Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia

Charles L. Bennett, Samuel M. Silver, Benjamin Djulbegovic, Athena T. Samaras, C. Anthony Blau, Kara J. Gleason, Sara E. Barnato, Kathleen M. Elverman, D. Mark Courtney, June M. McKoy, Beatrice J. Edwards, Cara C. Tigue, Dennis W. Raisch, Paul R. Yarnold, David A. Dorr, Timothy M. Kuzel, Martin S. Tallman, Steven M. Trifilio, Dennis P. West, Stephen Y. Lai & 1 others Michael Henke

Research output: Contribution to journalReview article

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)914-924
Number of pages11
JournalJAMA - Journal of the American Medical Association
Volume299
Issue number8
DOIs
StatePublished - Feb 27 2008

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Hematinics
Second Primary Neoplasms
Venous Thromboembolism
Erythropoietin
Anemia
Mortality
Neoplasms
Clinical Trials
Confidence Intervals
Erythropoietin Receptors
Safety
Information Storage and Retrieval
United States Food and Drug Administration
Standard of Care
MEDLINE
Odds Ratio
Placebos
Databases
Drug Therapy

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bennett, Charles L. ; Silver, Samuel M. ; Djulbegovic, Benjamin ; Samaras, Athena T. ; Blau, C. Anthony ; Gleason, Kara J. ; Barnato, Sara E. ; Elverman, Kathleen M. ; Courtney, D. Mark ; McKoy, June M. ; Edwards, Beatrice J. ; Tigue, Cara C. ; Raisch, Dennis W. ; Yarnold, Paul R. ; Dorr, David A. ; Kuzel, Timothy M. ; Tallman, Martin S. ; Trifilio, Steven M. ; West, Dennis P. ; Lai, Stephen Y. ; Henke, Michael. / Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. In: JAMA - Journal of the American Medical Association. 2008 ; Vol. 299, No. 8. pp. 914-924.
@article{52df0dfc36134b41952f400066803087,
title = "Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia",
abstract = "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 = "Bennett, {Charles L.} and Silver, {Samuel M.} and Benjamin Djulbegovic and Samaras, {Athena T.} and Blau, {C. Anthony} and Gleason, {Kara J.} and Barnato, {Sara E.} and Elverman, {Kathleen M.} and Courtney, {D. Mark} and McKoy, {June M.} and Edwards, {Beatrice J.} and Tigue, {Cara C.} and Raisch, {Dennis W.} and Yarnold, {Paul R.} and Dorr, {David A.} and Kuzel, {Timothy M.} and Tallman, {Martin S.} and Trifilio, {Steven M.} and West, {Dennis P.} and Lai, {Stephen Y.} and Michael Henke",
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month = "2",
day = "27",
doi = "10.1001/jama.299.8.914",
language = "English (US)",
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pages = "914--924",
journal = "JAMA - Journal of the American Medical Association",
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Bennett, CL, Silver, SM, Djulbegovic, B, Samaras, AT, Blau, CA, Gleason, KJ, Barnato, SE, Elverman, KM, Courtney, DM, McKoy, JM, Edwards, BJ, Tigue, CC, Raisch, DW, Yarnold, PR, Dorr, DA, Kuzel, TM, Tallman, MS, Trifilio, SM, West, DP, Lai, SY & Henke, M 2008, 'Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia', JAMA - Journal of the American Medical Association, vol. 299, no. 8, pp. 914-924. https://doi.org/10.1001/jama.299.8.914

Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. / Bennett, Charles L.; Silver, Samuel M.; Djulbegovic, Benjamin; Samaras, Athena T.; Blau, C. Anthony; Gleason, Kara J.; Barnato, Sara E.; Elverman, Kathleen M.; Courtney, D. Mark; McKoy, June M.; Edwards, Beatrice J.; Tigue, Cara C.; Raisch, Dennis W.; Yarnold, Paul R.; Dorr, David A.; Kuzel, Timothy M.; Tallman, Martin S.; Trifilio, Steven M.; West, Dennis P.; Lai, Stephen Y.; Henke, Michael.

In: JAMA - Journal of the American Medical Association, Vol. 299, No. 8, 27.02.2008, p. 914-924.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia

AU - Bennett, Charles L.

AU - Silver, Samuel M.

AU - Djulbegovic, Benjamin

AU - Samaras, Athena T.

AU - Blau, C. Anthony

AU - Gleason, Kara J.

AU - Barnato, Sara E.

AU - Elverman, Kathleen M.

AU - Courtney, D. Mark

AU - McKoy, June M.

AU - Edwards, Beatrice J.

AU - Tigue, Cara C.

AU - Raisch, Dennis W.

AU - Yarnold, Paul R.

AU - Dorr, David A.

AU - Kuzel, Timothy M.

AU - Tallman, Martin S.

AU - Trifilio, Steven M.

AU - West, Dennis P.

AU - Lai, Stephen Y.

AU - Henke, Michael

PY - 2008/2/27

Y1 - 2008/2/27

N2 - 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.

AB - 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.

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