Clinical Chemistry 63:1
82–90 (2017)
Consensus or Controversy?:
Evolution of Criteria for Myocardial Infarction After
Percutaneous Coronary Intervention
Pierluigi Tricoci1*
BACKGROUND: The definition and the clinical implica-
tions of myocardial infarction (MI) occurring in the set-
ting of percutaneous coronary intervention have been
subjects of unresolved controversy. As a result of the use
of more sensitive diagnostic tools such as cardiac tro-
ponin, the expanding evidence, and the ensuing debate,
the definition of procedural MI (pMI) has evolved, lead-
ing to several revisions, different proposed definitions,
and lack of standardization in randomized clinical trials.
CONTENT: In this review, we will describe the key clinical
data on cardiac biomarkers, creatine kinase isoenzyme
MB and cTn, in the setting of percutaneous coronary
intervention and the main issues that have lead to various
consensus documents with a proposed definition of pMI.
We will focus on the rationale of the current “Third
Universal Definition of Myocardial Infarction” and of
the alternative approach proposed by the Society for Car-
diovascular Angiography and Interventions.
SUMMARY: The definition of pMI is an evolving field
where the Third Universal MI definition represents the
best attempt to date to incorporate available evidence
along with scientific and clinical judgment into criteria to
ensure adequate specificity in the diagnosis and the rele-
vant prognostic significance, while trying to maintain
sensitivity. Questions on the recommended criteria and
their practical implementation remain, but the Third
Universal definition document represents an important
milestone toward a better standardization and enhanced
consensus on the pMI definition.
© 2016 American Association for Clinical Chemistry
1 2
Division of Cardiology and Duke Clinical Research Institute, Duke University Medical
Center, Durham, NC.
* Address correspondence to this author at: Division of Cardiology and Duke Clinical
Research Institute, Duke University Medical Center, 2400 Pratt St., 0311 Terrace
Level, Box 3850 DUMC, Durham, NC 27705. Fax 919-668-7058; e-mail
pierluigi.tricoci@duke.edu.
Received June 9, 2016; accepted September 20, 2016.
Previously published online at DOI: 10.1373/clinchem.2016.255208
© 2016 American Association for Clinical Chemistry
82
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The definition of myocardial infarction (MI)2 associated
with percutaneous coronary intervention (PCI) or
periprocedural MI (pMI) has been one of the most con-
troversial issues in cardiology. There have been disagree-
ments on diagnostic criteria, clinical relevance, and im-
portance as clinical trial end point.
Three main aspects have made the pMI controversy
difficult: first, the lack of a common pathophysiology
mechanism easily measurable in clinical practice and
trials; second, the confusion between “diagnosis” and
“prognosis” in the attempt to provide an accepted defi-
nition; third, the availability of cardiac troponins (cTns)
able to detect a very small amount of myocardial injury
has further raised concerns on clinical relevance.
The Early Definitions
PCI is performed 600000 times every year in the US
alone (1 ). Myocardial injury during the PCI is detected
by a release in the bloodstream of myocardial cell proteins
(2, 3 ). The most specific, sensitive, and validated mark-
ers of myocardial cell damage are creatine kinase isoen-
zyme MB (CK-MB), the most cardiac-specific isoform of
creatine kinase, and cardiac troponin T or cardiac tro-
ponin I. cTns are the gold standard to detect myocardial
injury and have evolved over the years into more sensitive
assays, until the more recent development of the high-
sensitivity cTn.
In the original document by WHO, the definition
of MI was based on the presence of at least 2 of 3 criteria:
symptoms of ischemia, increases in cardiac biomarker
concentrations, and typical electrocardiogram (ECG)
pattern (i.e., development of Q waves) (4 ).
