Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: a meta-analysis

Abstract

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 > or = .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.

Figure 1.

Study Selection ^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.

Figure 2.

Mortality and Myocardial Infarction 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. ^bPublished 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.

Figure 3.

Subgroup Analysis

Figure 4.

Cumulative Mortality and Myocardial Infarction NA indicates not applicable.