Electronic appendix
Consideration of a New Definition of Clinically Relevant Myocardial Infarction after
Coronary Revascularization
An Expert Consensus Document from the Society for Cardiovascular Angiography and
Interventions (SCAI)
Issam D. Moussa, Lloyd W. Klein, Binita Shah, Roxana Mehran, Michael J. Mack,
Emmanouil S. Brilakis, John P Reilly, Gilbert Zoghbi, Elizabeth Holper, Gregg W. Stone
Table of Contents
Page
Practical Recommendations for Assessment of Cardiac Biomarkers after PCI
2
Post-PCI Cardiac Biomarker Determinations: Quality of Care Indicator
4
Impact of the “Clinically Relevant” Myocardial Infarction Definition on Clinical Trial
Design
Table 1. Contributing Factors to Cardiac Biomarker Elevations After Coronary
5
7
Revascularization Procedures
Table 2. Prognostic Implications of Pre vs. Post-PCI Cardiac Biomarkers Elevations
8
Table 3A: Prognostic Implications of CK-MB Elevations After PCI
9
Table 3B: Prognostic Implications of Troponin Elevations After PCI
12
1
Practical Recommendations for Assessment of Cardiac Biomarkers after PCI
The accurate assessment of post-PCI MI is dependent on knowledge of whether
biomarker levels are elevated at baseline, both in patients with ACS and those undergoing
elective PCI, in whom cTn may be falsely elevated in 10% or more of patients due to crossreacting heterophilic antibodies (36), interference with the immunoassay by rheumatoid factor
(37), the presence of cTn T in diseased or regenerating skeletal muscle (38), cardiac conditions
not related to CAD (1), analytic errors and other reasons. Thus, all patients should preferably
have measurement of cardiac biomarkers prior to PCI.
Ideally, cardiac biomarkers should be tested at least twice within 24 hours post-PCI.
However, most interventionalists currently do not routinely measure cardiac biomarkers after an
uncomplicated PCI (39), either because of cost considerations, planned early discharge, or lack
of evidence that the knowledge of elevated biomarkers after an uncomplicated PCI affects
prognosis or should change clinical management. In the most recent ACCF/AHA/SCAI PCI
guidelines, routine assessment of cardiac biomarker levels after PCI is supported with a class I
recommendation in the patient with angiographic complications during PCI or clinical symptoms
or ECG changes after PCI, but with only a class IIb recommendation after an uncomplicated PCI
(40).
In the absence of routine testing we recommend the following: If cardiac biomarker
levels were not elevated (or were not measured) pre-PCI, the PCI procedure is uncomplicated,
and the patient is pain-free post procedure, a 12-lead electrocardiogram should be obtained
within 1-4 hours post-PCI. If the ECG is normal cardiac biomarkers do not need to be drawn. If
either clinical symptoms are present post-PCI, and/or transient or sustained angiographic
complications occurred, and/or the post-PCI ECG shows new ST-segment depression or
2
elevation, then CK-MB (or cTn in hospitals where CK-MB is not available) should be measured
8-12 hours post the procedure. If post-PCI cardiac biomarker elevation >ULN is noted, then
serial levels should be drawn q8-12 hours until they are falling. An ECG should also be repeated
in 24 hours or earlier if symptoms develop.
If a clinically relevant MI is diagnosed, an echocardiogram may be considered to assess
left ventricular function, and other routine post-MI medical measures may be initiated, including
beta-blockers and angiotensin converting enzyme inhibitors absent contraindications. Repeat
cardiac catheterization might be considered if there were no overt angiographic complications to
explain this level of myonecrosis and left ventricular function is depressed. Conversely, if lesser
levels of CK-MB elevation occur and/or Q-waves have not developed, and the patient is
ambulating without symptoms or signs of ischemia or heart failure, the patient may be
discharged on the day after the procedure. For classification purposes this might be considered
“myonecrosis without clinically relevant MI”.
