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Review | Clinician's Corner

Cell-Free Hemoglobin-Based Blood Substitutes and Risk of Myocardial Infarction and Death A Meta-analysis

Charles Natanson, MD; Steven J. Kern, BS; Peter Lurie, MD, MPH; Steven M. Banks, PhD; Sidney M. Wolfe, MD
JAMA. 2008;299(19):2304-2312. doi:10.1001/jama.299.19.jrv80007.
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Context Hemoglobin-based blood substitutes (HBBSs) are infusible oxygen-carrying liquids that have long shelf lives, have no need for refrigeration or cross-matching, and are ideal for treating hemorrhagic shock in remote settings. Some trials of HBBSs during the last decade have reported increased risks without clinical benefit.

Objective To assess the safety of HBBSs in surgical, stroke, and trauma patients.

Data Sources PubMed, EMBASE, and Cochrane Library searches for articles using hemoglobin and blood substitutes from 1980 through March 25, 2008; reviews of Food and Drug Administration (FDA) advisory committee meeting materials; and Internet searches for company press releases.

Study Selection Randomized controlled trials including patients aged 19 years and older receiving HBBSs therapeutically. The database searches yielded 70 trials of which 13 met these criteria; in addition, data from 2 other trials were reported in 2 press releases, and additional data were included in 1 relevant FDA review.

Data Extraction Data on death and myocardial infarction (MI) as outcome variables.

Results Sixteen trials involving 5 different products and 3711 patients in varied patient populations were identified. A test for heterogeneity of the results of these trials was not significant for either mortality or MI (for both, I2 = 0%, P ≥ .60), and data were combined using a fixed-effects model. Overall, there was a statistically significant increase in the risk of death (164 deaths in the HBBS-treated groups and 123 deaths in the control groups; relative risk [RR], 1.30; 95% confidence interval [CI], 1.05-1.61) and risk of MI (59 MIs in the HBBS-treated groups and 16 MIs in the control groups; RR, 2.71; 95% CI, 1.67-4.40) with these HBBSs. Subgroup analysis of these trials indicated the increased risk was not restricted to a particular HBBS or clinical indication.

Conclusion Based on the available data, use of HBBSs is associated with a significantly increased risk of death and MI.

Conclusion Published online April 28, 2008 (doi:10.1001/jama.299.19.jrv80007).

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Figure 1. Study Selection
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aPublished articles on Hemopure were not separately identified by the Food and Drug Administration (FDA). Instead, the FDA described a pooled analysis to enhance sample size but did not report the number of individual studies. We treated the FDA compilation as a single trial.

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Figure 2. Mortality and Myocardial Infarction
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The size of the data markers is proportional to the inverse variance of each point estimate. aTrials involved the randomization of patients to 1 of 3 doses, followed by independent randomizations to treatment and control groups.b Published articles on Hemopure were not separately identified by the Food and Drug Administration (FDA). Instead, the FDA described a pooled analysis to enhance sample size but did not report the number of individual studies. We treated the FDA compilation as a single trial. RR indicates relative risk; CI, confidence interval.

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Figure 3. Subgroup Analysis
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Figure 4. Cumulative Mortality and Myocardial Infarction
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NA indicates not applicable.

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