Myocardial Ischemia and Transfusion
Phase: PHASE3
Conditions: Myocardial Infarction, Anemia
Sponsor: Rutgers, The State University of New Jersey

Myocardial Ischemia and Transfusion 
NCT02981407 
October 24, 2017 

 
 
 
 
Jeffrey L Carson, MD 
Study Chair 
Principal Investigator, Clinical Coordinating Center 
Rutgers Robert Wood Johnson Medical School 
Maria Mori Brooks, PhD 
Principal Investigator, Data Coordinating Center 
University of Pittsburgh 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
A 
INTRODUCTION .......................................................................................................................................................... 8 
A1 
STATEMENT OF COMPLIANCE ................................................................................................................................... 8 
A2 
STUDY ABSTRACT .................................................................................................................................................... 9 
A3 
PRIMARY HYPOTHESIS ............................................................................................................................................. 9 
A4 
PURPOSE OF THE STUDY PROTOCOL ....................................................................................................................... 10 
A5 
SCHEMATIC OF STUDY DESIGN .............................................................................................................................. 11 
A6 
KEY ROLES ............................................................................................................................................................ 12 
B 
BACKGROUND .......................................................................................................................................................... 13 
B1 
PRIOR LITERATURE AND STUDIES .......................................................................................................................... 13 
B2 
RATIONALE FOR THIS STUDY: EQUIPOISE ............................................................................................................... 18 
C 
STUDY OBJECTIVES ................................................................................................................................................ 18 
C1 
PRIMARY AIM ........................................................................................................................................................ 18 
C2 
SECONDARY AIMS.................................................................................................................................................. 19 
C3 
TERTIARY AIMS ..................................................................................................................................................... 19 
C4 
RATIONALE FOR THE SELECTION OF OUTCOME MEASURES.................................................................................... 20 
D 
STUDY DESIGN .......................................................................................................................................................... 21 
D1 
OVERVIEW OR DESIGN SUMMARY ......................................................................................................................... 21 
D2 
SUBJECT SELECTION AND WITHDRAWAL ............................................................................................................... 22 
2.a 
Inclusion Criteria .............................................................................................................................................. 22 
2.b 
Exclusion Criteria ............................................................................................................................................. 23 
2.c 
Ethical Considerations ...................................................................................................................................... 23 

2.d 
Randomization Method and Blinding ................................................................................................................. 23 
2.e 
Subject Recruitment Plans and Consent Process ............................................................................................... 24 
2.f 
Risks and Benefits ................................................................................................................................................... 24 
2.g 
Early Withdrawal of Subjects from Transfusion Strategy and Trial Procedures ............................................... 25 
2.h 
When and How to Withdraw Subjects ................................................................................................................ 25 
2.i 
Data Collection and Follow-up for Withdrawn Subjects ........................................................................................ 25 
D3 
TRIAL TRANSFUSION STRATEGIES ........................................................................................................................... 26 
3.a 
Description ......................................................................................................................................................... 26 
3.b 
Transfusion Strategies ........................................................................................................................................ 26 
3.c 
Rationale for Transfusion Thresholds ................................................................................................................ 26 
3.d 
Method for Assigning Subjects to Treatment Groups ......................................................................................... 27 
3.e 
Preparation and Administration of Red Blood Cell Transfusions ...................................................................... 27 
3.f 
Subject Compliance Monitoring ............................................................................................................................. 28 
3.g 
Prior and Concomitant Therapy ........................................................................................................................ 29 
3.h 
Blinding of Study Intervention ............................................................................................................................ 29 
E 
STUDY PROCEDURES ............................................................................................................................................... 29 
E1 
SCREENING FOR ELIGIBILITY ................................................................................................................................... 29 
E2 
SCHEDULE OF MEASUREMENTS ............................................................................................................................... 29 
E3 
IN-HOSPITAL FOLLOW-UP ........................................................................................................................................ 30 
E4 
FOLLOW-UP AT 30 DAYS ......................................................................................................................................... 30 
E5 
FOLLOW-UP AT 6 MONTHS ...................................................................................................................................... 31 
E6 
SAFETY AND ADVERSE EVENTS .............................................................................................................................. 31 

6.a 
Safety and Compliance Monitoring .................................................................................................................... 31 
6.b 
Medical Monitoring ........................................................................................................................................... 31 
i 
Investigator Only................................................................................................................................................. 31 
ii 
Independent Expert to Monitor ........................................................................................................................... 32 
iii 
Independent Data and Safety Monitoring Board ................................................................................................. 32 
6.c 
Definitions of Adverse Events ............................................................................................................................ 33 
6.d 
Classification of Events ...................................................................................................................................... 34 
i 
Severity .............................................................................................................................................................. 34 
ii 
Relationship ........................................................................................................................................................ 34 
iii 
Expectedness ..................................................................................................................................................... 35 
6.e 
Data Collection Procedures for Adverse Events and Unanticipated Problems ................................................. 35 
6.f 
Reporting Procedures ............................................................................................................................................. 36 
6.g 
Adverse Event Reporting Period ........................................................................................................................ 37 
6.h 
Post-study Adverse Event ................................................................................................................................... 37 
E7 
STUDY OUTCOME MEASUREMENTS AND ASCERTAINMENT ..................................................................................... 37 
7.a 
Definitions of Outcomes ..................................................................................................................................... 37 
i 
Myocardial Reinfarction ...................................................................................................................................... 37 
ii 
Death and Cause of Death ................................................................................................................................. 38 
iii 
Unscheduled Coronary Revascularization (unstaged) ........................................................................................ 38 
iv 
Readmission to Hospital, overall and for primary cardiac diagnosis ................................................................... 38 
v 
Unstable Angina ................................................................................................................................................. 38 
vi 
Congestive Heart Failure .................................................................................................................................... 38 
vii 
TIA or Stroke ...................................................................................................................................................... 39 

viii 
Deep Venous Thrombosis or Pulmonary Embolism ........................................................................................... 39 
ix 
Bleeding ............................................................................................................................................................. 39 
x 
Infections ............................................................................................................................................................ 39 
xi 
Length of Stay and Intensive Care Unit Days ..................................................................................................... 40 
xii 
Quality of Life ..................................................................................................................................................... 40 
7.b 
Ascertainment .................................................................................................................................................... 40 
E8 
BASELINE AND INTERVENTION CLINICAL CHARACTERISTICS .................................................................................. 41 
F 
STATISTICAL PLAN .................................................................................................................................................. 41 
F1 
SAMPLE SIZE DETERMINATION AND POWER ................................................................................................................ 41 
F2 
INTERIM MONITORING AND EARLY STOPPING ............................................................................................................. 42 
F3 
ANALYSIS PLAN .......................................................................................................................................................... 46 
F4 
STATISTICAL METHODS ............................................................................................................................................... 46 
4.a 
Baseline Characteristics of the Enrolled Patient Sample ................................................................................... 46 
4.b 
Adherence to Assigned Intervention ................................................................................................................... 47 
4.c 
Primary Outcome Analysis ................................................................................................................................ 47 
4.d 
Analysis of Secondary and Tertiary Outcomes ................................................................................................... 47 
4.e 
Missing Outcome Data ....................................................................................................................................... 48 
4.f 
Subgroup Analyses ................................................................................................................................................. 49 
4.g 
Combining Vanguard and Main Trial Data ....................................................................................................... 49 
F5 
UNBLINDING PROCEDURES .......................................................................................................................................... 50 
G 
DATA HANDLING AND RECORD KEEPING ........................................................................................................ 50 
G1 
CONFIDENTIALITY AND SECURITY .......................................................................................................................... 50 

G2 
TRAINING ................................................................................................................................................................ 51 
G3 
CASE REPORT FORMS AND SOURCE DOCUMENTS ................................................................................................... 51 
G4 
RECORDS RETENTION ............................................................................................................................................. 52 
G5 
PERFORMANCE MONITORING .................................................................................................................................. 52 
H 
STUDY MONITORING, AUDITING, AND INSPECTING ..................................................................................... 52 
H1 
STUDY MONITORING PLAN ..................................................................................................................................... 52 
H2 
AUDITING AND INSPECTING..................................................................................................................................... 52 
I 
STUDY ADMINISTRATION ...................................................................................................................................... 53 
I1 
ORGANIZATION AND PARTICIPATING CENTERS ........................................................................................................... 53 
1.a 
Clinical Coordinating Center ............................................................................................................................ 53 
1.b 
Data Coordinating Center ................................................................................................................................. 53 
1.c 
Clinical Consortium ........................................................................................................................................... 54 
I2 
FUNDING SOURCE AND CONFLICTS OF INTEREST ......................................................................................................... 54 
I3 
COMMITTEES ............................................................................................................................................................... 54 
3.a 
Steering Committee ............................................................................................................................................ 54 
3.b 
Operations Committee ....................................................................................................................................... 55 
3.c 
Executive Committee .......................................................................................................................................... 55 
3.d 
Clinical Events Committee ................................................................................................................................. 55 
I4 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................................................... 55 
I5 
STUDY TIMETABLE ...................................................................................................................................................... 56 
J 
PUBLICATION PLAN ................................................................................................................................................. 57 
K 
REFERENCES ............................................................................................................................................................. 58 
L 
APPENDICES .............................................................................................................................................................. 66 

L1 
APPENDIX 1: STANDARDIZED APPROACH AND SCRIPT TO BE USED TO SEEK PERMISSION FROM ATTENDING 
PHYSICIAN TO RECRUIT A PATIENT ...................................................................................................................................... 67 
L2 
APPENDIX 2: MINT DATA ELEMENTS BY STUDY TIME POINT ................................................................................ 68 
L3 
APPENDIX 3: SAE AND UP EVENT REPORTING TIMELINES .................................................................................... 69 
L4 
APPENDIX 4: ACCRUAL TIMELINE MILESTONES .................................................................................................... 70 

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A1 Statement of Compliance 
 
The trial will be conducted in accordance with the ICH E6, the Code of Federal Regulations on the 
Protection of Human Subjects (45 CFR Part 46), and the NIH Terms of Award. The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place without prior 
agreement from the sponsor and documented approval from the Institutional Review Board (IRB), 
except where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel 
involved in the conduct of this study have completed Human Subjects Protection Training. 
 
I agree to ensure that all staff members involved in the conduct of this study are informed about their 
obligations in meeting the above commitments. 
Principal Investigator:   Jeffrey L Carson, MD 
 
Print/Type Name 
 
Signed:  
Date:  
 
Signature 
A Introduction 

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A2 Study Abstract 
Accumulating evidence from clinical trials suggests that a restrictive transfusion strategy is safe in 
most clinical settings. However, a low oxygen carrying capacity from moderate anemia may be 
deleterious in patients with cardiac ischemia. The potential for harm associated with anemia in 
patients with acute symptomatic coronary disease is supported by pathophysiological data that 
maintaining higher hemoglobin levels could benefit the ischemic heart by increasing oxygen delivery. 
Systematic reviews of clinical trials evaluating transfusion strategies in patients with known ischemic 
heart disease document the absence of high quality data, which has resulted in an ongoing 
controversy. The lack of high quality evidence to guide transfusions in patients with acute myocardial 
infarction has been cited in several major guidelines as well as by an NIH expert panel. 
This multicenter trial, the Myocardial Ischemia and Transfusion (MINT) trial, randomly allocates 3500 
patients with acute myocardial infarction and a hemoglobin concentration less than 10 g/dL to be 
treated either according to a liberal or restrictive blood transfusion strategy. Patients assigned to the 
liberal transfusion strategy receive one unit of packed red blood cells following randomization and 
enough blood to raise the hemoglobin concentration to 10 g/dL or above any time a concentration less 
than 10 g/dL is detected. Patients assigned to the restrictive transfusion strategy are permitted to 
receive a transfusion if the hemoglobin concentration falls below 8 g/dL or if angina symptoms clearly 
related to the anemia occur and are not controlled with anti-anginal medications. Only enough blood is 
given to reach a hemoglobin concentration of 8 g/dL or relieve the symptoms. Transfusion is strongly 
recommended if the hemoglobin concentration falls below 7 g/dL. 
The transfusion protocol is followed during the index hospitalization (up to 30 days). Each patient is 
contacted at 30 days for a comprehensive follow-up for assessment of several relevant clinical 
outcomes. Patients are contacted again at 180 days to ascertain vital status for assessment of six- 
month mortality. 
A3 Primary Hypothesis 
The primary hypothesis is that among patients with an acute myocardial infarction and a hemoglobin 
concentration less than 10 g/dL, a liberal transfusion strategy with a threshold of 10 g/dL reduces the 
rate of the composite outcome of all-cause mortality or recurrent nonfatal acute myocardial infarction 
through 30 days following randomization compared to a restrictive transfusion strategy with a 
threshold of 7 to 8 g/dL. 

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A4 Purpose of the Study Protocol 
The purpose of the trial is to assess red blood cell transfusion strategies that are currently used in 
clinical practice and important medical events. Red blood cells are a limited and expensive medical 
therapy. Physicians frequently transfuse patients to maintain specific (and often differing) hemoglobin 
levels, despite the lack of evidence supporting the strategy. The study results, which will determine 
the benefit (or risk) of a liberal transfusion strategy, will influence the allocation of red blood cells 
worldwide. 