Of note, the recent proliferation of “high-sensitivity” cTn assays offers the capability to
detect substantially lower levels of cTn. Compared to standard cTn assays, these tests offer
improved sensitivity and diagnostic accuracy for detection of myonecrosis, at the cost of poorer
specificity (41). However, while these tests may enhance the ability to identify patients
presenting with true ACS from non-cardiac conditions, their prognostic utility in assessing postPCI myonecrosis has not been evaluated. In addition, low levels of troponin elevation may be
detected in a high proportion of a healthy control population (42), and in patients with stable
CAD (43). While such elevations may identify a cohort of patients at increased risk of death and
MI (regardless of treatment) (44), their use cannot presently be recommended for assessment of
post-PCI (or CABG) myonecrosis.
3
Post-PCI Cardiac Biomarker Determinations: Quality of Care Indicator?
Because of a lowering of the threshold for its diagnosis (and switch from CK-MB to cTn
as the “preferred” biomarker), the incidence of type 4a MI has been increasing over the past
decade (39), despite an overall improvement in PCI outcomes in terms of survival and other
measures (45-47). When evaluated by the National Cardiovascular Data Registry, institutions
having excellent outcomes in the highest risk cases appear to also have the highest incidence of
type 4a MI (39). The authors concluded that this observation could be attributed to the fact that
the best institutions routinely measure cardiac biomarkers post-PCI and, hence, are more likely
to find them elevated. Also, as previously discussed, post-procedural biomarker elevations may
be a stronger marker of high-risk patients than of prognostically important procedural
complications (8). In this regard, most large administrative databases do not adjust for the extent
of coronary atherosclerosis. Thus, the use of post-PCI biomarker elevations to evaluate operators
or programs is fraught with inconsistencies due to ascertainment bias, inconsistent measure of
pre-PCI biomarker levels, and use of different biomarkers and assays, and is further confounded
by difficulty in adjusting for clinical and angiographic risk factors for peri-procedural
myonecrosis. Unless cardiac biomarkers are routinely determined at baseline and post procedure
in all procedures and in all programs and appropriately adjusted for patient and lesion risk, its
use as a quality measure should be discouraged.
4
Impact of the “Clinically Relevant” Myocardial Infarction Definition on Clinical Trial
Design
An important role for a standardized definition of MI is to allow for accurate comparisons
of the frequency of MI and the impact of pharmacologic and other invasive treatments across
different populations and trials. The Universal Definition criteria are relatively sensitive, and will
increase the number of patients who are classified as having MI compared to more specific
criteria. Caution is warranted with an overly sensitive MI diagnosis in clinical trials, as any gain
in power from greater event accrual may be attenuated by misclassification errors and noise (66).
In this regard cTn elevations are observed not infrequently in otherwise stable patients, and from
non-coronary related conditions such as pericarditis and myocarditis (67,68). Including such
patients in clinical trials risks over-diagnosing type 4a MI if the baseline value wasn’t assessed.
Moreover, including non-clinically relevant MI as part of the primary composite endpoint in
device and pharmacologic clinical trials may lead to improper assessment of treatment effects. In
some cases one therapy may be deemed superior to another on the basis of clinically nonrelevant biomarker elevations. In other cases use of overly sensitive biomarkers resulting in high
rates of peri-procedural MI may add noise, thereby obscuring the detection of clinically
important differences between therapies.
For example, in the COURAGE trial, the strategy of routine PCI plus optimal medical
therapy (OMT) was non-inferior for the occurrence of death or MI compared to OMT plus
provisional PCI in patients with stable CAD (69). However, the point estimates favored the PCI
group for the endpoints of spontaneous MI (which has been strongly related to late mortality in
numerous studies) as well as death. Conversely, the point estimate favored type 4a MI for the
OMT arm, driven by small biomarker elevations post PCI. Had those “MI” endpoints, most of
5
which have not been shown to be of prognostic importance, been excluded, the interpretation of
the COURAGE trial may have been quite different. In support of this concept, a recent metaanalysis of 12 randomized trials of PCI vs. medical therapy in stable CAD with 37,548 patientyears of follow-up has demonstrated a significant 24% reduction in spontaneous MI, which
parallelled a trend toward a 30% reduction in cardiovascular mortality with PCI, despite a
significant increase in peri-procedural MI with PCI (70). We therefore recommend that future
clinical trials utilize the clinically relevant definition of post revascularization MI introduced in
this document, rather than a more sensitive and less prognostically relevant definition.