The first consensus redefinition of MI published by
the Joint European Society of Cardiology and the Amer-
Nonstandard abbreviations: MI, myocardial infarction; pMI, periprocedural myocardial
infarction; PCI, percutaneous coronary intervention; cTns, cardiac troponins; CK-MB, cre-
atine kinase isoenzyme MB; ECG, electrocardiogram; URL, upper reference limit; ACS,
acute coronary syndrome; EARLY, Early Glycoprotein IIb/IIIa Inhibition in Patients With
Non-ST-segment Elevation; SYNERGY, Superior Yield of the New Strategy of Enoxaparin,
Revascularization and Glycoprotein IIb/IIIa Inhibitors; NSTE, non–ST-segment elevation;
ULN, upper limit of the reference interval; HR, hazard ratio; TRACER, Trial to Assess the
Effects of Vorapaxar in Preventing Heart Attack and Stroke in Participants With Acute
Coronary Syndrome; SCAI, Society for Cardiovascular Angiography and Interventions.
Definition of Periprocedural MI
ican College of Cardiology in 2000 indicated that MI is
diagnosed when concentrations of cTn, the preferred
biomarker, or CK-MB, in the setting of acute myocardial
ischemia, are above the 99th percentile of a healthy ref-
erence population (5 ). Reference values were to be deter-
mined as the 99th percentile of a healthy reference pop-
ulation [upper reference limit (URL)]. The same criteria
were used in the setting of PCI, where “an increase of
cardiac biomarkers is indicative of cell death” and “be-
cause this necrosis occurs as result of myocardial isch-
emia, it should be labeled as MI.” (5 ) Because the in-
crease in biomarkers indicates the same loss of cardiac
tissue, there should not be a different threshold set in the
setting of PCI, which means that any new increase in cTn
or CK-MB post-PCI meets the criteria for pMI. The
original definition was purely diagnostic and does not
account for clinical or prognostic implications. This led
to lack of acceptance or implementation in clinical prac-
tice and in large randomized clinical trials, because in-
creases of cTn and CK-MB are very common after suc-
cessful and otherwise uncomplicated PCI (6 ).
Post-PCI increases of CK-MB have been reported in
20%–25% of patients undergoing PCI for stable coro-
nary artery disease and even higher in acute coronary
syndrome (ACS) patients (6 – 8 ). A major challenge in
interpreting the post-PCI biomarkers in ACS patients is
that baseline (pre-PCI) biomarkers are often high, which
makes it difficult to distinguish new PCI-related increase
from the initial ACS event causing the increased concen-
trations. If biomarkers are still increasing before PCI, it is
virtually impossible to say with certainty if there has been
a new PCI-related increase (Fig. 1). In an analysis from
the Early Glycoprotein IIb/IIIa Inhibition in Patients
With Non-ST-segment Elevation (EARLY) ACS and
Superior Yield of the New Strategy of Enoxaparin, Re-
vascularization and Glycoprotein IIb/IIIa Inhibitors
(SYNERGY) trial databases, among non–ST-segment el-
evation (NSTE) ACS patients who had a decreasing or
stable CK-MB pattern before PCI, and thus had the post-
PCI biomarkers interpretable, nearly 65% had a new
increase of CK-MB post-PCI (9 ).
A large proportion of patients have abnormal values
of cTn after PCI, ranging from approximately 20%–
40% in stable coronary artery disease to 40%–50% in
ACS patients (10 –13 ). In NSTE ACS patients included
in the EARLY ACS and SYNERGY, among patients who
had cTn descending or stable prior PCI, we found that
74% of patients had a new increase in cTn concentra-
tions following PCI.
Biomarkers’ Threshold, cTn, and the Second
Universal Definition
Given the frequency of biomarker increases and the sen-
sitivity of these biomarkers to detect small amounts of
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myocardial necrosis, the diagnostic criteria have moved
in favor of establishing higher thresholds for biomarkers
to distinguish abnormal from “expected” increases, thus
strengthening the prognostic relevance of pMI.
