Use of hemoglobin-based blood substitutes associated with increased risk of death, heart attack

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Public release date: 28-Apr-2008

http://www.eurekalert.org/pub_releases/2008-04/jaaj-uoh042408.php

Contact: Sara Byars

JAMA and Archives Journals

Use of hemoglobin-based blood substitutes associated with increased risk

of death, heart attack

An analysis of studies involving the use of hemoglobin-based blood

substitutes indicates their use is associated with an increased risk of

death and heart attack, according to a JAMA study being released early

online, and will appear in print in the May 21 issue of JAMA.

The development of a blood substitute—a liquid that has a long

shelf-life, does not need refrigeration and does not cause

infection—would provide a potentially lifesaving option for surgical and

trauma patients with shock from loss of blood, especially in rural areas

and military settings. “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.

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. 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

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.”

(JAMA. 2008;299[19]:doi:10.1001/jama.299.19.jrv80007. Available

pre-embargo to the media at www.jamamedia.org)

Editor’s Note: Please see the article for additional information,

including other authors, author contributions and affiliations,

financial disclosures, funding and support, etc.

Editorial: The Future of Clinical Trials Evaluating Blood Substitutes

In an accompanying editorial, Dean A. Fergusson, M.H.A., Ph.D., and

lyn 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.”

###

The study and editorial will be published early online Monday. They will

appear in the May 21, 2008, print issue of JAMA.

(JAMA. 2008;299[19]:doi:10.1001/jama.299.19.jed80027. Available

pre-embargo to the media at www.jamamedia.org)

Editor’s Note: Please see the article for additional information,

including financial disclosures, funding and support, etc.

For more information, contact JAMA/Archives Media Relations at

312/464-JAMA (5262) or e-mail mediarelations@....

--

ne Holden, MS, RD

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