April 28, 2008 -- Patients treated with experimental blood substitutes were 30% more likely to die and more than twice as likely to have heart attacks as patients who did not get the blood substitute products, a pooled analysis of the research reveals.
Combined results from 13 published and three unpublished industry-sponsored trials showed the increase in risk for all the hemoglobin-based blood substitute products tested and for all populations studied, including trauma patients and those having heart, vascular, or elective surgery.
The study, conducted by researchers from the National Institutes of Health (NIH) and the consumer advocacy group Public Citizen, is scheduled for publication in the May 21 issue of The Journal of the American Medical Association.
But the findings were made public online Monday, the day before a planned two-day FDA-sponsored workshop examining the safety of the blood substitutes.
NIH researcher Charles Natanson, MD, says the analysis makes it clear that the products are too dangerous for use in human clinical trials.
One of the blood substitutes, Biopure Corp.'s Hemopure, is approved for use in humans in South Africa. None is approved for human use in the U.S., but there are five ongoing clinical trials involving the blood substitutes, Natanson says.
"I don't believe this research should go forward in humans until these products have been reformulated and animal studies show them to be less toxic," he tells WebMD.
The Hope for Blood Substitutes
Blood substitutes that need no refrigeration, have a long shelf life, and don't require blood type matching hold the promise of saving lives in remote and battlefield settings and easing blood shortages everywhere.
Fears of a tainted blood supply in the early days of the HIV pandemic created great interest in developing safe and effective blood substitutes. Much of that research has involved the protein hemoglobin, which gives red blood cells their ability to carry oxygen.
In the newly published analysis, Natanson and colleagues examined data from industry-sponsored studies of five hemoglobin-based products involving 3,711 patients.
"It makes sense to examine these products as a class because they all bind oxygen and have a common mechanism of toxicity," he says. "When we did this we found the risk of death and (heart attack) to be consistent across the products."
But in a statement released Monday, a spokesman for Biopure calls the analysis "significantly flawed."
"There are vast differences among these products that make any pooling of data flawed, especially across different clinical experiences," Biopure's Vice President of Medical Affairs A. Gerson Greenburg, MD, PhD, says in the statement.
FDA Failed, Researchers Say
Natanson and colleagues criticized the FDA for failing to do its own analysis of safety data from the clinical trials years ago.
They write that such an analysis would have demonstrated significant risks associated with the products as early as 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," they write. "Such data were not available to scientists, the public, institutional review boards, or competing [blood substitute] manufacturers."
Ottawa Health Research Institute senior scientist Dan Fergusson, PhD, agrees that more timely dissemination of the safety data probably would have saved lives.
Fergusson co-wrote an editorial accompanying the newly published analysis.
"A lot of the safety data was not made public, and it matters," he tells WebMD. "If I am someone designing and enrolling patients for the next trial, I need that information."
Fergusson says a registry of blood substitute trials is badly needed to address the issue of safety, along with regulatory changes to require prompt reporting of both negative and positive study findings.
In his editorial, he called for a critical and systematic review of all the hemoglobin-based blood substitute research before further human trials are considered.
But he tells WebMD that the blood substitute research should not be abandoned.
"A lot of good has come out of this research," he says. "We have a better understanding of the basic physiology of how oxygen is delivered to the tissues. But I think it is fair to say that many of the companies that did this research were not forthcoming with their safety data."