Trials show no benefit from fresher red cells

According to the most recent HHS National Blood Collection & Utilization Survey Report (2011), from 2008 to 2011, transfusion in the U.S. decreased by more than 11 percent, and the American Red Cross confirms the trend is continuing. Canada, too, has seen significant declines, says Nancy Heddle, MSc, director of the transfusion research program at McMaster University in Hamilton, Ontario, who is leading the 31,000-person INFORM study (Informing Fresh Versus Standard Issue Red Cell Management), which has recruited patients in the U.S., Canada, Australia, and Israel. “About five to seven years ago, there were a million red cell units transfused in Canada, and now I believe on a yearly basis it’s about 890,000, so about a 10 percent drop, which is pretty dramatic considering that the population is aging,” Heddle says.

Despite this trend, Dr. AuBuchon says, red cells are still essential to modern health care, and many blood centers are finding it increasingly difficult to recruit adequate numbers of blood donors. “In fact, blood collectors around the world are finding the same thing. Part of the BEST (Biomedical Excellence for Safe Transfusion) Collaborative has been comparing data over the last year, and all developed nations with the exception of Singapore are showing that their donor populations are aging.”

The ABLE study (Age of Blood Evaluation Randomized Controlled Trial), a multinational study based in Canada, enrolled 2,430 critically ill patients whose mortality rate was upward of 30 percent, says coauthor Paul C. Hébert, MD, professor of medicine and chief of the Department of Medicine at the Centre Hospitalier de l’Université de Montreal. But when the results came in, “we were unable to document any harmful effects of older blood overall and in any secondary analyses.”

Overall, Dr. Hébert was not surprised by this result. “However, it’s called ‘research’ because you don’t know what you’re going to find,” he says. “There were some counterintuitive findings—some small signals suggesting fresh blood might have actually been worse. There were no significant results, but in a few subgroups you would be noticing the fresh side is on the wrong side of the line. Interesting and unexpected.”

The authors concluded that fresh blood was definitely no better than standard issue in this population, Dr. Hébert says. “What we don’t know is: What about very old blood, stored from 35 to 42 days? It’s entirely possible that blood that is stored for over 35 days does more harm than good.”

Interestingly, he notes, another study called ARIPI (Age of Red Blood Cells in Premature Infants), on which he was second author a few years ago, found that even with neonates, no difference was detected in outcome between a group that received the assigned unit a quarter unit at a time while the unit “ages on the shelf,” and a group that received fresh blood each transfusion (Fergusson DA, et al. JAMA. 2012;308[14]:
1443–1451).

The ABLE study provides definitive evidence that fresh blood is no better than standard in the critically ill, Dr. Hébert says. Another large study, TRANSFUSE, is underway in Australia. “It’s still recruiting approximately 100 patients a month and will be almost twice as many patients as the ABLE study. However, the TRANSFUSE trial asks whether giving the freshest blood first is superior to giving the oldest blood first. So basically a ‘front of fridge’ approach versus ‘back of fridge.’

“This is a policy study—a different and complementary way of formulating the research question,” Dr. Hébert says. “This more pragmatic approach will help blood banks but risks having less of a difference in storage times between groups. In the ABLE trial, we decided to look at fresh versus standard issue. In doing so, that afforded us an 18-day spread in the age of the blood.”

Including the ARIPI study of neonates, “Three of the major trials that have been designed over the last 10 years have now been reported,” says McMaster University researcher Nancy Heddle. She was involved with a study published in the American Heart Journal that retrospectively looked at 2002 to 2006 data, finding that, as blood aged, there was a progressive increase in in-hospital mortality (2010;159[5]:737–743.e1). “So that observation fit with the hypothesis that all of these randomized, controlled trials have based their studies on. Everybody had the sense that old blood was harmful if it had been stored for a long time, and our results were consistent with that.”

That the ABLE study found an opposite trend was somewhat surprising, she says. “The 90-day mortality rate in the ‘fresh’ arm of the study was about 1.7 percent higher. It’s not statistically significant, but it’s in the wrong direction of what everyone thought it would be, so that was one of the intriguing things.”

That result fit nicely with the hypothesis raised in her study published in February on the age of transfused blood and in-hospital mortality in patients with cardiovascular diagnoses (Transfusion. 2015; 55[2]:364–372).

