Threshold for Transfusion in ACS: Still Room for Discretion

This transcript has been edited for clarity.

Michelle L. O'Donoghue, MD, MPH: Hi. This is Dr Michelle O'Donoghue, reporting for Medscape. Joining me today is Sunil Rao. He is a professor of medicine at NYU Grossman, as well as director of interventional cardiology at NYU Langone. Welcome, Sunil. Thanks for joining me today.

Sunil V. Rao, MD: Thanks for having me.

O'Donoghue: One of the more interesting trials that was both published last year in The New England Journal of Medicine and a subgroup analysis is being presented at the American College of Cardiology (ACC) Scientific Session 2024 is from the MINT trial.

Before we get into this new substudy from MINT, let's take a step back and think about strategy trials in general, in terms of thinking about transfusing people to a higher hemoglobin level vs just leaving people with anemia. We've known for years that lower hemoglobin is associated with worse outcomes, but the question mark has always been, do you transfuse people and does that translate into better outcomes?

Hemoglobin Threshold

Rao: I think you framed the question perfectly. There have been historical data that suggest that we should maintain the hemoglobin at 10 g/dL in patients who have coronary artery disease. There are observational data from patients who, for example, refused transfusions because of religious beliefs, suggesting that even in patients undergoing bypass surgery, you can push their hemoglobin down to 6 g/dL without any sequelae.

The question has always been not whether we should give a transfusion, but how much we should give and what is that transfusion trigger? On the basis of observational data, the two triggers that have emerged are a hemoglobin level of 8 vs 10 g/dL. There have been plenty of randomized trials, as you've noted, in other settings, such as critical care, infectious disease, and even gastrointestinal bleeding, suggesting that a so-called liberal or aggressive transfusion strategy is really no better than letting patients ride out a lower hemoglobin level.

Interestingly, most of those studies — in fact, probably all of them — have excluded patients with an acute coronary syndrome. In the acute coronary syndrome setting, one can imagine a rationale for pushing the hemoglobin higher because hemoglobin is part of the oxygen delivery equation. These patients have already manifested some kind of hypoxic insult with an acute myocardial infarction (MI), so potentially maintaining a higher hemoglobin level should be beneficial.

The flip side, of course, is that transfusion of packed red cells that are stored is not the same as the red cells that are in our bodies. They are depleted of nitric oxide and 2,3-diphosphoglyceric acid. They may not in fact deliver oxygen very well. Some data suggest that there may be some platelet activation as well, so there's potential for harm.

That is really what set up the MINT trial, which is a National Heart, Lung, and Blood Institute–funded study of 3500 patients with acute coronary syndrome. Acute MI and all kinds of MI were allowed in this trial: type 1 as well as type 2. They were randomized to maintain a hemoglobin of 8 g/dL, in the so-called conservative transfusion strategy, or 10 g/dL, in the so-called liberal transfusion strategy. It’s interesting that we use those terms in today's political environment, but those are exactly the terms that we use.

O'Donoghue: What did the primary results of MINT show?

Rao: It's a fascinating study. It's the largest randomized trial in this particular population. The trial just barely missed conventional statistical significance. We had to conclude that really there was no significant difference in terms of the two strategies, but all the point estimates lined up on the side of liberal transfusion, which was maintaining a hemoglobin level of 10 g/dL.

Cardiac death — the caveat being it was not adjudicated in the trial — actually favored the liberal transfusion strategy. I think from a pragmatic bedside standpoint, it does seem that a more liberal transfusion strategy probably is beneficial in patients with acute MI.

O'Donoghue: I think MINT was very interesting in the sense that yes, overall it was neutral, but certainly a very strong signal was seen toward there being benefit. You started to discuss this, but how do you reconcile that with prior studies that have not been in the acute coronary syndrome state, that have not suggested that a liberal transfusion strategy would be beneficial?

Rao: That's a great question. If I could extend your question a little bit, how do we reconcile with the prior observational data? Maybe that's an easier question to answer because the observational studies, and certainly I've been a coauthor on many of them, are probably confounded by indication. There's just no way to unravel that in the observational setting. You have to randomize.

