1. Evidence That D-dimer Levels Predict Subsequent Thromboembolic and Cardiovascular Events in Patients with Atrial Fibrillation during Oral Anticoagulant Therapy Tsuneaki SADANAGA Ueki Hospital, Kumamoto, Japan

2. 【 Purpose 】 Atrial fibrillation is associated with hemostatic abnormality even during oral anticoagulant therapy. Hypothesis: elevated D-dimer levels predict thromboembolic and cardiovascular events in patients with atrial fibrillation during oral anticoagulant therapy

3. Control 28 – 457 days ( INR 1.5-3.7) Oral anticoagulant therapy decreased D-dimer levels (30 paroxysmal Af, 13 chronic Af, n=43) p <0.01 0.5µg/ml 12/43 =28%, however… 29/43 =67% (µg/ml) D-dimer levels

4. 【 Methods 】 Single center, prospective, observational study Patients with atrial fibrillation (269 patients, 74±9 y/o, 152 male, 157 paroxysmal, 20 prosthetic valve) receiving anticoagulant therapy with warfarin are included. Exclusion: aortic aneurysm, deep vein thrombosis, malignancy (terminal stage), non-compliance (dementia) Entry periods: January 2006 - April 2007 Observational periods: January 2006 - December 2008 Follow-up duration: 756±221 (1-1091, median: 736) days D-dimer was measured only during entry periods PT-INR was measured every 1-2 month during observational periods

5. End points 1.Thromboembolic events (cerebral infarction, transient ischemic attack, peripheral embolism) 2.Combined cardiovascular events (thromboembolic events, cerebral hemorrhage, myocardial infarction, cardiovascular death) Secondary analysis Bleeding complications (intracranial bleeding, gastrointestinal bleeding requiring transfusion) The study protocol was approved by the institutional Ethics Committee and informed written consent was obtained from all the patients included in this study.

6. 6 lost to follow Follow-up 385-700 day → included in the analysis 4 discontinuation of warfarin Follow-up374-630 day → included in the analysis 1 bleeding (accidental fall) 3 physician’s decision (no recurrence of pAf) 259 (96%) completed follow-up at the end of observational periods or reached endpoints 【 Follow-up 】

7. HHD IHD Valve HCM DCM None HHD: hypertensive heart disease, IHD: ischemic heart disease, Valve: valvular heart disease, HCM: hypertrophic cardiomyopathy DCM: dilated cardiomyopathy Underlying heart disease (%)

8. CHF HBP Age>75y/o DM Stroke Prosthetic Valve Risk Factors for embolism CHF: Congestive heart failure. NYHA ≧ II, HBP: systolic BP ≧ 140, diastolic BP ≧ 90 mmHg, or medication, DM: Diabetes mellitus. fasting blood glucose ≧ 126mg/dl, HbA1c ≧ 6.1%, medication, or insulin use (%)

9. CHADS2 score distribution C: Congestive heart failure, H: Hypertension, A: Age ≧ 75y/o D: Diabetes mellitus, S: Stroke, * 26 patients. 24: Age ≧ 65y/o (%) * (n=245, 24 valvular AF are excluded)

10. Relationship between D-dimer levels and PT-INR 0.5µg/ml 63(23%) PT-INR (µg/ml) 1 2 3 4 230 (86%) D-dimer levels

11. D-dimer (+) (n= 63) D-dimer (-) (n=206) (≥ 0.5 μg/ml ) ( < 0.5 μg/ml ) p value Gender （ Male,%)5657n.s. Age (y/o)79±872±9p<0.01 Chronic Af (%)4939n.s. INR2.0±0.8 1.9±0.5n.s. D-dimer (μg/ml ) 1.4±1.3 0.2±0.2p<0.01 CHADS2 score (n=245) * 2.7±1.4(n=55)1.7±1.2(n=190)p<0.01 CHF(%)6735p<0.01 Hypertension (%)5257n.s. Age≥ 75y/o (%)7139p<0.01 Diabetes mellitus(%)2523n.s. History of Stroke (%)219p=0.014 【 Characteristics of patients with high D-dimer levels 】 * 24 patients with valvular AF are excluded

12. 【 Determinants of high D-dimer levels by logistic regression analysis 】 Univariate Analysis Genderp=0.86 Chronic Afp=0.16 PT-INR(entry)p=0.36 CHFp<0.01 Hypertensionp=0.54 Age≥75 y/op<0.01 Diabetes mellitusp=0.67 History of strokep<0.01 Multivariate Analysis Odds ratio (95% CI) Age≥75 y/o p<0.01 3.14 (1.66-5.94) CHF p<0.012.87 (1.54-5.36) History of strokep=0.0452.29 (1.02-5.16)