Several studies have analyzed the relationship be-
tween increases in CK-MB post-PCI and mortality, and,
overall, they have shown that such a relationship exists
(14 ). Using an ACS clinical-trial database, Roe and
colleagues showed a continuous relationship between
CK-MB and mortality with a 6% increased hazard of
6-month mortality per each 1⫻ upper limit of the refer-
ence interval (ULN) increase [hazard ratio (HR) 1.06;
96% CI, 1.01–1.11] (8 ). Here the ULN represents the
upper limit of the reference interval established at each of
the trials’ participating sites. In a categorical analysis,
CK-MB ⬎3⫻ ULN was associated with mortality,
whereas CK-MB 1–3⫻ ULN was not. Other studies as-
sessing the prognostic value of categorical CK-MB levels
indicated a modest increase in mortality with CK-MB
3–5⫻ ULN, whereas major CK-MB increases post-PCI
CK-MB (⬎5⫻ ULN) were independently associated
with mortality (15, 16 ).
In 2007, the American Heart Association, the
World Heart Federation, the European Society of Cardi-
ology, and the American College of Cardiology jointly
produced and released a revised definition of MI in the
“Universal Definition of Myocardial Infarction” docu-
ment (17 ). The 2007 document introduced the MI-
types classification, with pMI classified “type 4a” (type 1
is spontaneous MI). Two key changes were introduced in
the updated revision. First, the threshold to define MI
post-PCI was increased to an “arbitrary” threshold of
increase ⬎3⫻ the 99th percentile URL, which incorpo-
rates the concept of prognostic relevance in the definition
and acknowledges that the prognosis of pMI is different
than that of spontaneous MI, and thus requires higher
threshold. Despite the existing 2000 MI definition, large
randomized clinical trials were already adopting higher
cutoffs to define pMI, at 3⫻ or 5⫻ ULN (18 ). The 2007
Universal MI definition also recommended cTn as the
preferred biomarker for the definition of pMI. The adop-
tion of cTn as biomarker to define pMI has been met
with reluctance, as it went against the paradigm that
CK-MB is the biomarker to be used in post-PCI setting
and because increases in cTn after PCI are very frequent
(19, 20 ). Studies correlating cTn with mortality have
had conflicting results, with some studies supporting and
others denying the association between cTn and mortal-
ity (14 ). A metaanalysis including 20 studies assessing
the relationship between cTn post-PCI and mortality
showed a significant relationship with mortality after
16.5 months follow-up (odds ratio 1.35; 95% CI, 1.13–
1.60) (21 ). One major problem in interpreting studies
assessing the prognostic significance of post-PCI cTn was
the lack of properly accounted-for baseline, pre-PCI cTn
Clinical Chemistry 63:1 (2017) 83
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Fig. 1. Example of serial biomarker collection from the TRACER trial.

(A), descending troponin (blue dots) and CK-MB (red dots) pattern prior to PCI followed by new increase post-PCI. (B), ascending biomarkers
prior to PCI with further postprocedural increase that cannot be attributed to peri-PCI MI. IE, index event; R, randomization; DISC, discharge.

values, which is of key importance especially in ACS pa- death/MI in the multivariable model (22 ). However,
tients. An analysis including 2352 patients undergoing when cTn is increased pre-PCI, post-PCI values are likely
PCI in which cTnT was measured pre and post-PCI sug- predictive only if they represent a “new” increase and not
gested that only pre-PCI cTn was predictive of 12-month a natural rise following the initial spontaneous presenta-

84 Clinical Chemistry 63:1 (2017)

Definition of Periprocedural MI
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Fig. 2. Adjusted relationship between post-PCI troponin and mortality in ACS patients with stable and descending values prior to
procedure.
Results from an analysis of 10 119 patients with non–ST-segment elevation ACS undergoing PCI. The x axis plots troponin peak value post-PCI,
expressed as ratio to ULN. The y axis represents the log-transformed HR (per 10-fold troponin increase) of 1-year all-cause mortality. Contin-
uous line is the effect estimate and dotted line represents 95% CI. Analysis adjusted by age, ST-segment changes, Killip class, peripheral artery
disease history, creatinine clearance, weight, prior MI, heart rate, prior PCI or coronary artery bypass graft surgery, systolic blood pressure,
female sex, current smoker, diabetes, heart failure history, and baseline (pre-PCI) troponin. Reproduced with permission from Tricoci et al. (9 ).

