FREQUENCY AND PROGNOSTIC IMPORTANCE
OF TROPONIN AND CK-MB ELEVATIONS
FOLLOWING CABG: AN ANALYSIS FROM PRIMO
I AND PRIMO II
Robert W. Harrison, MD; Kyle White, MS; Michael J. Domanski, MD; Sorin J.
Brener, MD; Peter K. Smith, MD; Graham S. Hillis, MBChB, PhD; Milo Engoren,
MD; John H. Alexander, MD, MHS; Jerrold H. Levy, MD; Bernard R. Chaitman,
MD; Michael J. Mack, MD; Michael E. Farkouh, MD, MSc; Kenneth W.
Mahaffey, MD
Duke Clinical Research Institute, Durham, NC (RWH, KW, PKS, JHA, KWM); Mouth Sinai School of
Medicine, New York, NY (MJD, MEF); New York Methodist Hospital, Brooklyn, NY (SJB); The George
Institute for Global Health, Sydney, Australia (GSH); Mercy St. Vincent Medical Center, Toledo, OH
(ME); Emory University, Atlanta, GA (JHL); Saint Louis University Sch. of Med., St. Louis, MO (BRC);
Baylor Healthcare, Dallas, TX (MJM)
Disclosures:

R.W. Harrison: None

K. White: None

M.J. Domanski: None

S.J. Brener: None

P.K. Smith: None

G.S. Hillis: None

M. Engoren: None

J.H. Alexander: None

J.H. Levy: None

B.R. Chaitman: None

M.J. Mack: None

M.E. Farkouh: None

K.W. Mahaffey: None
Background

Postoperative myocardial infarction (PMI) is a
serious complication of CABG
 Incidence 3-20% depending on the definition

Traditionally, PMI defined by postoperative ECG
evidence of infarction

More recently, CK-MB and troponin have been
incorporated into the definition of PMI

Many contemporary CABG clinical trials have used
a combination of CK-MB elevations and Q-waves on
ECG to define PMI
Background

Troponin replacing CK-MB in the Universal
Definition of Myocardial Infarction1:
 Type 5 MI: Postoperative troponin > 10x ULN
when associated with ECG changes, or imaging
evidence of graft loss or new myocardial injury

Prior studies have demonstrated increased risk of
death with elevated CK-MB and troponin2
 Most have evaluated categorical elevations in
biomarkers
 >5-≤10xULN, >10-≤20xULN, etc.

Little evidence to support the use of specific
biomarker thresholds, particularly for troponin.
1. Thygesen K, et al. Circulation. 2012. 126(16):2020-2035
2. Domanski MJ, et al. JAMA. 2011. 305(6) P.585
Objectives

Population of clinical trial participants who
underwent systematic assessment of CK-MB and
troponin following CABG:
 Evaluate the incidence of CK-MB and troponin
elevations over a range of thresholds
 Assess the association between CK-MB or
troponin elevations and 30-day mortality
 Assess the independent prognostic importance
of ECG evidence of infarction
Methods

PRIMO-I and PRIMO-II:
 7,234 patients
 Multicenter randomized clinical trials to assess
the efficacy of intravenous pexelizumab in
patients undergoing CABG or combined CABG
and valve surgery
 All patients underwent serial CK-MB, troponin-I
(TnI), and ECG measurements over 96 hours
CK-MB: 4, 8, 12, 24, 36, 48, 96 hours
TnI: 24, 48, 96 hours
ECG: enrollment, 48, 96 hours
 Biomarkers and ECGs analyzed at a core
laboratory
PRIMO-I and PRIMO-II

Enrolled patient with 1 (PRIMO-I) or 2 (PRIMO-II) of the
following risk factors:
 Urgent CABG
 Diabetes mellitus
 Female sex
 Prior CABG
 Prior CVA or neurological event
 NYHA Class III-IV CHF
 2 prior MIs, or recent MI (within 4 weeks of CABG)

Preoperative CK-MB and/or TnI abnormalities
 Baseline troponin abnormal in 22.2%
 Baseline CK-MB abnormal in 8.0%

Overall 30-day mortality: 3.6%
Methods

Analyzed the distributions of peak postoperative CK-MB
and TnI elevations.