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A5 Schematic of Study Design 
 
 
 
 
 
 
 
 

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A6 Key Roles 
 
Principal Investigator, Clinical Coordinating Center and Study Chair 
Jeffrey L Carson, MD 
Provost, Rutgers Biomedical Health Sciences 
Rutgers Robert Wood Johnson Medical School 
125 Paterson Street 
New Brunswick, New Jersey 08901 
Telephone: 732-235-7122 
FAX: 732-235-7144 
Email:jeffrey.carson@rutgers.edu 
Principal Investigator, Data Coordinating Center 
Maria Mori Brooks, PhD 
Professor of Epidemiology 
University of Pittsburgh 
Graduate School of Public Health 
A530 Crabtree Hall / 130 DeSoto Street 
Pittsburgh, PA 15261 
Telephone: (412) 624-1618 
FAX: (412) 383-5891 
Email: mbrooks@pitt.edu 
 
Project Scientist 
Simone Glynn MD, MSc, MPH 
Branch Chief 
Blood Epidemiology and Clinical Therapeutics Branch 
Division of Blood Diseases and Resources 
National Heart, Lung, and Blood Institute 
Tel: 301-435-0065 
Fax: 301-480-0867 
Email: glynnsa@nhlbi.nih.gov 
 
Project Officer 
Pablo Cure, MD, MPH 
Program Officer 
Blood Epidemiology and Clinical Therapeutics Branch 
Division of Blood Diseases and Resources 
National Heart, Lung, and Blood Institute, NIH 
6701 Rockledge Drive, Room 9163 
Bethesda, MD 20892-7950 
Tel: +1-301-451-7431Email: pablo.cure@nih.gov 

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B1 Prior Literature and Studies 
Blood transfusion is a common medical intervention. In the United States, more than 16 million red 
blood cell units are transfused annually to 3.4 million patients.(1) Worldwide 108 million units of blood 
are collected per year.(2) Of all transfusions, approximately 25% of all red cells transfused are given 
to patients with a primary diagnosis of cardiac disease(3) and 8% of all cardiology admissions are 
transfused with RBCs.(4) The economic ramifications of this frequent intervention are significant. The 
latest estimates of the cost of a red blood cell unit range from $522 to $1183 (mean, $761+$294).(5) 
The safety of transfusion with respect to transmission of infectious agents has increased greatly 
throughout the past two decades, and complications are rare.(6, 7) 
Anemia and Cardiac Disease: Generating evidence to guide transfusion threshold decisions in 
patients with myocardial infarction is especially important because coronary artery disease is so 
common,(8) anemia is present frequently in this setting, and is associated with increased mortality. A 
study of 44,242 patients with non-ST segment elevation myocardial infarction from 400 US hospitals 
found 22.2% of patients had a hematocrit <30% (Hgb <10 g/dL).(9) In-hospital mortality was 10.4% in 
patients with Hgb <10 g/dL compared to 2.7% in patients with Hgb >10 g/dL.(10) In a second study 
involving 17,676 patients with acute myocardial infarction, hospital-acquired anemia (Hgb <11 g/dL) 
developed in 20.1% of patients during the hospitalization. Patients with Hgb <9 g/dL had a strong 
association with mortality (odds ratio=3.39).(10) The mechanism of early mortality in patients with 
acute cardiac injury and anemia may be related to a low ischemic threshold leading to myocardial 
injury, congestive heart failure and ventricular arrhythmia. 
Accumulating evidence from clinical trials suggests that a restrictive transfusion strategy is safe in 
most clinical settings(11-14) with the possible exception of patients with acute coronary syndrome. 
B Background 

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Most reviews and guidelines define a restrictive transfusion strategy as the administration of red cells 
once hemoglobin falls below either 7 or 8 g/dL while a liberal strategy is most often suggested as a 
transfusion trigger of 10 g/dL. 
Pathophysiology: The AABB (formerly called the American 
Association of Blood Banks) guidelines on Red Blood Cell 
Transfusion recently recommended the use of restrictive 
transfusion triggers in most patients with the exception of 
those with an acute coronary syndrome.(15, 16) Their 
rationale – in the absence of randomized trial evidence – was 
16 
 
 
13 
 
 
10 
 
 
7 
 
 
4 
 
 
1 
6 
7 
8 
9 
10 
11 
12+ 
Preoperative Hemoglobin g/dL 
the large body of basic physiology and observational data would suggest that a restrictive strategy 
may be deleterious. This is because oxygen delivery to the myocardium is flow dependent since the 
heart extracts a high percentage of oxygen. Therefore, myocardial ischemia may be precipitated or 
worsened by low hemoglobin concentrations, especially in patients with coronary stenosis or active 
plaques. Studies performed in canines suggest a decreased ability to tolerate anemia in the presence 
of coronary artery disease.(17-19) Electrocardiographic changes consistent with ischemia are seen 
at hemoglobin concentration below 5 g/dL in normal animals but at 7-10 g/dL with experimentally 
induced coronary artery disease. 
Data from patients who decline blood transfusion for religious reasons were congruent with animal 
data. In a retrospective cohort study that included 1,958 adult surgical patients who declined 
transfusion for religious reasons and found a significant interaction between underlying cardiovascular 
disease and preoperative Hgb level with respect to death (p=0.03).(20) In patients with underlying 
cardiovascular disease the adjusted odds of postoperative death began to rise sharply at Hgb level 
<10 g/dL while in patients without underlying cardiovascular disease there was a more subtle rate of 
increasing risk below 10 g/dL (see Figure 1). This study does not address whether transfusion would 
improve outcome. 
Transfusion could be harmful by several possible pathophysiological mechanisms. Transfusion has 
been shown to increase platelet reactivity and increase procoagulant proteins.(21) Stored red blood 
cells take time to replenish 2, 3 DPG levels impairing release of oxygen(22, 23) and have low levels of 
nitrous oxide impairing oxgen delivery and vasodilation.(24) The membranes of stored red blood cells 
may become deformed and plug microvascular vessels.(25, 26) 
 
 
 
 
 
Odds Ratio 

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Systematic Reviews, Observational Studies: We have identified or conducted systematic reviews 
of both observational studies and clinical trials. As expected, a systematic review of observational 
studies in all patients found that blood transfusion was associated with increased mortality and 
morbidity.(27) Two recent systematic reviews focusing specifically on patients with myocardial 
infarction identified 10 studies (9 observational and 1 pilot trial) reporting the effects of transfusions on 
mortality.(28, 29) Nearly all observational studies demonstrated an association between transfusion 
and higher mortality. The one exception was in a large study using Medicare billing data in 79,000 
patients with acute myocardial infarction.(30) Transfusion was associated with a lower risk of death 
when patients had an admission hematocrit below 0.33 (equal to a hemoglobin concentration of 11 
g/dL) (odds ratio= 0.69; 95% CI, 0.53-0.89) and relationship between transfusion and better outcomes 
increased as the hematocrit fell. Indeed, based on subgroup analyses, the authors of the systematic 
review report that the adverse effects of transfusion appear to be mitigated in patients with a 
hematocrit less than 0.33. Unfortunately, observational studies cannot be used to evaluate the effect 
of red blood cell transfusion since the use of blood transfusion is a marker for illness burden.(29, 31) 
Thus, no matter how refined the adjustment is for differences in illness burden, it is difficult, if not 
impossible, to completely adjust for differences between patients receiving and not receiving blood 
transfusion. 
Systematic Reviews, Clinical Trials: We have performed a systematic review of clinical trials 
evaluating transfusion triggers in a variety of populations that were published in the Cochrane 
database(32) and JAMA.(33) We have updated the review (34) and found that compared with higher 
hemoglobin transfusion thresholds (~10 g/dL), a hemoglobin transfusion threshold of 7 or 8 g/dL is 
associated with fewer red blood cell units transfused (mean difference, -1.22 units per patient), 
without adverse associations with mortality, cardiac morbidity, functional recovery, or length of 
hospital stay. The relative risk for the association of restrictive versus liberal transfusion on 30-day all- 
cause mortality was 0.99 (95% CI, 0.82 to 1.20). 
A recent meta-analysis of 11 selected trials enrolling patients with cardiovascular disease (including 
data obtained from authors from four trials) was recently reported. The risk ratio for the association 
between transfusion thresholds and 30-day mortality was 1.15 (95% confidence interval 0.88 to 1.50), 
but the risk of acute coronary syndrome in patients in the restrictive compared with liberal transfusion 
group was increased in nine trials (risk ratio 1.78, 95% confidence interval 1.18 to 2.70).(35). This 
analysis is limited by the fact that data are only included from 27% of the eligible trials. The results of 

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a meta-analysis in cardiac surgery patients reports trend favoring liberal transfusion (36) but the 
results conflict with another analysis in cardiac surgery patients in which no trend was evident. (34) 
Clinical Trials in Acute Coronary Syndrome: Our systematic review identified two pilot clinical trials 
that included patients suffering an acute coronary syndrome. The first was a small pilot trial including 
45 patients with acute myocardial infarction.(37) Patients with hematocrit less than 30% were 
randomly allocated to a liberal (hematocrit <30%) versus restrictive (hematocrit < 24%) transfusion 
threshold. The primary clinical safety measurement of in-hospital death, recurrent myocardial 
infarction, or new or worsening congestive heart failure occurred in 8 patients in the liberal arm and 3 
in the restrictive arm (p< 0.046). There were 2 deaths in restrictive group and 1 death in the liberal 
group. The authors concluded a definitive trial was urgently needed. 
In contrast, the MINT pilot enrolled 110 patients and found the pre-defined primary outcome of death, 
myocardial infarction, or unscheduled revascularization within 30 days occurred in 6 patients (10.9%) 
in the liberal-transfusion strategy and 14 (25.5%) in the restrictive-transfusion strategy p=0.054). 
Death at 30 days was less frequent with liberal transfusion 1 (1.8%) compared to restrictive 
transfusion 7 (13.0%); p=0.032. 
Overall, there were 2 deaths in the liberal transfusion strategy and 9 deaths in the restrictive 
transfusion strategy (relative risk= 3.74, 95% CI 0.80-17.49; p=0.09) when the two trials in acute 
coronary syndrome are combined. 
Other Trials (38) with Signal of Harm from Restrictive Transfusion: The two most recently 
published trials also found a higher mortality in patients in the restrictive transfusion group in patients 
with ischemic heart disease. The Titre2 trial contrasted liberal transfusion (9 g/dL) and restrictive 
transfusion (7.5 g/dL) in postoperative patients undergoing cardiac surgery. The short-term outcomes 
were comparable between the transfusion strategies, but at 90 days follow-up, overall mortality was 
higher in the restrictive transfusion strategy than the liberal transfusion strategy (hazard ratio=1.64; 
95% confidence interval, 1.00 to 2.67, p=0.045). In a cluster randomized trial in 939 patients with GI 
bleeding, the mortality was trending higher in subgroup of patients with underlying ischemic heart 
disease; liberal transfusion strategy was 3% and in the restrictive transfusion strategy was 12% 
(difference =10.7%; 95% confidence intervals -9.8 to 31.2; interaction p=0.11) 
Variation in Transfusion and Guidelines: The systematic reviews of observational studies and 
randomized trials evaluating the impact of anemia and transfusion highlight the lack of any study with 

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sufficient numbers of patients to guide clinical care. All of this uncertainty has helped fuel significant 
practice variation. Two older large studies in 44,242 patients with non-ST segment elevation 
myocardial infarction from 400 US hospitals(9) and 17,676 patients with acute myocardial infarction 
demonstrate substantial variation in transfusion.(10) Similar variation was observed in over 19,315 
hospitalized patients with a discharge diagnosis of myocardial infarction during 2009-2012 from the 
California Kaiser Permanente Health System (Percent transfused at nadir hemoglobin level >10 g/dL, 
0.2%; 9-9.9 g/dL, 12.5%; 8-8.9 g/dL, 48.9%; 7-7.9 g/dL, 78.3%; < 7 g/dL, 91.5%). (39) A significant 
proportion of patients had transfusion thresholds at every cut-off from 7 to 10 g/dL. An updated 
analysis demonstrates variation in hospital acquired anemia in 17,676 patients with myocardial 
infarction (40) and transfusion among 34,937 patients with a myocardial infarction hospitalized 
between 2000-2008 in 57 centers. (41) In a retrospective cohort study based on the CathPCI 
Registry data from 2009 to 2013, the risk adjusted rates of transfusion by hospital varied from 0.3% to 
9.3%. (42) The high transfusion hospitals used a threshold between 9 to 10 g/dL, and low transfusion 
hospitals used a threshold between 8 to 9 g/dL. More contemporary data in cardiac surgery patients 
from 2013 show continued variation in transfusion practice. (43) 
The variation in transfusion practice may further be exacerbated by the great variability in the 
transfusion guideline recommendations. While all conclude that there are too few high-quality studies, 
recommendations vary widely among organizations. The American Red Cross, AABB, British 
Committee for Standards in Haematology were not able to recommend a course of action,(44, 45) the 
American College of Physicians recommends 7-8 g/dL in patients with heart disease but is silent in 
acute coronary syndrome patients;(46) the American College of Cardiology/American Heart 
Association suggests avoidance of transfusion unless hemoglobin less than 8 g/dL(47, 48); National 
Comprehensive Cancer Network recommends 10 g/dL threshold in patients with coronary heart 
disease including patients with acute coronary syndrome (49), National Blood Authority of Australia 
recommends 8 g/dL threshold (50), and the European Society of Cardiology recommends transfusion 
only in case of compromised hemodynamic status and hemoglobin less than 7 g/dL.(51) The recently 
published guidelines from the AABB concluded that there was insufficient evidence in patients with 
acute MI and did not provide a specific recommendation, (52) while the UK National Clinical 
Guidelines Centre recommended transfusion at 8 g/dL (53). Given the lack of high quality evidence to 
guide transfusion in patients with acute myocardial infarction, it is not surprising that there is variation 
in recommendations emanating from different organizations. 

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C Study Objectives 
 
Despite the variation in guidelines for transfusion in patients with acute myocardial infarction, there 
has been a strong and consistent trend towards reducing the use of blood transfusion in the US. For 
example, red blood cell transfusions per 1000 US population fell by 13.9% between 2013 and 2015. 
(54) Data from California Kaiser Permanente Health System show that in 70,189 hospitalized patients 
with cardiovascular disease, the frequency of transfusion fell 25% between 2009 and 2013. (55) The 
pre-transfusion hemoglobin in patients with cardiovascular disease declined from 8.1 to 7.6 g/dL. This 
change in clinical practice may be due to the widespread implementation of blood management 
programs (54) and Choosing Wisely Campaigns which targeted “unnecessary” transfusions. (56) 
B2 Rationale for this Study: Equipoise 
Every day, clinicians encounter anemic patients who have acute ischemic heart disease where a 
decision to transfuse must be made. However, clinicians do not know what to do because: 1) 
Observational studies and randomized trials have come to different conclusions and are flawed; 2) 
Pathophysiological arguments can be made for liberal and restrictive strategies; 3) Some clinical trials 
in other settings suggest a restrictive transfusion approach is safe but other trials signal the possibility 
of reduced mortality with liberal transfusion in patients with cardiac disease; 4) Guidelines provide 
conflicting advice. This has led to practice variation(9, 57) and confusion in the clinical community with 
no clear guidance on when to transfuse. Thus, the NHLBI State of the Science expert panel 
concluded in March 2015 “equipoise for transfusion thresholds persists in patients with ischemic heart 
disease.” (58) The ACC/AHA guidelines for management of STEMI concluded, “the optimal 
hemoglobin level in the transfused patient is not known.”(47, 48) Furthermore, the recently published 
guidelines by the AABB identified acute coronary syndrome as clinical setting where the evidence is 
“judged to be insufficient” to recommend transfusion threshold.(16) Based on these findings and 
existing data there clearly is equipoise. For all these reasons, a high quality randomized trial to guide 
transfusion is urgently needed to answer this clinically relevant question. 
 
C1 Primary Aim 
The primary aim is to determine whether a liberal transfusion strategy with a threshold of 10 g/dL 
reduces the composite outcome of all-cause mortality or nonfatal myocardial reinfarction through 30 
days following randomization, compared to a restrictive transfusion strategy with a threshold of 7 to 8 

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g/dL among patients with an acute myocardial infarction and a hemoglobin concentration less than 10 
g/dL. 
C2 Secondary Aims 
1) To determine whether a liberal (10g/dL) transfusion strategy reduces all-cause mortality 
within 30 days, compared to a restrictive transfusion strategy. 
2) To determine whether a liberal (10g/dL) transfusion strategy reduces myocardial reinfarction 
within 30 days, compared to a restrictive transfusion strategy. 
3) To determine whether a liberal (10g/dL) transfusion strategy reduces the composite 
outcome of all-cause mortality, nonfatal myocardial reinfarction, 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, compared to a restrictive 
transfusion strategy. 
C3 Tertiary Aims 
1) To determine whether a liberal (10g/dL) transfusion strategy reduces all-cause mortality, 
nonfatal myocardial reinfarction, or unstable angina (i.e. acute coronary syndrome) within 30 days, 
compared to a restrictive transfusion strategy. 
2) To determine whether a liberal (10g/dL) transfusion strategy reduces ischemia driven 
unscheduled coronary revascularization within 30-days compared to a restrictive strategy. 
3) To determine whether a liberal (10g/dL) transfusion strategy reduces unscheduled 
readmission to hospital for ischemic cardiac diagnosis within 30 days, compared to a restrictive 
strategy. 
4) To determine whether a liberal (10g/dL) transfusion strategy increases congestive heart 
failure within 30 days, compared to a restrictive transfusion strategy. 
5) To determine whether a liberal (10g/dL) transfusion strategy reduces unscheduled 
readmission to hospital for any reason within 30 days, compared to a restrictive strategy. 

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6) To determine whether a liberal (10g/dL) transfusion strategy increases each of the 
individual thrombotic/hemorrhagic outcomes of stroke, pulmonary embolism or deep venous 
thrombosis, and bleeding within 30 days, compared to a restrictive strategy. 
7) To determine whether a liberal (10g/dL) transfusion strategy increases each of the 
individual infectious outcomes of pneumonia, blood stream, and urinary tract within 30 days, 
compared to a restrictive strategy. 
8) To determine whether a liberal (10g/dL) transfusion strategy reduces each of the individual 
in-hospital outcomes of length of hospital stay post randomization and number of days in intensive 
care unit, compared to a restrictive strategy. 
9) To determine whether a liberal (10g/dL) transfusion strategy increases patient reported 
quality of life using the EuroQol questionnaire (EQ-5D) at 30 days compared to a restrictive strategy 
10 To determine whether a liberal (10g/dL) transfusion strategy reduces all-cause mortality at 6- 
months following randomization, compared to a restrictive strategy. 
C4 Rationale for the Selection of Outcome Measures 
The study outcomes assess the clinically important benefits and harms of transfusion and anemia in 
vulnerable individuals with compromised myocardium. Blood transfusions may decrease ischemic 
injury and improve myocardial performance by improving oxygen delivery to the myocardium in high- 
risk patients. However, transfusions may also harm patients. Blood transfusions acutely increase 
blood volume in patients who may not adapt rapidly enough resulting in increased rates of pulmonary 
edema and heart failure. The increased blood volume could also lead to higher risk of bleeding from 
increased intravascular pressure. Blood transfusion is also associated with immunosuppression and 
may lead to infection. In addition, laboratory data suggest that transfusions may not enhance oxygen 
delivery and may be associated with increased platelet aggregation. 
If transfusion to maintain the hemoglobin concentration >10 g/dL does mitigate the clinical 
consequences of anemia in ischemic cardiac injury, there will be a reduction of mortality and 
reinfarction. Higher hemoglobin concentrations might also reduce other sequelae of decreased 
oxygen delivery to the myocardium; unscheduled coronary revascularization, hospital readmission for 
ischemic symptoms, unstable angina, and cardiovascular mortality. 

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D Study Design 
 
On the other hand, if transfusion results in clinically important fluid overload, immunosuppression, 
increased viscosity, and inflammation there will be an increase in congestive heart failure, infection, 
bleeding, stroke, and pulmonary embolism or deep venous thrombosis. Each of these may contribute 
to death or reinfarction. 
Higher hemoglobin levels may also be associated with a more positive feeling of well-being and a 
better perceived quality of life as measured by the EQ-5D. 
Outcomes are assessed at 30 days since blood transfusion will have its maximum effect within this 
time period. Mortality will also be assessed at 6 months to determine if early effects of blood 
transfusion persist. 
 
D1 Overview or Design Summary 
This is a randomized, unblinded, two group multicenter clinical trial. Eligible study patients are 
randomized to receive either the liberal or the restrictive transfusion strategy. Transfusion strategy 
assignment is not blinded. The transfusion protocol is followed during the Index hospitalization (for up 
to 30 days). Each patient will be contacted at 30 days to ascertain study outcomes and at 6 months 
when vital status will be verified. The 30-day and 6-month follow-ups will be administered by 
telephone, but the follow-up questions could be administered in person, for example, if the patient is in 
the hospital during the follow-up window. During the 30-day follow-up, readmissions to the hospital 
that have occurred within the 30 days are identified and medical records will be obtained. The Clinical 
Events Committee, masked to treatment allocation, will adjudicate occurrences of myocardial 
infarction within the 30-day window. 
Each of the transfusion strategies in this trial is routinely used in current medical practice. Study 
patients will be followed while they are in the hospital (for up to 30 days) during which time 
hemoglobin levels, cardiac biomarker of necrosis levels, electrocardiograms, and number of units of 
red blood cell transfusions administered will be collected. 
The transfusion strategies will be compared for differences in mortality, cardiac events and other 
important morbidity, hospital re-admissions, and patient perceived quality of life. 

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The goal of this study is to determine whether a liberal transfusion strategy is superior to a restrictive 
strategy in anemic patients with acute myocardial infarction. 
D2 Subject Selection and Withdrawal 
 
2.a 
Inclusion Criteria 
The eligible study population includes patients who meet all of the following criteria: 1) 18 years of age 
or older; 2) with either ST segment elevation myocardial infarction or Non ST segment elevation 
myocardial infarction consistent with the 3rd Universal Definition of Myocardial Infarction criteria (38) 
that occurs on admission or during the index hospitalization, 3) with a hemoglobin concentration less 
than 10 g/dL at the time of random allocation, and 4) the patient’s attending physician, with expertise 
in cardiovascular care, believes that both of the transfusion strategies are consistent with good 
medical care for the patient as determined by his/her clinical judgement. 
To simplify the diagnosis of acute myocardial infarction, we will require a rise in cardiac biomarker 
values [preferably cardiac troponin (cTn)] with at least one value above the upper reference limit of 
normal of the hospital. We anticipate (and will confirm) that the hospital upper limit of normal for 
troponin will be equivalent to or above the 99th percentile upper reference at all hospitals. 
In addition to evidence of myocardial necrosis, we require patients to have at least one of the 
following: (1) symptoms of ischemia; (2) new/presumed new ST segment or T wave (ST-T) changes 
or new left bundle branch block (LBBB); (3) development of pathological Q waves; (4) imaging 
evidence of new loss of viable myocardium or new regional wall motion abnormality; and/or (5) 
identification of an intracoronary thrombus by angiography. (37) We will include patients with Type 1 
(i.e., spontaneous MI presumably related to atherosclerotic plaque rupture, ulceration, fissuring, 
erosion, or dissection with resulting intraluminal thrombus in one or more of the coronary arteries, 
leading to decreased myocardial blood flow or distal platelet emboli with ensuing myocyte necrosis), 
Type 2 (i.e., secondary to an ischemic imbalance such that myocardial injury with necrosis occurs due 
to myocardial oxygen supply and/or demand mismatch),Type 4b (i.e., stent thrombosis at 
angiography), and Type 4c (i.e., severe in-stent restenosis without evidence of thrombus). 

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2.b 
Exclusion Criteria 
Patients will be excluded if any of the following criteria are met 1) uncontrolled acute bleeding at the 
time of randomization defined as the need for uncrossed or non-type specific blood; 2) decline blood 
transfusion; 3) scheduled for cardiac surgery during the current admission; 4) are receiving only 
palliative treatment; 5) if known that follow-up will not be possible at 30 days; 6) if previously 
participated in MINT 7) if currently enrolled in a competing study that interferes with the intervention or 
follow-up of MINT or enrolled in a competing study that has not been approved by the local IRB; or 8) 
if the attending physician does not believe the patient is an appropriate candidate for the trial for any 
reason. 
Patients who have had an episode of uncontrolled bleeding may be enrolled later if the hemoglobin 
remains below 10 g/dL, they are no longer actively bleeding, and they are otherwise still eligible. 
2.c 
Ethical Considerations 
Both transfusion strategies assessed in this trial are widely used in clinical practice. There is 
uncertainty about which strategy is better, and therefore there is clinical equipoise to conduct this 
study. Furthermore, at the time of recruitment, the investigator will request permission of the patient’s 
doctor to seek the patient’s consent and randomly allocate them to one of the transfusion arms. 
At the time consent is obtained, the clinical site study staff will also request the names and contact 
information of two additional individuals who may be contacted in the event study staff are not able to 
reach the patient directly at the follow-up time points. This will minimize loss to follow-up. This 
information will be retained at the clinical site and destroyed at the end of the trial. 
2.d 
Randomization Method and Blinding 
The Data Coordinating Center (DCC) will prepare the randomization schedules. Allocation of the 
transfusion intervention strategies will be in a 1:1 ratio. Given the diverse patient mix among 
participating clinical sites, the randomization will be stratified by clinical site, and a permuted block 
design with random block sizes will be used to balance treatment assignments within each clinical 
site. 

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Study patients and physicians caring for the patient cannot be masked to treatment assignment (i.e., 
administration of red blood cell transfusion). However, the central classification of the myocardial 
reinfarction component of the primary outcome is performed masked to assignment. 
2.e 
Subject Recruitment Plans and Consent Process 
The study recruits hospitalized patients diagnosed with acute myocardial infarction (Type 1, Type 2, 
Type 4b, or Type 4c). Prior to study initiation, each cardiologist at the clinical site will be personally 
contacted by the clinical site principal investigator or coordinator and permission will be sought to 
recruit patients who are eligible for the study. Patients of physicians who do not wish to participate in 
the trial will not be approached for recruitment. 
Study staff will identify potential study patients, confirm that the physician agrees that the patient can 
be randomized into the study (see script in Appendix 1) and approach the patient for consent. 
Surrogate consent, in accordance with local IRB rules, will be sought for each eligible patient who is 
not able to grant consent. A substantial number of patients eligible for this trial are likely to be critically 
ill, medicated, and/or cognitively impaired and unable to grant consent. It is essential that these 
patients be included as physicians routinely face the dilemma of whether or not they should be 
transfused. 
2.f 
Risks and Benefits 
In patients with heart disease, risks and benefits are considerably different than most other patient 
populations. Oxygen delivery to the myocardium is flow dependent since the heart extracts a high 
percentage of oxygen and myocardial ischemia may be precipitated or worsened by low hemoglobin 
concentrations, especially in patients with acute myocardial infarction. Anemia, if untreated may 
result in increased risks of further myocardial ischemia and injury. Transfusions, on the other hand, 
may result in increased risks of pulmonary edema and heart failure (Transfusion-Associated 
Circulatory Overload), from the significant amounts of volume given to patients with impaired ability of 
the heart to pump (systolic dysfunction) or ability to relax and fill (diastolic dysfunction). Other adverse 
effects of allogeneic blood transfusion were also a concern: immunologic (transfusion-related acute 
lung injury [TRALI],(59) and transfusion-related immune modulation [TRIM] possibly leading to 
increased bacterial infections).(60) Thus, there is clinical equipoise because it is unclear whether the 
benefits of immediate correction of anemia with transfusion are outweighed by the potential side 
effects of transfusion. 

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2.g 
Early Withdrawal of Subjects from Transfusion Strategy and Trial 
Procedures 
The study participant (i.e. patient) can be withdrawn from the transfusion strategy (liberal or restrictive 
transfusion allocation) at any time, either at the request of the treating physician or the patient 
themselves. The clinical site director may also withdraw a patient. Following the withdrawal, all 
transfusion decisions will be per treating physician. The patient or physician may also request 
withdrawal from any trial procedure or follow-up. 
2.h 
When and How to Withdraw Subjects 
There are few reasons why a patient or physician might want to withdraw from the trial. If the patient 
has an adverse effect from a prior transfusion or proves to be difficult to cross match, the physician or 
patient may choose to withdraw from the study. However, the most common reasons are likely to be 
patient’s preference not to participate in research or desire not to have extra blood tests or be 
contacted for follow-up. If a concern is raised and a request for withdrawal is made by the patient or 
the physician, study staff will confirm the issue (e.g., transfusion strategy, study required 
measurements and/or telephone follow-up) and try to address the concern. Study staff will be 
required to contact the MINT CCC PI to discuss the individual situation. If appropriate, the patient will 
be given the opportunity to refrain from the objectionable study procedure(s) and remain in the overall 
study. All efforts will be made to avoid a participant feeling unduly pressured to remain in the study. If 
no intermediate solution is acceptable to the patient and/or treating physician, the patient will be 
withdrawn from the study. The study staff will document the date of withdrawal, any known reasons 
for withdrawal and whether the patient will continue with any of the study procedures and/or follow-up. 
All treating physicians will be immediately notified of a withdrawal from the transfusion strategy (liberal 
or restrictive transfusion allocation). 
2.i 
Data Collection and Follow-up for Withdrawn Subjects 
At the time of withdrawal, the study staff will request permission to continue with data collection and 
follow-up through the 6-month study time window. However, the exact amount of follow-up performed 
will vary in accordance with the patients’ authorization. 

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D3 Trial Transfusion Strategies 
 
3.a 
Description 
We are comparing two commonly used approaches to transfusion therapy, both of which can be 
considered as “standards of care.” For both strategies, blood must be administered one unit at a time 
followed by a hemoglobin measurement. The transfusion strategy will be followed throughout the 
index hospitalization up to 30 days, discharge, or death. 
3.b 
Transfusion Strategies 
Restrictive Transfusion Strategy: Patients randomized to the restrictive transfusion strategy will be 
permitted to receive a transfusion if the hemoglobin concentration falls below 8 g/dL and will be 
strongly recommended to receive transfusion if the hemoglobin concentration is below 7 g/dL. 
Transfusion is also permitted if angina symptoms (i.e., retrosternal chest discomfort, chest discomfort 
described as pressure or heaviness) that are thought by the clinician to be related to anemia occur 
and are not controlled with anti-anginal medications (sublingual nitroglycerin or equivalent therapy). 
Blood will be administered one unit at a time and enough blood given to increase the hemoglobin 
concentration above 7 to 8 g/dL or to relieve symptoms of uncontrolled angina. 
Liberal Transfusion Strategy: Patients randomly allocated to the liberal transfusion strategy will 
receive one unit of packed red cells following randomization and will receive enough blood to raise the 
hemoglobin concentration to 10 g/dL or above any time the hemoglobin concentration is detected to 
be below 10 g/dL. A post transfusion hemoglobin measurement showing a hemoglobin level of at 
least 10 g/dL must be obtained. 
A patient in either group may be transfused at any time without a hemoglobin level if the patient is 
actively bleeding (e.g., brisk gastrointestinal bleeding) and the physician believes an emergency 
transfusion is needed. A patient in either group with history of congestive heart failure or low ejection 
fraction may receive diuretics prior to or after transfusion. 
3.c 
Rationale for Transfusion Thresholds 
The restrictive transfusion group reﬂects many current guidelines (including European guidelines)(51, 
61). A blood transfusion will be permitted in the restrictive group if the hemoglobin concentration is 
less than 8 g/dL. Discussions with many cardiologists suggested that many clinicians are not 

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comfortable with a threshold as low as 7 g/dL (as used in TRICC); however, individual clinicians may 
choose to use a threshold of less than 7 g/dL to trigger transfusions. Patients may be transfused for 
signs or symptoms when the clinician believes it is necessary although this did not occur in the pilot 
trial and was uncommon in the FOCUS trial which also incorporated symptoms in the restrictive 
transfusion protocol. 
In the liberal transfusion group, a threshold of less than 10 g/dL was chosen because oxygen delivery 
to the myocardium is flow dependent and myocardial ischemia may be precipitated or worsened by 
low hemoglobin concentrations in patients with coronary stenosis or active plaques. Studies 
performed in canines found electrocardiographic changes consistent with ischemia as high as 10 g/dL 
with experimentally induced coronary artery disease. Data from patients who decline blood 
transfusion for religious reasons were congruent with animal data and found the odds of death rose as 
the hemoglobin fell below 10 g/dL. 
3.d 
Method for Assigning Subjects to Treatment Groups 
Clinical site staff will obtain the randomly assigned transfusion strategy for each eligible consented 
patient using the MINT website. The randomization system will be available via a secure area of the 
MINT project website with access restricted to those clinical site personnel with permission to 
randomize patients. Those who are certified to use the randomization system will be trained to 
adhere to a strict randomization protocol. In particular, the clinical site personnel must confirm the 
patient’s eligibility status in the system before a transfusion strategy assignment is provided. If the 
web-based randomization system is not accessible, clinical site personnel will be instructed to follow 
back-up procedures in order to ensure that the clinical centers are able to randomize patient 24/7. 
3.e 
Preparation and Administration of Red Blood Cell Transfusions 
All red blood cell units are maintained and ordered through the hospital blood bank. The storage 
solution and storage time will be at the discretion of the blood bank, but only leukoreduced red blood 
cell transfusion will be used. The transfusions are administered by hospital staff in accordance with 
hospital policy. Study staff will alert the nursing and medical staff to the assigned transfusion strategy 
each time a new patient has been enrolled in the study. Treating staff will order (or not order) red cell 
transfusions in accordance with the protocol. 

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3.f 
Subject Compliance Monitoring 
There are two primary site based mechanisms to ensure adherence to the assigned transfusion 
strategy 1) study staff review of the medical record and, if necessary, direct discussion with the 
treating physicians and, 2) direct assistance from the blood bank. 
The clinical site is to obtain a daily hemoglobin level for each randomized patient for the first three 
days following randomization (or through hospital discharge, if sooner). Additional hemoglobin levels 
are measured as clinically indicated. Study staff will closely monitor each patient to ensure that each 
of the required hemoglobin levels are drawn, review the results, and confirm that the transfusions 
have been ordered (or not ordered) in accordance with the transfusion assignment. If there is a 
hemoglobin value that should trigger a transfusion and none is ordered or, as the alternative, a 
transfusion ordered without a hemoglobin value to trigger the transfusion, study staff will discuss the 
case with the treating physician. Likewise, if a required hemoglobin level has not been ordered, the 
study staff will alert the physician. The required hemoglobin measurements are of primary importance 
to verify that patients in the liberal strategy maintain a level of at least 10 g/dL. 
The clinical site will also request assistance from the blood bank to help prevent protocol violations in 
the restrictive strategy. Study staff will notify the blood bank each time a patient is assigned to the 
restrictive strategy and request notification prior to the release of any red blood cell transfusions that 
are ordered. The study staff will then review the medical record to verify that the transfusion is in 
accordance with the protocol. If administration of blood is a violation of the protocol, study staff will 
contact the ordering physician to discuss transfusion plans and to clarify the study protocol. However, 
study staff do not approve or disapprove the transfusion. The final decision on the transfusion is 
always the treating physician’s. 
Study wide, the DCC will centrally monitor transfusions and hemoglobin levels on an ongoing basis. 
Transfusion rates for each strategy will be measured overall and by clinical site. Specifically, the DCC 
will identify instances when 1) patients randomized to the liberal strategy do not receive a transfusion, 
2) patients randomized to the liberal strategy are discharged with a hemoglobin level < 10 g/dL and, 
3) patients randomized to the restrictive strategy without anginal symptoms and a hemoglobin level ≥ 
8 g/dL receive a transfusion. Reports of the protocol violations will be prepared by the DCC. The 
Clinical Coordinating Center (CCC) will review these reports and discuss as necessary with the 
clinical sites. 

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E Study Procedures 
 
3.g 
Prior and Concomitant Therapy 
Transfusion prior to randomization is at the discretion of the clinicians. An otherwise eligible patient 
may be randomized as long as the hemoglobin level is <10g/dL, regardless of prior transfusions at the 
time of randomization. Once the patient has been randomized all red cell transfusions are 
administered per the study protocol. The protocol will not control the administration of other blood 
products including platelets or fresh frozen plasma. Similarly, it will not mandate specific medical or 
procedural treatments to manage these patients. 
3.h 
Blinding of Study Intervention 
Due to the nature of the interventions, study patients and physicians caring for the patients cannot be 
blinded to transfusion assignment. However, transfusion strategy assignment will be concealed during 
the central classification of the myocardial reinfarction component of the primary outcome. 
 
E1 Screening for Eligibility 
Several approaches to screening for study patients will be used. Study staff will review the results of 
all troponin levels daily. Medical records for patients with values above the upper reference limit of 
normal are reviewed and assessed for eligibility. Study staff will screen all admissions to the cardiac 
care unit, and scheduled for cardiac catheterization. The physician of each eligible patient with a 
hemoglobin level <10 g/dL will be contacted to confirm that the patient can be entered into the trial 
using a standardized script (Appendix 1), and consent will be sought. Study staff will follow otherwise 
eligible patients with hemoglobin levels ≥ 10 g/dL and consent the patient if the hemoglobin level 
drops to the entry level. 
E2 Schedule of Measurements 
Each randomized patient is required to have hemoglobin levels, troponin levels, and 
electrocardiogram readings at specified time points (while in the hospital). The blood samples will 
normally be drawn with the daily morning blood phlebotomy. 

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The required time points for hemoglobin levels are: 1) within 24 hours prior to randomization 
(eligibility hemoglobin level), 2) day 1 post randomization, 3) day 2 post randomization, 4) day 3 post 
randomization. 
The required time points for the troponin levels are: 1) within 24 hours prior to randomization, 2) 12 
hours following randomization, 3) day 1 post randomization, 4) day 2 post randomization, 5) day 3 
post randomization. 
The required time points for the ECGs are: 1) within 24 hours prior to randomization, 2) day 1 post 
randomization, 3) day 2 post randomization, 4) day 3 post randomization. 
A listing of the types of data elements that will be collected at each time point is presented in 
Appendix 2. 
E3 In-hospital Follow-up 
Study staff will review the medical records and follow participants during the hospitalization, for up to 
30 days post randomization. They will carefully follow and document hemoglobin levels and 
transfusion status to assure that the transfusion protocol is being followed. In addition, during the first 
3 days following randomization they will confirm that each of the required cardiac biomarkers for 
necrosis, hemoglobin levels, and electrocardiograms has been ordered and the results are recorded. 
At 30 days post randomization, or hospital discharge if sooner, the study staff will complete and 
submit all study data related to the hospitalization including baseline health status, laboratory results, 
post randomization events and copies of all electrocardiograms performed. 
E4 Follow-up at 30 Days 
Study staff at the clinical sites will contact each patient at 30 days following randomization. In 
general, the 30-day follow-up will be administered by telephone, but the follow-up questions could be 
administered in person. The follow-up interview will include questions about the patient’s health and 
quality of life during the follow-up interval and will determine if there have been any re-admissions to a 
hospital within 30 days of randomization. Local site staff will obtain the hospital records for each re- 
admission. 

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There will be a 30-day window (from 30 days to 60 days following randomization) for study staff to 
obtain the 30-day follow-up information. In the event they are not able to contact the patient directly, 
they will try to reach the alternate contacts that have been provided, and a letter will be sent to the 
patient if needed. 
E5 Follow-up at 6 Months 
Study staff at the clinical sites will perform a final follow-up contact at 6 months following 
randomization to determine the patient’s vital status. There will be a 30-day window (from 180 days to 
210 days following randomization) to obtain the 6-month information. In the event that study staff are 
not able to contact the patient at the 6-month time point, they will follow the same procedure outlined 
at the 30-day follow-up. 
E6 Safety and Adverse Events 
 
6.a 
Safety and Compliance Monitoring 
The DCC will monitor key aspects of protocol compliance, and reports will be developed and 
disseminated to monitor the ongoing progress of the study. Protocol safety and compliance reports 
will include enrollment of ineligible patients, follow-up data collection outside of protocol-defined 
windows, deviations from the protocol, and adherence to established adverse event reporting and 
event adjudication procedures. Reports will be provided to the CCC, the Steering Committee, and the 
DSMB on a systematic basis. 
6.b 
Medical Monitoring 
The DCC is responsible for tracking the Serious Adverse Events (SAEs) reported by clinical sites in 
the MINT trial. The DCC will track the time for each step of the process to ensure that turnaround 
times adhere to acceptable reporting practices specified by the FDA and NIH. The current reporting 
guidelines from NHLBI (https://www.nhlbi.nih.gov/research/funding/human-subjects/adverse-event) 
will be followed, and the timelines are included in Appendix 3. 
i 
Investigator Only 
The clinical site will submit a SAE form to the DCC for unexpected serious adverse events occurring 
within 30 days of randomization and for unexpected deaths occurring within 6 months of 

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randomization. The clinical sites are responsible for notifying their local Institutional Review Board. 
Expected SAEs will be reported on the standard MINT in-hospital and follow-up data collection forms. 
ii 
Independent Expert to Monitor 
The DCC will notify the MINT Medical Safety Officer of unexpected SAEs submitted by a clinical site 
and make the relevant information available to the officer. The Medical Safety Officer will determine 
a) the severity of the event, b) the unexpectedness, and c) the relatedness to the study protocol. In 
accordance with safety reporting regulations, all SAEs that are determined by the Medical Safety 
Officer to be both unexpected and possibly, probably or definitely related to the study protocol will be 
subject to expedited reporting to the Data and Safety Monitoring Board (DSMB), NIH, and any other 
oversight entities as appropriate. The NIH Project Officer and the DSMB chairperson will review 
these documents and may decide to convene the DSMB to discuss issues related to monitoring such 
events. 
iii 
Independent Data and Safety Monitoring Board 
An external Data and Safety Monitoring Board (DSMB) consisting of members appointed by the 
National Heart, Lung, and Blood Institute (NHLBI) will monitor the study, advise the NIH Program 
Office and provide input to the Steering Committee. The MINT DSMB will include experts in 
cardiology, transfusion medicine, biostatistics and ethics. The DSMB will review the study protocol 
and provide NHLBI with recommendations including whether the protocol and patient recruitment can 
be initiated. NHBLI will approve the study protocol based on the DSMB recommendations before 
patient recruitment is initiated. Throughout the course of the trial, the Data and Safety Monitoring 
Board (DSMB) will review recruitment, retention, data completeness, and protocol deviations on a 
semi-annual basis and will provide recommendations to NHLBI. 
Adverse events will be monitored in four distinct ways: 1) the DSMB will review all reported adverse 
events and monitor the incidence rates of adverse events on a semi-annual basis, 2) the expedited 
review of unexpected Serious Adverse Events (SAE) that are related to the MINT protocol and 
unanticipated problems (UP), 3) all study outcomes will be evaluated by assigned treatment group on 
semi-annual basis, and 4) a formal statistical interim monitoring of the efficacy of the primary outcome 
by assigned treatment group will be performed on an annual basis. If unexpected safety concerns 
arise from the trial data or from external research or literature, safety data will be examined on an ad 
hoc basis. The DCC will work with the NIH and with the DSMB to make certain that the board 

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members have sufficient information to comprehensively monitor patient safety throughout the MINT 
trial. The DSMB may advise early termination of the trial for safety reasons or make other 
recommendations regarding modifications to the protocol. 
In order to ensure that the MINT trial has adequate power to test its primary aims, the DSMB will 
review an interim sample size/power analysis after half of the patients complete the 30-day follow-up. 
Revised sample size estimates will be calculated based on the observed overall event rate (i.e. the 
two transfusion groups combined) and the proposed power and effect size. 
6.c 
Definitions of Adverse Events 
An adverse event is defined as an untoward or unfavorable medical occurrence in a human 
participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with a person’s participation in the research, whether or 
not considered related to a person’s participation in the research. A Serious Adverse Event (SAE) is 
defined as an adverse event that meets any of the following criteria: 
• 
results in death; 
• 
is life-threatening i.e. places a participant at immediate risk of death from the event as it 
occurred; 
• 
requires inpatient hospitalization or prolongation of existing hospitalization; 
• 
results in a persistent or significant disability/incapacity; 
• 
results in a congenital anomaly/birth defect; OR 
• 
any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
participant’s health and may require medical or surgical intervention to prevent one of the 
other outcomes listed in this definition. 
 
An Unanticipated Problem (UP) is defined as any incident, experience, or outcome that meets all of 
the following criteria: 
• 
Unexpected in terms of nature, severity, or frequency, taking protocol research procedures 
and participation population characteristics into consideration. 
• 
Related or possibly related to a person’s participation in the research. 
• 
Places participants or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. 

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6.d 
Classification of Events 
 
i 
Severity 
The severity of the adverse event refers to the intensity of an event and is categorized as 1) Mild; 
asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated, 2) 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental 
activities of daily living, 3) Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
living, 4) Life-threatening consequences; urgent intervention indicated, 5) Death related to AE. 
ii 
Relationship 
Relatedness refers to the extent to which an adverse event is considered to be related to the 
intervention or study procedures. An adverse event is considered related if there is a reasonable 
possibility that the event may have been caused by the procedure. Note that the term “suspected” is 
also means possibly, probably or definitely related to the intervention or study procedures. 
The following definitions apply to relatedness: 
1. Unrelated 
• 
Adverse event is clearly due to extraneous causes (e.g., underlying disease, environment) 
 
2. Unlikely (adverse event must meet 2 of the following): 
• 
Does not have temporal relationship to intervention 
• 
Could readily have been produced by the participant’s clinical state 
• 
Could have been due to environmental or other interventions 
• 
Does not follow known pattern of response to intervention 
• 
Does not reappear or worsen with reintroduction of intervention 
 
3.  Possible (adverse event must meet 2 of the following): 
• 
Has a reasonable temporal relationship to intervention 
• 
Could not readily have been produced by the participant’s clinical state 
• 
Could not readily have been due to environmental or other interventions 
• 
Follows a known pattern of response to intervention 

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4. Probable (adverse event must meet 3 of the following): 
• 
Has a reasonable temporal relationship to intervention 
• 
Could not readily have been produced by the participant’s clinical state or have been due to 
environmental or other interventions 
• 
Follows a known pattern of response to intervention 
• 
Disappears or decreases with reduction in dose or cessation of intervention 
 
5. Definite (adverse event must meet 4 of the following): 
• 
Has a reasonable temporal relationship to intervention 
• 
Could not readily have been produced by the participant’s clinical state or have been due to 
environmental or other interventions 
• 
Follows a known pattern of response to intervention 
• 
Disappears or decreases with reduction in dose or cessation of intervention and recurs with re- 
exposure 
 
iii 
Expectedness 
An unexpected event is one that has not been documented previously as an established adverse 
reaction to the study intervention and that is not recognized as part of the natural progression of the 
disease. A particular event may also be considered unexpected if it has a higher severity grade than 
what has been documented or identified previously. 
6.e 
Data Collection Procedures for Adverse Events and Unanticipated 
Problems 
The clinical site staff will report all serious adverse events and unanticipated problems on the trial data 
collection forms. These events include those related to red blood cell transfusion including those 
specified in the informed consent form and those that are related to recent myocardial infarction. All 
of the expected SAEs are recorded on the in-hospital and the 30-day follow-up data collection 
forms. Site personnel are required to report and document all unexpected SAEs and unanticipated 
problems to the DCC. The DCC will send all unexpected SAEs (as reported by the site) to the study 
Medical Monitor for final assessment of severity, relatedness, and expectedness. The Medical Monitor 
will remain masked to the transfusion strategy while making his/her evaluation of the SAE. 

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6.f 
Reporting Procedures 
All reported SAEs and unanticipated problems will be included in systematic reporting to the DSMB on 
a semi-annual basis. This includes adverse events and problems previously transmitted through 
expedited reporting. 
The following three classes of events need to be reported to the NHLBI, the DSMB and the Local IRB 
in an expedited manner: 1) Fatal or life threatening unexpected suspected SAE, 2) Non-fatal, non-life 
threatening unexpected suspected SAE, and 3) Unanticipated problem. Fatalities that are related to 
blood transfusions must also be reported to the FDA within 7 days according to the guidelines 
(http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/B 
lood/ucm074947.htm). 
The site personnel will compete and submit a SAE form to the DCC within 72 hours of learning of the 
event whenever the event is both serious and unexpected. In cases where the event is not serious 
but places the patient at greater risk of physical, psychological, economic, or social harm, and is both 
unexpected and related to the study, the site PI will fill out an Unanticipated Problem form within 14 
days of learning about the problem. SAE forms are forwarded along with relevant patient history data 
to the Medical Monitor for review. The study Medical Monitor will assess the severity, relatedness, and 
expectedness of the event within 48 hours. Following the Medical Monitor’s feedback on the 
expectedness and relatedness of the SAE, the DCC will complete an SAE report categorized as 
serious, unexpected and related. A report will also be sent for unanticipated problems. The DCC will 
send the reports to the NHLBI DSMB Executive Secretary and the NHLBI Medical Monitor for review. 
All reporting (from the time that the Site learns about the event until it is reported to the NHLBI, 
DSMB, FDA and IRBs) will follow the NHLBI DSMB established timelines as specified in 
(https://www.nhlbi.nih.gov/research/funding/human-subjects/adverse-event) as shown in Appendix 3. 
If other SAEs are noted to occur with abnormally high frequency during the trial, these will be reported 
promptly by the MINT DCC to the DSMB, and the NHLBI DSMB Executive Secretary and the NHLBI 
Medical Monitor. Upon receipt of an expedited report, the DSMB chair will decide whether the event 
should be discussed at the next scheduled DSMB meeting or discussed as soon as possible at an ad 
hoc meeting. 
IRB actions regarding the MINT trial will be communicated to the NHLBI Project Officer and NHLBI 
Executive Secretary in an expedited fashion. If the IRB or ethics board at any MINT site, CCC or 

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DCC takes action regarding the MINT trial (e.g., the IRB places a hold on the trial or suspends the 
trial), the site will report this to the CCC within 24 hours of the action. This will be communicated by 
telephone and with an urgent help desk ticket through the MINT trial data management system. The 
Site will submit written documentation from the IRB, an explanation of the circumstances, and a plan 
of action to the CCC within 72 hours. The CCC will promptly communicate this information to the 
DCC and the NHLBI project officer. The DCC is responsible for notifying and the NHLBI Executive 
Secretary. A written report describing the IRB decision, the rationale for the decision and the plan of 
action based on this decision will be submitted to the NHLBI project officer and the NHLBI Executive 
Secretary within 7 days of the IRB action. 
6.g 
Adverse Event Reporting Period 
All randomized patients will be followed by the trial for 30-days from randomization, and vital status 
will be ascertained at 6 months from study enrollment. Serious adverse events that occur during the 
30-day time period and all deaths up to 6 months will be reported. 
6.h 
Post-study Adverse Event 
MINT will not collect or report information about adverse events that occur more than 30-days after 
randomization with the exception of death which will be reported through 6 months after 
randomization. Reporting of Adverse events will cease at the conclusion of the MINT trial. 
E7 Study Outcome Measurements and Ascertainment 
 
7.a 
Definitions of Outcomes 
 
i 
Myocardial Reinfarction 
Myocardial reinfarction will be classified by the Clinical Events Committee using The Joint European 
Society of Cardiology/American College of Cardiology Committee definitions. (47) Patients with 
reinfarction will need to demonstrate a fall in the troponin value and then a subsequent rise of at least 
20% with additional evidence (new ECG changes, imaging evidence, clinical history) as in the MI 
definition to diagnose a new event. Myocardial reinfarction will be classified as ST-segment elevation 
or non-ST Segment elevation. 

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ii 
Death and Cause of Death 
For each death, the cause will be determined by the site personnel into one of three categories (47): 
cardiovascular death (e.g., congestive heart failure, dysrhythmia), noncardiovascular death (e.g., 
infection, cancer), or undetermined cause of death. Information about the specific cause of death will 
also be collected. 
iii 
Unscheduled Coronary Revascularization (unstaged) 
Ischemia driven, unscheduled coronary revascularization (coronary artery bypass surgery or PCI) 
within 30 days of randomization will be recorded by the sites. Prior to randomization, the site will 
record if a coronary revascularization is planned (staged). All coronary revascularization procedures 
will be recorded, but an elective planned staged procedure will not be included as an outcome. 
Information about the reason for the procedure will also be collected to ensure that the 
revascularization was done to treat ischemic heart disease. 
iv 
Readmission to Hospital, overall and for primary cardiac diagnosis 
All re-admissions to the hospital that had not been planned prior to randomization will be captured, 
and the primary diagnosis for each hospitalization will be classified as: ischemic cardiac diagnosis 
(e.g., myocardial infarction, unstable angina), non-ischemic cardiac diagnosis (e.g. heart failure) or 
non-cardiac. 
v 
Unstable Angina 
The MINT trial sites will use 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular 
Endpoint Events in Clinical Trials to define unstable angina. (47) To diagnose unstable angina 
requires that four criteria be met: 1) worsening ischemic discomfort, 2) unscheduled hospitalization, 
3) negative cardiac biomarker, 4) objective evidence of myocardial ischemia. 
 
vi 
Congestive Heart Failure 
Sites personnel will use 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular 
Endpoint Events in Clinical Trials to define congestive heart failure. (47) New or worsening symptoms 
of congestive heart failure on presentation (increasing dyspnea, paroxysmal nocturnal dyspnea, 
orthopnea), has objective evidence of new or worsening heart failure, and receives initiation or 
intensification of treatment specifically for heart failure. 

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vii 
TIA or Stroke 
The 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in 
Clinical Trials will be used to define stroke. (47) A transient ischemic attack (TIA) is defined as “a 
transient episode of focal neurological dysfunction caused by brain, spinal cord, or retinal ischemia, 
without acute infarction.” Stroke is defined on the basis of the presence of acute infarction as 
demonstrated by imaging or based on the persistence of symptoms more than 24 hours. 
viii 
Deep Venous Thrombosis or Pulmonary Embolism 
Deep vein thrombosis will be diagnosed if duplex ultrasound, magnetic resonance venogram (MRV), 
or venogram is definite or probable positive. Site investigators will record if location is proximal or 
distal. Pulmonary embolism will be diagnosed with a high probability ventilation perfusion lung scan, 
CT scan, or pulmonary angiogram. 
ix 
Bleeding 
Major bleeding will be defined as 1) fatal bleeding, and/or 2) symptomatic bleeding in a critical area or 
organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra- articular or pericardial, or 
intramuscular with compartment syndrome, and/or 3) bleeding causing a drop in hemoglobin 
concentration of 2 g/dL or greater (62) from the last hemoglobin concentration prior to randomization 
to the nadir hemoglobin concentration during hospitalization or up to 30 days post randomization. The 
drop in hemoglobin concentration will account for each unit of red blood cell transfusion transfused by 
subtracting 1 g/dL for each unit administered. 
x 
Infections 
 
x.1 Pneumonia 
Pneumonia will be diagnosed using CDC criteria (48) which includes radiographic abnormalities and 
combination of symptoms (i.e., cough), signs (i.e., fever, tachypnea, or laboratory abnormalities (i.e., 
white blood cell count, hypoxemia). 
x.2 Blood Stream Infection 
Blood stream infection will be defined using CDC criteria which includes a recognized pathogen 
cultured from 1 or more blood cultures and organism cultured from blood is not related to an infection 
at another site, at least 1 of the following signs or symptoms: fever, chills, or hypotension and signs 

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and symptoms and positive laboratory results are not related to an infection at another site and 
common skin contaminant is cultured from 2 or more blood cultures drawn on separate occasions. 
x.3 Urinary Tract Infection 
Urinary Tract Infection will be defined using CDC criteria (48) which include one of the following signs 
or symptoms: fever (>38.0°C) or localized pain or tenderness, and laboratory evidence for infection. 
xi 
Length of Stay and Intensive Care Unit Days 
The trial will collect the number of days post randomization that patient is in the hospital and in 
intensive care unit. 
xii 
Quality of Life 
The EuroQol questionnaire (EQ-5D), a standardized instrument that measures health related quality 
of life in 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression, will 
be used as a measure of patient perceived global health status 30 days after randomization. 
7.b 
Ascertainment 
Relevant data will be collected from the medical record during the index hospitalization. During the 
first 3 days following randomization (or hospital discharge if sooner) active surveillance is performed 
to ensure all occurrences of myocardial reinfarction are detected. It is required that the site obtains 
troponin levels (every 12 hours for 1 day, and then daily for the next 2 days) and electrocardiograms 
(daily for the first 3 days). These results, in combination with any additional cardiac biomarkers for 
necrosis and electrocardiograms and medical findings, will be reviewed by the Clinical Events 
Committee for each randomized patient, irrespective of a site identified event. We will therefore be 
able to identify myocardial reinfarction events that were not clinically recognized, in addition to those 
had been. 
Study staff will contact the patient at 30 days to ascertain vital status, administer the quality of life 
questionnaire, and determine if there has been a subsequent hospital admission. Study staff will 
obtain and review the medical records for each readmission and record all relevant data and identify 
the study outcomes. If there is a suspect cardiac event the staff will submit de-identified copies of the 
documentation (from either the index admission or the readmission) for the Clinical Events Committee 

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F Statistical Plan 
 
adjudication. Study staff will perform a final follow-up contact at 6 months following randomization to 
ascertain the patient’s vital status. 
 
 
 
E8 Baseline and Intervention Clinical Characteristics 
Baseline demographic (e.g., age, gender, race), co-morbidity (e.g. cardiovascular risk factors), 
characteristics of cardiac disease (e.g., left ventricular function, number of coronary vessels 
obstructed), renal disease, and medications (e.g., aspirin, P2Y12 receptor inhibitor, anticoagulant, 
beta-blocker statins) will be collected to reflect patient status at the time of randomization. 
Characteristics describing the study intervention including red blood cell transfusion information (e.g. 
expiration date, leukoreduction, storage solution, ABO) will be recorded. In hospital, hemoglobin 
levels and the number and timing of transfusions will be recorded for the two assigned transfusion 
strategies. 
 
 
 
F1 
Sample Size Determination and Power 
In the MINT pilot trial, the composite 30-day rate of death and myocardial infarction was 16.4%. 
Higher rates were observed in the Kaiser System preliminary data. Thirty-day rates of 16.4%, 18%, or 
20% are reasonable for this trial since the proposed study population will not exclude the sickest 
patients as was done in the MINT pilot study. Using a two-sided inequality test and a simple chi- 
square statistic with alpha=0.05, we determined the samples sizes required to provide 80% and 90% 
power to detect varying relative reductions in the 30-day event rates for death and myocardial 
infarction between the two assigned treatment groups. Based on these estimates, we plan to enroll a 
sample of 3500 patients. If the rate of missing outcome data is no more than 5%, the trial would have 
3324 patients with analyzable outcome data at 30-days. Assuming an overall event rate of 16.4%, the 
trial will have 80% power to detect a 20% relative reduction (i.e. 18.2% vs. 14.6%) and >90% power to 
detect a 25% relative reduction. If the overall event rate is 18%, then the trial will have >80% power to 
detect a 20% relative reduction (i.e. 20% vs. 16%), and if the overall event rate is 20%, the trial will 
have close to 90% power to detect 20% relative reduction (i.e. 22.2% vs. 17.8%). We also performed 

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a simulation study to compute the power for a log binomial model with a random intercept for site and 
a final alpha-level=0.045 to account for the interim monitoring. We simulated 1000 trials where each 
trial had 60 strata representing the sites, 56 participants within each stratum (i.e. N=3360 patients in 
total), and a mean intra-class correlation (ICC) of 0.05 to 0.08. The simulations indicate that the 
power is comparable for the proposed log binomial model and the simple chi-square statistic used for 
the original sample size calculations. Based on the simulations, the trial will have 81% power to 
detect a 20% relative reduction from 18.2% to 14.6%, and 90% power to detect a 25% relative 
reduction from 18.2% to 14.0%. In addition, the trial will have 85% power to detect a 20% relative 
reduction from 20% to 16%, and 89% power to detect a 20% relative reduction from 22.2% to 17.8%. 
This pragmatic randomized clinical trial has excellent power to detect clinically meaningful differences 
between the two transfusion strategies with respect to the critical 30-day composite outcome of death 
and myocardial infarction on both the absolute and the relative scales. After half of the patients have 
been enrolled and followed, we will monitor the overall event rate in the trial to ensure that the trial has 
adequate power to detect clinically relevant treatment effects. 
F2 
Interim Monitoring and Early Stopping 
The DSMB will review interim analyses of the outcomes by assigned treatment group annually. The 
interim monitoring is designed to test for evidence of beneficial effect with either treatment strategy 
while maintaining the overall type I error at the pre-specified level. Stopping rules are based on the 
information (i.e. number of primary outcome events) that has accumulated by each inspection time 
and the shape of the predetermined alpha-spending function. We recommend that the Lan-DeMets 
approach be used to allocate the type 1 error (i.e. alpha-level) at each interim time point and use of 
O’Brien Fleming monitoring boundaries. The DSMB may advise early termination of the trial for safety 
reasons or make other recommendations regarding modifications to the protocol. 
The MINT trial will have 4 years of recruitment with a goal of enrolling N=3500 patients by June 2021. 
With this timeline, we propose that formal statistical interim monitoring will occur in August or 
September of 2018, 2019, and 2020 based on N=298 patients enrolled through June 1, 2018, N=872 
patients enrolled through June 1, 2019, and N=1905 patients enrolled through June 1, 2020, 
respectively. All calculations assume an overall trial alpha of 0.05. 
With an alpha-spending method, the alpha level to be used at any given look is based upon the 
amount of information available at the monitoring time. Once alpha is calculated, boundaries for the 

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standardized Z-test statistic are constructed. A standardized Z-test statistic is calculated based on the 
estimated relative risk from the log-binomial model which includes assigned transfusion strategy 
(according to the intention to treat principle) as the independent variable. If the observed Z-test 
statistic crosses the boundary the difference is considered statistically significant at that monitoring 
time. The “α spending function approach” allows the number and frequency of monitoring times to be 
changed at any point during the trial. 
Based on the anticipated accrual shown in Appendix 4, below is the table of the expected percent of 
information, estimated number of participants, the Z-test statistic boundary level and the 
corresponding alpha spent based on the O’Brien-Fleming boundaries. 
Estimated Boundary Values at Each Interim Monitoring Time Point 
 
O’Brien Fleming 
Stage 
Information Level 
Boundary Values 
Proportion 
Number 
Recruited 
Bound 
Alpha 
Spent 
1 
0.0900 
298 
. 
. 
2 
0.2500 
872 
±4.33 
<0.001 
3 
0.5400 
1905 
±2.84 
0.005 
4 
1.0000 
3500 
±1.97 
0.045 
 
 
The O’Brien and Fleming (1979) repeated significance tests combined with the Lan and DeMets 
(1983) flexible alpha-spending curves are proposed due to their common usage and their 
conservative nature when the amount of accumulated data in the trial is small. They are designed to 
stop earlier in the trial if there is overwhelming evidence that there is a difference between the two 
treatment groups. The ability to detect a difference between the groups becomes easier as the 
amount of information in the trial increases. 
The form of the O’Brien-Fleming alpha –spending function is: 
𝜶(𝒌) = 𝟐 − 𝟐𝝓 (𝒁𝜶⁄𝟐) 
√𝒊𝒌 
where: 
α(k) = cumulative alpha at inspection k 
k = inspection number 
ϕ(x) = the cumulative distribution function of the standard normal curve evaluated at x. 

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Zα = the value of the standard normal curve where α is the area in the tail 
ik = the amount of information accumulated in the trial at inspection k 
 
 
We assume a symmetric 2-sided boundary, with each side spending α=0.025. Below are plots of the 
cumulative O’Brien-Fleming alpha-spending curve and the corresponding boundary plot. We assume 
a symmetric 2-sided boundary, with each side spending α=0.025. 
 
 

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It is possible that the test statistic will cross the monitoring boundary. Statistical interim monitoring 
results should be taken as one component to the decision as to whether or not to stop a trial. To stop 
the trial for efficacy, results should be definitive enough to be able to change clinical practice. The 
DSMB will use the monitoring information to determine its recommendation to NHLBI. The DSMB can 
recommend that the MINT trial should continue as proposed, that the MINT protocol should be 
modified based on the results seen in one treatment comparison or in some well-defined subgroup of 
patients, or that the MINT trial should be terminated early. The final decision to stop trial rests with the 
NHLBI. If recommendation is to stop the trial, the MINT trial principal investigators shall be consulted 
before a final decision is made. 
In order to ensure that the MINT trial has adequate power, an interim analysis to assess sample size 
will be conducted after when half of the participants are projected to have completed the 30-day 
follow-up. Revised sample size estimates will be calculated based on the original power and effect 
size estimates from the trial hypothesis (80% power to detect a RR=0.80) and on the observed overall 
event rate (i.e. the two transfusion groups combined). The DSMB will evaluate whether the trial 
sample size needs to be increased in order to restore power to maintain the ability to detect a 
clinically meaningful effect size. 

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Since the MINT trial compares two established transfusion strategies with different resource and cost 
implications, a null result from a well-powered trial would be important for establishing treatment 
guidelines and policy. Thus, no interim futility analyses will be conducted in the MINT trial. 
F3 
Analysis Plan 
A Screening Log will be developed to include the number of patients with acute myocardial infarction 
and hemoglobin level < 10 g/dL, eligibility and enrollment status. Proportions of eligible and enrolled 
patients will be presented, and reasons why patients are not eligible or enrolled in the trial will be 
tabulated. Enrollment patterns will be compared across clinical sites and patient groups defined by 
sex and race/ethnicity. The baseline characteristics and co-interventions of the patients who are 
randomized in the MINT trial will be described, and characteristics of patients in the two assigned 
treatment groups will be compared. The proportion of enrolled patients who adhere to the assigned 
intervention will be ascertained by evaluating the hemoglobin levels and the number of units of blood 
transfused during the index hospitalization. The intention-to-treat principle will be used to compare the 
primary outcome (the composite of all-cause mortality and myocardial infarction by 30 days from 
randomization) and each pre-specified secondary outcome by the randomized transfusion strategy 
groups. A select number of subgroup analyses will be performed based on baseline factors identified 
prior to the initiation of the trial. 
F4 
Statistical Methods 
 
4.a 
Baseline Characteristics of the Enrolled Patient Sample 
Descriptive statistics will be examined for all relevant baseline measures collected on the MINT 
randomized patients. Transformations of measures will be considered on the basis of distribution 
diagnostics and outlier analysis. The baseline characteristics and co-interventions of the patients in 
the overall study will be described using frequencies, proportions, means and standard deviations, or 
medians and first and third quartiles. Characteristics of patients in the two arms of the trial will be 
compared using chi-square statistics for categorical variables and t-tests or Wilcoxon rank-sum 
statistics for continuous variables. 

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4.b 
Adherence to Assigned Intervention 
The mean hemoglobin concentration at 1, 2, and 3 days post-randomization will be compared 
between the assigned treatment groups with a Student’s t-test. Mixed random effect models will be 
used to describe the daily mean hemoglobin concentrations during the initial hospitalization following 
randomization and to compare these repeated measures by assigned treatment group. The mean 
number of red blood cell transfusions in each randomized treatment group will be described, and a 
simple Poisson test will be used to test whether the number of units of blood differs significantly by 
assigned transfusion strategy. 
4.c 
Primary Outcome Analysis 
The intention-to-treat principle will be used for all randomized transfusion strategy comparisons of 
study outcomes. A two-sided test will be used with an alpha-level=0.05 for the primary outcome, the 
composite of all-cause mortality and myocardial infarction (death/MI) by 30 days from randomization. 
The 30-day event rate for the primary outcome will be compared by assigned transfusion strategy 
using an unadjusted log-binomial regression model with a fixed effect variable for assigned treatment 
strategy and a random effect for clinical site. The primary analysis will involve the estimated relative 
risk and significance level obtained from the model accounting for interim monitoring and missing 
data. Event rates, the relative risk and the absolute difference will be from the observed data will also 
be presented, and 95% confidence intervals will be calculated. 
If significant imbalances in baseline risk factors are detected between the two randomized treatment 
groups (p<0.05), multivariable log-binomial regression will be used to adjust for potential confounding 
factors as a sensitivity analysis. If adherence to the protocol is lower than expected, a per protocol 
analysis, including only patients who undergo transfusion according to their assignment and adjusting 
for baseline factors that are associated with adherence to the treatment protocol, will be conducted as 
a sensitivity analysis. 
4.d 
Analysis of Secondary and Tertiary Outcomes 
Event rates, the relative risk and the absolute difference between transfusions strategy groups for the 
dichotomous secondary and tertiary outcomes will be calculated with their 95% confidence intervals 
using log-binomial regression methods accounting for clinical site with random effects. The length of 
hospital stay from randomization and from admission will be analyzed using non-parametric Wilcoxon 

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rank sum tests, and long-term mortality will be analyzed with Kaplan-Meier methods and the log rank 
statistic. The Kaplan-Meier estimated mortality rate in each treatment group at 180 days, the absolute 
difference between the assigned treatment groups at 180 days, and the 95% confidence interval for 
the difference will be presented. Transfusion strategy comparisons of the EQ-5D quality life 
measures at 30 days will be based on t-tests or the Wilcoxon rank sum test. No adjustment of the 
alpha level will be made for the secondary and tertiary analyses. Rather the results will be interpreted 
based upon the observed findings, their designation as secondary or tertiary outcomes, and in 
comparison to the primary outcome result. 
The secondary outcomes include: 1) all-cause mortality within 30 days; 2) myocardial reinfarction 
within 30 days; and 3) the composite outcome of all-cause mortality, nonfatal myocardial reinfarction, 
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 tertiary outcomes include: 1) all-cause mortality, nonfatal myocardial reinfarction, and unstable 
angina (i.e. acute coronary syndrome) 2) ischemia driven unscheduled coronary revascularization 
within 30-days; 3) readmission to the hospital for ischemic cardiac diagnosis, 4) congestive heart 
failure within 30 days; 5) unscheduled readmission to hospital for any reason within 30 days; 6) each 
of the individual cardiovascular outcomes of stroke, pulmonary embolism or deep venous thrombosis, 
and bleeding within 30 days; 7) each of the individual infectious outcomes of pneumonia, blood 
stream, and urinary tract within 30 days; 8) each of the individual in-hospital outcomes of length of 
hospital stay post randomization and number of days in intensive care unit; 9) patient reported quality 
of life measures based on the EuroQol questionnaire (EQ-5D) at 30 days; and 10) all-cause mortality 
at 6-months. 
4.e 
Missing Outcome Data 
For the analysis of the primary outcome, standard multiple imputation methods will be used to impute 
missing 30-day data. We expect that missing 30-day outcome data will be very low in this trial. All 
patients should have non-missing death and MI data from randomization to hospital 
discharge. Markov Chain Monte Carlo (MCMC) multiple imputation methods will be used to impute 
the missing 30-day outcome values (yes/no) for death and MI. Specifically, a log-binomial regression 
model to estimate the relationship between the outcome and key covariates (observed baseline and 

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in-hospital variables that are clinically relevant and related to the “missingness” of the 30-day 
outcomes) in the participants with full data. This model will be used to predict the probability of the 
outcome for participants who are missing the 30 day outcomes. Based on these probabilities, ten 
imputed data sets will be created. A log-binomial model with random effects for site will be estimated 
for each imputed data set, and the results will be pooled to obtain a single estimate of treatment effect 
with an appropriately adjusted standard error. As a sensitivity analysis, a log-binomial model with 
random effects for site will be created based on the non-missing 30-day death/MI data. Missing data 
will not be imputed for the analyses of the secondary and tertiary hypotheses unless critical issues are 
noted while investigating the missing 30-day data. 
4.f 
Subgroup Analyses 
Subgroup analyses will be performed based on baseline factors identified prior to the initiation of the 
trial. Clinically relevant subgroup variables include: ST segment elevation MI / non ST segment 
elevation MI, Universal Definition type 1 MI / type 2 MI, type 4b and 4c, baseline hemoglobin level (<8, 
8-9, 9-10 g/dL), revascularization for treatment of index MI, bleeding, sex, race/ethnicity (White, Black, 
Other Race and Hispanic, non-Hispanic), age (<70, ≥70 years old), left ventricular dysfunction, 
diabetes status, and creatinine clearance (eGFR <30, 30-59, ≥60). The 30-day event rates by 
assigned transfusion strategy will be compared within each pre-defined subgroup. The reported 
significance-level will account for the number of treatment comparisons conducted in the study using 
the false discovery rate (FDR) algorithm developed by Benjamini and Hochberg. In addition, for each 
subgroup variable, a log-binomial regression model including treatment assignment, subgroup 
variable and the interaction between the subgroup variable and treatment assignment will be created, 
and the significance of the interaction term will be used to test whether the randomized treatment 
effect is significantly modified by the designated subgroup variable. Cox proportional hazards 
regression models will be created with similar covariates in order to test whether the effect of the 
randomized transfusion strategy for 6-month mortality varies significantly according to the pre- 
specified subgroup variables. 
4.g 
Combining Vanguard and Main Trial Data 
In 2016, the Canadian Institutes of Health Research (CIHR) funded a MINT Pilot trial. This pilot is 
coordinated by the University of Montreal, and the clinical sites are in Canada. The DCC and CCC 
have collaborated with the University of Montreal to ensure that the protocol (eligibility criteria, 

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G Data Handling and Record Keeping 
 
interventions, and outcomes) as well as the randomization scheme and the data to be collected are 
nearly identical to those for the main MINT trial. The CIHR MINT pilot trial was funded to enroll 60 
patients. This pilot trial will serve as a “Vanguard phase” for the MINT trial and will allow us to 
evaluate the feasibility of the MINT protocol. After the MINT protocol is approved by the 
DSMB/NHLBI and the appropriate ethics committees in Canada, patients randomized at the Canadian 
Sites will be enrolled as MINT participants. All data collection and data coordination for the MINT 
participants will occur through the University of Pittsburgh DCC. Patients who are randomized prior to 
the transition date will remain CIHR pilot trial participants throughout their follow-up. The complete 
Vanguard datasets housed at the University of Montreal will be transferred to the University of 
Pittsburgh DCC. The Vanguard patient data will be merged with the MINT trial data based on 
rigorous comparisons of variable definitions and variable coding. All Vanguard patients will be 
included in the target sample size and presented in DSMB and published data reports for the MINT 
trial. 
 
 
 
F5 
Unblinding Procedures 
Patients and providers are not blinded in the MINT trial, and thus unblinding procedures are not 
required for patient safety. Trial monitors and adjudicators are blinded to transfusion strategy, and the 
DSMB may choose to be blinded to transfusion strategy as they monitor the outcome data. The 
Medical Monitor and DSMB can request to be unblinded if they deem this necessary. 
 
 
 
G1 Confidentiality and Security 
Patient identifiers (e.g. name and social security number) will not be sent to the trial DCC, however, 
some personal health information (e.g. birth date and hospitalization admission date) will be collected 
centrally. The University of Pittsburgh DCC has a strictly enforced security policy with standard 
operating procedures addressing key security risk areas. Procedures include password protection, 
limited access to study computers, encryption, IP restriction, basic or digest authentication, and 
firewalls between the Internet and the DCC network and servers. Regularly scheduled backups and 

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archives are performed at least once daily with backup media copies of project files stored off-site in a 
secure location. Virus detection will be enforced at the DCC. All servers will be connected to 
uninterruptible power supplies and housed in a computer room with an alarm. 
Patient contact information will be maintained exclusively by the local site and stored in a secure 
location. Only local study staff responsible for the 30 day and 6 month telephone calls will have 
access to this contact information. 
G2 Training 
DCC personnel at the University of Pittsburgh will work with CCC personnel at Rutgers / Robert Wood 
Johnson to provide the training necessary for uniform data collection, protocol compliance, and data 
processing. Major elements to be covered are inclusion and exclusion criteria, procedures and tools 
to monitor adherence to protocol, randomization procedures, event adjudication procedures, adverse 
event reporting, methods for extracting data from different sources, follow-up schedules, what to do 
about missing information, reporting requirements, and use of the Manual of Operations and study 
website. Instruction will be provided for entering the data, transmitting them to the DCC, interpreting 
edit reports and correcting data. 
On-going training will be required due to the addition of new clinical sites as well as turnover of staff at 
the existing clinical sites. The CCC and DCC will utilize webinars and conference calls to conduct 
detailed distance training sessions. On-line protocol and data collection training modules will be 
available on the trial website, and focused training sessions will be conducted in conjunction with 
Steering Committee meetings as required. Throughout the trial, there will be regularly scheduled 
conference calls with the coordinators and data collectors at all sites to discuss issues that arise with 
protocol and data collection. 
G3 Case Report Forms and Source Documents 
The data collection forms for this trial have been developed to facilitate enrollment and follow-up while 
still collecting the essential information needed to answer the trial hypotheses. A web-based 
distributed data management system will be used for data entry. Source documents will be 
maintained at the clinical site. 

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H Study Monitoring, Auditing, and Inspecting 
 
G4 Records Retention 
Trial patient records will be retained at the clinical sites and at the Coordinating Centers for 6 years 
after MINT data collection is completed. 
G5 Performance Monitoring 
The DCC will monitor study performance. Routine reports will be developed to monitor the ongoing 
progress of the study including enrollment and retention. Protocol adherence reports include 
enrollment of ineligible patients, follow-up data collection outside of protocol-defined windows, and 
deviations from protocol. The timeliness of data collection and data entry is routinely monitored at the 
DCC using information entered into the data system (evaluation date and data collection date), and 
information stored in the systems inventory files (dates of entry, verification, and submission). The 
DCC will provide reports to the MINT CCC and clinical site coordinators including scheduling and 
delinquency. Inadequate performance of a site will be reported to the CCC and the site. The DCC 
and CCC will work with the site to find solutions to challenges. The DCC and CCC will evaluate the 
performance at that site to determine whether corrections have been made. Should problems persist, 
the Operations Committee will be notified along with recommendations for resolving persisting 
inadequacies. Trial and site performance reports will be provided to the sites, the CCC, the Steering 
Committee, and the DSMB. 
 
H1 Study Monitoring Plan 
The CCC will coordinate the study monitoring site visits to each clinical site. In addition, the DCC will 
conduct data monitoring site visits to clinical sites where specific data issues are identified or data 
concerns arise based on a risk-based monitoring plan. The risk-based monitoring plan will be based 
on site performance metrics as well as the results of CCC safety and compliance monitoring visit. 
H2 Auditing and Inspecting 
During monitoring site visits, CCC personnel will review source documents, including informed 
consent documents, for a random sample of patients and for a defined subset with an exceptional 
number of inconsistencies identified through the data monitoring processes to confirm that data are 

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I 
Study Administration 
 
collected and entered accurately. Problems adhering to study protocols, data collection, entry, and 
management will be identified and corrective procedures will be addressed. 
 
I1 
Organization and Participating Centers 
 
1.a 
Clinical Coordinating Center 
The Rutgers Robert Wood Johnson School of Medicine, Division of General Internal Medicine is 
responsible for clinical coordination of the trial. The responsibilities of the Clinical Coordinating Center 
are to: 1) Provide administrative and fiscal support for the Clinical Sites; 2) Provide technical, patient 
assessment and Protocol adherence advice to Clinical Site staff; 3) Assist Clinical Sites to correct 
problems with recruitment, Protocol adherence and data collection; 4) Participate in site visits; 5) 
Provide advice about any aspect of the trial; and 6) Lead presentation and publication of study results 
for the scientific and lay press. 
A Canadian subsidiary clinical coordinating center to Rutgers Robert Wood Johnson Medical School 
will be housed at the University of Montreal. The Canadian Coordinating Center will carry out the 
clinical coordinating center responsibilities listed above for the Canadian sites and will be supervised 
by Dr. Paul Hebert and Dr. Jeffrey Carson. The Canadian Coordinating Center will have no data 
coordinating function. 
1.b 
Data Coordinating Center 
The Epidemiology Data Center at the University of Pittsburgh is responsible for the data coordination 
of the trial. The DCC will provide statistical leadership and resources for data management, quality 
control, and analysis. The responsibilities of the DCC include: 1) Maintain study website and provide 
all study materials, including the Manual of Procedures (MOP) and Data Collection Forms ; 2) Provide 
a 24 hour randomization service; 3) Establish and maintain an electronic database to receive study 
data and to verify for completeness, retrieving any missing data from the centers; 4) Conduct routine 
data edits; 5) Monitor performance to detect problems with recruitment, protocol adherence and data 
collection; 6) Participate in site visits; 7) Provide advice about any aspect of the trial; 8) Perform 
interim and final analyses. 