tion. In that case, the initial increase likely has a stronger
prognostic impact. We analyzed systematically the pre-
PCI cTn trends in 10199 NSTE ACS patients who un-
derwent PCI during the index hospitalization in EARLY
ACS and SYNERGY trials, in which cTn and CK-MB
were collected serially (9 ). Forty-one percent of patients
had rising pre-PCI cTn and 57% had descending or sta-
ble cTn concentrations before PCI and thus an interpreta-
ble post-PCI cTn. In this group post-PCI cTn was signifi-
cantly associated with 1-year mortality in a multivariable
model, with 7% increase in the hazard of 1-year death for
each 10⫻ ULN increase in cTn (HR 1.07; 95% CI, 1.02–
1.11; P ⫽ 0.0038) (Fig. 2). Once the noise derived from
baseline cTn had been attenuated, an incremental prognos-
tic impact of cTn post-PCI could be measured.
Troponin or CK-MB after PCI?
CK-MB is less sensitive than cTn and for the same in-
crease times the 99th percentile URL, the corresponding
amount of necrotic myocardium is expectedly larger with
CK-MB. In the Evaluation of Drug Eluting Stents and
Ischemic Events (EVENT) registry, a cTn increase of
20⫻ ULN (i.e., established MI diagnostic limit at partic-
ipating sites) was equivalent to a 3⫻ CK-MB increase on
1-year mortality (23 ). In NSTE ACS patients, we found
that increase in cTn 60⫻ ULN (i.e., established MI di-
agnostic limit at participating sites) post-PCI was equiv-
alent to 3⫻ ULN of CK-MB both in terms of 1-year
mortality and prevalence of pMI. In a study of 32 pa-
tients undergoing cardiac MRI with late gadolinium en-
hancement before and after PCI, the diagnostic accuracy
of CK-MB 3⫻ 99th percentile was equivalent to cTn
40⫻ 99th percentile (24 ).
These studies support the concept that the “equiva-
lence” point between CK-MB and cTn threshold is at
higher values of cTn. However, the variability of the
equivalence point found suggests that one single equiva-
lent cutoff cannot be applicable to any cTn assay.
Spontaneous vs pMI
Prognostic significance of pMI has been benchmarked
against spontaneous MI. In an analysis published of 9087
NSTE ACS patients undergoing PCI, pMI (CK-MB
⬎3⫻ ULN) was associated with a significant increase in

Clinical Chemistry 63:1 (2017) 85

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1-year death (HR 1.39; 95% CI, 1.01–1.89), much
lower than increased mortality observed with spontane-
ous MI (HR 5.37; 95% CI, 3.90 –7.38) (25 ). A post-PCI
increase in CK-MB ⬎27.7⫻ ULN was found to achieve
a prognostic significance comparable to spontaneous MI.
Only 6% of pMI had increases in CK-MB above that
level.
In the Acute Catheterization and Urgent Interven-
tion Triage Strategy (ACUITY) trial among 7773 NSTE
ACS patients who underwent PCI, 1-year death was
much higher with spontaneous MI (16.0%) than pMI
(6.0% vs 2.6% of patients without MI) (26 ). After mul-
tivariable adjustment including angiographic character-
istics, pMI was no longer a significant predictor of death,
unlike spontaneous MI. The authors concluded that pMI
was not an independent predictor of death, but rather a
marker of baseline risk, atherosclerosis burden, and pro-
cedural complexity.
