Rationale and design for the myocardial ischemia and transfusion (MINT) randomized clinical trial

doi:10.1016/j.ahj.2022.11.015

American Heart Journal

Volume 257, March 2023, Pages 120-129

, , , , , , , , , , , , , , , , , , , …

https://doi.org/10.1016/j.ahj.2022.11.015 Get rights and content

ABSTRACT

Background

Accumulating evidence from clinical trials suggests that a lower (restrictive) hemoglobin threshold (<8 g/dL) for red blood cell (RBC) transfusion, compared with a higher (liberal) threshold (≥10 g/dL) is safe. However, in anemic patients with acute myocardial infarction (MI), maintaining a higher hemoglobin level may increase oxygen delivery to vulnerable myocardium resulting in improved clinical outcomes. Conversely, RBC transfusion may result in increased blood viscosity, vascular inflammation, and reduction in available nitric oxide resulting in worse clinical outcomes. We hypothesize that a liberal transfusion strategy would improve clinical outcomes as compared to a more restrictive strategy.

Methods

We will enroll 3500 patients with acute MI (type 1, 2, 4b or 4c) as defined by the Third Universal Definition of MI and a hemoglobin <10 g/dL at 144 centers in the United States, Canada, France, Brazil, New Zealand, and Australia. We randomly assign trial participants to a liberal or restrictive transfusion strategy. Participants assigned to the liberal strategy receive transfusion of RBCs sufficient to raise their hemoglobin to at least 10 g/dL. Participants assigned to the restrictive strategy are permitted to receive transfusion of RBCs if the hemoglobin falls below 8 g/dL or for persistent angina despite medical therapy. We will contact each participant at 30 days to assess clinical outcomes and at 180 days to ascertain vital status. The primary end point is a composite of all-cause death or recurrent MI through 30 days following randomization. Secondary end points include all-cause mortality at 30 days, recurrent adjudicated MI, and the composite outcome of all-cause mortality, nonfatal recurrent MI, ischemia driven unscheduled coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting), or readmission to the hospital for ischemic cardiac diagnosis within 30 days. The trial will assess multiple tertiary end points.

Conclusions

The MINT trial will inform RBC transfusion practice in patients with acute MI.

Section snippets

Background

Blood transfusion is a common medical intervention, with 118.5 million units of blood collected worldwide each year.¹ Physicians often transfuse patients based on a specific hemoglobin threshold, although it is unclear at what threshold the benefits of increasing hemoglobin outweighs the risks of transfusion.

In most clinical settings, trials have demonstrated that a restrictive transfusion strategy using a hemoglobin threshold of 7 to 8 g/dL is as effective as a liberal transfusion strategy

Trial aims and objectives

The MINT trial was designed to determine whether a liberal transfusion strategy with a threshold of 10 g/dL reduces the composite outcome of all-cause mortality or nonfatal recurrent MI through 30 days, compared with a restrictive transfusion strategy with a threshold of 7 to 8 g/dL among patients with an acute MI and a hemoglobin concentration less than 10 g/dL.

Study design

The MINT trial is a randomized, open-label, 2 group multicenter clinical trial. The trial is being conducted in approximately 144

Sample size and power

The composite 30-day rate of death and MI for the combined liberal and restrictive transfusion strategies was 16.4% in the MINT pilot trial.⁴ Assuming a 16.4% event rate and that <5% of patients will have missing 30-day outcome data, a sample size of N = 3500 provides the MINT trial 80% power to detect a 20% relative risk reduction and 90% power to detect a 25% relative reduction for the trial primary end point with alpha = 0.05. Initial power calculations were performed using a 2-sided

Discussion

The risks and benefits of a liberal vs a restrictive transfusion strategy remain unresolved in anemic patients presenting with acute MI. Observational data suggests an association between a liberal transfusion strategy and increased mortality.¹⁵ Prior to the initiation of the MINT trial, 2 small trials comparing liberal to restrictive transfusion in patients with acute MI suggested that mortality may be higher in patients treated with restrictive transfusion.³^,⁴ The REALITY trial was completed

Summary

In patients with acute MI, the risks and benefits of RBC transfusion may be different than in other patient populations. Anemia, if untreated, may result in increased risks of further myocardial ischemia, injury, or infarction. Transfusions, on the other hand, may result in increased risks of volume overload and other adverse effects. Thus, it is unclear whether the benefits of immediate correction of anemia with transfusion are outweighed by the potential side effects of transfusion.

Author contribution

The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents.

Disclosures

JLC: DSMB member for Cerus Corporation project. MMB: DSMB member for Cerus Corporation project. JDA: Research funding MicroPort, Boston Scientific. Advisory Boards Philips, Medtronic. Consulting Abbott, Shockwave, Penumbra, Recor. SGG: Research grant support (eg, steering committee or data and safety monitoring committee) and/or speaker/consulting honoraria (eg, advisory boards) from: Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring,

Funding

This trial is supported by the National Heart Lung and Blood Institute U01 HL 133817-Clinical Coordinating Center, U01HL132853 - Data Coordinating Center. The vanguard phase was supported by a peer-reviewed grant 342193 from the Canadian Blood Services and the Canadian Institutes of Health Research (CIHR) Institute of Circulatory and Respiratory Health ClinicalTrials.gov Identifier: NCT02981407.

