Disclosures:

1. 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 Frequency and prognostic importance of troponin and CK-MB elevations following CABG: An analysis from PRIMO I and PRIMO II 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)

2. 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

3. 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

4. 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. • Thygesen K, et al. Circulation. 2012. 126(16):2020-2035 • Domanski MJ, et al. JAMA. 2011. 305(6) P.585

5. 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

6. 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

7. 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%

8. 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 CK-MB 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

9. Results: Baseline data

10. Results: Biomarker elevation distributions

11. Results: Biomarker and ECG changes • Proportion of patients affected according to: • Biomarker thresholds • Concomitant ECG changes ECG changes: new Q-waves or LBBB on postoperative ECG

12. 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.

13. Results: Adjusted analysis • Adjusted HR for 30-day mortality • Biomarkers and ECG changes as independent predictors of death • 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

14. 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

15. 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