In the Trial to Assess Improvement in Therapeutic
Outcomes by Optimizing Platelet Inhibition With
Prasugrel–Thrombolysis in Myocardial Infarction 38
(TRITON-TIMI 38) study, pMI (CK-MB ⬎3⫻ ULN
in 2 samples or ⬎5⫻ ULN on a single sample was an
independent predictor of 6-month mortality after adjust-
ment for baseline covariates (HR 2.4; 95% CI, 1.6 –1.7)
(27 ). In the Clinical Evaluation of the XIENCE V®
Everolimus Eluting Coronary Stent System (SPIRIT IV)
study, pMI retrospectively redefined with cTn or
CK-MB ⬎3⫻ ULN was not associated with increased
mortality (28 ). In a study of 5850 patients from coronary
stent clinical trials, pMI was associated with 1-year mor-
tality only in patients who had unsuccessful PCI (6 ).
Generally, analyses from multicenter clinical trial data-
bases define ULN as the established MI diagnostic
thresholds from each participating site.
Role of Angiography and Imaging
Overall evidence suggested that isolated biomarker increase
post-PCI has a modest prognostic significance, lower than is
observed with spontaneous MI. Moreover, most studies did
not address the issue of angiographic confounders and ques-
tions remained on whether the prognosis associated with
pMI is simply a reflection of increased patient complexities
and disease burden. Correlating increased cardiac bio-
marker with coronary imaging may be valuable in increasing
the specificity of the diagnosis and potentially augmenting
the clinical and prognostic relevance.
Park and colleagues systematically identified coro-
nary angiographic features of pMI using a database from
11 prospective PCI studies in which angiographies of
patients with pMI (CK-MB ⬎3⫻ ULN) were reviewed
independently by an angiographic core laboratory (Table 1)
(29 ). Of the 23604 patients, 1677 had pMI. Long le-
sions and number of stents were the strongest angio-
86 Clinical Chemistry 63:1 (2017)
Table 1. Underlying angiographically detected causes of
peri-PCI MIs.a
Percentage
Underlying causes (no. of patients)
Side-branch occlusion 57.3 (961)
Slow-flow or no-reflow (abrupt closure) 9.3 (156)
Distal embolization 3.3 (55)
Thrombus 4.1 (69)
Flow-limiting dissection 4.0 (67)
Disruption of collateral flow 0.1 (2)
Others 0.9 (15)
Nonidentifiable mechanical causes 21.0 (352)
a
Reproduced with permission from Park et al. (29 ).
graphic risk factors of pMI, with others including use of
drug-eluting stent, bifurcation lesion, multivessel disease,
left anterior descending, and left main disease. Interest-
ingly, contrary to the concept that most increases in
CK-MB following PCI are “isolated,” the vast majority of
pMI had an identifiable angiographic complication and
only 21% of the peri-PCI MI did not have an identifiable
cause. By far the most common mechanism was side-
branch closure (57.3% of pMI), followed by slow-flow/
no-reflow (9.3%). Distal embolization, which is thought
to be one of the main mechanisms of pMI, was only
identified in 3.3% of cases. Thrombus and flow-limiting
dissection were reported in 4.1% and 4.0%, respectively.
In a combined analysis including 13038 NSTE ACS
patients undergoing PCI from the EARLY ACS and Trial
to Assess the Effects of Vorapaxar in Preventing Heart
Attack and Stroke in Participants With Acute Coronary
Syndrome (TRACER) clinical-trial databases, our group
showed that local investigators reported complications
on angiography in only 193 of 657 (29.4%) of pMI
(CK-MB ⬎3⫻ ULN) (30 ).
