We're unable to sign you in at this time. Please try again in a few minutes.
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Review |

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. doi:10.1001/jama.299.8.914.
Text Size: A A A
Published online

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.

Figures in this Article

Sign in

Purchase Options

• Buy this article
• Subscribe to the journal
• Rent this article ?


Place holder to copy figure label and caption
Figure 1. Search Strategy and Selection of Phase 3 Trials That Reported Survival and Venous Thromboembolism Outcomes
Graphic Jump Location

FDA indicates US Food and Drug Administration; ODAC, Oncologic Drug Advisory Committee.

aOf the 13 studies added for this meta-analysis for survival, 12 studies were reported between April 2005 and January 17, 2008. A 13th study was not included in the 2006 Cochrane Review,24 because it was published only as an abstract.

Place holder to copy figure label and caption
Figure 2. Meta-analysis of Overall Mortality Rates for Phase 3 Oncology Trials With ESAs vs Placebo or Control, Comparing Anemia of Cancer and Treatment-Related Anemia Trials
Graphic Jump Location

ESAs indicate erythropoiesis-stimulating agents; CI, confidence interval; NR, not reported. Weights are from random-effects analysis. P = .11 for overall is the P value for the test for I2 (the variation in ESA attributable to heterogeneity). ESA-associated mortality (treatment effect on outcomes), P = .03.

Place holder to copy figure label and caption
Figure 3. Meta-analysis of VTE Rates in Phase 3 Trials of ESAs vs Placebo or Control
Graphic Jump Location

VTE indicates venous thromboembolism; ESA, erythropoiesis-stimulating agent; CI, confidence interval. Weights are from random-effects analysis. Some trials are represented more than once due to having more than 1 group within the trial. Each ESA-containing group in these trials evaluated different doses of ESAs in comparison with controls. The point estimates and CIs for the bottom 3 trials could not be calculated because no events were reported in these studies.



Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.


Some tools below are only available to our subscribers or users with an online account.

405 Citations

Sign in

Purchase Options

• Buy this article
• Subscribe to the journal
• Rent this article ?

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles