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Research
JAMA | Original Investigation
Effect of a Restrictive vs Liberal Blood Transfusion Strategy
on Major Cardiovascular Events Among Patients
With Acute Myocardial Infarction and Anemia
The REALITY Randomized Clinical Trial
Gregory Ducrocq, MD, PhD; Jose R. Gonzalez-Juanatey, MD; Etienne Puymirat, MD; Gilles Lemesle, MD, PhD; Marine Cachanado, MSc;
Isabelle Durand-Zaleski, MD, PhD; Joan Albert Arnaiz, MD, PhD; Manuel Martínez-Sellés, MD, PhD; Johanne Silvain, MD, PhD;
Albert Ariza-Solé, MD; Emile Ferrari, MD; Gonzalo Calvo, MD, PhD; Nicolas Danchin, MD; Cristina Avendaño-Solá MD; Jerome Frenkiel, MD;
Alexandra Rousseau, PhD; Eric Vicaut, MD, PhD; Tabassome Simon, MD, PhD; Philippe Gabriel Steg, MD; for the REALITY Investigators
Visual Abstract
IMPORTANCE The optimal transfusion strategy in patients with acute myocardial infarction
Supplemental content
and anemia is unclear.
OBJECTIVE To determine whether a restrictive transfusion strategy would be clinically
noninferior to a liberal strategy.
DESIGN, SETTING, AND PARTICIPANTS Open-label, noninferiority, randomized trial conducted
in 35 hospitals in France and Spain including 668 patients with myocardial infarction and
hemoglobin level between 7 and 10 g/dL. Enrollment could be considered at any time during
the index admission for myocardial infarction. The first participant was enrolled in March
2016 and the last was enrolled in September 2019. The final 30-day follow-up was accrued in
November 2019.
INTERVENTIONS Patients were randomly assigned to undergo a restrictive (transfusion
triggered by hemoglobin ⱕ8; n = 342) or a liberal (transfusion triggered by hemoglobin
ⱕ10 g/dL; n = 324) transfusion strategy.
MAIN OUTCOMES AND MEASURES The primary clinical outcome was major adverse
cardiovascular events (MACE; composite of all-cause death, stroke, recurrent myocardial
infarction, or emergency revascularization prompted by ischemia) at 30 days. Noninferiority
required that the upper bound of the 1-sided 97.5% CI for the relative risk of the primary
outcome be less than 1.25. The secondary outcomes included the individual components of
the primary outcome.
RESULTS Among 668 patients who were randomized, 666 patients (median [interquartile
range] age, 77 [69-84] years; 281 [42.2%] women) completed the 30-day follow-up,
including 342 in the restrictive transfusion group (122 [35.7%] received transfusion; 342 total
units of packed red blood cells transfused) and 324 in the liberal transfusion group (323
[99.7%] received transfusion; 758 total units transfused). At 30 days, MACE occurred in 36
patients (11.0% [95% CI, 7.5%-14.6%]) in the restrictive group and in 45 patients (14.0%
[95% CI, 10.0%-17.9%]) in the liberal group (difference, −3.0% [95% CI, −8.4% to 2.4%]).
The relative risk of the primary outcome was 0.79 (1-sided 97.5% CI, 0.00-1.19), meeting the
prespecified noninferiority criterion. In the restrictive vs liberal group, all-cause death
occurred in 5.6% vs 7.7% of patients, recurrent myocardial infarction occurred in 2.1% vs
3.1%, emergency revascularization prompted by ischemia occurred in 1.5% vs 1.9%, and
nonfatal ischemic stroke occurred in 0.6% of patients in both groups.
CONCLUSIONS AND RELEVANCE Among patients with acute myocardial infarction and anemia,
a restrictive compared with a liberal transfusion strategy resulted in a noninferior rate of
MACE after 30 days. However, the CI included what may be a clinically important harm.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02648113
JAMA. 2021;325(6):552-560. doi:10.1001/jama.2021.0135
552
Author Affiliations: Author
affiliations are listed at the end of this
article.
Group Information: The REALITY
Investigators are listed in
Supplement 2.
Corresponding Author: Philippe
Gabriel Steg, MD, Hôpital Bichat,
Assistance Publique-Hôpitaux de
Paris, 46 rue Henri Huchard, 75018
Paris, France (gabriel.steg@aphp.fr).
