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Venous Thromboembolism and Mortality Associated With Recombinant Erythropoietin and Darbepoetin Administration for the Treatment of Cancer-Associated Anemia
Charles L. Bennett, MD, PhD;
Samuel M. Silver, MD, PhD;
Benjamin Djulbegovic, MD, PhD;
Athena T. Samaras, BA;
C. Anthony Blau, MD;
Kara J. Gleason, BS;
Sara E. Barnato, MD;
Kathleen M. Elverman;
D. Mark Courtney, MD;
June M. McKoy, MD, MPH, JD;
Beatrice J. Edwards, MD;
Cara C. Tigue, BA;
Dennis W. Raisch, PhD;
Paul R. Yarnold, PhD;
David A. Dorr, MD, MS;
Timothy M. Kuzel, MD;
Martin S. Tallman, MD;
Steven M. Trifilio, RPh;
Dennis P. West, PhD;
Stephen Y. Lai, MD, PhD;
Michael Henke, MD
JAMA. 2008;299(8):914-924.
Context 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.
Data Sources 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).
Study Selection Phase 3 trials comparing ESAs with placebo or standard of care for the treatment of anemia among patients with cancer.
Data Extraction 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.
Data Synthesis 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.
Author Affiliations: VA Chicago Healthcare System, Departments of Medicine, Dermatology, and Emergency Medicine, Northwestern University Feinberg School of Medicine, and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois (Drs Bennett, Barnato, Courtney, McKoy, Edwards, Yarnold, Kuzel, Tallman, and West, and Mss Samaras, Gleason, Elverman, and Tigue); University of Michigan Health System, Ann Arbor (Dr Silver); Interdisciplinary Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa (Dr Djulbegovic); Department of Medicine/Hematology and the Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle (Dr Blau); University of New Mexico, VA Cooperative Studies Program Clinical Research Pharmacy, Albuquerque (Dr Raisch); Department of Medical Informatics and Clinical Epidemology, Oregon Health and Science University, Portland (Dr Dorr); Department of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois (Mr Trifilio); Departments of Otolaryngology and Pharmacology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (Dr Lai); and University Hospital of Freiberg, Freiburg, Germany (Dr Henke).
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