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Blood substitutes tied to higher risk of heart attack, death

  • Story Highlights
  • Expert: Human tests on experimental blood substitutes should be halted
  • In clinical trials, blood substitutes increased risk of heart attack, death
  • Tests completed as long as 12 years ago raised concerns about products' safety
  • Efforts under way for more than a decade to find a reliable substitute for blood
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(CNN) -- A government researcher said Monday that experimental blood substitutes are linked to an increased risk of heart attack and death, and suggested that studies on people should be halted.

Blood substitutes could prove invaluable on the battlefield, where fresh blood supplies can be limited.

Dr. Charles Natanson, a senior scientist at the National Institutes of Health, led a team that pooled data from 16 trials of five products involving 3,711 patients and found 164 deaths among the patients who got the blood substitutes versus 123 deaths among controls -- a more than 30 percent increase in mortality.

More striking was the difference in heart attacks. There were 59 heart attacks among the treated patients and 16 among controls, an additional 2.7 times as many.

Investigators should return to laboratory-based work to improve their products before initiating any further studies involving people, he said.

The government researcher said institutional review boards should review the trials currently under way to see whether they should be continued. "I cannot myself see a justification for doing so," he said.

A clinical trial's moral foundation exists only if there is genuine uncertainty about whether a given intervention could help. In this case, said Dean A. Fergusson, a senior scientist in clinical epidemiology at the Ottawa Health Research Institute in Ottawa, Ontario, the companies had amassed enough data years ago to know it would not. Video Watch more on blood substitutes »

Even before human trials began, animal trials showed evidence that the product causes constriction of blood vessels that could lead to heart attack. "That sure as hell should be reported to patients or prospective patients," Natanson said.

Efforts have been under way for more than a decade to find a reliable substitute for blood, which must be refrigerated, lasts only a short time and -- if impure -- can cause infection.

Such an alternative -- called a hemoglobin-based blood substitute (HBBS) -- could prove invaluable on the battlefield and in small, rural hospitals where fresh blood products may be in short supply.

South Africa has already approved a substitute blood product containing hemoglobin -- the molecule that carries oxygen -- and clinical trials are under way in at least eight countries.

But that analysis by Natanson's team -- published Monday in the Journal of the American Medical Association -- reported that randomized clinical trials completed as long as 12 years ago raised concerns about the products' safety and showed no clinical benefit.

The researchers theorized that the free hemoglobin in the products scavenges nitric oxide from the blood, resulting in blood vessel constriction and the buildup of platelets, both of which can increase the risk of heart attacks.

Had the data been made public as it became available, the products' danger would have been apparent years ago and a moratorium on trials could have been ordered, most likely saving the lives of some of those who went on to participate in the tests, the researchers said.

"However, such data were not available to scientists, the public, institutional review boards, or competing HBBS manufacturers," they wrote.

They urged that all results of trials on experimental agents involving people be made available to doctors and scientists, boards that approve human testing and competing HBBS makers.

"The case study detailed here underscores both the scientific inefficiency and the real risks to patients of the current failure to report data promptly," they said.

In a written statement, the maker of one of the products said the conclusions of the meta-analysis are not reliable because it unfairly lumps different products together.

"There are vast differences among these products that make any pooling of data flawed, especially across different clinical experiences," said Dr. A.G. Greenburg, vice president of medical affairs for Biopure Corporation, maker of Hemopure, the South Africa product.

"Moreover, the analysis of Biopure's experience, based on pooling of heterogeneous trials, we believe to be significantly flawed as it fails to meet the homogeneity criteria of meta-analysis, thus invalidating the conclusions."

He said an analysis of the company's trial of its product will be published shortly.

But Fergusson said the basic findings are uniform across all the products scrutinized. "The general consistency of harm across all HBOC (hemoglobin-based oxygen carrier) products regardless of technology ... and important subgroups suggests that the findings are robust," he wrote in an accompanying editorial.

Further trials of the products involving people should not be conducted, he wrote.

"Until the mechanisms and potential toxicities of HBOC products are better understood, patients cannot be placed at unacceptable risk."

In a telephone interview with CNN, he said he does not blame the biotech companies. It is Congress, he said, that should change the laws governing secrecy.

"If you allow companies to have secret science, you cannot fault them for not reporting the results," he said. "They're not doing anything against the rules."

It was only after a suit was filed by the advocacy group Public Citizen, which was involved in the study, that the FDA released data considered by its advisory committee, he said.

"Full disclosure is required to protect the American public, for science to build upon experience of previous work," Natanson said in a telephone interview.

In an e-mail, Baxter spokeswoman Deborah Spak said it discontinued its work on hemoglobin-based blood substitutes more than five years ago, "and has no continued interest or involvement in hemoglobin therapeutics, so we have no comment on this week's JAMA article or the FDA workshop."

She added, "The research and clinical studies we sponsored in the 1990s were conducted in a responsible and transparent manner, and were presented or published in many peer-reviewed settings over the years. We are proud of the important role Baxter played in advancing the science and understanding in this field of research."

The study was sent last week to journalists with the proviso that they not publish stories on it until Monday -- a day before the FDA is to hold a workshop on the matter. Asked whether the embargo could in itself have added to the time that study participants were at risk, Fergusson acknowledged that it may have.

"I would agree with that," he said.

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Natanson agreed: "If one person was hurt, then it should have been released immediately," he said.

A JAMA media relations person who said she could not be quoted said the study was made available as quickly as possible. It is to appear in the May 21 edition. E-mail to a friend E-mail to a friend

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