Can transfusing blood prevent MIs in high-risk surgical patients?
TOP trial brings a little something for everyone to the debate
Most critically ill patients either arrive anemic or become so during their ICU stays. Many years ago, they were routinely transfused to near-normal hemoglobin targets until the TRICC trial (NEJM 1999) strongly suggested that withholding red cell transfusion until hemoglobin fell to ≤7 g/dL was safe (but not superior, from a mortality or secondary-outcome standpoint).
In a rare example of replicability, dozens of subsequent randomized trials and meta-analyses generally confirmed the safety of restricting transfusion to Hb ≥ 7 or 8 g/dL for most hospitalized patients, including the critically ill and those with active GI bleeding. Restrictive strategies can reduce the total volume of transfused blood by ~50%, in aggregate, without apparent harm (or benefit).
Guidelines from multiple specialty societies have since advised a restrictive approach to transfusion for hospitalized patients generally.
Guidelines on Red Cell Transfusion (Review)
Anemia is the norm among critically ill patients, who were historically transfused to normal or near-normal hemoglobin levels in the hope of optimizing their physiology and chances for recovery.
Patients with ischemic heart disease have been a lingering question mark. Those with significant cardiac morbidity, and especially active cardiac ischemia, were either excluded from these trials or were treated off-protocol with liberal transfusions.
The MINT trial is the only randomized study of any significant size to test transfusion targets in patients with acute myocardial infarction. Its few exclusion criteria produced a very ill, real-world population.
In MINT (n=3,500), liberally transfused patients received more than three times as much blood (~2.5 units per patient vs 0.7 per patient). Blood was spared, but the results were not reassuring, safety-wise:
Recurrent myocardial infarction or death, the composite primary outcome (~17% in restrictive, 14.5% in liberal)
Death (~10% in restrictive, ~8% in liberal)
Recurrent MI (8.5% in restrictive, ~7% in liberal)
Cardiac death (5.5% in restrictive, ~3% in liberal)
Confidence intervals included 1.0, but just barely, suggesting occasional harm.
Guidelines Tilt Toward Liberal Transfusion for Acute MI
Swayed by the MINT data, major professional societies gently nudged clinicians toward more liberal transfusion of patients with acute coronary syndromes:
ESICM weakly recommended a target hemoglobin of 9 to 10 g/dL, citing low-certainty evidence.
A U.S. critical care society recommended against using a restrictive strategy (Hb 7 to 8 g/dL) based on trials using 10 g/dL as the permissive comparator.
A new randomized trial recently added to the body of data on red cell transfusions for patients at high risk for perioperative MIs.
The TOP Trial
TOP enrolled adults at 16 Veterans Affairs medical centers in the United States from 2018 through 2023 who had recently undergone major vascular or general surgery, were anemic (Hb <10g/dL), and at elevated cardiac risk (by RCRI).
More than 1,400 patients were randomized to either transfusion and maintenance of ≥10 g/dL until discharge, or transfusion only when hemoglobin was <7 g/dL.
More than 90% underwent vascular surgery, half had diabetes, and peripheral arterial disease and coronary artery disease were common (i.e., at high risk for periop MIs and strokes).
Transfusion rates (2 units vs 0 median) and hemoglobin separation (~2 g/dL divergence at day 5) were meaningful.
But at 90 days, the composite of all-cause death, myocardial infarction, coronary revascularization, acute kidney failure, or ischemic stroke had occurred almost equally often in 9% of patients in the liberal group vs. 10% in the restrictive group, a nonsignificant difference.*
*To build their power calculations, the authors over-pessimistically assumed the primary outcome would occur in 30% of the restricted patients, and over-optimistically assumed that liberal transfusion would reduce this occurrence by 25% (to 22.5%). This decision had the salutary effect (for the trialists) of drastically reducing the required enrollment to an attainable level, but reduced the TOP trial’s power to detect smaller effects.
Fewer Non-MI Cardiac Complications in the Liberally-Transfused
The liberally transfused patients had a lower rate of cardiac complications other than MI (arrhythmias, heart failure, and nonfatal cardiac arrest): 5.9% with liberal transfusion, 9.9% with restriction. This was a prespecified endpoint and was statistically significant.
Rates of the individual components of the primary outcome (mortality, MI, AKI, stroke) occurred infrequently and did not differ statistically between groups.
Does TOP “Refute” MINT?
TOP was not an acute MI trial, instead enrolling postoperative patients at high cardiac risk, almost none of whom had an active myocardial infarction at enrollment. MINT enrolled patients already experiencing MIs; TOP sought to prevent them in the perioperative period.
TOP’s topline negative finding suggests that high cardiac risk alone isn’t reason enough to routinely transfuse every postoperative patient to hemoglobin ≥10 g/dL.
But nor does it prove that hemoglobin 7 g/dL is always safe in cardiovascularly high-risk surgical populations. The confidence interval leaves room for benefit or harm, and the secondary cardiac-complication signal aligns with MINT.
TOP was negative, but it was also designed with unreasonably high event rate assumptions and was underpowered to detect small but potentially clinically important differences. (It was also stopped slightly early for funding concerns, but even at full enrollment would have remained underpowered.)
Other Trials Didn’t Show Benefits of Prophylactic Transfusions Either
More support for the thesis that every high-risk patient need not be liberally transfused perioperatively comes from the FOCUS trial (Carson et al NEJM 2011). In more than 2,000 older patients undergoing hip fracture surgery who had cardiovascular disease or cardiovascular risk factors, liberal and restrictive transfusion strategies had similar outcomes (although MIs were, again, about an absolute 1% lower in the liberally transfused).
The TRICS-III trial (Mazer et al NEJM 2017) found no significant difference in its composite outcome in 5,243 cardiac bypass surgery patients transfused to either Hb ≥7.5 or ≥10 g/dL (numerically favoring the restricted-transfusion arm by 1%).
Conclusions
For stable postoperative patients with cardiac risk factors but no active ischemia, TOP, FOCUS and TRICS-III support continuing a restrictive approach rather than reflexively transfusing to 10 g/dL.
For a patient with acute MI, MINT and subsequent professional society guidance point toward a higher threshold, perhaps hemoglobin 9 to 10 g/dL, though the evidence remains low certainty.
For the patient in between (postoperative anemia plus severe coronary disease, tachyarrhythmias, heart failure, dynamic troponin elevation, ischemic symptoms, or tenuous hemodynamics), careful individualized decision-making is required. TOP offered something for both the restrictive (virtually identical mortality in both groups) and the liberal clinician (fewer non-MI complications as a secondary outcome).
There is no ongoing trial comparable to MINT testing transfusion in active MI. The TRICS-IV trial is further testing restrictive vs. liberal transfusion strategies in ~1,400 younger adults undergoing cardiac bypass surgeries. Results are expected in 2026.
References
FOCUS trial (Carson et al NEJM 2011)
TRICS-III trial (Mazer et al NEJM 2017)