. Ann Med Surg (Lond). 2024 Jan 24;86(3):1570-1574. doi: 10.1097/MS9.0000000000001763. PMID: 38463100; PMCID: PMC10923353.Santosh Saraf, Robert Molokie, Michel Gowhari, Johara Hassan, Victor R. Gordeuk; Clinical Efficacy and Safety of Erythroid Stimulating Agents in Sickle Cell Disease. Blood2012; 120 (21): 3218. doi:Little JA, McGowan VR, Kato GJ, Partovi KS, Feld JJ, Maric I, Martyr S, Taylor JG 6th, Machado RF, Heller T, Castro O, Gladwin MT. Combination erythropoietin-hydroxyurea therapy in sickle cell disease: experience from the National Institutes of Health and a literature review. Haematologica. 2006 Aug;91(8):1076-83. PMID: 176885048; PMCID: PMC3522485.