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Daniela Pedicino, Rocco Vergallo, More blood for patients with myocardial infarction and anaemia?, European Heart Journal, Volume 45, Issue 9, 1 March 2024, Pages 651–652, https://doi.org/10.1093/eurheartj/ehad832
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Comment on ‘Restrictive or Liberal Transfusion Strategy in Myocardial Infarction and Anemia’ which was published in the New England Journal of Medicine, https://doi.org/10.1056/NEJMoa2307983.
The Myocardial Ischemia and Transfusion (MINT) study is a multicentre, open-label, randomized controlled trial (RCT), funded by the US National Heart, Lung, and Blood Institute and others, designed to evaluate the efficacy and safety of a conservative haemoglobin transfusion threshold [<7–8 g per decilitre (g/dL)] vs. a liberal transfusion threshold (<10 g/dL) in patients with myocardial infarction (MI) and anaemia (haemoglobin level <10 g/dL).1
A total of 144 sites in the United States, Canada, Australia, New Zealand, France, and Brazil enrolled and randomized 3504 patients (mean age, 72 years; 45% women; 71% Whites) with a diagnosis of ST-segment elevation MI (STEMI, 19%) or non-STEMI (NSTEMI, 81%) and a mean basal haemoglobin level of 8.6 g/dL. According to the Third Universal Definition of MI,2 patients had type 1 (42%), 2 (56%), or 4a and 4b (2%) MI. Two-thirds of patients had multivessel coronary artery disease, 22% had acute heart failure, and nearly half had renal insufficiency (12% in renal dialysis).
In the restrictive strategy group, transfusion was permitted but not required when the haemoglobin level was <8 g/dL and was strongly recommended when the level was <7 g/dL or in the presence of persistent anginal symptoms despite medical therapy. In the liberal strategy group, one unit of packed red cells was transfused after randomization, and red cells were administered as needed to maintain the haemoglobin level at or above 10 g/dL until hospital discharge or until 30 days.
The primary outcome was a composite of MI or death from any cause up to 30 days after randomization. Pre-specified secondary endpoints were the individual components of the primary outcome and the composite outcome of death, MI, ischaemia-driven revascularization, or hospital readmission for an ischaemic cardiac condition through 30 days. The enrolment of 3500 patients would provide the trial with 80% power to detect a 20% relative between-group difference in the incidence of the primary outcome. Analyses were conducted with two-sided hypothesis tests for superiority. Risk ratios (RR) were used to assess the risk with the restrictive strategy as compared with the liberal strategy (with values >1 favouring the liberal strategy).
Discontinuation of the protocol in the restrictive strategy group occurred in 46 patients (3%), mostly for clinical reasons, including surgery and bleeding. Discontinuation in the liberal strategy group occurred in 241 patients (14%), about one-third for clinical reasons (including adverse effects, fluid overload, dialysis, and transfusion reactions).
The primary outcome occurred in 295 patients (16.9%) in the restrictive strategy group and in 255 (14.5%) in the liberal strategy group [RR modelled with multiple imputation for incomplete follow-up, 1.15; 95% confidence interval (CI), 0.99–1.34; P = .07]. At 30 days, all-cause death occurred in 9.9% of patients in the restrictive strategy group and in 8.3% of those in the liberal strategy group (RR, 1.19; 95% CI, 0.96–1.47) and recurrent non-fatal MI in 8.5% and 7.2% of patients, respectively (RR, 1.19; 95% CI, 0.94–1.49). Cardiac death was more frequent in the restrictive strategy group than in the liberal strategy group (5.5% vs. 3.2%, respectively; RR 1.74; 95% CI, 1.26–2.40); transfusion-associated cardiac overload (TACO) events were less frequent in the restrictive strategy group (0.5% vs. 1.3%; RR, 0.35; 95% CI, 0.16–0.78), with similar rates of heart failure in the two groups (5.8% vs. 6.3%, RR, 0.92; 95% CI, 0.71–1.20). The results were consistent across all pre-specified subgroups, including age, gender, type of index MI, type of anaemia (acute/chronic), and diabetes.