Importantly, the level of biomarker elevations post-CABG vs. post-PCI that reflect
equivalent levels of myonecrosis have not been determined. As such, biomarkers should not be
used to compare the rates of MI between PCI and CABG procedures (except perhaps for the
occurrence of new Q-wave MI). In addition, patients and caregivers in the post-CABG and postPCI settings have different thresholds (or patient ability, if intubated) for reporting chest pain,
different rates of routine ECG assessment, different thresholds to perform repeat catheterization,
etc. The lack of uniformity in classification, assessment and understanding of the prognostic
relevance of post-CABG and post-PCI MIs (as currently defined) represents a major limitation of
past and recent studies that have attempted to compare these revascularization modalities.
6
Table 1. Contributing Factors to Cardiac Biomarker Elevations After Coronary
Revascularization Procedures
Percutaneous coronary intervention
Distal embolization (inherent or device-
Coronary artery bypass graft surgery
Systemic inflammatory response due to
related)
cardiopulmonary bypass
- Platelet-fibrin aggregates
Global ischemia due to aortic cross-clamping
- Atheromatous debris
Direct trauma
- Calcified plaque
Atheroembolism
- Thrombus (pre-existing or iatrogenic)
Coronary dissection
Side-branch occlusion (small or large)
Reperfusion injury
Transient abrupt closure or balloon-
Perioperative coronary vasospasm
induced ischemia
Stenosis or occlusion of bypass graft
Coronary dissection
- Loss of small branches
- Compromised distal flow
Coronary vasoconstriction or vasospasm
Air embolism
Endothelial dysfunction
Plaque characteristics
Soft core with thin cap
Marked eccentricity
Ulcerated lesion surface
Large plaque volume
7
Table 2. Prognostic Implications of Pre vs. Post-PCI Cardiac Biomarkers Elevations
Study
Gustavsson71
Population
327 patients
Biomarkers
cTn I >1x ULN
CK-MB >1x ULN
Study findings
Patients with normal baseline cTn:
cTn, compared to CK-MB, more often resulted in the
diagnosis of type 4a myocardial infarction
Patients with elevated baseline cTn:
The degree in increase in baseline cTn correlated with
post-PCI CK-MB levels rather than post-PCI cTn levels.
(The association between post-PCI cardiac biomarker
elevation and the risk of subsequent events was not
assessed)
Miller72
2352 patients
cTn T and CK-MB
Patients with normal baseline cTn:
Post-PCI cTn elevation did not lead to increased longterm mortality (median follow-up 11.9 months).
Patients with elevated baseline cTn:
Further elevation in post-PCI cTn level was not
