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Purpose: Sickle cell disease (SCD) is an inherited red blood cell disease caused by a mutation in the gene encoding the β-subunit of adult hemoglobin that leads to hemolysis, anemia, vaso-occlusive crises (VOCs), morbidity, and mortality. This study provides a real-world assessment of the clinical burden and health care resource utilization (HCRU) associated with SCD with recurrent VOCs in England., Methods: This retrospective study linked primary care records from the Clinical Practice Research Datalink database with secondary care records from the Hospital Episode Statistics database to identify patients with SCD with recurrent VOCs between July 1, 2008, and June 30, 2018. A VOC was defined as SCD with crisis, acute chest syndrome, or priapism. Eligible patients had SCD, ≥2 VOCs/year in any 2 consecutive years after a diagnosis of SCD, and ≥1 year of follow-up data from the index date. Patients were exact matched with 5 controls from the general population in the databases. Demographics were assessed at index. Mortality, clinical complications, and HCRU were summarized during follow-up., Findings: After applying eligibility criteria, 1117 patients with SCD with recurrent VOCs and 5585 controls were included in the study. Mean age at index was 25 years in both groups. The proportion of deaths (3.67% vs 0.68%; P < 0.001) and mortality rate (0.78 deaths per 100 person-years vs 0.16 deaths per 100 person-years) were substantially higher in patients with SCD with recurrent VOCs versus matched controls. Mean (standard deviation [SD]) age of death in patients with SCD with recurrent VOCs who died during the follow-up period was 40.17 (14.09) years. The mean (SD) rate of VOCs for patients with SCD with recurrent VOCs was 5.84 (12.50) per patient per year (PPPY) during follow-up. Compared with matched controls, patients with SCD with recurrent VOCs had substantially higher mean [SD] rates PPPY of inpatient hospitalizations (7.59 [14.50] vs 0.32 [2.71]), prescriptions (31.06 [60.62] vs 7.58 [27.77]), and outpatient visits (9.60 [10.69] vs 1.78 [4.18]). Older patients and those with increased numbers of VOCs had increased mortality, frequency of clinical complications, and HCRU., Implications: Despite currently available care, patients with SCD with recurrent VOCs in England have increased mortality, substantial clinical complications, and significant HCRU driven by VOCs and hospitalizations. Elevated mortality and clinical complications in patients with SCD with recurrent VOCs highlight the need for novel therapies in this space., Competing Interests: Declaration of competing interest C. Udeze and N. Li are employees of Vertex Pharmaceuticals Incorporated and hold stock or stock options in the company. N.F. Ly, F.C. Ingleby, and S.D. Fleming are employees of IQVIA. S.C. Conner is an employee of Vertex Pharmaceuticals Incorporated and holds stock or stock options in the company and received a grant from the National Heart, Lung, and Blood Institute. J. Howard is an employee of Vertex Pharmaceuticals Incorporated and may hold stock or stock options in the company; reports advisory board and Delphi panel participation for Global Blood Therapeutics/Pfizer; advisory board participation for Novo Nordisk; was a member of a speaker's bureau and a steering committee for Novartis Pharma AG; and received research funding from bluebird bio. F. Shah received payment or honoraria from Bristol Myers Squibb, Chiesi Limited, Novartis Pharma AG, bluebird bio, Global Blood Therapeutics/Pfizer, Agios Pharmaceuticals, Abfero Pharmaceuticals, Silence Therapeutics, and Roche; served as an adjudication or data monitoring committee member for Agios, IQVIA, and Abfero Pharmaceuticals. This study was supported by Vertex Pharmaceuticals Incorporated., (Copyright © 2024 Vertex Pharmaceuticals Funded the Research. Published by Elsevier Inc. All rights reserved.)

