Myocardial ischaemia and transfusion trial: a glimmer in the fog

Anaemia among patients hospitalized with an acute myocardial infarction (MI) is common (1–16.8%) and associated with an increased risk of in-hospital mortality.1–6 Prior randomized controlled trials have demonstrated that a restrictive transfusion threshold of 70–80 g/L is either non-inferior or safer compared with a more liberal haemoglobin transfusion target of 90–100 g/L among patients who are critically ill, undergoing cardiac or non-cardiac surgery, or with gastrointestinal bleeding.7–10 Whether more restrictive transfusion applies to patients with an acute MI who may physiologically require more myocardial oxygen delivery remains less clear. There have been three prior randomized trials in this population.11 The largest study was the Restrictive and Liberal Transfusion Strategies in Patients With Acute Myocardial Infarction (REALITY) open-label, non-inferior, randomized trial, which enrolled 668 patients from 35 centres to either a restrictive (haemoglobin transfusion trigger ≤ 80 g/L) or a liberal (haemoglobin transfusion trigger ≤ 100 g/L) transfusion strategy. The primary 30-day composite outcome of all-cause death, stroke, recurrent MI, or emergency ischaemic-driven revascularization met the pre-specified criteria for non-inferiority [11% restrictive vs. 14% liberal, relative risk 0.79; one-sided 97.5% confidence interval (CI) 0.00–1.19].12 Importantly, the study was underpowered for superiority. Currently, guidelines provide no recommendation for transfusion threshold in inpatient with an acute MI or ischaemic heart disease due to insufficient evidence.11 The myocardial ischaemia and transfusion (MINT) trial is the largest randomized controlled trial of conservative vs. liberal haemoglobin transfusion targets in patients hospitalized with an acute MI.13 The MINT trial was designed to evaluate the efficacy and safety of a conservative haemoglobin transfusion threshold (<80 g/L or for persistent angina despite medical therapy) or liberal transfusion threshold (<100 g/L) in patients with a haemoglobin < 100 g/L. The primary composite outcome was 30-day all-cause mortality or recurrent MI. The secondary endpoints included individual components of the primary outcomes and the composite of all-cause mortality, non-fatal recurrent MI, ischaemia-driven revascularization, or ischaemic-driven readmission through 30 days. Selected tertiary endpoint included heart failure, infectious complications, and patient-reported quality of life through 30 days. The MINT trial was an open-label, multicentre randomized controlled trial that enrolled patients from 144 sites in the USA, Canada, Australian, New Zealand, France, and Brazil. In a pragmatic trial design, standard clinical criteria for MI diagnosis and the detection of anaemia were based on routine testing. In the conservative arm, patients were to receive a transfusion below 80 g/L, and transfusion was strongly recommended below 70 g/L. Transfusion was also permitted when anginal symptoms were felt to be related to anaemia and not controlled with anti-anginal medications. The study planned to enrol 3500 patients and assumed a 16.5% event rate with <5% drop-out or event missingness.13 The study has 80% power to detect a 20% relative risk reduction and a 90% power to detect a 25% relative risk reduction. The study planned a primary intention-to-treat analysis with a per-protocol sensitivity analysis. A Data Safety Monitoring Board oversaw study endpoints and adverse events. The study inclusion criteria included patients 18 years or older with either ST or non-ST segment elevation MI (STEMI/NSTEMI) that met Third Universal Definition of MI criteria14 for Type I, 2, 4b, or 4c MI that occurred during the index hospitalization with a haemoglobin level of <100 g/L. Selected exclusion criteria included uncontrolled acute bleeding, scheduled cardiac surgery, patients receiving palliative treatment, or patients who would decline a blood transfusion. The study randomized 1749 subjects to the restrictive arm and 1755 subjects to the liberal arm. The mean age was 72.1 years, 45.5% were female, and 76% were Caucasian. A fifth of the qualifying infarctions (82%) were NSTEMI, and the mechanism of the qualifying MI was thought to be Type 2 in 55%. The mean LVEF was 47–48% with a baseline haemoglobin of 86 g/L. There was adherence to the study transfusion protocol with a mean haemoglobin of 110 g/L in the liberal arm and 88 g/L in the restrictive arm. Discontinuation of the study protocol was noted in 2.6% in the restrictive arm compared with 13.6% in the liberal