associated with a increase in long-term events (Only
baseline cTn has prognostic significance; death,
myocardial infarction: HR 1.14 (95% CI 1.07-1.22)
8
Table 3A: Prognostic Implications of CK-MB Elevations After PCI
Study
Patient population
Biomarkers
Incidence
Follow-up Long-term mortality
Kini73
Year
Published
1999
1,675 patients
CK-MB normal
CK-MB 3-5x ULN
CK-MB >5x ULN
81.3%
3.5%
2.4%
13 ± 3
months
1.3%
1.7%
7.5% (p<0.05 vs. other groups)
Hong74
1999
1,693 patients:
CK-MB normal
CK-MB 1-5x ULN
CK-MB >5x ULN*
52.7%
32.1%
15.2%
1 year
4.8%
6.5%
11.7% (OR 3.3)
Tardiff75
1999
2,341 patients
CK-MB normal
CK-MB 3-5x ULN
CK-MB 5-10x ULN
CK-MB >10x ULN
76.0%
3.6%
3.7%
2.9%
6 month
Post-PCI CK-MB associated
with 6-month MACE
(r2=32.56, p<0.0001)
Stone24
2001
7,147 patients:
69% with ACS
CK-MB normal
CK-MB 3-5x ULN
CK-MB 5-8x ULN
CK-MB >8x ULN*
Q-wave MI*
62.1%
6.1%
4.1%
7.7%
0.6%
1.4 ± 1.2
years
7.0%
4.3%
6.3%
14.5% (OR 2.2)
38.6% (OR 9.9)
Brener25
2002
3,478 patients
64% with ACS
CK-MB normal
CK-MB 3-5x ULN
CK-MB 5-10x ULN
CK-MB >10x ULN*
76%
4.5%
2.9%
2.4%
15±15
months
Death or MI: 9.4%
13.5%
16.7%
30.5% (OR 1.89)
(OR 1.78 if > 3 x ULN)
Dangas76
2002
4,085 patients:
67% with ACS
CK-MB >5x ULN*
12.8%
1 year
OR 1.5
9
Ellis77
2002
8,409 patients
63% with ACS
CK-MB normal
CK-MB 1-5x ULN
CK-MB >5x ULN
82.8%
13.6%
3.6%
4 years
15.1%
16.9%
19.4%
Ioannidis78
(meta-analysis)
2003
23,230 patients
CK-MB 1-5x ULN
CK-MB >5x ULN
19%
6%
6 to 34
months
Risk ratio: 1.5
Ajani79
2004
1,326 patients
85.4% with ACS
CK-MB normal
CK-MB >3x ULN*
55%
20%
1 year
3.4%
9.3% (OR 1.57 for death or MI)
Jeremias14
(meta-analysis)
2004
5,850 patients
CK-MB normal
CK-MB 3-8x ULN
CK-MB >8x ULN or
Q-wave MI
78.6%
6.1%
2.6%
1 year
1.9%
2.6%
4.7%
Jang80
2008
1,807 patients
40.9% with ACS
CK-MB normal
CK-MB 1-5x ULN
CK-MB >5x ULN
79.1%
14.6%
6.4%
13 ± 7
months
MACE: 5.0%
6.1%
10.4%
Andron81
2008
3,864 patients
30.4% with ACS
CK-MB normal
CK-MB 3-5x ULN
CK-MB >5x ULN*
70.6%
4.4%
5.1%
22 months
2.4%
7.2%
7.6% (HR 2.26)
Lindsey26
2011
6,347 patients
100% elective PCI
CK-MB <5 ng/mL
CK-MB 5-15 ng/mL
CK-MB 15-25 ng/mL
CK-MB 25-50 ng/mL
CK-MB >50 ng/mL
74.5%
17.6%
3.9%
2.5%
1.5%
1 year
2%
3%
3%
4%
12% (adjusted HR 4.87)
10
3.1
Bonaca19
2012
13,608 patients
100% with ACS
CK-MB >3x URL with
2 samples or
>5x URL with 1
sample
4.4%
180 days
Adjusted HR 2.4 for
cardiovascular death
Damman28
(meta-analysis)
2012
5,467 patients
100% with ACS
FRISC II:
CK-MB >1.5x ULN
ICTUS:
CK-MB >1x ULN
RITA 3:
CK-MB >2x ULN
3.9%
5 years
No association between procedural-related
MI and 5-year cardiovascular mortality
* Predictor of outcomes by multivariable analysis.
