Restrictive or Liberal Transfusion Strategy in Myocardial Infarction and Anemia (MINT Trial)

Background: Concurrent anemia worsens outcomes in patients that present with acute myocardial infarctions. Transfusions increase the oxygen carrying capacity of blood which can improve the perfusion of at-risk cardiac tissue. However, transfusions are also asso ciated with immunosuppression, thrombotic phenomena, volume overload, and inflammatory reactions. An optimal transfusion hemoglobin cutoff has not yet been established in these patients. prior randomized trials comparing liberal versus restrictive transfusions strategies were limited by relatively small sample sizes and inconsistent results. The Myocardial Ischemia and Transfusion (MINT) trial is the largest study to date examining the impact of a liberal versus restrictive transfusion strategy on outcomes in this patient population.

Paper: Carson JL, et al. Restrictive or Liberal Transfusion Strategy in Myocardial Infarction and Anemia. N Engl J Med. 2023. PMID 37952133

Clinical Question: In patients with acute myocardial infarction and anemia, does a restrictive or liberal transfusion strategy affect the risk of death or recurrent myocardial infarction at 30 days?

What They Did:

• Multicenter, open-label, randomized trial
• 144 sites in the United States, Canada, France, Brazil, New Zealand, and Australia
• Enrollment from April 2017 to April 2023
• Patients with acute myocardial infarction and anemia randomized 1:1 to either:
  • Restrictive Transfusion Strategy
    • pRBC transfusion strongly recommended if hemoglobin was < 7 g/dl
    • pRBC transfusion strongly recommended when anginal symptoms were not controlled with medications
    • pRBC transfusion permitted but not required if hemoglobin < 8 g/dl
  • Liberal Transfusion Strategy (hemoglobin cutoff < 10 g/dl)
    • 1unit pRBC was administered at a time and pRBCs were transfused to maintain hemoglobin at or above 10g/dl

Outcomes:

• Primary:Composite of myocardial infarction or death from any cause up to 30 days after randomization
• Secondary:Individual components of death, myocardial infarction, secondary composite*

* Secondary composite outcome of death, myocardial infarction, nonscheduled coronary revascularization, or rehospitalization for cardiac ischemia with 30 days

Inclusion:

• Adults > 18 years of age
• STEMI or NSTEMI myocardial infarction^** and anemia within the past 24hrs (Hgb <10 g/dL)
  • Diagnosis of acute myocardial infarction required a rise in cardiac biomarker values with at least one value above the upper reference limit of normal.
  • Additionally, patients needed to have at least one of the following:
    • Symptoms of ischemia
    • New/Presumed new ST segment or T wave changes or new LBBB
    • Development of pathological Q waves
    • Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality
    • Angiographic evidence of intracoronary thrombus
• ^** Thygesen K, et al. Third universal definition of myocardial infarction. Circulation. 2012;126(16):2020-2035. PMID: 22958960

Exclusion:

• Uncontrolled bleeding requiring blood transfusion
• Receiving palliative treatment
• Schedule for cardiac surgery during admission
• Declined blood transfusion

Results:

• 3504 patients analyzed
  • Restrictive Strategy (n = 1749) vs. Liberal Strategy (n = 1755)

• Well balanced patient characteristics (Restrictive vs Liberal Strategy)
  • Median age 72.2 vs. 72.1 years
  • Female sex 44.3 vs 46.7%
  • Baseline hemoglobin 8.6 vs. 8.6 g/dl
  • Prior myocardial infarction 33.7 vs. 31.3%
  • Prior heart failure 30.1 vs. 30.7%
  • Index Myocardial Infarction
    • NSTEMI 81.8 vs. 80.8%
    • Type 1: 41.7 vs 41.6%
    • Type 2: 55.3 vs 56.3%
  • Active bleeding 14.1 vs. 12.2%

• Primary Outcome (Restrictive vs Liberal Strategy)
  • Death or myocardial infarction, 295 (16.9%) vs. 255 (14.5%)
    • Crude Risk Ratio, 1.16 (95% CI: 1.00 – 1.35)
    • Missing Data Imputed RR, 1.15 (95% CI: 0.99 – 1.36), p=0.07
    • The primary outcome was NOT statistically different
• Secondary Outcomes (Restrictive vs Liberal Strategy)
  • Death, 173 (9.9%) vs. 146 (8.3%), RR 1.19 (95% CI: 0.96 – 1.47)
  • Myocardial Infarction, 149 (8.5%) vs. 126 (7.2%), RR 1.19 (95% CI: 0.94 – 1.49)
  • Secondary Composite^**, 342 (19.6%) vs. 305 (17.4%), RR 1.13 (95% CI: 0.98 – 1.29)
• Other Outcomes (Restrictive vs Liberal Strategy)
  • Heart Failure, 102 (5.8%) vs. 111 (6.3%), RR 0.92 (95% CI: 0.71 – 1.20)
  • Cardiac Death, 97 (5.5%) vs. 56 (3.2%), RR 1.74 (95% CI: 1.26 – 2.40)
  • PE or DVT, 26 (1.5%) vs. 34 (1.9%), RR 0.77 (95% CI: 0.46 – 1.27)
  • Pneumonia or bacteremia, 166 (9.5%) vs. 153 (8.7%), RR 1.09 (95% CI: 0.88 – 1.34)
  • Mean RBC transfused, 0.7 vs. 2.5 units
• Subgroup analysis – Primary outcome in patients with: (Restrictive vs Liberal Strategy)
  • Type 1 MI, 133 (18.2%) vs. 101 (13.8%), RR 1.32 (95% CI: 1.04 – 1.67)
  • Type 2 MI, 153 (15.8%) vs. 149 (15.1%), RR 1.05 (95% CI: 0.85– 1.29)