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Effect of Restrictive vs Liberal Blood Transfusion Strategy on Adults With Myocardial Infarction and Anemia
A
nemia, with or without overt bleeding, is common in patients with acute myocardial infarction (AMI) and affects prognosis. Even moderate levels of anemia
(hemoglobin level of 10-12 g/dL) are associated with increased
cardiovascular mortality compared with normal hemoglobin
values in the context of acute coronary syndromes.1 Transfusion is often considered to be indicated when the hemoglobin
level falls below 10 g/dL, with large variations in clinical practice due to lack of robust data. Observational studies have
yielded conflicting results2-4 and only 2 small randomized trials
(including 45 and 110 patients) have compared restrictive with
liberal transfusion strategies in this setting.5,6 Large randomized trials have compared transfusion strategies in patients with
gastrointestinal bleeding7 and those undergoing surgical
procedures8-10 and generally found benefit from a restrictive
strategy, but these trials excluded patients with AMI.11
In addition to uncertain benefit in patients with AMI, transfusion has potential adverse effects, logistical implications (particularly for blood supply), and cost. The objective of this study,
the Restrictive and Liberal Transfusion Strategies in Patients
With Acute Myocardial Infarction (REALITY) randomized trial,
was to determine whether a restrictive transfusion strategy was
clinically noninferior to a liberal transfusion strategy.
Methods
The protocol and statistical analysis plan are presented in
Supplement 1. The trial was approved by the Comité de Protection des Personnes, Ile de France-I, France, and the ethics
committee at the Hospital Clinic, Barcelona, Spain. Patients provided written informed consent.
Trial Population
To be eligible for inclusion, patients had to be aged at least 18
years and have AMI (with or without ST-segment elevation with
a combination of ischemic symptoms occurring in the 48 hours
before admission and elevation of biomarkers of myocardial
injury) and a hemoglobin level between 7 and 10 g/dL. Enrollment could be considered at any time during the index admission for myocardial infarction. Exclusion criteria were shock
at the time of randomization (systolic blood pressure
8 g/dL hemoglobin
threshold (including 1 with exclusion criterion)
1 Underwent repeat transfusion despite reaching
target hemoglobin level after initial transfusion
324 Randomized to liberal transfusion strategy
group (triggered by hemoglobin ≤10 g/dL)
323 Underwent transfusion as planned
(including 1 with exclusion criterion)
1 Did not undergo transfusion
342 Included in as-randomized analyses
327 Included in as-treated analyses
324 Included in as-randomized analyses
322 Included in as-treated analyses
failure, and severe allergic reactions. All components of the primary efficacy clinical outcome as well as acute heart failure were
adjudicated by a critical event committee blinded to treatment
assignment and hemoglobin levels. The third universal definition of myocardial infarction was used.12 All other safety outcomes were investigator-reported. Outcome definitions are detailed in eAppendix 1 in Supplement 2.
Statistical Analysis
Based on unpublished observations from the French nationwide FAST-MI registry of AMI,13,14 we assumed the percentages of patients with MACE at 30 days of approximately 11%
in the restrictive transfusion group and 15% in the liberal transfusion group. Noninferiority was assessed using a CI method
with a 1-sided 97.5% CI and without any other statistical tests,
as recommended by the International Conference on
Harmonization.15 The noninferiority margin was set using a
relative, rather than absolute, risk margin to minimize the risk
of overestimating event rates when planning the trial, because this can make it easy to achieve noninferiority if the overall event rate is lower than expected.16,17 With these assumptions, a sample size of 300 patients per group would provide
80% power to demonstrate noninferiority of the restrictive
group, with a margin corresponding to a relative risk equal to
1.25. With a conservative hypothesis of 5% of patients with major protocol violations, 630 patients (315 per group) were required for the trial to be adequately powered for the noninferiority analysis. Because there was no established clinical
superiority of either transfusion strategy and no randomized
trial of transfusion vs no transfusion, the choice of a noninferiority margin was based on clinical judgment based on what
clinicians would be prepared to accept as potential loss of efficacy of a restrictive transfusion strategy compared with a liberal strategy given the expected theoretical benefits of the for554
a
The initial protocol specified
a threshold of 7 g/dL. This was
changed to 8 g/dL to maximize
investigator adherence to the
protocol before inclusion of the first
patient. Enrollment took place at
any time during hospitalization.
No screening log was maintained.
mer of sparing scarce blood resources,18 reducing transfusion
adverse effects, and reducing logistical burden and costs. A
relative margin of 1.25 appeared an acceptable compromise,
given that observational studies relating hemoglobin levels and
outcomes after myocardial infarction have shown that the likelihood of MACE increased, with an adjusted odds ratio of 1.45
for each 1-g/dL decrement in hemoglobin below 11 g/dL,1 and
the expected difference in hemoglobin values between treatment groups would be expected to exceed 1 g/dL.
The analysis of the primary efficacy outcome used relative risk, defined as p1/p2, with p1 = n11/ n1 and p1 = n21/ n2, where
n11 is the event number and n1 is the total number of patients
in the restrictive group and n21 is the event number and n2 is
the total number of patients in the liberal group. Ninety-five
percent CIs were estimated using the Wald method. The analysis was performed among both the as-treated population,
which included all patients without a major protocol violation (including eligibility criteria not fulfilled), and the asrandomized population, which included all randomized patients with the exception of 2 patients (1 without a consent form
and 1 who withdrew consent immediately after randomization). Concordance in the noninferiority analysis between the
as-randomized and the as-treated populations was required
to establish noninferiority. The use of multiple imputation
methods was planned in the statistical analysis plan in the case
of missing data for the primary clinical outcome. Given the absence of missing data at day 30, imputation was not needed.
Because the trial was conducted at multiple sites, site effect
was accounted for in a post hoc sensitivity analysis using a generalized linear regression mixed model with binary distribution and a log link function with strategy as a fixed effect and
center as a random effect. If clinical noninferiority of the restrictive strategy was established, a test of superiority of the
restrictive strategy was planned.
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Effect of Restrictive vs Liberal Blood Transfusion Strategy on Adults With Myocardial Infarction and Anemia
Original Investigation Research
Table 1. Baseline Characteristics of the As-Randomized Population in a Study of the Effect of a Restrictive
vs Liberal Blood Transfusion Strategy on Patients With Acute Myocardial Infarction and Anemia
No. (%)a
Characteristic
Age, median (IQR), y
Restrictive (n = 342)
78 (69-85)
Liberal (n = 324)
76 (69-84)
Men
201 (58.8)
184 (56.8)
Women
141 (41.2)
140 (43.2)
Sex
Race (self-reported)
n = 336
n = 322
White
298 (88.7)
266 (82.6)
North African
29 (8.6)
36 (11.2)
African/Caribbean
7 (2.1)
9 (2.8)
Indian
2 (0.6)
5 (1.6)
Other Asian
0
6 (1.9)
26.9 (5.3) [n = 334]
26.4 (5.0) [n = 317]
Hypertension
272 (79.5)
256 (79.0)
Dyslipidemia
189 (55.3)
201 (62.0)
Diabetes
176 (51.5)
158 (48.8)
BMI, mean (SD)
Risk factorb
Tobacco smoking status
n = 316
n = 293
Never
149 (47.2)
141 (48.1)
Former
116 (36.7)
111 (37.9)
Current
51 (16.1)
41 (14.0)
46 (13.6) [n = 337]
43 (13.4) [n = 321]
Acute coronary syndrome
121 (35.4)
119 (36.7)
Percutaneous coronary intervention
114 (33.3)
111 (34.3)
Angina
55 (16.1)
44 (13.6)
Family history of premature coronary artery disease
Cardiac history before index eventb
Atrial fibrillation
54 (15.8)
65 (20.1)
CABG
44 (12.9)
42 (13.0)
Congestive heart failure
44 (12.9)
38 (11.7)
Internal cardiac defibrillator
14 (4.1)
8 (2.5)
61 (17.8)
62 (19.1)
Previously treated
42 (12.3)
44 (13.6)
Receiving treatment
25 (7.3)
18 (5.6)
COPD
34 (9.9)
40 (12.3)
Dialysis
25 (7.3)
30 (9.3)
23 (6.7)
20 (6.2)
234 (68.4)
231 (71.3)
Noncardiac medical historyb
Chronic anemiac
Cancer
History of bleeding requiring hospitalization
and transfusion
Index hospitalization
Myocardial infarction type
Non–ST-segment elevation
Abbreviations: BMI, body mass index
(calculated as weight in kilograms
divided by height in meters squared);
CABG, coronary artery bypass graft;
COPD, chronic obstructive pulmonary
disease; IQR, interquartile range.
a
Percentages may not add to 100
due to rounding.
108 (31.6)
93 (28.7)
b
Collected through chart review.
n = 336
n = 321
c
I
189 (56.3)
183 (57.0)
Preexisting anemia not caused by
acute bleeding.
