Antithrombotic Therapy in Patients with Atrial Fibrillation

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1 Antithrombotic Therapy in Patients with Atrial Fibrillation June Soo Kim, M.D., Ph.D. Department of Medicine Cardiac & Vascular Center, Samsung Medical Center Sungkyunkwan University School of Medicine

2 Classification of AF First-detected: 1 st detected episode Paroxysmal: self-terminating < 7 days Persistent: not self-terminating > 7 days Permanent: cardioversion failed or not attempt

3 Clinical Significance of AF The most common arrhythmia 1/3 of all hospitalizations for cardiac rhythm disturbances The prevalence of AF increases with age Associated with an increased risk of stroke, heart failure, and all-cause mortality

4 Prevalence of AF (Go et al., JAMA 2001;285:2370-5)

5 Projected Prevalence of AF in the USA (Miyasaka et al., Circulation 2006;114:119-25)

6 Projected Number of Patients With AF in the USA (Go et al., JAMA 2001;285:2370-5)

7 Stroke Rates in Relation to Age (Atrial fibrillation Investigators, Arch Intern Med 1994;154: )

8 Spontaneous Echo Contrast in Left Atrial Appendage Thrombus in Left Atrial Appendage

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10 Background Warfarin was prescribed to 45% of AF patients in the United States. (Walker et al. Heart Rhythm 2008;5: ) 24.7% of AF patients received appropriate antithrombotic therapy in Taiwan. Bleeding risk factors, hypertension, coronary artery disease, throtoxicosis, and old age were associated with low rates of warfarin use. (Lin et al. Clin Ther 2008;30: ) There are racial/ethnic differences in the prevalence of certain polymorphisms in genes that influence warfarin pharmacokinetics and pharmacodynamics (e.g. cytochrome P450 2C9 and vitamin K epoxide reductase). The Asian population generally appear to require the lowest daily dose of warfarin to maintain a given INR target, with the white population requiring an intermediate daily dose and the black population requiring the highest daily dose. (Shen et al. CNS Drugs. 2008;22:815-25)

11 Pharmacological Treatment Options Aspirin 81~325mg daily Aspirin 325mg daily plus low-intensity, fixed-dose warfarin (target INR 1.2 ~ 1.5) Aspirin 75~100mg daily plus clopidogrel 75mg daily Adjusted-dose warfarin (target INR 2~3) Surgical obliteration of LAA Percutaneous LAA transcatheter occlusion

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13 Cumulative Mortality in the Rhythm-Control Group and the Rate-Control Group (Wyse et al. N Engl J Med 2002:347: )

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16 Conclusion Oral anticoagulation therapy is superior to clopidogrel plus aspirin for prevention of vascular events in patients with atrial fibrillation at high risk of stroke, especially in those already taking oral anticoagulation therapy. (Lancet 2006; 367: )

17 (Lancet 2006; 367: )

18 Risk Factors of Thromboembolism High-Risk Factors Previous stroke, Transient ischemic attack, Embolism Mitral stenosis Prosthetic heart valve Moderate-Risk Factors Age > 75 years Hypertension Heart failure LV EF <35% Diabetes Mellitus Less Validated or Weaker Risk Factors Female gender Age 65 to 74 years Coronary artery disease Thyrotoxicosis (Fuster et al. ACC/AHA/ESC Practice Guidelines Circulation 2006;114:700-52)

19 Stroke Risk in Nonvalvular AF C Cardiac failure H Hypertension A Age D Diabetes S2 Stroke (Walraven et al., Arch Intern Med 2003;163:936-43; Gage et al., JAMA 2001;285: )

20 Antithrombotic Therapy Risk Category Recommended Therapy No risk factors One moderate-risk factor Aspirin, 81 to 325mg daily Aspirin, 81 to 325mg daily or Warfarin (INR 2.0 to 3.0, target 2.5) Any high-risk factor or Warfarin (INR 2.0 to 3.0, target 2.5)* More than 1 moderate-risk factor If mechanical valve, target INR greater than 2.5 ((Fuster et al. ACC/AHA/ESC Practice Guidelines. Circulation 2006;114:700-52)

21 RR of 61% (95% CI 47% to 71 %) (Hart et al. Ann Intern Med 1999;131: )

22 RR of 19% (95% CI 2% to 34 %) (Hart et al. Ann Intern Med 1999;131: )

23 Stroke With Intermittent Atrial Fibrillation:Incidence and Predictors During Aspirin Therapy Robert G. Hart, MD,* Lesly A. Pearce, MS, Robert M. Rothbart, MD, FACC, John H. McAnulty, MD, FACC, Richard W. Asinger, MD, FACC,\ Jonathan L. Halperin, MD, FACC, for the Stroke Prevention in Atrial Fibrillation Investigators CONCLUSIONS: In this large cohort of AF patients given aspirin, those with intermittent AF had stroke rates similar to patients with sustained AF and similar stroke risk factors. Many elderly patients with recurrent intermittent AF have substantial rates of stroke and likely benefit from anticoagulation. High-risk patients with intermittent AF can be identified using the same clinical criteria that apply to patients with sustained AF. (J Am Coll Cardiol 2000;35:183 7)

24 (Hart et al. J Am Coll Cardiol. 2000;35:183-7)

25 Antithrombotic Therapy in Clinical Practice Difficulty in maintaining target INR level Bleeding complications

26 (Hylek et al. Ann Intern Med 1994;120: ) (Oden et al. Thromb Res 2006;117:493-9)

