High-sensitivity Troponin T Predicts Recurrent Cardiovascular Events in Patients with Stable Coronary Heart Disease: KAROLA Study 8 Year FU

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1 ESC Congress 2011 Paris, France, August KAROLA Session: Prevention: Are biomarkers worth their money? Abstract # High-sensitivity Troponin T Predicts Recurrent Cardiovascular Events in Patients with Stable Coronary Heart Disease: KAROLA Study 8 Year FU W. Koenig 1, L. Breitling 2, H. Brenner 2, D. Rothenbacher 2,3 1 Department of Internal Medicine II - Cardiology, University of Ulm Medical Centre, Ulm, Germany 2 Division of Clinical Epidemiology and Aging Research, German Cancer Research Centre, Heidelberg, Germany 3 Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany

2 Presenter Disclosure Information High-sensitivity Troponin T Predicts Recurrent Cardiovascular Events in Patients with Stable Coronary Heart Disease: KAROLA Study 8 Year FU The following relationships exist related to this presentation: W. Koenig Honoraria for lectures/consultancy to Roche L. Breitling nothing to disclose H. Brenner nothing to disclose D. Rothenbacher nothing to disclose

3 Background Troponins (Tn) are established biomarkers for cardiomyocyte necrosis in acute coronary syndromes (ACS) - even slight elevations are associated with increased adverse events. High-sensitivity (hs) assays have been developed that enable earlier diagnosis with increased sensitivity and only slight decreases in specificity. A cut-off for hstnt has been defined as 14 ng/l which represents the 99 th percentile in a healthy population. So far two studies (Omland et al NEJM 2009, Kavsak et al Clin Chem 2011) have investigated the clinical relevance of slightly elevated TnT levels in selected patients with stable CHD from the PEACE and HOPE trials.

4 Aims of the Study To assess determinants of hstnt in a large cohort of wellcharacterized patients from routine clinical care in Germany (KAROLA cohort). To evaluate the predictive value of elevated levels of TnT for cardiovascular outcomes after adjustment for potential confounders, including potent emerging risk markers, like cystatin C and NT-proBNP.

5 KAROLA HsTnT and Risk of Future CV Events: The KAROLA Cohort Study ,050 men aged years with manifest CHD/ 3 weeks after ACS (inpatient rehabilitation program) Standardized assessment of cardiovascular risk factors Hs TnT and NT-proBNP (Elecsys 170, Roche, Mannheim, Germany, inter-assay CVs % and %. Lp-PLA 2 (diadexus PLAC ); spla2 (ELISA, Cayman Co, USA). CRP (latex enhanced hs immunonephelometry), cystatin C (immunonephelometry, Siemens, Marburg, Germany, inter-assay CVs 6-7%, 16.5%, %, and %, respectively). Qx sent to patients 1, 3, 4 and 8 years after rehab. Endpoint assessment by Qx to GPs (cardiovascular death, non-fatal MI and stroke/tia)

6 KAROLA Statistical Methods The relation of hstnt with CVD events during FU assessed by the Kaplan-Meier and life table method, quantified by means of the log-rank test. The Cox proportional hazards model to assess the independent association of hstnt with risk of secondary CVD events. Measures of model accuracy: Model fit: Likelihood ratios, AIC, BIC Discrimination: C statistics (AUC, 95%) Reclassification: IDI and NRI Calibration: Observed versus expected

7 KAROLA Baseline Characteristics in 1,050 Patients With Clinically Manifest CHD (1) Characteristics at Baseline Age (years) (, SD) Men, n (%) 893 (85.1%) History of myocardial infarction, n (%) 611 (58.2%) History of heart failure, n (%) 129 (12.3%) Clinical score (angiographic evaluation) 1 vessel disease 256 (25.6%) 2 vessel disease 281 (28.1%) 3 vessel disease 448 (44.8%) unknown 50 (4.8%) School education <10 yr, n (%) 627 (59.7%)