II
87 (25.9)
88 (27.4)
d
III
54 (16.1)
39 (12.1)
IV
6 (1.8)
11 (3.4)
1.6 (0.8-3.6)
1.9 (0.8-3.6)
Killip class was determined by the
investigator according to clinical
examination. Class I indicates no
sign of congestion; class II, basal
rales on auscultation; class III, acute
pulmonary edema; and class IV,
cardiogenic shock.
e
Active bleeding identified and
documented during the index
admission prior to randomization.
f
According to the Chronic Kidney
Disease Epidemiology Collaboration
formula.
ST-segment elevation
Killip class at admissiond
Delay between admission and randomization,
median (IQR), d
Active bleedinge
36 (10.5)
49 (15.1)
1 active bleed
29 (80.6)
42 (85.7)
2 active bleeds
6 (16.7)
6 (12.2)
1 (2.8)
1 (2.0)
45.1 (27.2-73.2) [n = 338]
46.6 (24.9-73.2) [n = 321]
3 active bleeds
Creatinine clearance at randomization,f
median (IQR), mL/min/1.73 m2
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Research Original Investigation
Effect of Restrictive vs Liberal Blood Transfusion Strategy on Adults With Myocardial Infarction and Anemia
Table 2. Hemoglobin Levels and Transfusions Among the As-Randomized
Population in a Study of the Effect of a Restrictive vs Liberal Blood Transfusion
Strategy on Patients With Acute Myocardial Infarction and Anemia
No. (%)
Variable
Restrictive
(n = 342)
Liberal
(n = 324)
10.0 (1.7)
10.1 (1.6) [n = 322]
Hemoglobin level, mean (SD), g/dL
At admission
Most recent prior to randomization 9.0 (0.8)
9.1 (0.8) [n = 323]
Lowest value during hospital stay
8.3 (0.9)
8.8 (0.9) [n = 323]
At discharge
9.7 (1.0) [n = 337] 11.1 (1.4) [n = 320]
Red blood cell transfusion
Patients who received ≥1 unit
of packed red blood cells
Units transfused, No.
122 (35.7)
323 (99.7)a
342
758
Per patient transfused,
mean (SD)
2.9 (3.7)
2.8 (2.7)
Per patient transfused,
median (IQR)
2.0 (2.0-3.0)
2.0 (2.0-3.0)
Units transfused
0
220 (64.3)
1 (0.3)
1
25 (7.3)
43 (13.3)
2
62 (18.1)
128 (39.5)
3
12 (3.5)
47 (14.5)
≥4
19 (5.6)
54 (16.7)
≥1 (exact No. not available)
4 (1.2)
Duration of red blood cell storage, 20.0 (17.0-25.0)
median (IQR), d
No. of units for which data
were available
90
51 (15.7)
21.0 (15.0-30.0)
299
Transfusion
Fresh frozen plasma
3 (0.9)
7 (2.2)
Platelet
4 (1.2)
6 (1.9)
Abbreviation: IQR, interquartile range.
a
One patient had been transferred to a non–study site where local physicians
declined to implement transfusion.
All secondary analyses were performed on the asrandomized population with available data. In a secondary
analysis of the main outcome, survival was estimated using
the Kaplan-Meier method and groups were compared using a
log-rank test. A stratified Cox proportional hazards model was
used to estimate the hazard ratios and 95% CIs for the effect
of transfusion strategy on MACE-free survival and each component of the MACE outcome. Data for patients with no evidence of MACE were censored at 30 days. The risk proportionality hypothesis was verified by testing the interaction between
interest variable and time.
Differences and 95% CIs between strategies were estimated using the Wald method, with continuity correction for
binary variables. No adjustment was planned for multiplicity
and there was no prespecified hierarchy for secondary efficacy outcomes. Because of the potential for type I error due to
multiple comparisons, analyses of secondary end points should
be interpreted as exploratory. The effect of transfusion strategy on the primary composite outcome was explored in subgroups of clinical interest (age, sex, body weight, presence or
absence of diabetes, smoking status, presence or absence of hypertension, presence or absence of dyslipidemia, Killip class, kid556
ney function [creatinine clearance], presence or absence of active bleeding, hemoglobin levels at the time of randomization,
ST- vs non–ST-segment elevation myocardial infarction, and revascularization by percutaneous coronary intervention for the
index event before or after randomization); the interaction between subgroup and transfusion strategy was tested using logistic regression. For safety adverse events, only point estimates of treatment effects with 2-sided 95% CIs are provided.
All superiority tests and 95% CI were 2-sided, and P values 1.00).19 Subgroup analyses based on age; sex;
body weight; smoking status; Killip class; kidney function (creatinine clearance); type of myocardial infarction (ST- vs non–
ST-segment elevation myocardial infarction); presence or absence of diabetes, hypertension, dyslipidemia, and active
bleeding; and hemoglobin levels at the time of randomization
yielded results consistent with the main analysis, and results
of the tests for interaction were not statistically significant (eFigure in Supplement 2).