Strengths:

• Largest randomized trial to date comparing transfusion strategies in patients with acute myocardial infarction
• Randomization process was sound: web-based system, permuted blocks with random blocks of 4 and 6, stratified by clinical site
• Well balanced and representative sampling with broad inclusion criteria improves generalization to other populations
• Pragmatic trial design and clinically relevant primary outcome increase applicability
• Analyzed patients in Intention to Treat
• Multitude of clinical sites and locations increases generalizability of results
• Minimal loss to follow up
• Hypothesis generating results for subgroups such as Type 1 vs. Type 2 MI, STEMI vs. NSTEMI, chronic vs. acute anemia, and presence of heart failure
• Relevant safety factors such as stroke, pulmonary embolus, and bacteremia were examined

Limitations:

• Clinicians and patients were not blinded to the trial arms which may have influenced the usage of other interventions and the determination of cardiac death in secondary outcomes
• Moderate (86.3%) adherence to the liberal transfusion strategy due to factors such as fluid overload and the timing of hospital discharge leading to protocol violations
• Use of composite primary and secondary outcomes
• Population was fairly homogenous with respect to age and ethnicity
• There is little information provided on interventions done other than the use of transfusion which may lead to cointervention bias
• Not all outcomes were centrally adjudicated which is problematic in an open-label trial design
• The prioritization of imputation missing data adjustments over confounder adjustments or crude data is of unclear benefit and may alter interpretation of the results

Discussion:

• The authors state that although not statistically significant, the liberal transfusion strategy was consistently favored in point estimates for the primary outcome as well as for various other outcomes in this study. But these findings must be interpreted with a somewhat healthy dose of skepticism.
• One of the big limitations is that this is an unblinded study which opens the possibility of introducing ascertainment bias due to knowledge about which intervention the participants are receiving.
• When the lack of blinding is coupled with potentially subjective outcomes and composite endpoints, it may further bias the results of the study. For example, if you look at the Kaplan Meier estimates for the composite primary outcome, the liberal strategy has a slightly better trend, but it is noted early after randomization with no divergence of the curves. Could this be due to mandatory troponin testing that may have revealed a delta with symptoms that have variable inter-rater reliability with respect to “ischemia”. This may have had an impact on the adjudication of myocardial infarction leading to questionable results.

• Similarly, the lack of blinding may also have potentially led to the Hawthorne effect, where the care team was more careful when aware of the group assignments.
• The liberal arm of this trial had significant increased rates of protocol discontinuation compared to the restrictive arm. This is another avenue where the observed treatment effect may be inaccurate.
• Another interesting thing in this trial was that close to a third of patients in both groups (34.2% in restrictive and 36.4% in liberal) received a blood transfusion (2.3 units in restrictive and 2.1 units in liberal) prior to randomization, and this is a confounding variable in regard to the observed effects post-randomization.
• Additionally, the trial was created to have 80% power to detect a 20% relative reduction in the incidence of the primary outcome, but their observed effect was a relative difference of approximately 15%. This coupled with their p value of 0.07 as well as their primary outcome confidence interval certainly limits the overall confidence in the trial results. Even when looking at the secondary outcomes and subgroup analysis, the authors themselves state that the trial analyses were not adjusted for multiplicity, so caution must be used in interpreting the results beyond the primary outcome.
• These findings contrast with the results of previous transfusion trials, but it adds to the body of literature while remaining an overall negative trial. It opens the door for further research to definitively answer the question posed by this study.
• As this current time, availability of resources, risks, and benefits need to be considered and an individualized approach to transfusion needs to continue based on this trial.
• Additional studies are needed to confirm the results presented in this study and to identify specific patient populations that would benefit more from a liberal transfusion strategy.

Author Conclusion: “In patients with acute myocardial infarction and anemia, a liberal transfusion strategy did not significantly reduce the risk of recurrent myocardial infarction or death at 30 days. However, potential harms of a restrictive transfusion strategy cannot be excluded.”

Clinical Take Home Point: In the largest randomized trial to date for patients presenting with myocardial infarction and anemia, there was no significant difference in the incidence of myocardial infarction or death at 30 days in patients randomized to a liberal versus a restrictive transfusion strategy. The data suggesting a potential favorable trend from the liberal strategy is not robust enough in the face of the study limitations to recommend a change from current practice.

References:

Carson JL, Brooks MM, Hébert PC, et al. Restrictive or Liberal Transfusion Strategy in Myocardial Infarction and Anemia. N Engl J Med. PMID 37952133

Cooper HA, Rao SV, Greenberg MD, et al. Conservative versus liberal red cell transfusion in acute myocardial infarction (the CRIT Randomized Pilot Study). Am J Cardiol. PMID 21791325

Carson JL, Brooks MM, Abbott JD, et al. Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease. Am Heart J. PMID 23708168

Ducrocq G, Gonzalez-Juanatey JR, Puymirat E, et al. Effect of a Restrictive vs Liberal Blood Transfusion Strategy on Major Cardiovascular Events Among Patients With Acute Myocardial Infarction and Anemia: The REALITY Randomized Clinical Trial. JAMA. PMID 33560322

Guest Post By:

Clifford Chang, MD
PGY-2 Emergency Medicine Resident
Inspira Medical Center, Vineland, NJ

Muhammad Durrani, DO
Assistant Clerkship Director, Assistant Research Director

Inspira Medical Center, Vineland, NJ

Twitter/X: @ibbydurrani

Post Peer Reviewed By: Marco Propersi, DO (Twitter/X: @marco_propersi)and Salim R. Rezaie, MD (Twitter/X: @srrezaie)