Unadjusted and adjusted hazard ratios for 30-day
mortality determined over a range of thresholds for CKMB and TnI elevations
 Cox Proportional Hazards

Multivariate model incorporates the following predictors:
 Biomarker above threshold
 Presence/absence of new ECG changes
 Covariates:
age, sex, previous MI, renal insufficiency, ejection fraction,
diabetes, peripheral vascular disease, hypertension, number
of grafts used, cross clamp time, concurrent valve surgery,
and use of the internal mammary artery

Results: Baseline data
Variable
N
Age, median (IQR)
Overall Cohort
7016
60.0 (58.0-74.0)
Female, %
34.0
White, %
90.6
Ejection fraction, median (IQR)
50.0 (40.0-60.0)
Prior MI, %
36.3
Prior PCI, %
25.1
Prior CABG, %
9.0
NYHA Class III-IV, %
35.8
Concomitant valve surgery, %
14.7
On-Pump CABG, %
97.9
Cross-clamp time, median (IQR)
62 (44-86)
Results: Biomarker elevation distributions
CK-MB
Median, xULN
IQR
6.2
3.9-10.9
Troponin-I
Median, xULN
IQR
21.4
10.3-54
Results: Biomarker and ECG changes

Proportion of patients affected according to:
 Biomarker thresholds
 Concomitant ECG changes
Biomarker > Threshold
Biomarker > Threshold &
ECG Changes
Threshold
CK-MB
Troponin-I
CK-MB
Troponin-I
5x ULN
61.4%
92.0%
3.8%
4.3%
10x ULN
28.0%
75.8%
2.6%
3.9%
20x ULN
10.9%
52.0%
1.6%
3.5%
40x ULN
3.4%
32.1%
0.7%
2.8%
80x ULN
17.4%
2.0%
100x ULN
14.0%
1.8%
ECG changes: new Q-waves or LBBB on postoperative ECG
Results: Unadjusted HR for 30-day Mortality
Hazard ratios for 30-day mortality were calculated over a range
of peak CK-MB and cTnI thresholds defined relative to the ULN.
Results: Adjusted analysis

Adjusted HR for 30-day mortality
 Biomarkers and ECG changes as independent
predictors of death
Biomarker
Threshold
5x ULN
CK-MB >
Threshold
2.3 (1.5-3.5)
New ECG
changes
1.7 (1.0-2.8)
Troponin-I >
Threshold
9.2 (1.3-66.5)
New ECG
changes
1.9 (1.1-3.2)
10x ULN
2.6 (1.8-3.6)
1.5 (0.9-2.5)
2.8 (1.5-5.1)
1.8 (1.1-3.1)
20x ULN
4.7 (3.2-6.7)
1.2 (0.7-2.1)
2.4 (1.6-3.7)
1.7 (1.0-2.9)
40x ULN
7.6 (4.8-11.9)
1.1 (0.6-1.9)
3.0 (2.1-4.2)
1.5 (0.9-2.6)
80x ULN
4.3 (3.0-6.1)
1.4 (0.8-2.3)
100x ULN
4.9 (3.4-7.0)
1.3 (0.8-2.2)
Covariates: age, sex, previous MI, renal insufficiency, ejection fraction, diabetes,
peripheral vascular disease, hypertension, number of grafts used, cross clamp time,
concurrent valve surgery, and use of the internal mammary artery
Limitations

Post-Hoc analysis

Preoperative CK-MB and/or TnI abnormalities
 Sensitivity analysis performed
HRs varied <10% after excluding those with baseline
abnormal biomarkers

PRIMO-I and PRIMO-II enrolled patients at intermediate to
high risk of perioperative events

Standard TnI assay used. Results may not be comparable
for high sensitivity assays have lower ULN.

Wide confidence intervals for HRs at low ( 5x ULN for
CKMB, 10x ULN for TnI) thresholds
 Few patients with few events
 Requires cautious interpretation of these point estimates
Conclusions:

Postoperative increases in CK-MB and Troponin-I are
common
 A higher TnI threshold, vs. CK-MB, is required to affect a
similar proportion of patients
CKMB >10xULN (28%) ~ TnI >40xULN (32%)
 Concomitant ECG changes occur in a small percentage
of patients

CK-MB and TnI elevations were independently predictive of
30-day mortality at all thresholds > 5 x ULN.
 Trend: higher thresholds associated with higher HR

New Q-waves or LBBB were weakly associated with 30-day
mortality
 Prognostic importance wanes at higher biomarker
thresholds