8 KAROLA Baseline Characteristics in 1,050 Patients With Clinically Manifest CHD (2) Characteristics at Baseline Body mass index (kg/m 2 ), (, SD) History of diabetes, n (%) 179 (17.1%) Total cholesterol (mg/dl) (, SD) (32.8) LDL-cholesterol (mg/dl) (, SD) (29.1) HDL-cholesterol (mg/dl) (, SD) 39.4 (10.5) C-reactive protein (mg/l) * 3.48 (1.25; 8.40) Creatinine Clearance (ml/min) * 93.2 (78.2; 114.7) Cystatin C (mg/l)* 1.03 (0.93; 1.19) NT-proBNP (pg/ml)* (277.9; ) * median, 25 th and 75 th quantile cut-point

9 HsTnT According to Various Sociodemographic Characteristics, CV Risk Factors, and ECG Findings (1) Sociodemographic characteristics N hstnt, ng/l Median All IQR ( ) Above detection limit Above 99 th percentile Gender Female Age (years) * Kruskall-Wallis-Test > 3 ng/l = 83.1% >14 ng/l = 37.1% p-value* Male <0.0001

10 HsTnT According to Various Sociodemographic Characteristics, CV Risk Factors, and ECG Findings (2) Sociodemographic Characteristics N hstnt, ng/l Median Family status Married p-value* other Body mass index (kg/m 2 ) < > Smoking status Never Ex Current History of diabetes Yes No < History of MI Yes * Kruskall-Wallis-Test No

11 HsTnT According to Various Sociodemographic Characteristics, CV Risk Factors, and ECG Findings (3) * Kruskall-Wallis-Test Clin. Characteristics N hstnt, ng/l, Median p-value* History of hypertension Yes No History of heart failure Yes No Angiographic score Zero/one (number of affected vessels) Two Three < Initial management of CHD Conservative PCI CABG < Left ventricular function* No/only little (degree of impairment) - Modest/severe Unknown <

HsTnT According to Various Sociodemographic Characteristics, CV Risk Factors, and ECG Findings (4) ECG Characteristics N hstnt, ng/l, Median p-value* Sinus tachycardia Yes 48 15.15 No 1002 10.60 0.

12 HsTnT According to Various Sociodemographic Characteristics, CV Risk Factors, and ECG Findings (4) ECG Characteristics N hstnt, ng/l, Median p-value* Sinus tachycardia Yes No Atrial flutter / fibrillation Yes No Left ventricular hypertrophy Yes No Anterior wall infarction Yes No < Posterior wall infarction Yes No * Kruskall-Wallis-Test

13 Partial Spearman Rank Correlation Coefficients (R) (1) hstnt, ng/l R p-value Total cholesterol [mmol/l] HDL cholesterol [mmol/l] LDL cholesterol [mmol/l] Leukocytes C-reactive protein [mg/l] 0.19 < Interleukin-6 [pg/ml] 0.15 < Adiponectin [µg/ml] 0.17 <

14 Partial Spearman Rank Correlation Coefficients (R) (2) hstnt, ng/l R p-value Creatinine clearance [ml/min] < Cystatin C [mg/l] 0.32 < NT-proBNP [pg/ml] 0.61 < Lp-PLA 2 mass [ng/ml] 0.18 < Lp-PLA 2 activity [nmol/min/ml] spla 2 mass [ng/ml] 0.16 < spla 2 activity [nmol/ml/min] 0.13 <

5 0 500 1000 1500 2000 2500 3000 3500 HsTnT (ng/l) N Secondary CVD Event During FU; N (Incidence*) p-value** <

15 Proportion of Event-free Survivors KAROLA 1.0 Kaplan-Meier Estimates of Secondary Fatal and Non-Fatal CVD Events Q1 Q2 Q3 Q HsTnT (ng/l) N Secondary CVD Event During FU; N (Incidence*) p-value** < 5.03 (bottom quartile (11.4) > (15.1) > (21.3) >18.6 (top quartile) (37.5) < (21.0) * per 1000 patient years, ** Log Rank Test FU [days]