I think there are fundamental differences between the acute MI population and the other populations that were studied. My guess is that one size doesn't fit all when it comes to transfusion strategies, and that acute MI population probably is a particularly special population that, again, has already manifested some kind of an ischemic insult with their acute MI.

Type 1 vs Type 2 MI in MINT

O'Donoghue: Here at ACC, an important subgroup analysis is being presented that looked at type of MI that was enrolled — so type 1 and type 2 MI. It's interesting that there was a pretty even split between the two in MINT.

I have to say, the results of the subgroup analysis are somewhat counterintuitive to me, because it's suggested that there was greater benefit in patients with type 1 MI and kind of neutral benefit in the type 2 patients. One might think that, with a supply-demand mismatch, the supply question would be answered by a more liberal transfusion strategy.

Rao: I think that's exactly right. We were surprised as well. Again, it's a subgroup analysis of an overall neutral trial. All the caveats apply. It is interesting, isn't it? The type 1 MIs, so-called plaque rupture, with the supply-demand mismatch are the ones who benefited more (if you want to use that term) from a liberal strategy. Again, there probably are differences between those two patient groups. It's possible there are some competing risks in the type 2 MI population.

I find this really fascinating. I think it goes in that category of other recent trials that are calling into question what our fundamental concepts of physiology really are. I think there are probably going to be more data coming out about type 2 MI in general that may help to put some of these results in context.

The type 2 MI population is really interesting because it is a very heterogeneous population. It's possible that, again, one size doesn't fit all when it comes to transfusion. There may be some patients who benefit from a more aggressive transfusion strategy. For example, if their ischemic event is precipitated by MI, then maybe there's a benefit.

Right now, though, based on the MINT trial, I don't think we can actually make any conclusions about the type 2 MI patients because the benefit does seem to be concentrated in the type 1 MI patients.

O'Donoghue: If there truly is benefit in the type 1 MI patients, the pathobiology is interesting there, too, because I would imagine that most of these patients were revascularized. Does that suggest that there was some ongoing ischemia that the liberal transfusion would in some way benefit or ameliorate?

Rao: I think that's the hypothesis. We are diving very deep into the revascularization population. We're hoping to present those data later this year. Again, that's nonrandomized, so there are patients who are, of course, going to be selected for revascularization.

As you can imagine, in this overall population of trial patients, there are patients who are very, very sick. These are older patients who have many comorbid conditions. The ones who were selected for revascularization were a little bit healthier, as you can imagine. There's going to be a little bit of work to untangle all that, but we hope to have more data on that a little bit later this year.

O'Donoghue: That'll be interesting. In terms of key takeaways, what do you do right now in your clinical practice? The other thing to factor in as well is that blood is not in infinite supply. It's not always easy to think about how to allocate those resources.

Rao: Again, that's a great question. I think if you were to implement what we and the trial group led by Jeff Carson think is the right message from MINT, it has larger implications than just for the patients that we're treating. There are societal implications in terms of blood supply and cost issues in terms of more aggressive transfusion.

I can tell you that, based on the observational data, many hospitals have put into place guardrails where no transfusion is allowed unless the hemoglobin level is < 8 g/dL in an acute MI patient. My personal opinion — and I'm certainly not speaking on behalf of any organization or any group — is that I think that's probably wrong. I think that we probably do need to think about maintaining a higher hemoglobin level in acute MI patients.

We're actively having discussions at our hospital, for example, thinking about how to alter our algorithm for patients who are anemic and who come in with acute MI. Again, those conversations are going to be nuanced and very complicated as we think about the blood supply.

O'Donoghue: It'll be interesting to see what else we can learn from MINT as more subgroup analysis get presented. Thanks again for joining me.

Rao: Thank you.

O'Donoghue: Signing off for Medscape, this is Dr Michelle O'Donoghue.

Michelle O'Donoghue is a cardiologist at Brigham and Women's Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she's never strapped on hockey skates.

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