In addition to plain coronary angiography, other
invasive and noninvasive imaging techniques may pro-
vide further information useful to identify mechanisms
of pMI. In a cardiac MRI study, cTn increase post-PCI
correlated with late gadolinium enhancement due to
side-branch occlusion in 43% of cases and late gadolin-
ium enhancement distal to the stent (i.e., embolism) in
47% of cases (31 ). Histology studies on captured debris
during PCI have shown that thrombotic components
represent the majority of the debris (75%), while plaque
material accounted for only 25% (32 ). In the Coronary
Assessment by Near-Infrared of Atherosclerotic Rupture-
prone Yellow (CANARY) study, near-infrared spectros-
copy of atherosclerotic plaques in patients undergoing
stent implantation identified lipid-rich plaques as carry-
ing the highest risk of pMI, supporting embolization as
Definition of Periprocedural MI
central mechanism (33 ). Because side-branch occlusion
is one of the most frequent mechanisms of pMI, it is
possible that shifts in large lipid core at bifurcation
may cause vascular occlusion. In an analysis of 110
patients undergoing multimodality coronary imaging
(optical coherence tomography, intravascular ultra-
sound, near-infrared spectroscopy), multivariate anal-
ysis identified thin cap-thickness as the only indepen-
dent predictor of cardiac troponin I increases ⬎3⫻
ULN post-PCI (single assay defined as 0.5 ng/mL)
(34 ). A thin fibrous cap indicates the presence of large
necrotic core, supporting the concept of large lipid
core as a main risk factor for pMI. The adoption of
imaging criteria in the definition of pMI has been one
of the major changes in the updated 2012 definition.
The Third Universal Definition of Myocardial
Infarction
In 2012, the joint European Society of Cardiology/
American College of Cardiology/American Heart
Association/World Heart Federation published the “Third
Universal Definition of Myocardial Infarction” including
several major revisions aimed at increasing the specificity of
pMI diagnosis and its prognostic relevance (35 ).
The Third Universal MI definition increased the
threshold for diagnosis of pMI to 5⫻ 99th percentile
URL, confirming cTn as the preferred marker. This new
cutoff is arbitrary and based on “clinical judgment and
societal implications of the label of peri-procedural
MI.” Given the arbitrary threshold, however, one
could expect to see further revision. There is emphasis
on the importance of measuring biomarkers before
PCI to assess whether biomarkers are stable (normal or
falling). If cTn is not stable, the diagnosis of post-PCI
MI cannot be made, as it is impossible to distinguish
between new PCI-related necrosis from evolution of
the presenting MI (Fig. 1). If cTn is increased (but
stable) an increase of ⬎20% from the pre-PCI value is
required to define a pMI.
According to the Third Universal definition, iso-
lated biomarker increase is no longer sufficient for diag-
nosis of pMI but associated criteria are required to in-
crease diagnostic specificity. These are: (a) prolonged
(ⱖ20 min) ischemic symptoms; (b) ischemic ST changes
or new Q waves on ECG; (c) angiographic finding con-
sistent with procedural complication: loss of major artery
of side branch, decreased coronary flow, embolization;
and (d) new loss of viable myocardium or new motion
abnormality on imaging.
The new criteria significantly raise the bar for the
diagnosis and capture the key diagnostic aspects of the
peri-PCI MI (symptoms, ECG, angiography).
There are questions that remain regarding the new
definition: first, the impact on the incidence of pMI
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in randomized clinical trials; second, the impact of
the additional clinical and angiographic criteria on the
selection of cTn diagnostic cutoff for pMI; third, the
prognostic implications of the new angiographic crite-
ria; finally, with the advent of high-sensitivity cTn,
data are needed to establish pMI diagnostic cutoff, but
the capability to detect smaller amounts of necrosis
reinforces the need for a definition based on clinical/
electrocardiographic features and procedural compli-
cation corroborating post-PCI biomarker increases as
clinically meaningful events.
An important practical consideration is whether the
new angiographic criteria are applicable (and reliable) in
randomized clinical trials relying on site-reported angio-
graphic complications or whether a central angiographic
core laboratory is needed.
In the angiographic substudy of the EARLY ACS
study intraprocedural complications were detected by
systematic review of angiograms by an independent an-
giographic core laboratory in 166 (11.4%) of 1452
NSTE ACS patients undergoing PCI (36 ). Patients with
intraprocedural complications had a significant increase
in 30-day death or MI (28.3% vs 7.8%). In a combined
analysis from EARLY ACS and TRACER of 1785 pa-
tients with new cTn increase ⬎5⫻ ULN (i.e., diagnostic
MI threshold at each participating site) post-PCI, only
258 (14.4%) had clinical (symptoms/ECG) or angio-
graphic complications reported by site investigators (30 ).