Secondary Efficacy Outcomes
Components of 30-day MACE are detailed in Table 3. In the restrictive group vs the liberal group, all-cause death occurred
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a
Composite of all-cause death,
stroke, recurrent myocardial
infarction, or emergency
revascularization prompted by
ischemia at 30 days.
b
Given the potential for type I error
due to multiple comparisons, no
formal statistical comparisons were
made for secondary outcomes.
c
Type of myocardial infarction was
adjudicated by a blinded event
committee, according to the third
universal definition of myocardial
infarction.12
Figure 2. Rate of Major Adverse Cardiovascular Events in a Study
of the Effect of a Restrictive vs Liberal Blood Transfusion Strategy
Among Patients With Acute Myocardial Infarction and Anemia
0.2
Log-rank P = .21
Rate of major adverse
cardiovascular events
Secondary (individual outcomes
in the as-randomized population)b
Liberal group
0.1
Restrictive group
0
0
5
10
15
20
25
30
278
305
275
305
Days after randomization
No. of patients at risk
Liberal group
324
Restrictive group 342
301
326
293
319
285
314
281
307
Results shown are of analyses including the as-randomized population. All
patients were followed up to the first event or 30 days. Major adverse
cardiovascular events are a composite of all-cause death, stroke, recurrent
myocardial infarction, or emergency revascularization prompted by ischemia.
in 5.6% vs 7.7% of patients, recurrent myocardial infarction occurred in 2.1% vs 3.1% of patients, emergency revascularization prompted by ischemia occurred in 1.5% vs 1.9% of patients, and nonfatal ischemic stroke occurred in 0.6% of
patients in both groups. Secondary outcomes in the astreated population are provided in eTable 6 in Supplement 2.
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Research Original Investigation
Effect of Restrictive vs Liberal Blood Transfusion Strategy on Adults With Myocardial Infarction and Anemia
Table 4. Adverse Events Among the As-Randomized Population in a
Study of the Effect of a Restrictive vs Liberal Blood Transfusion Strategy
on Patients With Acute Myocardial Infarction and Anemia
No. (%)
Adverse event
Restrictive
(n = 342)
At least 1 adverse event
40 (11.7)
36 (11.1)
Acute kidney injurya
33 (9.7)
23 (7.1)
Acute heart failureb
11 (3.2)
12 (3.7)
Severe allergic reactiona
3 (0.9)
0
Acute lung injury/ARDSa
1 (0.3)
7 (2.2)
Multiorgan system dysfunctiona
1 (0.3)
3 (0.9)
Infectiona,c
0
5 (1.5)
Liberal (n = 324)
Abbreviation: ARDS, acute respiratory distress syndrome.
a
According to investigator judgment.
b
Adjudicated according to the following criteria: new or worsening symptoms
due to congestive heart failure, objective evidence of new congestive heart
failure (physical examination, laboratory, imaging or hemodynamic evidence),
and initiation or intensification of chronic heart failure treatment.
c
Documented bacterial infection/bacteremia acquired at any time after the first
transfusion.
Adverse Events
Adverse events are presented in Table 4 for the as-randomized
population and in eTable 6 in Supplement 2 for the as-treated
population.
Discussion
Among patients with AMI and anemia, a restrictive compared with a liberal transfusion strategy resulted in a noninferior rate of MACE after 30 days. However, the CI included
what may be a clinically important harm.