11
Table 3B: Prognostic Implications of Troponin Elevation After PCI
Study
Garbarz82
Year Published Patient population
1999
109 patients
46% with ACS
Biomarkers
cTn I >1x ULN
Incidence
27%
Follow-up Outcomes
8±3
Not predictive of MACE
months
Bertinchant83
1999
cTn I >1x URL
18%
19 ± 10
months
Not predictive of MACE
Fuchs84
2000
cTn I >3x ULN*
15.4%
8 months
Predictor of major in-hospital complications
(OR 2.1, 95% CI 1.2-3.9)
105 patients
(baseline cTn
normal)
1126 patients:
70.9% with ACS
Not predictive of long-term death
Cantor85
Herrmann86
Nallamothu87
2002
481 patients:
100% with ACS
2002
2002
278 patients:
3,5739.7%
patients
with ACS
2003
cTn I >1x ULN
48%
3 months
Not predictive of MACE
cTn T >1x ULN*
CK-MB normal
CK-MB 3-5x ULN
CK-MB 5-10x ULN
CK-MB >10x ULN*
17.3%
62%
6%
6%
5%
7.8 ± 5.3
months
3 years
Predictor of MACE
(HR
7.0%
3.27, 95% CI 1.14-9.41)
14.7%
14.5%
17.7% (HR 1.1)
1157 patients:
36.5% with ACS
cTn I 1-3x ULN
cTn I 3-5x ULN
cTn I 5-8x ULN
cTn I ≥ 8x ULN*
Q-wave MI*
16.0%
4.6%
2.0%
6.5%
0.3%
11 ± 7
months
Predictors of long-term mortality:
cTn >8xULN: HR 2.4, 95% CI 1.2-5.0
Q-wave MI: HR 8.9, 95% CI 1.3-62.6
Kizer88
2003
212 patients:
84% with ACS
cTn T >1x ULN*
11%
5.6 years
Predictor of MACE at 1 year
(HR 2.39, 95% CI 1.09-5.26)
Natarajan89
2004
1,128 patients
cTn I ≥5x ULN*
9.1%
1 year
Predictor of in-hospital (not 1-year)
MACE (OR 3.8, 95% CI 1.1-12.6)
12
Kini90
2004
2,873 patients
(normal baseline
cTn)
cTn I 3-5x ULN
cTn I >5x ULN
CK-MB 3-5x ULN
CK-MB >5xULN*
8.4%
14.1
2.3%
1.6%
12 ± 6
months
CK-MB >5x ULN (not cTn) predictor of
long-term mortality
(HR 6.7, 95% CI 1.9-22.9)
Cavallini91
2004
3,494 patients :
50.8% with ACS
cTn I >1x ULN
CK-MB >1x ULN*
44.2%
16%
2 years
Nageh92
2005
316 patients:
cTn I >1x ULN*
31%
18 months
CK-MB (not cTn) predictor of
long-term mortality
(OR per unit 1.04, 95% CI 1.01-1.07)
Predictor of MACE on follow-up
(OR 18.9, 95% CI 9.7-37)
2,352 patients
(31% with elevated
baseline cTn)
1,949 patients:
47.9% with ACS
cTn T >1x ULN
62.8%
12 months
Pre-PCI, not post-PCI, cTn
predictor of death or MI
cTn T >1x ULN*
19.6%
3 years
Double post-PCI TnT associated with a
partial HR 1.20 (95% CI 1.02-1.40)
(22% with angiographic
complications)
Miller72
2006
Prasad93
2006
Prasad17
2008
5,487 patients
(37% with elevated
baseline cTn)
cTn T >1x ULN
---
28 months
Pre-PCI , but not post-PCI, troponin
predictor of long-term mortality
Nienhuis94
(meta-analysis)
2008
cTn >1x ULN*
32.9%
16.3
months
Predictor of composite mortality or MI
OR 1.59 (95% CI 1.29–1.95)
Hubacek95
2009
15,581 patients
(baseline cTn
normal)
1,208 patients
64% with ACS
cTn T >3x ULN
19.7%
1 year
Not predictive of MACE
De Labriolle96
2009
3,200 patients
100% elective PCI
cTn I >3x ULN
23.4%
1 year
Not predictive of MACE
Feldman97
2009
1,601 patients
43.3% with ACS
cTn I ≥5x ULN*
19.0%
25 ± 8
months
Predictor of long-term mortality
(HR 1.81, 95% CI 1.02-3.21)
13
Cavallini98
2010
2,362 patients:
45.1% with ACS
Feldman99
(meta-analysis)
2011
Novack22
2012
cTn I >3x URL
19.8%
2 years
Not predictive of MACE
22,353 patients
cTn >1x ULN*
(baseline Tn normal)
---
17.7
months
Predictor of long-term all-cause mortality
OR 1.45 (95% CI 1.22-1.72)
4,930 patients
100% elective PCI
7.2%
24.3%
7.0%
1 year
Mortality: 5.8% (Adjusted HR 2.5)
4.5% (Adjusted HR 1.7)
6.8% (Adjusted HR 2.6)
CK-MB >3x ULN
cTn >3x ULN
cTn >20x ULN
*p < 0.05 for multivariable analysis
14