Purpose: Patients with transfusion-dependent β-thalassemia (TDT) have reduced levels of β-globin, leading to ineffective erythropoiesis and iron overload. Patients with TDT depend on regular red blood cell transfusions (RBCTs) and iron chelation therapy for survival and management of disease- and treatment-related clinical complications. This study describes the clinical and economic burden in patients with TDT in England., Methods: This longitudinal, retrospective study linked the Clinical Practice Research Datalink (CPRD) database with secondary care data from the Hospital Episode Statistics database to identify patients with a diagnosis of β-thalassemia between July 1, 2008, and June 30, 2018. Included patients had a diagnosis of β-thalassemia prior to the index date, ≥8 RBCTs per year for ≥2 consecutive years, and ≥1 year of follow-up data available from the index date. Each eligible patient was exact matched with up to 5 controls in the CPRD. Proportions of deaths and rates of mortality, acute and chronic complications, and healthcare resource utilization (HCRU) were calculated during the follow-up period., Findings: Of 11,359 identified patients with β-thalassemia, 237 patients with TDT met the eligibility criteria and were matched with 1184 controls. The mean age at the index date was approximately 25 years in the patient and control groups. The proportion of deaths (7.17% vs 1.18%; P < 0.05) and mortality rate (1.19 deaths per 100 person-years vs 0.20 deaths per 100 person-years) were higher among patients with TDT compared to controls. Endocrine complications and bone disorders were the most prevalent complications among patients with TDT (58.23%) and included osteoporosis (29.11%), diabetes mellitus (28.27%), and hypopituitarism (28.27%). Patients with TDT had a mean of 13.62 RBCTs per patient per year (PPPY). HCRU was substantially higher among patients with TDT, wherein patients with TDT had higher rates of prescriptions recorded in primary care (24.09 vs 8.61 PPPY), outpatient visits (16.69 vs 1.31 PPPY), and inpatient hospitalizations (17.41 vs 0.24 PPPY) than controls. Inpatient hospitalizations were primarily <1 day, with 16.62 events PPPY lasting <1 day and 0.79 events PPPY lasting ≥1 day. Patients with TDT aged ≥18 years had increased rates of mortality, clinical complications, and HCRU than those aged <18 years., Implications: Patients with TDT in England have higher mortality than matched controls, substantial disease-related clinical complications, and substantial HCRU. High mortality and clinical complications highlight the need for additional innovative therapies for TDT., Competing Interests: Declaration of competing interest C. Udeze and N. Li are employees of Vertex Pharmaceuticals Incorporated and hold stock or stock options in the company. N.F. Ly, F.C. Ingleby, and S.D. Fleming are employees of IQVIA. S.C. Conner is an employee of Vertex Pharmaceuticals Incorporated and holds stock or stock options in the company and received a grant from the National Heart, Lung, and Blood Institute. J. Howard is an employee of Vertex Pharmaceuticals Incorporated and may hold stock or stock options in the company; reports advisory board and Delphi panel participation for Global Blood Therapeutics/Pfizer; advisory board participation for Novo Nordisk; was a member of a speaker's bureau and a steering committee for Novartis Pharma AG; and received research funding from Bluebird Bio. F. Shah received payment or honoraria from Bristol Myers Squibb, Chiesi Limited, Novartis Pharma AG, Bluebird Bio, Global Blood Therapeutics/Pfizer, Agios Pharmaceuticals, Abfero Pharmaceuticals, Silence Therapeutics, and Roche; served as an adjudication or data monitoring committee member for Agios, IQVIA, and Abfero Pharmaceuticals., (Copyright © 2024 Vertex Pharmaceuticals Incorporated. Published by Elsevier Inc. All rights reserved.)

Introduction: Concerns of the persistence and severity of the adverse effects of fluoroquinolones, mainly involving the nervous system, muscles and joints, resulted in the 2018 referral procedure led by the European Medicines Agency (EMA). They advised to stop prescribing fluoroquinolones for infections of mild severity or of a presumed self-limiting course and for prevention of infections, plus to restrict prescriptions in cases of milder infections where other treatment options are available, and restrict in at-risk populations. We aimed to examine whether the impact of EMA regulatory interventions implemented throughout 2018-2019 had an impact on fluoroquinolone prescribing rates., Methods: A retrospective population-based cohort study was conducted using electronic health care records from six European countries between 2016 and 2021. We analysed monthly incident fluoroquinolone use rates overall and for each fluoroquinolone active substance through flexible modelling via segmented regression to detect time points of trend changes, in monthly percentage change (MPC)., Results: The incidence of fluoroquinolone use ranged from 0.7 to 8.0/1000 persons per month over all calendar years. While changes in fluoroquinolone prescriptions were observed over time across countries, these were inconsistent and did not seem to be temporally related to EMA interventions (e.g., Belgium: February/May 2018, MPC - 33.3%, 95% confidence interval [CI] - 35.9 to - 30.7; Germany: February/May 2019, MPC - 12.6%, 95% CI - 13.7 to - 11.6]; UK: January/April 2016, MPC - 4.9%, 95% CI - 6.2 to - 3.6)., Conclusion: The regulatory action associated with the 2018 referral did not seem to have relevant effects on fluoroquinolone prescribing in primary care., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Macrolides are widely prescribed antibiotics for many different indications. However, there are concerns about adverse effects such as ototoxicity., Objectives: To investigate whether macrolide use is associated with tinnitus and hearing loss in the general population., Methods: Cross-sectional (n = 4286) and longitudinal (n = 636) analyses were performed within the population-based Rotterdam Study. We investigated with multivariable logistic regression models the association between macrolides and tinnitus, and with multivariable linear regression models the association between macrolides and two different hearing thresholds (both ears, averaged over 0.25, 0.5, 1, 2, 4 and 8 kHz and 2, 4 and 8 kHz). Both regression models were adjusted for age, sex, systolic blood pressure, alcohol, smoking, BMI, diabetes, education level, estimated glomerular filtration rate and other ototoxic or tinnitus-generating drugs. Cumulative exposure to macrolides was categorized according to the number of dispensed DDDs and duration of action., Results: In the fully adjusted model, ever use of macrolides was associated with a 25% higher likelihood of prevalent tinnitus (OR = 1.25; 95% CI 1.07-1.46). This association was more prominent in participants with a cumulative dose of more than 14 DDDs and among users of intermediate- or long-acting macrolides. Macrolide use in between both assessments was associated with more than a 2-fold increased risk on incident tinnitus. No general association between macrolides and hearing loss was observed. A borderline significant higher hearing threshold in very recent users (≤3 weeks) was found., Conclusions: Macrolide use was significantly associated with both prevalent and incident tinnitus. Macrolide-associated tinnitus was likely cumulative dose-dependent., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)