arm. Patients in the liberal arm received 2.5 ± 2.3 units of packed red blood cells (PRBC) compared with 0.7 ± 1.6 units of PRBC in the restrictive arm. The primary outcome at 30 days of death or MI was 14.5% with the liberal and 16.9% in the restrictive arm: risk ratio (RR) of 1.16; 95% CI 1.00–1.35, favouring the liberal strategy. An imputed analysis due to incomplete ascertainment of data at study termination (20 in restrictive vs. 27 in liberal) lowered the benefit observed to a RR of 1.15; 95% CI 0.99–1.34. Cardiac death was 5.5% with a restrictive strategy compared with 3.2% in the liberal arm (RR 1.74; 95% CI 1.26–2.40). This numerical benefit was consistent across various pre-specified subgroups including the type of index MI (STEMI/NSTEMI), mechanism of index MI (Type1/Type 2), type of anaemia (acute/chronic), age, gender, and presence/absence of diabetes. Secondary outcomes of death, MI and the composite of death, MI, revascularization, and readmission all favoured a liberal transfusion arm but were not statistically significant. Despite increased blood transfusion, the rate of heart failure in the liberal arm was 6.3%, similar to the 5.8% observed in the restrictive arm. The MINT study investigators should be congratulated for completing a large, pragmatic, randomized clinical trial addressing a common clinical dilemma often encountered by the cardiovascular practitioner. In a well-conducted trial, a clinically significant 2.4% reduction in death or MI is noted with a liberal transfusion strategy targeting a transfusion-assisted haemoglobin of 100 g/L over a baseline haemoglobin of 86 g/L. This numerical benefit was noted early after randomization and sustained over 30 days with no additional divergence of the curves. Although speculative, protocol-mandated troponin testing in the initial 3 days following randomization may have had an impact on MI adjudication and the early benefit noted. The increased rates of protocol discontinuation in the liberal arm may also have impacted on the observed treatment effect. The incomplete endpoint ascertainment and the borderline P-value obtained using traditional frequentist statistics limit our confidence in the overall trial results. Evaluating the data set utilizing an alternate Bayesian approach may provide further insight in this setting. The observed results, while biologically plausible, provide a lack of clarity on the mechanism of benefit. Death was not centrally adjudicated in this clinical trial and details with regard to the mechanism and mode of CV death (death due to MI, sudden cardiac death, arrhythmia, heart failure, and procedural complications), and the characteristics of the resultant MI (type 1 vs. 2) in the study population would enable a better understanding of the cause-and-effect relationship arising from the allotted transfusion strategy. In the setting of a borderline statistical benefit, unreported confounding post-randomization variables like asymmetry in the completeness of revascularization and other non-measured clinical actions could also potentially be playing a role. Finally, it is also notable that a third of patients in both groups received a blood transfusion prior to randomization. Despite these limitations, the MINT study provides reassurance that blood transfusion in the post-acute MI setting is safe and well tolerated, with no apparent early harm. No adverse signals from the theoretical concerns of provoking heart failure and increasing risk of infection or increased thrombotic risks due to inflammation and increase in viscosity were noted. Consequently, given the numerical benefit noted, the results of MINT will likely result in clinicians utilizing blood transfusion to raise haemoglobin in anaemic patients following an MI to haemoglobin levels of >100 g/dL, especially in patients with tenuous coronary anatomy with significant myocardium in jeopardy. The availability of PRBC remains a limited and life-saving commodity that is critical in multiple clinical settings including trauma, surgery, and the treatment of various blood disorders. The favourable data from the liberal arm of MINT is not robust enough to currently recommend this limited resource as an intervention in all patients with anaemia following MI. All clinicians need to remain responsible stewards of this life-saving product. Future publications from MINT will hopefully shed mechanistic light that will guide clinicians to better target this precious resource in the acute MI setting. None declared. No new data were generated or analysed in support of this research.

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