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 MVenous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 299: 914-924

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.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 03/2008; 299(8):914-24. DOI: 10.1001/jama.299.8.914
Source: PubMed


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.
To evaluate VTE and mortality rates associated with ESA administration for the treatment of anemia among patients with cancer.
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).
Phase 3 trials comparing ESAs with placebo or standard of care for the treatment of anemia among patients with cancer.
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.
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).
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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Available from: Benjamin Djulbegovic, Dec 19, 2013
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    • "In 2006, Bohlius et al reported a meta-analysis identifying a 1.57-fold increased thromboembolic risks with ESA administration to cancer patients undergoing chemotherapy (Bohlis et al, 2006). These findings were replicated in numerous meta-analyses, including the one by Bennett et al in 2008. The history of ESAs and their effects on QOL followed similar trajectories. "
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    • "No increased risk of serious adverse events was found in these meta-analyses. ESAs have also been shown to be effective in improving Hb levels and quality of life in several chronic conditions (dialysis [35], chronic heart failure [36], cancer [41], rheumatoid arthritis [42]), although an increased risk for thromboembolism and mortality was found in some studies [43]. "
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    ABSTRACT: Anemia is considered the most common systemic complication of inflammatory bowel disease (IBD). We aimed to provide all available evidence regarding the safety and efficacy of therapy existing today to correct anemia in IBD. Systematic review and meta-analysis of randomized controlled trials that compared any treatment for anemia in patients with IBD. We searched electronic databases, conference proceedings and clinical trials registries. Two reviewers independently extracted data from included trials. The primary outcome was the effect of treatment for anemia in IBD on the hemoglobin (Hb) response, defined as rate of patients who achieved an increase of 2 g/dl in Hb concentration at the end of the follow-up. Secondary outcomes included disease severity scores, iron indices, Hb levels, inflammatory markers, adverse effects, and mortality. Dichotomous data were analysed by calculating the relative risk (RR) for each trial with the uncertainty in each result being expressed using 95% confidence intervals (CI). A fixed effect model was used, except in the event of significant heterogeneity between the trials (P<0.10, I(2)>40%), in which we used a random effects model. Nine trials fulfilled the inclusion criteria, to a total of 973 patients. We were able to perform meta-analysis for intravenous (IV) versus oral iron and for ESAs versus placebo. IV iron was associated with a higher rate of achieving Hb response in comparison to oral iron; RR 1.25 (95% CI 1.04-1.51, I(2) = 2%, 4 trials), CRP levels and disease activity indexes were not significantly affected by IV iron. IV iron was associated with a decrease in adverse events that required discontinuation of intervention and without an increase in serious adverse. Treatment for anemia in IBD should include IV iron and not oral iron replacement, due to improved Hb response, no added toxicity and no negative effect on disease activity.
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    • "Finally, this is a meta-analysis at study level, and confounding variables at patient level cannot be assessed properly and incorporated into the analysis. However, a review by Bennett et al. (2008) showed that the results between patient and study level were remarkably similar. "
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