Troponin I elevation increases the risk of death and stroke in patients with atrial fibrillation a RE-LY substudy. Ziad Hijazi, MD

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1 Troponin I elevation increases the risk of death and stroke in patients with atrial fibrillation a RE-LY substudy Ziad Hijazi, MD Uppsala Clinical Research Center (UCR) Uppsala University, Sweden Co-authors: Jonas Oldgren, Ulrika Andersson, Stuart J. Connolly, Michael D. Ezekowitz, Paul A. Reilly, Agneta Siegbahn, Salim Yusuf and Lars Wallentin

2 Disclosures The RE-LY trial was sponsored by Boehringer-Ingelheim Ziad Hijazi Institutional research grant from Boehringer-Ingelheim

3 Background Atrial fibrillation (AF) increases the risk of ischemic stroke by a 5-fold and mortality by two-fold 1 Strategies for identifying AF-patients at risk for stroke and other adverse outcomes are mainly based on clinical variables, such as the CHADS 2 score Troponin is a biomarker of myocardial damage predictive of adverse outcome in patients with various cardiac diseases 2-5 The prevalence of elevated troponin levels and its relation to stroke and other cardiovascular events in patients with AF are unknown 1. Wolf, et al. Stroke 1991;22: Peacock, et al. N Engl J Med 2008;358: Antman, et al. N Engl J Med 1996;335: Omland, et al. N Engl J Med 2009;361: Lindahl, et al. N Engl J Med 2000;343:

4 RE-LY In the RE-LY trial dabigatran 110 mg b.d. or 150 mg b.d. were compared to adjusted-dose warfarin for prevention of stroke and other adverse outcomes in patients with AF 1 Primary endpoint: Stroke or systemic embolism Secondary endpoint: Cardiovascular death, myocardial infarction, pulmonary embolism and major bleeding Median duration of follow-up was 2.0 years Dabigatran 110 mg was non-inferior to warfarin for prevention of stroke, with lower rates of major bleeding and intracranial hemorrhage 2 Dabigatran 150 mg was superior to warfarin concerning stroke with similar rates of major bleeding and lower rates of intracranial hemorrhage 2 1. Ezekowitz, et al. Am Heart J 2009;157: Connolly, et al. N Engl J Med 2009;361:

5 RE-LY Troponin Substudy Hypothesis: Troponin levels are related to outcomes in patients with AF Material: 6224 (out of 18113) patients in the RE-LY trial Blood sampling: Venous blood obtained (EDTA tubes) at randomization Centrifuged within 30 minutes, frozen at -20 C or below Centrally analyzed at UCR laboratory Uppsala, Sweden

6 RE-LY Troponin Substudy Method: Cardiac troponin I (ctni) with Access AccuTnI assay (Beckman Coulter, Inc.) Lowest concentration with a coefficient of variation <10%: ug/l 1, 99th percentile upper reference limit: 0.04 ug/l 2 Patients divided into 4 groups based on ctni levels: 10% Group 1: ctni <0.01 ug/l, n=2681 Group 2: ctni = 0.01 ug/l, n= % 28% Group 3: ctni ug/l, n=1725 Group 4: ctni 0.04 ug/l, n=614 19% 1. Eggers, et al. Circulation 2007;116: Uettwiller-Geiger, et al. Clin Chem 2002;48:

7 Baseline characteristics in relation to troponin I Troponin I (ug/l) < Number of patients Age (yrs) (SD) 70.4 (8.3) 71.5 (8.2) 72.3 (8.2) 71.1 (9.8) Male sex (%) AF type (%) Permanent Congestive heart failure (%) Hypertension (%) Diabetes mellitus (%) Previous Stroke/TIA (%) CHADS 2 score (%) Prior myocardial infarction (%) Coronary artery disease (%) Cox proportional hazards model with troponin I level, treatment, Age, Sex, Smoking status, AF duration, AF type, diabetes, previous stroke/see/tia, coronary artery disease, heart failure, hypertension, treatment with statins and non-study anticoagulants at baseline as covariates No significant interactions between troponin I groups and study treatment effects on outcomes

8 Cumulative Hazard Rate Stroke and systemic embolism in relation to troponin I ug/l ug/l 0.01 ug/l <0.01 ug/l HR 2.24; 95%CI HR 2.03; 95%CI HR 1.65; 95%CI Months p = (effect of ctni group)

9 Cumulative Hazard Rate All cause mortality in relation to troponin I ug/l ug/l 0.01 ug/l <0.01 ug/l HR 3.04; 95%CI HR 2.07; 95%CI HR 1.39; 95%CI Months p < (effect of ctni group)

10 Cumulative Hazard Rate Composite endpoint in relation to troponin I (stroke, systemic embolism, pulmonary embolism, myocardial infarction, CV death) ug/l ug/l 0.01 ug/l <0.01 ug/l HR 3.34; 95%CI HR 2.02; 95%CI HR 1.54; 95%CI Months p < (effect of ctni group)

11 Cumulative Hazard Rate Major bleeding in relation to troponin I ug/l ug/l 0.01 ug/l <0.01 ug/l Months HR 2.11; 95%CI HR 1.64; 95%CI HR 1.35; 95%CI p < (effect of ctni group)

12 Yearly events (%) 238 Composite outcome in relation to Troponin I and CHADS 2 risk score Composite outcome: stroke, systemic embolism, pulmonary embolism, myocardial infarction, CV death ctni (ug/l) 0.01 < CHADS 2 score CHADS 2 risk score: Congestive heart failure, Hypertension, Age 75 years, Diabetes, Prior Stroke or TIA

13 Conclusions Elevated troponin I levels are common in patients with atrial fibrillation Troponin I is a strong and independent predictor of stroke and other adverse outcomes in atrial fibrillation Troponin I may contribute to risk stratification with clinical variables, e.g. CHADS 2 -score, in patients with AF