Anemia is common in patients with AMI and is associated
with worse clinical outcomes.1 In theory, transfusion should increase oxygen delivery, which would argue for a liberal transfusion strategy in patients with acute myocardial ischemia. However, data suggest that oxygen delivery is not necessarily
increased in patients receiving transfusions, due to red blood
cell depletion in nitric oxide and 2,3-diphosphoglyceric acid during storage, and that, conversely, transfusion may increase platelet activation and aggregation and produce vasoconstriction.20,21
Observational studies have yielded uncertain results and are
susceptible to unmeasured confounding,22 highlighting the need
for randomized trials.23 To our knowledge, only 2 small randomized trials that examine transfusion in individuals with myocardial infarction are available, and they reported opposite conclusions. The first trial, which included 45 patients, found
apparent benefit of a restrictive over a liberal transfusion strategy and the second pilot trial, which included 110 patients, found
numerically fewer cardiac events and deaths with a liberal strategy, but no statistically significant difference, and led the authors to support the need for a definitive trial.6,22 There is wide
variation in clinical practice regarding the use of transfusion for
patients with AMI.24 Given the persistent equipoise in the clinical community regarding what transfusion strategy is optimal
558
in the specific setting of AMI, there have been multiple calls for
generating more evidence from randomized trials.4,11,22,25
Uncertainty exists on the optimal transfusion strategy and
on what hemoglobin level should trigger transfusion in this
population. In patients with AMI and anemia, the current trial
showed statistical noninferiority of the restrictive strategy compared with the liberal strategy in both the as-randomized and
as-treated populations, providing some confidence in the
results.26 However, determination of the margin used to declare noninferiority is critical to the interpretation of the result. This determination can be based on computation of preservation of at least a fraction of the benefit of an established
treatment (often in the range of 50% preservation of the benefit). In the case of AMI, no trial to our knowledge has compared transfusion with no transfusion. However, a large observational analysis of the relationship between anemia and
mortality after AMI showed that the risk of MACE increased,
with an adjusted odds ratio of 1.45 (95% CI, 1.33-1.58) for each
1-g/dL decrement in hemoglobin below 11 g/dL.1 A 25% relative noninferiority margin would preserve a substantial fraction of the expected benefit of transfusion, because the anticipated difference in hemoglobin value was expected to
exceed 1 g/dL (as was actually observed). The noninferiority
margin should also be justifiable on clinical grounds based on
the estimate of what clinicians would find clinically acceptable as a potential loss of efficacy with an “experimental” strategy compared with an established strategy, given the benefits of the former. In the present setting, the theoretical
advantages of the restrictive strategy would be reduced consumption of increasingly scarce blood resources,18 reduced adverse effects from transfusion, potential cost savings, and logistical benefits related to the implementation of transfusion.
The choice of a 25% relative increase as the margin for noninferiority was more conservative than the margin used in many
recent large trials,27-31 but did not eliminate inferiority. In any
case, it is recommended that clinicians use their own judgment in interpreting noninferiority thresholds.32 Although the
30-day primary clinical outcome was numerically lower with
the restrictive strategy, this difference did not achieve statistical significance for superiority. Although the decision to initiate transfusion should not be based on hemoglobin level
alone, the observed result suggests there may be merit to a restrictive strategy, which had no apparent downside in terms
of logistics. Heart rate was not factored in the decision to initiate transfusion, particularly because most patients with AMI
receive β-blockers.
Limitations
This study has several limitations. First, it was of moderate size
and thus was not powered for evaluating the superiority of
either strategy. A noninferiority margin of 1.25 includes potentially clinically important harm and may be considered too
large. Even the observed confidence limit ranges up to an 18%
increase in cardiac events, which would be clinically meaningful. A larger trial with a similar clinical design is ongoing in
individuals with AMI (MINT trial; NCT02981407) and is powered for clinical superiority using the composite outcome of
all-cause mortality and nonfatal recurrent AMI. Second, the
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Effect of Restrictive vs Liberal Blood Transfusion Strategy on Adults With Myocardial Infarction and Anemia
trial was open-label due to the logistical challenges of blinding transfusion in the setting of AMI. However, assessment of
clinical efficacy relied on objective outcomes, which were
blindly adjudicated. Third, because qualifying hemoglobin levels could be collected at any time during hospitalization, some
patients may have qualified for enrollment due to shifts after
catheterization, repeated blood draws during a long stay, or active bleeding from medications or procedures. Therefore, a
mixture of individuals with anemia, bleeding, and dilution
were included in the eligible population.33 However, subgroup analyses based on the presence or absence of preexisting anemia or of active bleeding yielded results consistent with
the main analysis. Fourth, this report was limited to analysis
ARTICLE INFORMATION
Accepted for Publication: January 7, 2021.