Comment
Anaemia is a common condition in acute myocardial infarction (MI), being present in up to 40% of elderly patients hospitalized with an acute MI, and is associated with worse outcomes.3–5 However, due to the lack of randomized controlled trials (RCTs) with a superiority design, current guidelines do not recommend any specific transfusion threshold for patients with an acute MI.6–8
Although a restrictive transfusion strategy decreased blood use by 50% without adversely affecting clinical outcomes in other settings,9,10 the evidence supporting the use of such a strategy in patients with acute MI remains elusive. The rationale behind a liberal transfusion strategy in MI is related to the increase in myocardial oxygen delivery; in contrast, the fluid overload associated with frequent transfusions may lead to adverse outcomes in patients with cardiac dysfunction.
The Myocardial Ischemia and Transfusion (MINT) trial is by far the largest RCT exploring the efficacy and safety of conservative vs. liberal haemoglobin transfusion targets in patients hospitalized with an acute MI and anaemia.1 The large population enrolled, four times as large as the enrolment in all the other studies in this setting combined, and the pragmatic trial design, with standard clinical criteria for MI diagnosis and routine testing for the detection of anaemia, are the major strengths of the trial, which addresses a frequent dilemma encountered in clinical practice. While the trial did not demonstrate a statistically significant difference between the two transfusion strategies for the primary outcome, the results suggest that liberal blood transfusion in a post-MI setting is well tolerated and relatively safe, in terms of heart failure events and other early adverse effects. Of note, the trial showed a trend towards increased rates of both the primary composite endpoint and its components in the restrictive strategy group. It should be emphasized that MINT was designed to detect a 20% relative between-group difference and the observed effect was a relative difference of ∼15%, which the trial had inadequate statistical power to detect. However, the 95% CI (0.99–1.34) contains values that suggest a clinical benefit for the liberal transfusion strategy but does not include values that suggest a benefit for the more restrictive transfusion strategy.
Nevertheless, the results of this trial should be interpreted with caution for a number of reasons. The open-label design implies that clinicians were aware of which strategy participants were assigned to. This may have led to the high discontinuation rate seen in the liberal strategy arm, probably linked to concerns about potential fluid overload consequences or to the timing of hospital discharge, given that hospitalization for uncomplicated MI can be shorter than 5 days, and this time is not always sufficient to bring haemoglobin levels to >10 g/dL. Moreover, the trial analyses were not adjusted for multiplicity; thus, it is not possible to draw any conclusion from the results beyond the primary outcome, including the difference in cardiac death. Alongside, recurrent MI was the only outcome confirmed by an independent committee, while the cause of death was ascertained by the research team at the enrolment hospital, with a lack of details clarifying the specific causes of cardiac death. A more detailed description of patients’ characteristics and management, such as completeness of revascularization and other procedural aspects, would have been useful for the interpretation of MINT results and their applicability to clinical practice; of note, about one-third of patients underwent revascularization and red blood cell transfusion before randomization. Patients with active bleeding and in dialysis represented 13% and 12% of the entire population, respectively, with half having renal impairment. Different causes of anaemia usually require different therapeutic approaches; however, no information was provided about other medical treatments for anaemia. These aspects do not allow a clear understanding of the mechanisms underlying anaemia and make it difficult to identify which patient might benefit most from the different transfusion strategies.
In conclusion, the MINT trial shows that in patients with acute MI and anaemia, a liberal transfusion strategy is not clearly superior to a restrictive strategy with respect to all-cause death or non-fatal MI at 30 days. A number of factors will continue to influence the clinical decision around blood transfusion, including patients’ characteristics, costs, staffing issues, and shortage of blood supply. While waiting for longer-term follow-up, the favourable trend for the liberal strategy is not robust enough to recommend this practice in all MI patients presenting with anaemia.
Declarations
Disclosure of Interest
D.P. received speaker’s fees from Daiichi-Sankyo, outside the submitted work. R.V. received consulting or lecturing fees from Abbott Vascular, Abiomed, Amgen, Daiichi-Sankyo, Medtronic, and Terumo, outside the submitted work.
