title: Cardiovascular Morbidity and Pure Red Cell Aplasia Associated With Epoetin Theta Therapy in Patients With Chronic Kidney Disease: A Prospective, Noninterventional, Multicenter Cohort Study.
abstract: OBJECTIVE
  The European Medicines Agency recommends limiting the hemoglobin (Hb) concentration to 10 to 12 g/dL in adults with chronic kidney disease (CKD) receiving erythropoiesis-stimulating agents such as epoetin theta. This postauthorization study assessed the incidence and intensity of cardiovascular events, including ischemic stroke, in patients receiving epoetin theta for anemia associated with CKD. A secondary end point was adverse drug reactions, including pure red cell aplasia.
  
  
  METHODS
  In this prospective, noninterventional, multinational cohort study, consecutive patients with advanced or end-stage renal disease and receiving epoetin theta were followed up for 6 months. Data on reportable adverse events (RAEs) (cardiac disorders, cardiac failure, myocardial infarction, and ischemic stroke and respective subterms), epoetin theta dosage, and Hb concentrations were collected. A post hoc exploratory analysis assessed the incidences of RAEs according to tertiles for individual mean Hb concentration (≤10.7, >10.7-11.47, and >11.47 g/dL for low, intermediate, and high, respectively) and mean weekly epoetin theta dosage (≤62, >62-125, and >125 IU/kg/wk for low, intermediate, and high).
  
  
  RESULTS
  Data from 1039 patients were included (577 men, 462 women; mean age, 68.7 years). A total of 101 RAEs were documented in 89 patients (8.6%), for an event rate of 0.1985/person-year. Sixty-four patients (6.1%) died; none of the deaths was considered related to epoetin theta use. The incidence of RAEs was lowest at intermediate Hb concentrations (6.2%) compared with low (11.3%) and high (7.8%) Hb concentrations. The incidence of ischemic stroke was 1.5% at high Hb concentrations versus 0.6% at both the low and intermediate Hb concentrations. The incidence of any RAE was greater in the high-dose group (10.1%) than in the intermediate-dose (8.0%) and low-dose (7.6%) groups. The risk for any cardiovascular RAE or ischemic stroke was greatest in the high-dose/high-Hb group (13.3%), followed by high dose/low Hb (12.6%) and low dose/low Hb (12.1%). The risks for RAEs were lowest at high dose/intermediate Hb (3.8%) and low dose/intermediate Hb (5.3%). The event rate of adverse drug reactions other than the predefined RAEs was 0.0161/person-year. No cases of pure red cell aplasia were reported.
  
  
  CONCLUSIONS
  The findings from the present study suggest that, for maintaining the optimal target Hb concentration (10-12 g/dL according to the current summary of product characteristics for epoetin theta; 10-11.5 g/dL according to the current guideline from Kidney Disease Improving Global Outcomes) in anemic adults with CKD, the lowest approved, effective dose epoetin theta should be used.
authors.affiliation: Biosimilars Clinical Development, Teva Ratiopharm, Merckle GmbH, Ulm, Germany. Electronic address: andreas.lammerich@ratiopharm.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lammerich
authors.affiliation: Department of Internal Medicine, University Hospital St. Poelten and Karl Landsteiner Institute of Nephrology and Hematology, St. Poelten, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Balcke
authors.affiliation: Biosimilars Clinical Development, Teva Ratiopharm, Merckle GmbH, Ulm, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bias
authors.affiliation: Biosimilars Clinical Development, Teva Ratiopharm, Merckle GmbH, Ulm, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Mangold
authors.affiliation: Department of Internal Medicine, University Hospital St. Poelten and Karl Landsteiner Institute of Nephrology and Hematology, St. Poelten, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Wiesholzer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000188:drug therapy*; D015331:Cohort Studies; D004921:Erythropoietin / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006333:Heart Failure / Q000453:epidemiology; D006397:Hematinics / Q000008:administration & dosage; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology; D011446:Prospective Studies; D012010:Red-Cell Aplasia, Pure / Q000453:epidemiology*; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D020521:Stroke / Q000453:epidemiology / Q000209:etiology; D055815:Young Adult
chemical_list: D006397:Hematinics; C555712:epoetin theta; D004921:Erythropoietin
keywords: adverse reaction; anemia; cardiovascular morbidity; chronic kidney disease; epoetin theta; safety; tolerability