Lack of agreement between angiographic core laborato-
ries and operators in the assessment of angiographic mea-
sures has been reported (37 ). In the EARLY ACS angio-
graphic core laboratory substudy of the procedural
complication detected by an angiographic core labora-
tory, only 25% were reported by site investigators (30 ).
These results highlight the likelihood of underreporting
of procedural complication by sites and suggest the need
for an angiographic core laboratory to systematically ap-
ply the Third Universal definition. Implementing an an-
giographic core laboratory in clinical trials is complex and
costly. Therefore, the need of using a core laboratory
should be assessed based on the importance of pMI as end
point. In studies planned to obtain regulatory approval
where pMI is a critical efficacy end point, use of angio-
graphic core laboratory should be considered to properly
implement the Third Universal definition. When use of
core laboratory is not possible due to costs, one should
rely on angiographic site reports, but this requires addi-
tional validation to understand the prognostic impact of
investigator-only reported events and the possible conse-
quences of missed/misclassified end points. When assess-
ment of pMI is unlikely to affect significantly the ascer-
tainment of treatment effect, using an angiographic core
laboratory may not be cost-effective.
Clinical Chemistry 63:1 (2017) 87
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Table 2. Differences between Third Universal and SCAI definitions of peri-PCI MI.a

Universal definition SCAI definition

Symptoms of ischemia ≥20 min
Timing of biomarker Before and 3–6 h later Ideally twice within 24 h, then 8–12 h if no symptoms
measurement or angiographic complications and not necessary
if ECG is normal at 1–4 h
Biomarker elevation >5× 99th-percentile URL within 48 h or Isolated CK-MB ≥10× local laboratory ULN or
>20% if baseline elevated troponin ≥70× ULN. If new Q waves or new LBBBb
CK-MB ≥5× ULN or troponin ≥35× ULN CK-MB
Choice of biomarker Troponin CK-MB
Baseline biomarkers ≤99th-percentile URL and stable or Stable or falling. If not stable or falling, a new rise as
falling above plus new ST-segment elevation or
depression (not defined) plus new onset of
worsening heart failure or sustained hypotension
(not defined)
Associated features
Ischemic ST-segment ST 20.5 mm New ST-segment elevation or depression
changes
New Q waves New Q waves
New LBBB New LBBB
New ST-segment elevation defined
with sex cuts
Angiographic
complications
Embolization Yes No
Loss of patency of Yes No
major artery or side
branch
Persistent slow-flow or Yes No
no-reflow
New regional wall motion Yes No
abnormality
Imaging evidence of new Yes No
loss of viable
myocardium
Myocardial injury Biomarkers ≤5× 99th-percentile URL —
with associated features
>5× 99th-percentile URL in absence of
ischemic, angiographic, or imaging
findings
Myonecrosis without — Biomarkers less than cutpoints as above without Q
clinically relevant MI waves, symptoms or signs of ischemia (not
defined), or heart failure

a
Reproduced and adapted with permission from White (39 ).
b
LBBB, left bundle branch block.

The Society for Cardiovascular Angiography
and Interventions Definition
The Society for Cardiovascular Angiography and Inter-
ventions (SCAI) defines a “clinically relevant MI” aiming
at capturing only pMI that are thought to be “prognos-
tically significant,” rather than focusing on diagnostic
sensitivity (38 ). “Clinically relevant MI” are defined as
any increase of CK-MB ⱖ10⫻ ULN post-PCI in pa-
tients with normal pre-PCI biomarkers. A cTn ⱖ70⫻
ULN is required if CK-MB are not available. In patients
with increased pre-PCI CK-MB (or cTn) in whom bio-
markers are stable or falling, any new absolute increment
of CK-MB ⬎10⫻ ULN (or cTn ⱖ70⫻ ULN) is diag-
nostic of pMI. If biomarkers are not falling before PCI,
the diagnosis of pMI is made by an absolute increase of
biomarkers by the same amount indicated above, plus
new ST-segment elevation or depression and clinical
signs of relevant MI (new onset or worsening heart failure
or sustained hypotension).
