Critical Care Plus: EPO Safe Despite Paris Report, Experts Say 

Misinformation About Oxygen Therapeutics Still Widespread

Recent reports from Paris that scores of patients developed aplastic anemia after receiving eprex, the oxygen therapeutic drug known generically as erythropoietin (EPO), have some stateside researchers puzzled. A huge number of patients have been treated with EPO throughout the western world, says Aryeh Shander, MD, medical director of the New Jersey Institute for the Advancement of Bloodless Medicine, but the number who contracted aplastic anemia is extremely small.

"Similar numbers of patients receive Eprex in Germany and in France, yet the number of patients who develop aplastic anemia is much higher in France than in Germany," Shander says.

David J. Pierson, MD, professor of medicine at the University of Washington and medical director of respiratory care at Harborview Medical Center in Seattle, observes that despite educational efforts, a lot of misinformation and unwarranted fear about blood products and their infection risks remains within the medical community.

The question of whether the aplasia is due to subcutaneous injection of patients with chronic renal failure, the population that has experienced aplastic anemia, needs more investigation, Shander says. "For these patients, IV administration may be the safer way to go."

EPO, one of three classes of oxygen therapeutics presented at a conference organized last year by the American Association of Blood Banks, is the all-time best-selling genetically engineered drug. It’s also one of the largest-selling drugs of any kind in the world: Worldwide, more than $13 billion worth of EPO products were sold in 2001.

Most of the 141 cases of red cell aplasia reported in EPO users have involved Eprex, marketed by Johnson & Johnson in Europe, Canada and Australia. Shander points out that aplastic anemia has occurred in patients treated with other brands of EPO, including Procrit, Johnson & Johnson’s brand name for the EPO it sells stateside.

Restrictive Laws May Be Premature

Shander adds that in some cases when EPO administration has been stopped until patients recover from aplastic anemia, the condition doesn’t recur when the drug is reintroduced. He notes the possibility of EPO-restrictive legislation passed because of public response to incomplete news reports.

"If the public panics, the legislature reacts, not always in ways that are rational," Shander says. "It may actually prevent the majority of patients from receiving a fairly safe drug."

Shander and his colleagues define oxygen therapeutics as drugs that deliver oxygen, not as blood substitutes.

"We need more data about the efficacy of these agents in acute anemia such as trauma," Shander says. "The advantage is that they can be given before the ambulance reaches the hospital because they don’t require type and crossing the way blood does. The problem is that we don’t know if giving them early on will result in increased survival or increased morbidity."

Shander says a great deal of such trauma-efficacy testing is currently under way, but says he can’t reveal the "where, who or how" of these tests.

He adds that current data from trials for perfluorocarbon (PFC), the oxygen therapeutic that could be manufactured at the lowest cost, is shaky.

"The design for the PFC study may have been too complex," Shander says. "Whatever happened, right now the hemoglobin-based oxygen carriers are our therapeutic mainstay."

It’s important for critical care practitioners to understand that each of the oxygen therapeutic products currently available or nearing completion of FDA phase III trials has its own chemistry, biologic activity, half-life and specific characteristics, says Harvey G. Klein, MD. Klein, who heads the department of transfusion medicine at the Warren G. Magnuson Clinical Center of the National Institutes of Health in Bethesda, Md, is also past president of the American Association of Blood Banks. However, he adds that each has potential in as yet inadequately explored applications.

These agents, Klein says, carry oxygen in a manner fundamentally differently from red blood cells. "They are very small molecules that actually go right through the vessels into the tissues," Klein says. "Critical care physicians should be asking if this could have new applications for which blood is not very helpful. It’s conceivable there will be some benefit to MI and stroke patients, and in severe sickle cell crisis."

Klein observes that the Food and Drug Administration, which appears to be concerned about wider use of oxygen therapeutics once they are licensed, expects manufacturers to provide data for other uses before a specific-use application will be approved.

Availability of Oxygen Therapeutics Will Drive Education

A. Gerson Greenburg, MD, Ph.D., surgeon in chief at Miriam Hospital in Providence, RI, and professor of surgery at Brown University, agrees that doctors still need to better understand the indications for transfusion of red cells. "Having the option of oxygen therapeutics will drive educational efforts to apply guidelines," Greenburg notes.

Though costs of these therapeutic agents are likely to be higher than blood, Greenburg notes that the true costs of both blood and blood products tends to be elusive because blood, the essential element, is donated. He adds that the phase III cardiac surgery trial for the Canadian-made hemoglobin-based oxygen carrier Hemosol showed a decrease in the use of banked blood and blood products, an unexpected but welcome factor that could increase the overall blood supply by the percentage of blood it saves.

"If currently 20% of the blood supply goes to cardiac surgery and the savings is a decrease of 50%, the impact on the overall blood supply would be 10%, which is significant," Greenburg says.

A study Greenburg and colleagues performed found that the actual use of banked red cells was roughly 10% of the amount used in standard practice, a reduction which effectively increased the available blood supply by 18%.

Despite such impressive figures, Shander doesn’t foresee a time when transfusing blood will be completely unnecessary. "We may become more restrictive about whose blood we select, and having more alternatives means we can reduce the size of the blood pool and therefore the risk of blood-borne diseases," he says. "And these new agents make it possible to easily measure the cost-benefit of blood. But I can categorically say there will always be some need to transfuse blood. When the benefit exceeds the risk and when fresh blood is available and easy to give, you’d probably rather give it." (For more information contact Aryeh Shander, MD, at [888] 766-2566; Harvey G. Klein, MD, at [301] 496-9702; and A. Gerson Greenburg, MD, at [401] 793-2500.)