Author Affiliations: Université de Paris, AP-HP,
French Alliance for Cardiovascular Trials (FACT),
INSERM U1148, Paris, France (Ducrocq, Steg);
Cardiology Department, University Hospital, IDIS,
CIBERCV, University of Santiago de Compostela,
Santiago de Compostela, Spain
(Gonzalez-Juanatey); Université de Paris, AP-HP,
Hôpital Européen Georges Pompidou, French
Alliance for Cardiovascular Trials (FACT), Paris,
France (Puymirat, Danchin); Institut Cœur Poumon,
Centre Hospitalier Universitaire de Lille, Faculté de
Médecine de Lille, Université de Lille, Institut
Pasteur de Lille, Inserm U1011, Lille, France
(Lemesle); French Alliance for Cardiovascular Trials
(FACT), Paris, France (Lemesle); Department of
Clinical Pharmacology and Clinical Research
Platform of the East of Paris (URC-CRC-CRB),
AP-HP, Hôpital St Antoine, Paris, France
(Cachanado, Rousseau, Simon); AP-HP Health
Economics Research Unit, Hotel Dieu Hospital,
INSERM UMR 1153 CRESS, Paris, France
(Durand-Zaleski, Frenkiel); Clinical Trials Unit,
Clinical Pharmacology Department, Hospital Clinic,
Barcelona, Spain (Arnaiz, Martínez-Sellés); Servicio
de Cardiología, Hospital Universitario Gregorio
Marañón, CIBERCV, Universidad Europea,
Universidad Complutense, Madrid, Spain (Arnaiz,
Martínez-Sellés); Sorbonne Université, ACTION
Study Group, Institut de Cardiologie, Hôpital
Pitié-Salpêtrière (AP-HP), INSERM UMRS 1166,
Paris, France (Silvain); University Hospital Bellvitge,
Heart Disease Institute, Barcelona, Spain
(Ariza-Solé); Université Côte d’Azur, CHU de Nice,
Hôpital Pasteur 1, Service de Cardiologie, Nice,
France (Ferrari); Àrea del Medicament, Hospital
Clínic of Barcelona, University of Barcelona,
Barcelona, Spain (Calvo); Clinical Pharmacology
Service, Hospital Universitario Puerta de
Hierro-Majadahonda, Madrid, Spain (
Avendaño-Solá); AP-HP, Department of
Biostatistics, Université Paris-Diderot,
Sorbonne-Paris Cité, Fernand Widal Hospital,
France (Vicaut); Department of Clinical
Pharmacology-Clinical Research Platform
(URCEST-CRB-CRCEST), AP-HP, Hôpital Saint
Antoine, French Alliance for Cardiovascular Trials
(FACT), Sorbonne-Université, Paris, France (Simon);
Royal Brompton Hospital, Imperial College, London,
United Kingdom (Steg).
Author Contributions: Dr Steg had full access to all
of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the
jama.com
Original Investigation Research
of 30-day outcomes. Longer follow-up to 1 year is being accrued and will allow evaluation of the potential long-term effects of the 2 transfusion strategies as well as assessment of
potential quality of life and incremental cost-utility ratio differences between the groups.34
Conclusions
Among patients with AMI and anemia, a restrictive compared with liberal transfusion strategy resulted in a noninferior rate of major cardiovascular events after 30 days. However, the CI included what may be a clinically important harm.
data analysis. All authors vouch for the integrity and
the accuracy of the analysis and for the fidelity of
the study to the protocol.
Concept and design: Ducrocq, González Juanatey,
Puymirat, Durand-Zaleski, Silvain, Calvo, Danchin,
Rousseau, Vicaut, Simon, Steg.
Acquisition, analysis, or interpretation of data:
Ducrocq, González Juanatey, Lemesle, Cachanado,
Durand-Zaleski, Arnaiz, Martínez-Sellés, Silvain,
Ariza Solé, Ferrari, Calvo, Danchin, Avendaño-Solá,
Frenkiel, Rousseau, Vicaut, Simon, Steg.
Drafting of the manuscript: Ducrocq, González
Juanatey, Cachanado, Durand-Zaleski, Simon, Steg.
Critical revision of the manuscript for important
intellectual content: Ducrocq, González Juanatey,
Puymirat, Lemesle, Durand-Zaleski, Arnaiz,
Martínez-Sellés, Silvain, Ariza Solé, Ferrari, Calvo,
Danchin, Avendaño-Solá, Frenkiel, Rousseau,
Vicaut, Simon, Steg.
Statistical analysis: Cachanado, Durand-Zaleski,
Frenkiel, Rousseau, Vicaut.
Obtained funding: Ducrocq, Durand-Zaleski, Silvain,
Calvo, Danchin, Avendaño-Solá, Simon, Steg.
Administrative, technical, or material support:
Ducrocq, González Juanatey, Arnaiz, Silvain, Ferrari,
Calvo, Danchin, Avendaño-Solá, Simon, Steg.
Supervision: Ducrocq, González Juanatey, Arnaiz,
Silvain, Ariza Solé, Calvo, Danchin, Avendaño-Solá,
Simon, Steg.