There are several differences between the SCAI and
the Third Universal definitions (Table 2). First, SCAI
recommends much higher biomarker cutoffs. The SCAI
definition indicates CK-MB as the preferred biomarker,

88 Clinical Chemistry 63:1 (2017)

Definition of Periprocedural MI
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considering CK-MB to be more validated in post-PCI
setting. The SCAI definition does not refer to the more
sensitive 99th percentile of URL as limit of normal, but
to the ULN, based on the fact that most studies validating
CK-MB and cTn have used multiple of ULN and not the
99th percentile. There is some practical advantage in us-
ing ULNs, which needs to be balanced against what is lost
on sensitivity. We concur that in large multicenter clini-
cal trials it is not easy to retrieve 99th percentiles from
several hundred laboratories around the world, as usually
laboratories report local ULN.
The Third Universal definition recommends bio-
marker assessment before PCI and 3– 6 h after, while the
SCAI definition recommends measuring biomarkers
(8 –12 h post-PCI) only if complication occurs, or an
ECG done 1– 4 h post-PCI shows ST-segment abnor-
malities. A potential challenge with the SCAI approach
in clinical trials is that biomarker ascertainment relies
solely on local-investigator reporting of procedural com-
plication, which is problematic as discussed, making it
impossible to identify or confirm pMI unless procedural
complications are reported. The SCAI MI definition
does not require stable biomarkers before PCI, but in-
stead implies the existence of a new pMI in presence of
other clinical signs of ischemia. Finally, the SCAI defini-
tion does not include ischemic symptoms or angio-
graphically detected complication as required criteria,
pointing out that a systematic application of the angio-
graphic criteria requires the use of angiographic core lab-
oratory. However, using a very high cutoff and ignoring
the presence of procedural complication may result in
missing clinically relevant events that are not associated
with marked increase of biomarkers, especially if less sen-
sitive CK-MB is used. cTn, in addition to being more
sensitive and specific for the detection of PCI-related
injury, also allows better accuracy in detecting stable or
falling pattern pre-PCI (19 ). Finally, attempting to attri-
bute a new diagnosis of pMI when biomarkers are in-
creasing before PCI, which occurs in 30%– 40% of ACS
patients, cannot be done with certainty, and lack of di-
agnostic specificity may impact a large group of patients
(9 ). The use of a set biomarker cutpoint to diagnose pMI
is unreliable with increasing pre-PCI values. A purely
clinical/angiographic definition of pMI in patients with
rising pre-PCI biomarker, based on unequivocal clinical
evidence (i.e., new intraprocedural ST-segment elevation
with ischemic symptoms, new/acute coronary occlusion,
loss of major side-branch, major dissection) could be
considered in these cases, however the challenge of deter-
mining which degree of new myocardial cell necrosis has
occurred will remain.
More needs to be learned about implementation and
prognostic validation of these 2 definitions. It may also be
helpful for clinical trials to design data collection to be
able to derive end point using both definitions.
Conclusion
pMI is a common end point in many cardiovascular clin-
ical trials, but its significance and definition have been
the subject of an ongoing controversy and multiple revi-
sions. The Third Universal definition has incorporated
several key aspects to increase the specificity and the
prognostic significance and in our opinion has now set a
solid standard for contemporary cardiovascular trials.
However, more information is needed on the practical
aspect of its systematic application, its prognostic valida-
tion and the incorporation of new high-sensitivity bio-
marker assays.
Author Contributions: All authors confirmed they have contributed to
the intellectual content of this paper and have met the following 3 require-
ments: (a) significant contributions to the conception and design, acquisi-
tion of data, or analysis and interpretation of data; (b) drafting or revising
the article for intellectual content; and (c) final approval of the published
article.
Authors’ Disclosures or Potential Conflicts of Interest: No authors
declared any potential conflicts of interest.

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