title: Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia.
abstract: BACKGROUND
  The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin are licensed to treat chemotherapy-associated anemia in patients with nonmyeloid malignancies. Although systematic overviews of trials have identified venous thromboembolism (VTE) risks, none have identified mortality risks with ESAs.
  
  
  OBJECTIVE
  To evaluate VTE and mortality rates associated with ESA administration for the treatment of anemia among patients with cancer.
  
  
  METHODS
  A published overview from the Cochrane Collaboration (search dates: January 1, 1985-April 1, 2005) and MEDLINE and EMBASE databases (key words: clinical trial, erythropoietin, darbepoetin, and oncology), the public Web site of the US Food and Drug Administration and ESA manufacturers, and safety advisories (search dates: April 1, 2005-January 17, 2008).
  
  
  METHODS
  Phase 3 trials comparing ESAs with placebo or standard of care for the treatment of anemia among patients with cancer.
  
  
  METHODS
  Mortality rates, VTE rates, and 95% confidence intervals (CIs) were extracted by 3 reviewers from 51 clinical trials with 13 611 patients that included survival information and 38 clinical trials with 8172 patients that included information on VTE.
  
  
  RESULTS
  Patients with cancer who received ESAs had increased VTE risks (334 VTE events among 4610 patients treated with ESA vs 173 VTE events among 3562 control patients; 7.5% vs 4.9%; relative risk, 1.57; 95% CI, 1.31-1.87) and increased mortality risks (hazard ratio, 1.10; 95% CI, 1.01-1.20).
  
  
  CONCLUSIONS
  Erythropoiesis-stimulating agent administration to patients with cancer is associated with increased risks of VTE and mortality. Our findings, in conjunction with basic science studies on erythropoietin and erythropoietin receptors in solid cancers, raise concern about the safety of ESA administration to patients with cancer.
authors.affiliation: VA Chicago Healthcare System, Department of Medicine, Northwestern University Feinberg School of Medicine, and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA. cbenne@northwestern.edu
authors.forename: Charles L
authors.initials: CL
authors.lastname: Bennett
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Silver
authors.forename: Benjamin
authors.initials: B
authors.lastname: Djulbegovic
authors.forename: Athena T
authors.initials: AT
authors.lastname: Samaras
authors.forename: C Anthony
authors.initials: CA
authors.lastname: Blau
authors.forename: Kara J
authors.initials: KJ
authors.lastname: Gleason
authors.forename: Sara E
authors.initials: SE
authors.lastname: Barnato
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Elverman
authors.forename: D Mark
authors.initials: DM
authors.lastname: Courtney
authors.forename: June M
authors.initials: JM
authors.lastname: McKoy
authors.forename: Beatrice J
authors.initials: BJ
authors.lastname: Edwards
authors.forename: Cara C
authors.initials: CC
authors.lastname: Tigue
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Raisch
authors.forename: Paul R
authors.initials: PR
authors.lastname: Yarnold
authors.forename: David A
authors.initials: DA
authors.lastname: Dorr
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Kuzel
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.forename: Steven M
authors.initials: SM
authors.lastname: Trifilio
authors.forename: Dennis P
authors.initials: DP
authors.lastname: West
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Lai
authors.forename: Michael
authors.initials: M
authors.lastname: Henke
mesh_terms: D000740:Anemia / Q000188:drug therapy* / Q000209:etiology*; D017326:Clinical Trials, Phase III as Topic; D000068256:Darbepoetin alfa; D004921:Erythropoietin / Q000009:adverse effects* / Q000031:analogs & derivatives*; D006397:Hematinics / Q000009:adverse effects*; D006801:Humans; D009369:Neoplasms / Q000150:complications*; D011994:Recombinant Proteins; D012306:Risk; D015996:Survival Rate; D054556:Venous Thromboembolism / Q000453:epidemiology*
chemical_list: D006397:Hematinics; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068256:Darbepoetin alfa