Conflict of Interest Disclosures: Dr Danchin
reported receiving personal fees from Amgen,
AstraZeneca, Bayer, Bristol Myers Squibb,
Boehringer Ingelheim, Intercept, MSD, Novo
Nordisk, Pfizer, Sanofi, Servier, UCB, and Vifor
outside the submitted work. Dr Ducrocq reported
receiving personal fees from Amgen, AstraZeneca,
Bayer, Bristol Myers Squibb, Janssen, Sanofi,
and Terumo outside the submitted work.
4Dr Durand-Zaleski reported receiving grants from
the Ministry of Health during the conduct of the
study and personal fees from Vifor outside the
submitted work and being the chair of the scientific
committee of the French Blood Establishment.
Dr Lemesle reported receiving personal fees from
Amgen, AstraZeneca, Bayer, Bristol Myers Squibb,
Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, MSD,
Mylan, Novartis, Novo Nordisk, Pfizer, Sanofi
Aventis, and Servier outside the submitted work.
Dr Puymirat reported receiving fees for lectures
and/or consulting from Amgen, AstraZeneca, Bristol
Myers Squibb, Bayer, Biotronick, Boehringer
Ingelheim, Daiichi-Sankyo, Eli Lilly, MSD, Novartis,
Pfizer, The Medicines Company, Sanofi, St Jude
Medical, and Servier. Dr Silvain reported receiving
grants and personal fees from AstraZeneca;
personal fees from Bayer HealthCare, Boehringer
Ingelheim France, BPI France, CSL Behring, Gilead
Science, Sanofi-Aventis France, and Zoll; and
nonfinancial support from Abbott Medical France
and Terumo France and being a stockholder in
Pharmaseeds outside the submitted work.
Dr Simon reported receiving grants from the
Programme de Recherche Medico Economique and
the Instituto de Salud Carlos III (PI15/01543) for
Spanish centers in the trial during the conduct of
the study and personal fees from AstraZeneca,
Novartis, Sanofi, Astellas, and MSD and grants from
AstraZeneca, Bayer, Boehringer, Daiichi-Sankyo,
Eli Lilly, GlaxoSmithKline, Novartis, and Sanofi
outside the submitted work. Dr Steg reported
receiving grants from the French Ministry of Health
and the Spanish Ministry of Industry during the
conduct of the study and grants from Amarin,
Bayer, Sanofi (Odyssey Outcomes co-chair), and
Servier (CLARIFY registry chair) and personal fees
from Amgen, AstraZeneca, Bayer, Bristol Myers
Squibb, Boehringer Ingelheim, Idorsia, Novartis,
Novo Nordisk, Pfizer, Sanofi, Myokardia, Phase Bio,
and Janssen outside the submitted work. Dr Vicaut
reported receiving personal fees from Abbott for
consulting outside the submitted work. No other
disclosures were reported.
Funding/Support: The trial was designed by the
French Alliance for Cardiovascular Trials and was
funded via a grant from the Programme de
Recherche Médico-Economique (PRME) 2015 from
the French Ministry of Health and a grant from the
Instituto de Salud Carlos III (Spanish Ministry of
Economy and Competitiveness; grant PI15/01543).
There was no industry support. The sponsor of the
trial was Délégation à la Recherche Clinique et au
Développement, Assistance Publique-Hôpitaux de
Paris, Paris, France.
Role of the Funder/Sponsor: The funders and
sponsor had no role in the design and conduct of
the study; collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Group Information: A list of the REALITY
Investigators is available in eAppendix 2 in
Supplement 2.
Data Sharing Statement: See Supplement 3.
Additional Contributions: Editorial support was
provided by Sophie K. Rushton-Smith, PhD (MedLink
Healthcare Communications, London), who was
compensated via a grant from the Programme de
Recherche Médico-Economique from the French
Ministry of Health for her contribution.
(Reprinted) JAMA February 9, 2021 Volume 325, Number 6
© 2021 American Medical Association. All rights reserved.
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559
Research Original Investigation
Effect of Restrictive vs Liberal Blood Transfusion Strategy on Adults With Myocardial Infarction and Anemia
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JAMA February 9, 2021 Volume 325, Number 6 (Reprinted)
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jama.com
Team Journal Club Critique
1) The study looked at patients aged 69-84 but according to the WHO anemia affects 1.74
billion (24.8%) of the world’s population aging from children to the elderly. Additionally,
according to the WHO CVD kills 17.9 million people each year, with more than four out of
five CVD deaths related to myocardial infarction and strokes, and one third of these
deaths occur in people under the age of 70. Given these age ranges and seeing how
these events affect people
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