27 Difficulty in Maintaining Target INR

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32 Major Bleeding Complications in AF Studies Studies Annual rate of Annual rate of Annual rate of major bleedings(%) Warfarin Control major bleedings(%) Aspirin Control major bleedings(%) Warfarin Aspirin AFASAK- I AFASAK-II BAATAF CAFA SPAF-I SPAF-II < 75 > SPINAF EAFT

33 New Antithrombotic Drugs

34 Targets for Novel Anticoagulants in the Coagulation Pathway (betrixaban) (Bates et al. Br J Haematol 2006;134:3-19)

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38 Trend of warfarin therapy in Korean patients with atrial fibrillation - KORean Atrial Fibrillation (KORAF) Study - June Soo Kim, M.D., Young Soo Lee, M.D., Yoon Nyun Kim, M.D., Young-Hoon Kim, M.D., and KORAF investigators

39 Included patients Total enrolled patients: 5,569 Gender: Male 3,174 (56.9%) Mean age: 63.6 ± 12.3 years

40 Antithrombotic therapy in Korean patients with atrial fibrillation 24.3% 28.4% 47.3% warfarin antiplatelet none

41 Factors limiting warfarin use 35.8% 37.7% 0.2% 13.6% 3.7% 1.8% 1.8% 1.8% 1.6% 0.2% 1.8% Intolerance Poor Compliance Older age Uncomfortable Bleeding Dementia High-risk patients High risk to Bleeding Reject Uncontrolled HTN Unknown

42 INR & daily warfarin dose INR daily warfarin dose (mg) (weekly warfarin dose: 25.9 mg)

43 Weekly warfarin dose among different ethnic groups (Dang et al., Ann Pharmacother. 1005;39: )

44 INR level according to age groups Total Male Female Total p < INR INR Total Male Female Total (Yrs) Total Male Female

45 Daily warfarin dose according to age groups Total Male Female Total p <0.001 <0.001 <0.001 Daily warfarin dose (mg) Daily warfarin dose(mg) Total Male Female Total (Yrs) Total Male Female

46 Proportion of INR range of 2-3 according to age groups Total Male Female Total % 43.2 % 41.7 % 42.5 % 39.2 % 47.9 % 42.6 % 41.4 % 45.1 % 41.5 % 43.2 % 39.6 % 46.4 % 40.7 % 41.7 % 40.9 % 42.8 % 38.8 % Proportion of optimal INR level (%) Total Total Male Female (Yrs)

47 Proportion of INR level 4.1 % 1.2 % INR 42.4 % 13.2 % 29.2 % 19.0 % 32.3 %

48 Small-scaled studies in Korean AF patients How well does the target INR level maintain in warfarin-treated patients with nonvalvular atrial fibrillation (Kim et al., Yonsei Med J in press) Factors affecting the interindividual variability of warfarin dose requirement in adult Korean patients (Cho et al., Pharmacogenomics 2007;8:329-37)

49 How well does the target INR level maintain in warfarin-treated patients with nonvalvular atrial fibrillation Jun Hyung Kim, M.D., Young Bin Song, M.D., Dae Hee Shin, M.D., Je Sang Kim, M.D., Young Kun On, M.D., June Soo Kim, M.D. Division of Cardiology, Department of Medicine, Cardiac and Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (Kim et al., Yonsei Med J in press)

50 INR stability in Korean patients with nonvalvular AF INR Stability: 60.9 ± 14.9 % (N=129) INR stability = 100 X number of INRs within 2.0 to 3.0 / total number of INR measurements after first achievement of adequate INR range (%) (Kim et al., Yonsei Med J in press)

51 Correlation between weekly warfarin dose and age R 2 = P < (Kim et al., Yonsei Med J in press)

52 Factors affecting INR stability 3.1% 1.1% 13.2% 10.0% 19.8% 52.8% Unknown Noncompliance Food Drug Alcohol herbal remedy (Kim et al., Yonsei Med J in press)

53 Role of CYP2C9 & VKORC1 in warfarin metabolism (Yin et al., Thrombosis Research 2007;120:1-10)

54 CYP2C9*1/*3 intermediate metabolizer 7 Warfarin 4mg/day 2-3mg/day 1-2mg/day 6 5 PT INR Date

55 CYP2C9 polymorphisms affecting warfarin metabolism (Gage, Hematology 2006:467-73)

56 Frequencies of VKORC1 (Yin et al., Thrombosis Research 2007;120:1-10)

57 Factors affecting the interindividual variability of warfarin dose requirement in adult Korean patients Hyun-Jung Cho 1, Kie-Ho Sohn 2, Hyang-Mi Park 2, Kyung-Hoon Lee 3, Bo Young Choi 4, Seonwoo Kim 5, June-Soo Kim 6, Young-Keun On 6, Mi-Ryung Chun 1, Hee-Jin Kim 1, Jong-Woo Kim 1, Soo-Youn Lee 1 Sungkyunkwan University School of Medicine, Department of Laboratory 1, Department of Pharmacy 2, Department of Molecular Cell Biology 3, Department of Medicine 6, Clinical Trial Center 4, Biostatistics Unit, Samsung Biomedical Research Institute 5, Samsung Medical Center, Seoul, Korea (Cho et al., Pharmacogenomics 2007;8:329-37)

58 (Cho et al., Pharmacogenomics 2007;8:329-37)

59 (Cho et al., Pharmacogenomics 2007;8:329-37)

60 Conclusions Warfarin is currently the most effective antithrmobotic oral drug to prevent thromboembolism in atrial fibrillation. Warfarin is underused in Korean patients with atrial fibrillation due to multiple factors. Korean patients require a much lower maintenance dose of warfarin to reach optimal INR compared with Caucasians. New novel anticoagulants are now undergoing large-scale studies for stoke prevention in patients with AF.