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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.

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Presentation on theme: "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."— Presentation transcript:

1 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)

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 Infarction 1 :  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 troponin 2  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

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 VariableOverall Cohort N7016 Age, median (IQR)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)

10 Results: Biomarker elevation distributions CK-MB Median, xULN6.2 IQR3.9-10.9 Troponin-I Median, xULN21.4 IQR10.3-54

11 Results: Biomarker and ECG changes Biomarker > Threshold Biomarker > Threshold & ECG Changes ThresholdCK-MBTroponin-ICK-MBTroponin-I 5x ULN61.4%92.0%3.8%4.3% 10x ULN28.0%75.8%2.6%3.9% 20x ULN10.9%52.0%1.6%3.5% 40x ULN3.4%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  Proportion of patients affected according to:  Biomarker thresholds  Concomitant ECG changes

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 Biomarker Threshold CK-MB > Threshold New ECG changes Troponin-I > Threshold New ECG changes 5x ULN 2.3 (1.5-3.5) 1.7 (1.0-2.8)9.2 (1.3-66.5)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)  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


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