Effectiveness of blood substitute examined in large clinical trial
A predicted shortfall of more than 4 million units of blood worldwide is driving the need to develop an alternative to red blood cells.
In a recently concluded Phase 3 multicenter clinical trial, academic and industry researchers found the use of up to three units of a blood substitute to be relatively safe in patients under 80 with a moderate need for transfusions.
Published in the June edition of the Journal of Trauma, the study, which was conducted at 46 sites in the United States, Europe and South Africa, is the first Phase 3 trial to compare a blood substitute to regular blood.
"The majority of patients who received the blood substitute did well," said Dr. Jonathan Jahr, professor of clinical anesthesiology at the David Geffen School of Medicine at UCLA and lead author of the study.
The six-week study involved 688 patients, age 18 and older, who were undergoing elective orthopedic surgery, procedures that often have a high need for blood transfusions. Patients initially received either one unit (32.5 grams) of real blood or two units (65 grams) of the blood-substitute product HBOC-201, a hemoglobin-based oxygen carrier manufactured by Biopure Corp.
Made from a bovine source after multiple purifications, HBOC-201 can be kept at room temperature for up to three years and does not need to be matched to one's blood type.
Patients in the HBOC-201 group could receive up to 10 units of the blood substitute during a six-day period, while those in the regular-blood group could receive unlimited transfusions. Subjects were evaluated daily and six weeks post-operatively.
"We found that we eliminated the need for blood transfusions for 59 percent of the 350 patients who received the blood substitute," said study author Dr. Colin F. Mackenzie, professor and former director of the National Study Center for Trauma and Emergency Medical Systems at the University of Maryland School of Medicine. "The blood substitute worked best in those under 80 years old with a moderate transfusion need."
For those over 80 with more acute health issues and higher transfusion needs, the blood substitute did not work as well as blood. As a result, many of these patients were crossed over into the other group to receive regular blood.
A number of adverse events involving the cardiac and central nervous systems were found in 21 of these older patients receiving the blood substitute. Analysis revealed that the issues were due to advanced age, heart failure or possibly undertreatment.
"For this specific older acute patient population, we suggest using a blood substitute only if blood is not available. These patients also need to be carefully monitored for vascular volume status and avoidance of fluid overload," said study author Dr. A. Gerson Greenburg, vice president of medical affairs at Biopure.
Mortality rates among those with moderate transfusion needs in both study groups were low — at 1 percent. The higher transfusion-need groups reported a 5-percent mortality rate in the blood-substitute group and a 3-percent rate in the group receiving regular blood, which are comparable, according to researchers.
Many of the less serious adverse effects seen in the overall group receiving the blood substitute were due to temporary, expected physiological effects of this class of drugs, which can include skin discoloration interpreted as jaundice, elevation of blood pressure and an increase in levels of the enzymes troponin and lipase.
"Although these temporary side effects didn't lead to any clinical problems in most patients, these should be studied in future trials," said UCLA's Jahr.
The majority of the 350 patients in the study arm using the blood substitute received an average of five or less units. On average, the 338 patients receiving regular blood were given less than two units.
"This product has a definite place where blood is not an option — such as in patients whose immune system attacks red blood cells or those whose religion forbids blood transfusions — and in situations where blood is not available," Mackenzie said.
The next stage of research will include studies in military and trauma situations and further studies in anemia and ischemia.
Biopure, the manufacturer of HBOC-201, funded the study. Jahr has served as principal investigator on one additional Biopure study and owns Biopure stock. He also has been a researcher on other blood-substitute products at other companies. Jahr has a large, independent lab that has published more than 80 manuscripts, reviews and abstracts on blood substitutes, independent of any company or company funding. Mackenzie has been a consultant for Biopure and has received funding as a site principal investigator to conduct this study.
Additional authors include L. Bruce Pearce, Ph.D., and Arkadiy Pitman of Biopure.