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1.c 
Clinical Consortium 
The clinical sites recruiting patients into MINT comprise the Clinical Consortium of participating 
hospitals. Each site will be led by the Clinical Site Director and Clinical Site Coordinator. The Clinical 
Site Director and Coordinator will work closely together to assure successful performance of the trial. 
The responsibilities of the Clinical Site Director include: 1) To insure that all medical staff involved with 
the care of myocardial infarction patients are well informed about the trial; 2) To insure that all patients 
with myocardial infarction are routinely considered for the trial; 3) To insure that the transfusion 
strategy is followed, i.e., blood is given in the Restrictive Transfusion Strategy only for symptoms from 
anemia or when the lower threshold is reached and blood is given in the Liberal Transfusion Strategy 
when Hgb < 10 g/dL; 4) To communicate with Clinical Coordinating Center staff and Data 
Coordinating Center staff any problems or concerns related to the study; and 5) To assist the Clinical 
Site Coordinator as necessary. 
The responsibilities of the Clinical Site Coordinator include: 1) To identify myocardial infarction 
patients for the trial; 2) To obtain informed consent from the patient or surrogate; 3) To inform treating 
staff of the patient’s treatment assignment assigned transfusion strategy; 4) To complete data 
collection forms and process data edit queries; 5) To perform 30 and 180 day telephone follow-up; 6) 
To obtain and submit all relevant source documents for the Clinical Event Committee adjudication; 7) 
To participate in telephone calls with the Clinical Coordinating Center; 8) To train assistant site 
coordination and other staff at the Clinical Site. 
I2 
Funding Source and Conflicts of Interest 
This trial is supported by the National Heart Lung and Blood Institute. All investigators will be required 
to declare any potential conflicts of interest. 
I3 
Committees 
 
3.a 
Steering Committee 
The primary decision making body of the MINT trial will be the Steering Committee and will include 
the Principal Investigators of the CCC and DCC, experts in cardiology, transfusion medicine, 
biostatistics, and the NHLBI project officers. The Steering Committee will have quarterly conference 

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calls and annual in-person meetings. The group will focus on the science of the study and to review 
priorities on a regular basis. 
3.b 
Operations Committee 
A smaller committee, the Operations Committee, will be a subset of the Steering Committee that will 
meet approximately twice per month via conference call and will be charged with reviewing 
operational and scientific issues for the trial and formulating recommendations for consideration by 
the full Steering Committee. The Operations Committee will be chaired by Dr. Carson and will include 
DCC PI, selected Steering Committee members, and the CCC and DCC project directors. 
The Operations Committee will be empowered to execute operational decisions, and the Operations 
Committee Chair will have the authority to set meeting agendas and appoint committee chairs as 
needed. The committee will ensure that recruitment for the network is progressing as planned for the 
clinical trial. In addition to reviewing monthly recruitment reports and quarterly follow-up data 
collection reports, the group will make specific recommendations for strategies to improve recruitment 
and protocol implementation. 
3.c 
Executive Committee 
A small Executive Committee will identify high level study design and implementation issues that are 
to be discussed by the Steering Committee and to resolve issues that require immediate action. The 
committee will include the PIs of the CCC and the DCC and the lead clinical investigator from the 
United States and from Canada. 
3.d 
Clinical Events Committee 
A Clinical Events Committee will be responsible for adjudication of myocardial infarctions. Committee 
members will be masked to transfusion strategy assignment when they review and adjudicate patient 
event packets. 
I4 
Subject Stipends or Payments 
Study patients will not receive any stipends or payments 

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I5 
Study Timetable 
This study will require 5 years for completion. The timeline and benchmarks are as follows: 
 
Benchmarks 
Timeline 
Planning and Organization Phase 1: Finalize the Manual of Operations and 
data collection instruments. Communicate with the Clinical Site Directors at 
each study site. Obtain IRB approval at clinical sites with assistance from CCC 
staff. Develop computer software for randomization and data entry. 
Months 1-4 
(9/1/16 – 
12/31/16) 
Planning and Organization Phase 2: Communicate final study protocol and 
procedures. Plan and schedule training. Hold annual Collaborators’ Meeting 
for Clinical Site Directors and Coordinators. Distribute final forms. 
Months 5-6 
(1/1/17 – 
2/28/17) 
Recruitment and Follow-up Phase: Initiate patient enrollment at the clinical 
sites. Recruitment will start once a site has IRB approval, an executed contract, 
and staff have been trained. Continue for 4.0 years, until patient recruitment is 
completed, or the study is stopped early. Hold annual Collaborators' Meetings. 
Month 7- Year 
4. 5. 
(3/1/17– 
2/28/21) 
Close-out and Analysis Phase: Complete follow-up and data cleaning. Perform 
data analysis. Discuss results at Collaborators’ Meeting. Present trial results. 
Year 4. 5 
(3/1/21 – 
8/31/21) 
 
 
The planned accrual timeline, including the target and the cumulative target enrollment for each 
quarter, is provided in Appendix 4. 

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The Publications Committee will include physicians, scientists, and statisticians involved with the 
MINT trial. The chair of the committee will rotate bi-annually. This committee will be charged with 
coordinating the publication of study results and ensuring that these publications move forward 
according to schedule. Our plan is that the primary results of the trial will be submitted for publication 
within 9 months of the completion the trial. This will allow three months for data management and 
cleaning, three months for analysis and three months for manuscript preparation. 
Dr. Carson will coordinate the effort for the primary results paper and the author byline will include the 
writing team “and the MINT Trial Investigators”. The primary results writing team will be comprised of 
the members of the Steering Committee. An appendix listing all of the MINT investigators including 
the Steering Committee members, the Site Investigators, the NIH program officers, the DSMB and 
other relevant contributors to the trial will appear at the end of the paper. 
There will be additional papers that evaluate secondary hypotheses. The Publications Committee will 
review proposals for all non-primary papers. Approval of a paper proposal will require that the topic is 
clinically relevant, the paper does not overlap with an existing topic, and the general methodology is 
sound. Secondary papers will have individually named authors and will include “for the MINT Trial 
Investigators” in the author byline. The investigators who propose the concept will automatically be 
part of the writing team. Investigators from the Steering Committee and the Sites will have the 
opportunity to sign up for proposed writing teams. If more than 12 investigators sign up for an 
individual writing group, the Publications Committee will allocate investigators to writing teams based 
on contributions to the trial and expertise on the specific topic. 
In order to ensure that the trial is using its resources to report the topics of greatest clinical relevance, 
the trial Investigators will be asked for ideas for papers and the Steering Committee will be asked to 
identify the ten most important papers. If a paper on this list is not moving forward according to 
schedule, the Publication Committee will notify the Steering Committee and may recommend a 
change in leadership for the paper. The Steering Committee will make final decisions about the 
leadership for papers. 
J Publication Plan 

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L Appendices 

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L1 Appendix 1: Standardized approach and script to be used to 
seek permission from attending physician to recruit a patient 
 
 
For each patient who is potentially eligible for the trial, the MINT site investigator or coordinator 
will contact the patient’s attending physician, with expertise in cardiovascular care, and use the 
following script: 
“Dr. <name> I am calling to seek your permission to approach your patient <name> for 
consent to participate in the MINT trial. This is an NIH-sponsored trial that enrolls 
patients with an acute myocardial infarction and a hemoglobin level <10. According to 
the protocol, those assigned to the Liberal Arm receive red blood cell transfusions to 
maintain a hemoglobin level ≥ 10. Those assigned to the Restrictive Arm will be 
permitted to receive a transfusion if the hemoglobin concentration falls below 8 g/dL and 
will be strongly recommended to receive transfusion if the hemoglobin concentration is 
below 7 g/dL and you determine that a transfusion is in the patient’s best 
interest. Transfusion is always permitted for active bleeding or if there are angina 
symptoms that you believe are related to the anemia and are not adequately controlled 
with medications. Patients can be withdrawn from the transfusion protocol if clinical 
circumstance change and adherence to the protocol places the patient at risk.” 
“We want to confirm that <name> is an appropriate candidate for the trial; and that in 
your clinical judgement both approaches to transfusion are consistent with good medical 
care for this patient.” 
The first paragraph of the script will be used the initial time the trial team contacts the physician 
but could be skipped if the physician is already familiar with the protocol. The second 
paragraph will be stated when contacting an attending physician for any potential patient 
whether or not the physician has been contacted by the MINT team in the past. Patients will 
only be approached for consent if their physician confirms his/her belief that either transfusion 
strategy is appropriate, per the second paragraph. 
 
 
 
 
 

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L2 Appendix 2: MINT Data Elements by Study Time Point 
 
Screening 
Baseline 
Randomization 
12 hours Post 
Randomization 
Day 1 
Day 2 
Day 3 
Daily Up to 
30 Days 
Hospital 
Discharge/ 
30 Days 
30 Day 
Follow-up 
6 Month 
Follow-up 
Confirm Eligibility 
X 
Informed Consent 
X 
Hemoglobin Levela 
Xb,c 
Xb 
Xb 
Xb 
X 
Troponin Levela 
Xb,c 
Xb 
Xb 
Xb 
Xb 
X 
ECGa 
Xb,c 
Xb 
Xb 
Xb 
X 
Demographics 
X 
Medical History 
X 
Medications 
X 
Implement Transfusion Strategy 
X ----------------------------------------------------------------------------------------------- X 
RBC Transfusionsd 
X ----------------------------------------------------------------------------------------------- X 
Study Outcomes 
X 
X 
Xe 
Quality of Life (EQ-5D) 
X 
Vital Status 
X 
X 
X 
Assessment of AEs and UPs 
Safety Monitoring 
X ------------------------------------------------------------------------------------------------------------------------------------------------- X 
a in addition to required time points, all performed for clinical reasons are collected 
b required, if still in hospital 
c within the 24 hours prior to randomization 
d including unit information (e.g, leukoreduction) 
d mortality outcome only 
 
 

 
L3 Appendix 3: SAE and UP Event Reporting Timelines 
 
What Event is Reported 
When is Event Reported 
By Whom is 
Event Reported 
To Whom is Event 
Reported 
Fatal or life-threatening 
unexpected, suspected serious 
adverse reactions 
Within 7 calendar days of initial 
receipt of information 
Investigator 
Local/internal IRBs 
NHLBI and/or Data 
Coordinating Center (DCC) 
Sponsor or 
designee1 
FDA (if IND study) 
Non-fatal, non-life-threatening 
unexpected, suspected serious 
adverse reactions 
Within 15 calendar days of initial 
receipt of information 
Investigator 
Local/internal 
IRBs/Institutional Officials 
NHLBI and/or DCC 
Sponsor or 
designee 
FDA (IND/Marketed 
Products) 
All participating 
investigators 
Unanticipated adverse device 
effects 
Within 10 working days of 
investigator first learning of effect 
Investigator 
Local/internal IRBs 
NHLBI and/or DCC 
Sponsor or 
designee 
FDA (if IDE study) 
Unanticipated Problem that is not 
an SAE 
Within 14 days of the investigator 
becoming aware of the problem 
Investigator 
Local/internal 
IRBs/Institutional Officials, 
NHLBI and/or DCC 
All Unanticipated Problems2 
Within 30 days of the IRB’s 
receipt of the report of the UP 
from the investigator. 
IRB 
OHRP 
Investigator3 
External IRBs 
 
1. Designee is appointed by the sponsor; for example, DCC, CRO. 
2. Per OHRP guidance: only when a particular AE or series of AEs is determined to meet the criteria for 
an UP should a report of the AE(s) be submitted to the IRB at each institution under the HHS 
regulations at 45 CFR part 46. Typically, such reports to the IRBs are submitted by investigators. 
3. Investigators should also take into account local IRB guidance if reporting timelines for UPs are 
shorter than OHRP guidance 
 
 
 
 
 
 
 
 
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L4 Appendix 4: Accrual Timeline Milestones 
 
 
The principles guiding the accrual timeline are as follows. The specific target numbers are 
provided in the table. 
• 
Recruitment will start 6 months after funding of the trial 
• 
50% of the projected sites will initiate recruitment between month 6 and 12 
• 
All sites will be recruiting by month 18 
• 
Recruitment will extend for 4 years 
• 
The recruitment rate will get faster over time. 
• 
Total sample size is 3500 patients. 
 
 
 
Date 
Proposed 
Target Accrual 
Proposed 
Cumulative 
Accrual 
6/1/17 
Start 
Start 
9/1/17 
43 
43 
12/1/17 
63 
106 
3/1/18 
86 
192 
6/1/18 
106 
298 
9/1/18 
121 
419 
12/1/18 
136 
555 
3/1/19 
151 
706 
6/1/19 
166 
872 
9/1/19 
191 
1063 
12/1/19 
227 
1290 
3/1/20 
275 
1565 
6/1/20 
340 
1905 
9/1/20 
380 
2285 
12/1/20 
400 
2685 
3/1/21 
405 
3090 
6/1/21 
410 
3500 

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