“It’s a retrospective study, so it can only be hypothesis-generating, but we found this pattern of older blood possibly being more harmful in the data up to 2006. Then, when we analyzed the data up to 2011 and 2012, the signal disappeared. It no longer appeared that old blood was bad; rather, it appeared that fresh blood may have an increased effect in hospital mortality.”

However, it turns out that just at the time of the switch, Canada had changed the way it processes blood. “We went with a system called ‘buffy coat’ processing that is not used in the U.S. Then, all of a sudden, fresher blood appeared to be worse. So we at least raised the hypothesis that the manufacturing or processing method for whole blood donations might actually have an impact on patient outcomes.”

Buffy coat processing has been common in Europe for the past 10 years, she says, because it produces more plasma from whole blood donations, which helps support the supply of other products, and appears to produce a better platelet product. “But some people just assumed that because the platelet product is better, then the red cell product would be better too, and that may or may not be the case.” (In the U.S., she notes, platelets are produced through apheresis, not from whole blood.)

There are only a handful of centers in the world that are able to link large databases of blood donor, product, and patient transfusion information, Heddle says. “We were fortunate to have one of those databases to look at factors that affect patient outcomes.” It happens that the ABLE study’s finding of 1.7 percent higher mortality in the “fresh” arm fits well with her hypothesis. But “all we can say is over a 10-year period, for the first four or five years there was a higher risk of in-hospital mortality with old blood, and in the last four or five years the risk was higher with fresh blood.”

While she cannot announce the results yet (they will be reported in October), she has compared outcomes for the two processing methods, buffy coat and whole blood filtration, for every unit of blood transfused at her center from 2008–2014.

As for decreasing the storage window, as the U.K. and the Netherlands have done, “To my knowledge there are no discussions of that in Canada,” Heddle says. “The concern is you might not have enough blood supply or you might waste units. I don’t think a week is going to make a difference.” Canada used to allow blood to be stored for only 21 days, she adds. “So it’s doubled in the years I’ve been in the field.”

In the next year and a half, three more large age-of-blood studies will be published, including the INFORM study being conducted at McMaster University. “With over 30,000 patients, that will be the largest of all the studies,” and its results should be available in spring 2016, Heddle says. The ABC PICU study (Age of Blood in Children in Pediatric Intensive Care Units) and the critical care study in Australia, TRANSFUSE, are the two remaining trials.

But there remain a lot of unsettled questions and unexpected discoveries. “The hypothesis we generated—that depending on how different countries make blood, there may be potentially a risk of fresher blood being bad—who would have ever thought of that? You would never think the freshest jug of milk would be bad. So if anything, these additional studies are only going to serve to confirm that stored blood probably does not carry additional risk, but they will also help determine whether fresh blood may cause risk.”

What happens to red cells during storage is only partly understood, and basic research on this subject is likely to get a boost as more questions are raised, Heddle believes. “There certainly is basic science research going on trying to understand the biological mechanisms that might be associated with the storage of blood and patient outcomes. People have hypothesized a lot of things—whether it’s promoting inflammation, or whether the iron coming from red cells may be detrimental. So there are a lot of different frameworks and hypotheses out there. I suspect we’ll see an increase in activity once all the results from these studies come out.”

From here, Dr. Hébert predicts, transfusion research dollars are likely to shift to two other big areas: transfusion triggers in specific subpopulations and studies evaluating the use of plasma. “For transfusion triggers, we still don’t know what to do in certain subpopulations, such as heart attack patients or traumatic brain injury. Maybe people with really acute injuries to the heart or brain are different. These remain unanswered questions with limited high-quality data. Then we also need a lot more research on the use of plasma to determine when it is truly beneficial. This area of research is in its infancy. There is so much to explore.”

For the time being, the RBC storage duration studies completed so far are showing there is no evidence that older blood stored up to 42 days causes harm to patients, Dr. AuBuchon says. “I think the last half decade or longer that this controversy has been swirling—we will look back on it decades from now as indicating how one can be trapped into an unsupportable belief by retrospective studies.” He believes the blood collectors of the world, who always have to worry about potential shortages, are pleased because, based on these prospective, randomized trials, a strong push to reduce the storage window for red cells will now be unlikely.

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Anne Paxton is a writer in Seattle.