References (22)

HA Cooper et al.
Conservative versus liberal red cell transfusion in acute myocardial infarction (the CRIT Randomized Pilot Study)
Am J Cardiol
(2011)
KP Alexander et al.
Transfusion practice and outcomes in non-ST-segment elevation acute coronary syndromes
Am Heart J
(2008)
KE Thorpe et al.
A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers
J Clin Epidemiol
(2009)
K Thygesen et al.
Third universal definition of myocardial infarction
J Am Coll Cardiol
(2012)
JL Carson et al.
Effect of anaemia and cardiovascular disease on surgical mortality and morbidity
Lancet
(1996)
WHO. Blood Transfusion. In;...
J.L. Carson et al.
Cochrane Database Sys Rev
(2021)
JL Carson et al.
Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease
Am Heart J
(2013)
JL Carson et al.
Clinical practice guidelines from the AABB: red blood cell transfusion thresholds and storage
JAMA
(2016)
MM Mueller et al.
Patient blood management: recommendations from the 2018 Frankfurt Consensus Conference
JAMA
(2019)

AC Salisbury et al.

Hospital-acquired anemia and in-hospital mortality in patients with acute myocardial infarction

Am Heart J

(2011)

Cited by (11)

Is a Full Heart a Happy Heart?: February 2024 Annals of Emergency Medicine Journal Club
2024, Annals of Emergency Medicine
Surviving Sepsis After Burn Campaign
2023, Burns
The Surviving Sepsis Campaign was developed to improve outcomes for all patients with sepsis. Despite sepsis being the primary cause of death after thermal injury, burns have always been excluded from the Surviving Sepsis efforts. To improve sepsis outcomes in burn patients, an international group of burn experts developed the Surviving Sepsis After Burn Campaign (SSABC) as a testable guideline to improve burn sepsis outcomes.
The International Society for Burn Injuries (ISBI) reached out to regional or national burn organizations to recommend members to participate in the program. Two members of the ISBI developed specific “patient/population, intervention, comparison and outcome” (PICO) questions that paralleled the 2021 Surviving Sepsis Campaign [1]. SSABC participants were asked to search the current literature and rate its quality for each topic. At the Congress of the ISBI, in Guadalajara, Mexico, August 28, 2022, a majority of the participants met to create “statements” based on the literature. The “summary statements” were then sent to all members for comment with the hope of developing an 80% consensus. After four reviews, a consensus statement for each topic was created or “no consensus” was reported.
The committee developed sixty statements within fourteen topics that provide guidance for the early treatment of sepsis in burn patients. These statements should be used to improve the care of sepsis in burn patients. The statements should not be considered as “static” comments but should rather be used as guidelines for future testing of the best treatments for sepsis in burn patients. They should be updated on a regular basis.
Members of the burn community from the around the world have developed the Surviving Sepsis After Burn Campaign guidelines with the goal of improving the outcome of sepsis in burn patients.
Recent advances in electrochemical nanobiosensors for cardiac biomarkers
2023, TrAC - Trends in Analytical Chemistry
The WHO reports heart diseases, especially MI, are the leading cause of death. During a heart attack and damage to myocardial cells, cardiac biomarkers are released into the bloodstream. Their accurate measurement can be beneficial in the rapid screening of patients and the initiation of treatment. Rapid diagnosis of MI prevents secondary complications such as heart failure and will significantly reduce the mortality rate of patients. Electrochemical biosensors are cutting-edge diagnostic tools that successfully track the quantitative detection of several cardiac biomarkers. They are composed of three primary components: a biorecognition element, a signal transducer, and a detector. Here, the latest electrochemical biosensors developed in 2021–2023 have been collected and categorized, and their main features have been reviewed, analyzed, and compared. The most crucial biorecognition elements used in these biosensors include antibodies, oligonucleotides (especially: aptamers), and peptide sequences that are specifically selected and used to detect analytes. Equipping electrochemical biosensors with nanomaterials has increased diagnostic performance (especially sensitivity), facilitating reliable detection. These nanomaterials have been employed by modifying the surface of the signal transducer or optimizing the biorecognition element, or both. Investigating the most up-to-date platforms for detecting cardiac biomarkers and presenting their essential assembly features and diagnosis mechanisms can provide subsequent research avenues.
Analysis of the incidence and risk factors of blood transfusion in total knee revision: a retrospective nationwide inpatient sample database study
2024, BMC Musculoskeletal Disorders
Adherence to a restrictive red blood cell transfusion strategy in critically ill patients: An observational study
2024, Acta Anaesthesiologica Scandinavica
Restrictive or Liberal Transfusion Strategy in Myocardial Infarction and Anemia.
2023, New England Journal of Medicine

View all citing articles on Scopus

¹: Jeffrey L. Carson and Maria Mori Brooks both contributed equally to this work.

^⁎: Index MINT Investigators from Supplementary Appendix E

View full text

Trial DesignsRationale and design for the myocardial ischemia and transfusion (MINT) randomized clinical trial

ABSTRACT

Background

Methods

Conclusions

Section snippets

Background

Trial aims and objectives

Study design

Sample size and power

Discussion

Summary

Author contribution

Disclosures

Funding

Am J Cardiol

Am Heart J

J Clin Epidemiol

J Am Coll Cardiol

Lancet

Cochrane Database Sys Rev

Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease

Am Heart J

Clinical practice guidelines from the AABB: red blood cell transfusion thresholds and storage

JAMA

Patient blood management: recommendations from the 2018 Frankfurt Consensus Conference

JAMA

Hospital-acquired anemia and in-hospital mortality in patients with acute myocardial infarction

Am Heart J

Trial Designs
Rationale and design for the myocardial ischemia and transfusion (MINT) randomized clinical trial