16 Association of hstnt Concentration at Baseline With Fatal and Non-Fatal CV Events During Follow-Up HsTnT [ng/l] HR (95% CI) Adjusted for age and gender Results of Multivariate Analysis HR (95% CI) *Adjusted for multiple covariates Bottom Quartile 1 referent 1 referent 1 referent HR (95% CI) Adjusted for multiple covariates Second 1.21 ( ) 1.25 ( ) 1.26 ( ) Third 1.60 ( ) 1.63 ( ) 1.54 ( ) Top Quartile 2.88 ( ) 2.83 ( ) 2.27 ( ) p for trend < p for trend < p for trend < Per unit increase** 1.48 ( ) 1.45 ( ) 1.30 ( ) * adjusted for age, gender, smoking status, history of diabetes mellitus, initial management of CHD (conservative, PCI, CABG), rehabilitation clinic, HDL-cholesterol, LDL-cholesterol, treatment with lipid-lowering drugs (according to variable selection criteria) adjusted for above listed variables (*) and NT-proBNP, CRP and Cystatin C ** after log-transformation

KAROLA Measures of Model Accuracy Without and With hstnt (1) Basic Model* Basic Model plus hstnt Model fit LR 53.84 (df = 11, p < 0.0001) 72.83 (df = 12, p < 0.0001) AIC 1984.9 1967.8 BIC 2018.0 2003.

17 KAROLA Measures of Model Accuracy Without and With hstnt (1) Basic Model* Basic Model plus hstnt Model fit LR (df = 11, p < ) (df = 12, p < ) AIC BIC Discrimination C-statistic (AUC, 95% CI) ( ) ( ) Reclassification IDI NRI (p<0.001) 17.2% (p<0.029) IDI=Integrated Discrimination Improvement, NRI=Net reclassification index LR=Likehood ratio; AIC=Akaike`s Information Criterion; BIC=Bayesian Information Criterion

18 KAROLA Measures of Model Accuracy Without and With hstnt (2) Basic Model* Calibration**: Observed vs. Expected events (p) Basic Model plus hstnt Bottom quintile 15 / 12.1 (0.400) 12 /10.3 (0.593) 2 nd quintile 14 / 20.1 (0.176) 15 / 17.2 (0.601) 3 rd quintile 30 / 25.5 (0.375) 24 / 24.9 (0.864) 4 th quintile 34 / 34.7 (0.906) 38 / 33.6 (0.449) Top quintile 57 / 57.6 (0.933) 61 / 64.1 (0.701) *adjusted for age, gender, smoking status, history of diabetes mellitus, initial management of CHD (conservative, PCI, CABG), rehabilitation clinic, HDL-cholesterol, LDL-cholesterol, treatment with lipid-lowering drugs (according to variable selection criteria) ** May-Hosmer`s simplification of the Gronnesby-Borgan test: patients were divided into quintiles according to their rank in an estimated risk score (p> 0.05 for comparison of observed with expected cases indicate good model calibration.

19 KAROLA Summary and Conclusions In this routine setting of patients with stable manifest CHD, mostly after an ACS, hstnt is a strong predictor of long-term prognosis even in extensively adjusted models. However, before hstnt is routinely measured in these patients, more data are needed to further prove its clinical utility. Prediction might be further improved by the combination of various biomarkers reflecting different pathophysiological pathways.

20 Department of Cardiology University of Ulm Medical Center The New York Times, Sunday May 8, 2005 University of Ulm Medical Center

Long-term prognostic value of N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) changes within one year in patients with coronary heart disease

Long-term prognostic value of N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) changes within one year in patients with coronary heart disease D. Dallmeier 1, D. Rothenbacher 2, W. Koenig 1, H. Brenner