Patient‐focused inquiry on hydroxyurea therapy adherence and reasons for discontinuation in adults with sickle cell disease
Authors: Christopher Bradford, Hope Miodownik, Merin Thomas, Ugochi O. Ogu, Caterina P. Minniti
Journal: American Journal of Hematology (2021)

For decades, Hydroxyurea (HU) was the only Food and Drug Administration (FDA) approved medication for treating adults with sickle cell disease (SCD) with demonstrated efficacy in reducing the frequency of painful crises, hospitalizations, and blood transfusions.1-4 While recently approved agents have been found to offer reductions in the frequency of painful crises and hospitalizations (L-glutamine), in the number of painful crises (crizanlizumab), and in anemia and hemolysis (Voxelotor), HU remains the first-line agent for individuals with SCD over the age of 2 years.5-7 Despite its proven utility, many patients are either not prescribed it or are not taking the medication.8, 9 Few studies exist to date that evaluates reasons behind this phenomenon from the patient's perspective. Between October 2017 and February 2019, patients with SCD seen at the Montefiore Medical Center's Sickle Cell Center for Adults completed a survey instrument that collected demographic information, disease course, and past and current treatments. Surveys were offered in English and Spanish. Data from 224 adults were available for analysis. Additional information was collected from the electronic medical record (EMR), and survey results were verified using the EMR. This study was approved by Montefiore Institutional Review Board (IRB) as exempt from consent. Patient demographics for the 224 patients surveyed are presented in Table S1. Of the 224 patients, 57 had "mild" disease genotypes (HbSC or Hb Beta Thal +) and 167 had "severe" genotype (HbSS or HbS Beta/0 thal). Overall, 77.2% of patients surveyed had ever been prescribed HU. Of those who had ever been prescribed HU, 65.3% reported taking it at the time of this study. Among patients with "mild" SCD genotypes, 42.1% reported ever having been prescribed HU, with 50% of these patients taking it at the time of this study. For those with severe disease genotypes, 91.0% had ever been prescribed HU, 68.4% of whom reported taking it at the time of this study. Of 146 patients who were currently taking the medication, patients reported variable duration of HU use: 8.1% had taken HU for less than or equal to 1 year; 31.2% for a period of at least 1–5 years; 12.7% for a period of at least 5–10 years; and 9.8% for greater than 10 years. Length of use was not reported by 38.2% of patients and it could not be reliably verified in the EMR. Among the 173 patients who had ever taken HU, 17.3% reported side effects (Table 1), with fatigue (16.7% of those reporting side effects), hair loss (16.7%), and gastrointestinal distress (16.7%) the most commonly cited. HU had been discontinued at some point by 35.3% of patients. Side effects were cited as the direct cause for discontinuation by 24.6% of those who had stopped taking HU Table 2). Other reasons for discontinuation included perceived ineffectiveness (16.4%), physician direction (14.8%), reproductive health (8.2%), ulcer formation (8.2%), and general dissatisfaction with HU (8.2%). Reason for discontinuation was not specified by 19.7% of patients. HU remains first-line therapy for management of SCD. Furthermore, it is the only drug with an extensive body of literature demonstrating reduction in patient morbidity and mortality.10 Most studies in the literature report HU use based on the presence of a prescription of HU in the EMR. In our study, we report HU use based on patient's account. In this patient-oriented survey, despite physicians prescribing HU in 91% of patients with HbSS and/or HbSB0 and 42% of HbSC/HbSβ+, only 68% and 50%, respectively, were actually taking the drug. Thus, almost half of the patients that were "on HU" according to the provider's and the EMR, were actually taking it. Among all patients, about one-third of them (35.3%) had been prescribed HU in the past but discontinued their treatment at some point. The most common reason for discontinuation among were medication's side effects (24.6%), followed by perceived "ineffectiveness" and physician's instructions to discontinue it. Some patients reported side effects that are well described in the literature (e.g., weight gain, cytopenias, and hair loss). Others, however, reported side effects that may not be directly related to HU use (e.g., back pain and depression). The effectiveness of HU has been demonstrated in numerous publications worldwide and it is mostly evident with long-term use. However, only a minority of patients surveyed (about one-tenth) in this adult cohort reported having taken HU for more than 10 years. As SCD morbidity and mortality often relate to cumulative disease burden over time, physicians and patients may need to discuss the delicate balance of potential long-term benefits versus immediate results and side effects. Our results provide evidence that clinicians are indeed prescribing HU to patients with severe SCD genotypes (SS/Sβ0) at high rates, with 91.0% having ever been prescribed HU. However, patients report a substantially lower and short-lived HU utilization, due to various hindrances. A fuller understanding of patient experience with HU, including side effects and perceptions of the medication, is needed to further improve rates of prescribing and adherence among adult patients with SCD. By identifying variability in reported side effects and reasons for discontinuation, this descriptive study highlights the need for clinicians to maintain an open line of communication with their patients and remain diligent in their prescribing and management of SCD. The authors declare no competing financial interests. Concept and design: Ugochi Ogu, Caterina P. Minniti. Acquisition, analysis, or interpretation of data: Christopher Bradford, Hope Miodownik, Merin Thomas, Ugochi Ogu, Caterina P. Minniti. Drafting of the manuscript: Christopher Bradford, Hope Miodownik, Caterina P. Minniti. Data sharing not applicable to this article as no datasets were generated or analysed during the current study Table S1 Patient demographics. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.