A meta-analysis published in JAMA reports that the use of hemoglobin-based blood substitutes is associated with an increased risk of heart attack and death.
Blood substitutes are liquids that have long shelf lives, do not need to be refrigerated, and do not cause infection. Interest in their development is driven by the potential to save lives in surgical and trauma situations where there is severe blood loss as well as in rural and military settings where blood may be in scarce supply. Researcher Charles Natanson, M.D. (National Institutes of Health, Bethesda, Md.) and colleagues indicate that, “To date, a large proportion of blood substitutes in development have been hemoglobin-based products [hemoglobin is the oxygen-carrying protein in the red blood cells]. Yet randomized controlled trials completed as early as 1996 have raised questions about the safety of these products and have failed to demonstrate clinical benefit. Nonetheless, at least 1 of these products is approved for use outside the United States and new clinical trials are being conducted or planned worldwide.”
In order to organize existing findings regarding the efficacy and safety of hemoglobin-based blood substitutes (HBBSs), researchers conducted a meta-analysis of several earlier studies. Analyzing reports of trials that used HBBSs in surgical, trauma, and stroke patients, Natanson and colleagues focused on the potential association between HBBSs and the risk of heart attack and death. They combed through databases and other sources, specifically noting randomized controlled trials of patients who were age 19 years and older and received HBBSs therapeutically. Included in the analysis were 16 trials of five different HBBSs and 3,711 patients.
Combining the results from all of the studies, the researchers note 164 deaths among patients treated with HBBSs and 123 deaths among patients in control groups. They found that treatment with HBBS products increased the likelihood of death by 30%. Among patients treated with HBBSs, 59 suffered from heart attacks compared to 16 patients in control groups. This translates to 2.7 times increase in risk of having a heart attack for patients treated with HBBSs.
The authors did not find a difference in risk increases based on the particular type of HBBS or clinical indication. The authors write that, “The pattern of increased risk demonstrated by a variety of HBBSs across an array of clinical settings argues for a policy whereby any new or existing HBBSs should be subjected to pre-clinical studies in animal models that replicate the known toxicities of HBBSs demonstrated in humans before further clinical trials of this class of product are allowed to proceed.”
Reporting on the regulatory processes that allowed these trials despite questionable levels of safety, the authors write:
“Sponsors are required by law to report their results to the Food and Drug Administration (FDA) in a timely fashion after studies are completed, even if they do not publish their findings. However, the data reported by sponsors to the FDA are not made public by the FDA unless the product is approved or an advisory committee is convened to discuss the product. The cumulative mortality analysis . indicates that prompt meta-analyses of the HBBS trials by the FDA most likely would have demonstrated significant risks by 2000. Had the agency placed a moratorium on trials at that point, product-related deaths and [heart attacks] in subsequent trials most likely would have been prevented. However, such data were not available to scientists, the public, institutional review boards, or competing HBBS manufacturers.”
In the US, researchers are planning at least one trial, and five HBBS trials currently exist in eight other countries.
“The results of all trials of experimental agents conducted in human beings-from phase 1 to phase 4-should be fully and expeditiously disclosed to the scientific and medical communities. The case study detailed here underscores both the scientific inefficiency and the real risks to patients of the current failure to report data promptly,” conclude the authors.
An accompanying editorial, written by Dean A. Fergusson, M.H.A., Ph.D. and Lauralyn McIntyre, M.D., M.Sc. (Ottawa Health Research Institute and the University of Ottawa Faculty of Medicine, Ottawa, Canada), comments on how it is both necessity and ethical for researchers to report all findings, whether positive or negative. They write:
“Natanson et al provide evidence that study results were made public well after the trials had stopped enrollment. Thus, it was not possible for ethics boards to properly review proposed studies because they did not have all available information. Additionally, patients or proxy decision makers were not in a position to make well-informed decisions at the time of providing informed consent. Regardless of whether studies are conducted under the auspices of commercial or academic entities, studies need to be centrally registered and their findings duly reported. Not doing so places patients at unnecessary risk.”
“Based on the findings of Natanson et al and the consistency of these results with pre-clinical evidence of potential toxicity, further phase 3 trials of hemoglobin-based oxygen carriers (HBOCs) should not be conducted. There has been a tremendous amount of resources expended and knowledge gained from the pursuit of HBOCs. This vast body of knowledge should be reviewed critically and systematically, including theoretical constructs, animal studies, mechanistic studies, and early-phase clinical trials before further phase 3 trials are undertaken.” They conclude that, “Until the mechanisms and potential toxicities of HBOC products are better understood, patients cannot be placed at unacceptable risk.”
Cell-Free Hemoglobin-Based Blood Substitutes and Risk of Myocardial Infarction and Death: A Meta-analysis
Charles Natanson; Steven J. Kern; Peter Lurie; Steven M. Banks; Sidney M. Wolfe
JAMA. (2008). 299[19]:
doi:10.1001/jama.299.19.jrv80007
Written by: Peter M Crosta