The Impact of Hemoglobin Level on Risk of End-Organ Damage among Patients with Sickle Cell Disease - A Large-Scale, Longitudinal Analysis
Authors: Ershler William B , De Castro Laura M , Pakbaz Zahra , Moynahan Aaron , Weycker Derek , Pham Nhat , Delea Thomas E , Agodoa Irene , Cong Ze 
Published: February 2021

Background: Sickle cell disease (SCD) is an inherited, chronic, and multifaceted condition. Anemia affects most patients with SCD, and low hemoglobin (Hb) levels have been demonstrated to be correlated with end-organ damage (EOD) such as stroke, chronic kidney disease (CKD), end-stage renal disease (ESRD), and pulmonary hypertension (PH). This study sought to estimate the relationship between Hb and risk of EOD based on large-scale, longitudinal analyses of recent data.
Methods: Patients with SCD aged 12 years and older and at least 1 Hb level reported from January 2013 to March 2019 in the large, US-representative, provider-centric Symphony Health claims database were included. For each qualifying patient, Hb values were identified and included as separate observations. Onset of new EOD, including stroke, CKD (including ESRD), and PH were ascertained during the 1-year period after the date of each Hb assessment (index date). History of EOD and other comorbid conditions were identified using claims from the database start date (January 1, 2012) or first activity date, whichever was later, up to the index date, to differentiate from newly diagnosed EOD. Patient demographics and clinical characteristics were summarized descriptively. Bivariate analyses of Hb levels and EOD were assessed using generalized estimating equations (GEE) regression with a logistic link function to account for clustering of observations at the patient level. Multivariable GEE regression was employed to evaluate the independent association between Hb and EOD, adjusting for patient demographics and other SCD complications.
Results: A total of 16,754 patients with SCD aged 12 years and older were identified (mean age: 34.7 years, 37.7% male), contributing 41,692 observations of Hb levels (mean [SD], 9.8 [2.0] g/dL). In univariate analyses, higher Hb levels were significantly associated with lower odds of new EOD of any type (Figure). In multivariable analyses, after controlling for age, gender, and history of other SCD complications, patients with Hb b %12 g/dL had significantly lower odds of new EOD versus patients with Hb &lt;7 g/dL (reference group): any of the 3 types of EOD by 63% (P&lt;0.001), CKD by 64% (P&lt;0.001), and PH by 79% (P&lt;0.001). Patients with Hb b %10 g/dL also had significantly lower odds of stroke (by 34% [P=0.026]) versus patients with Hb &lt;7 g/dL (Table). In addition to lower Hb, patients of older age, those who were publicly insured versus commercially insured, and patients with cardiovascular comorbidities (eg, heart failure or myocardial infarction) or other SCD chronic conditions generally had significantly higher odds of new EOD, regardless of type. Previous CKD and stroke were statistically and significantly associated with presence of new EOD of any type and with any of the other 2 types of EOD studied (previous CKD and new PH: P&lt;0.01, new stroke: P&lt;0.05; previous stroke and new CKD: P&lt;0.01, new PH: P&lt;0.05).
Conclusions: In this large-scale, longitudinal analysis, a significant reduction in the risk of new EOD was observed among SCD patients with higher Hb levels. History of any EOD significantly correlated with presence of new EOD. New SCD treatments that can increase Hb levels can potentially offer clinical and economic value.

Disclosures
Ershler: Pharmacosmos Therapeutics Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. De Castro:GlycoMimetics: Membership on an entity's Board of Directors or advisory committees; FORMA Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees. Pakbaz:Amgen: Membership on an entity's Board of Directors or advisory committees; Dova: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Terumo BCT: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Global Blood Therapeutics: Speakers Bureau. Moynahan:Global Blood Therapeutics: Research Funding; Novartis: Research Funding; Policy Analysis Inc.: Current Employment. Weycker:Policy Analysis Inc.: Current Employment, Current equity holder in publicly-traded company; Global Blood Therapeutics: Research Funding; Novartis: Research Funding. Pham:Policy Analysis Inc.: Current Employment; Global Blood Therapeutics: Research Funding; Novartis: Research Funding. Delea:Policy Analysis Inc.: Current Employment, Current equity holder in private company; Global Blood Therapeutics: Research Funding; Novartis: Research Funding. Agodoa:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Cong:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company.