13. 【 Results 】 D-dimer (+) D-dimer (-) (n= 63) (n=206) p value Thromboembolic events82p<0.01 Cardiovascular events189p<0.01 Total mortality148p<0.01 Bleeding complications81p<0.01 Thromboembolic events101.8 % /year Cardiovascular events274.8 %/ year Total mortality223.9 %/year Bleeding complications91.6 %/year

14. Follow-up duration (day) Thromboembolic events D-dimer < 0.5μg/ml (n = 206) Event free rate p < 0.01 (Log rank test) 8 cerebral infarction, 1 transient ischemic attack, 1 peripheral embolism D-dimer ≥ 0.5μg/ml (n = 63) 0.4 0.5 0.6 0.7 0.8 0.9 1.0 020040060080010001200

15. 【 Risk factors for thromboembolic events by Cox proportional hazard analysis 】 Univariate Analysis D-dimerp<0.01 INR<1.5 (at the time of event)p<0.01 Gender p=0.30 CHFp=0.012 Hypertensionp=0.36 Age≥75 y/op=0.36 Diabetes mellitusp=0.60 History of strokep<0.01 Multivariate Analysis Hazard ratio (95% CI) D-dimer p=0.0137.72 (1.53-38.8) History of strokep<0.015. 67 (1.57-20.4) CHF p=0.0597.66 (0.93-63.1)

16. Follow-up duration (day) Combined cardiovascular events D-dimer < 0.5μg/ml (n = 206) p < 0.01 (Log rank test) Event free rate 10 thromboembolisms, 9 deaths from heart failure, 3 sudden deaths, 2 myocardial infarctions, and 3 cerebral hemorrhages D-dimer ≥ 0.5μg/ml (n = 63) 0.4 0.5 0.6 0.7 0.8 0.9 1.0 020040060080010001200

17. 【 Risk factors for combined cardiovascular events by Cox proportional hazard analysis 】 Univariate Analysis D-dimerp<0.01 Genderp=0.35 CHFp<0.01 Hypertensionp=0.45 Age≥75 y/op<0.01 Diabetes mellitusp<0.01 History of strokep<0.01 Multivariate Analysis Hazard ratio (95% CI) D-dimer p<0.014.20 (1.83-9.68) CHF p<0.0112.5 (2.92-53.7) Diabetes mellitusp=0.0472.18 (1.01-4.71) History of strokep<0.014.08 (1.84-9.08)

18. Follow-up duration (day) Total mortality D-dimer < 0.5μg/ml (n = 206) D-dimer ≥ 0.5μg/ml (n = 63) Event free rate p < 0.01 (Log rank test) 18 cardiovascular deaths, 3 pneumonias, 1 lung cancer 0.4 0.5 0.6 0.7 0.8 0.9 1.0 020040060080010001200

19. 【 Risk factors for total mortality by Cox proportional hazard analysis 】 Univariate Analysis D-dimerp<0.01 Genderp=0.85 CHFp<0.01 Hypertensionp=0.46 Age≥75 y/op<0.01 Diabetes mellitusp<0.01 History of strokep<0.01 Multivariate Analysis Hazard ratio (95% CI) D-dimer p=0.0462.67 (1.02-7.00) CHF p<0.0122.7 (2.99-172) History of strokep<0.015.52 (2.11-14.4) Diabetes mellitusp=0.0642.25 (0.95-5.33) Age≥75y/op=0.0742.70 (0.91-8.03)

20. Follow-up duration (day) Bleeding complications 4 intracranial hemorrhage, 5 gastrointestinal bleeding requiring transfusion Event free rate 020040060080010001200 D-dimer < 0.5μg/ml (n = 206) p < 0.01 (Log rank test) D-dimer ≥ 0.5μg/ml (n = 63) 0.4 0.5 0.6 0.7 0.8 0.9 1.0

21. 【 Risk factors for bleeding complications by Cox proportional hazard analysis 】 Univariate Analysis D-dimerp<0.01 INR>3.0(at the time of bleeding)p<0.01 Gender(female)p=0.054 CHFp=0.33 Hypertensionp=0.98 Agep<0.01 Diabetes mellitusp=0.15 History of strokep<0.01 Multivariate Analysis Hazard ratio (95% CI) D-dimer p<0.01 18.1 (2.2-150) INR>3.0(at the time of bleeding)p<0.0126.4 (5.80-120) Gender(female)p=0.01210.8 (1.69-68) History of strokep=0.0136.84 (1.51-31.1)

22. 【 Conclusion 】 Persistent elevation of D-dimer Levels despite proper anticoagulant therapy can predict thromboembolic and cardiovascular events in patients with atrial fibrillation Further larger scale, multicenter studies are needed to confirm these findings.