Hemoglobin-based Blood Substitutes Linked with
Increased Risk of Death, Heart Attack
Heart attack risk jumps 2.7 times, death risk
increases by 30 percent
April 28, 2008 - What seems like a great idea - a
liquid blood substitute with a long shelf-life, that does not need
refrigeration and does not cause infection - is turning into a
nightmare. Studies of hemoglobin-based blood substitutes indicate their
use is associated with an increased risk of death and heart attack,
according to a report published online by the Journal of the American
Medical Association.
This blood substitute appeared to provide a
potentially lifesaving option for surgical and trauma patients with
shock from loss of blood, especially in rural areas and military
settings, say the authors of the study which will also appear in print
in the May 21 issue of JAMA.
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, the authors write.
Charles Natanson, M.D., of the National Institutes
of Health, Bethesda, Md., and colleagues conducted an analysis of
previous studies to examine the association between hemoglobin-based
blood substitutes (HBBSs) and the risk of heart attack and death in
trials using these products in surgical, trauma and stroke patients.
The authors searched databases and other sources
for randomized controlled trials that included patients age 19 years and
older who received HBBSs therapeutically. Sixteen trials that met the
authors criteria were identified, involving five different products and
3,711 patients.
There were a total of 164 deaths among HBBS-treated
patients and 123 deaths among patients in the control groups. Overall,
the HBBS products were associated with a 30 percent increased risk of
death.
There were a total of 59 heart attacks among HBBS-treated
patients and 16 heart attacks among patients in the control groups. For
these studies combined, there was a 2.7 times increased risk of heart
attack among patients receiving HBBSs.
Subgroup analysis of these trials indicated the
increased risk was not restricted to a particular HBBS or clinical
indication. 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, the authors write.
The researchers also discussed the regulatory
process that permitted repeated trials with these agents despite
persistent safety concerns.
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," according to the article.
"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, the authors write.
Five trials of HBBSs reportedly are ongoing in
eight different countries outside the United States and at least one
trial is being planned for the U.S.
The results of all trials of experimental agents
conducted in human beingsfrom phase 1 to phase 4should 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.
Editorial: The Future of Clinical Trials
Evaluating Blood Substitutes
In an accompanying editorial, Dean A. Fergusson,
M.H.A., Ph.D., and Lauralyn McIntyre, M.D., M.Sc., of the Ottawa Health
Research Institute and the University of Ottawa Faculty of Medicine,
Ottawa, Canada, write that the timely reporting of all evidence
independent of positive or negative findings is not only essential but
ethical.
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 write.
Until the mechanisms and potential toxicities of
HBOC products are better understood, patients cannot be placed at
unacceptable risk.
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