DECLARATION OF CONFLICT OF INTEREST

DECLARATION OF CONFLICT OF INTEREST

Risk Stratification in Antithrombotic Management: Is There Room for Improvement? August 28, 2011 Elaine M. Hylek, MD, MPH Boston University

DISCLOSURE INFORMATION Research: NIH/NINDS, NIH/NHLBI Executive Steering Committee ARISTOTLE trial- Sponsors-BMS and Pfizer; Executive Steering Committee ORBIT-AF Registry- Sponsor-Johnson & Johnson, Ortho-McNeil Advisory Boards: Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Ortho-McNeil, Merck, Pfizer Lecture Honorarium: Bayer, Boehringer Ingelheim

Stanford Stroke Center, Albers G.

TEE depicting a large LAA thrombus attached to the lateral wall Hesse, B. et al. Circulation 2006;113:e456-457e

Efficacy of Warfarin in Atrial Fibrillation Five Randomized Trials in Non-Rheumatic AF Study Warfarin (#) Cont. (#) INR RR p-value AFASAK 335 336 2.8-4.2 60% 0.027 SPAF 210 211 2.0-4.5 67% 0.01 BAATAF 212 208 1.5-2.7 86% <0.05 CAFA* 187 191 2.0-3.0 45% 0.25 SPINAF 260 265 1.4-2.8 79% 0.001 *Stopped early due to published positive results 68% overall risk reduction for stroke

Hazards of Anticoagulant Medications #1 in 2003 and 2004 in the number of mentions of deaths for drugs causing adverse effects in therapeutic use 1 Warfarin-6% of 702,000 ADEs treated in ED per year; 17% require hospitalization 1 21 million warfarin prescriptions in 1998>>>31 million in 2004 2 The incidence AC-related intracranial hemorrhage quintupled during this time period 3 1 Wysowski DK, et al. Arch Intern Med. 2007;167:1414-1419. 2 Budnitz DS, et al. JAMA. 2006;296:1858-1866. 3 Flaherty ML, et al. Neurology. 2007;68:116-121.

Optimizing Benefit and Reducing Risk Hemorrhage Thrombosis AF stroke associated with a 30-day mortality of 24%.

Validation of Clinical Classification Schemes for Predicting Stroke Results From the National Registry of Atrial Fibrillation CHADS 2 Score Points Congestive heart failure = 1 Hypertension = 1 Age 75 years of age = 1 Diabetes = 1 Prior stroke/tia/systemic embolus = 2 82 y.o. male with HTN and prior stroke (CHADS 2 Score = 4) Gage B, et. al. JAMA. 2001;285:2864-2870

Estimated Stroke Risk by CHADS 2 Score CHADS 2 Score Adjusted Stroke Rate (%/y) 0 1.9 (1.2 to 3.0) 1 2.8 (2.0 to 3.8) 2 4.0 (3.1 to 5.1) 3 5.9 (4.6 to 7.3) 4 8.5 (6.3 to 11.1) 5 12.5 (8.2 to 17.5) 6 18.2 (10.5 to 27.4) Gage B, et al. JAMA 2001; 285:2864-2870

Risk Categorization, Incidence of TE* and Predictive Ability for Risk Schema among the Euro Heart Survey Patients Categorization of TE Risk (% in risk category) Predictive ability Low Intermediate High c-statistic AFI 1994 16.7 12.2 71.1 0.573 SPAF 1999 26.2 44.8 29.0 0.549 CHADS 2 -revised 20.4 34.9 44.7 0.586 Framingham 48.3 41.5 10.2 0.638 ACCP 2008 19.6 33.4 47.0 0.574 *Ischemic *Ischemic stroke, stroke, pulmonary pulmonary embolism embolism or peripheral or peripheral embolism embolism Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijns HJGM. Chest 2010

Stroke in AF Working Group Systematic review: 4 consistent independent risk factors for stroke: hypertension, age, diabetes, prior stroke/tia For patients with AF who have 1 or more of the following less well-validated risk factors either aspirin or a vitamin K antagonist is reasonable for prevention of TE: age 65 to 74 y, female gender, or CAD. Neurology 2007;69:546-54 Circulation 2006; August. Neurology 2007;69:546-54

CHA 2 DS 2 -VASc Congestive heart failure/lv dysfunction =1 Hypertension =1 Age 75 =2 Diabetes mellitus =1 Stroke/TIA/TE =2 Vascular disease (MI, PAD, aortic plaque) =1 Age 65-74 =1 Sex category (Female gender) =1 0=low risk; 1=intermediate risk; 1=high risk Lip GYH, et al. Chest 2010;137:263-72

Risk Categorization, Incidence of TE* and Predictive Ability for Risk Schema among the Euro Heart Survey Patients Categorization of TE Risk (% in risk category) Predictive ability Low Intermediate High c-statistic AFI 1994 16.7 12.2 71.1 0.573 SPAF 1999 26.2 44.8 29.0 0.549 CHADS 2 -revised 20.4 34.9 44.7 0.586 Framingham 48.3 41.5 10.2 0.638 ACCP 2008 19.6 33.4 47.0 0.574 CHA 2 DS 2 -VASc 9.2 15.1 75.7 0.606 *Ischemic stroke, pulmonary embolism or peripheral embolism Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijns HJGM. Chest 2010

Risk Categorization, Incidence of TE and Predictive Ability for Risk Schema among the Euro Heart Survey Patients CHA 2 DS 2 -VASc Low Risk 0% CHADS 2 Low Risk 1.4% SPAF Low Risk 1.8% Intermediate Risk 0.6% vs 3% Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijns HJGM. Chest 2010

Wyse G, Gersh B. Circulation.

1. Obesity What about other Touted Risk Factors for Stroke in AF? 2. Inflammation 3. Renal dysfunction 4. Genetics 5. Echocardiography-LAA anatomy, LAA emptying velocity 6. Endothelial dysfunction-vwf 7. D-dimer, markers of platelet activation, tissue factor (TF) induction in mononuclear cells (MNCs) and granulocytes 8. New onset AF

Age- and sex-adjusted hazards of progression from paroxysmal to permanent AF by BMI Tsang T S et al. Eur Heart J 2008;29:2227-2233 Published on behalf of the European Society of Cardiology. All rights reserved. The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Touted Pathogenetic Mechanisms Linking Obesity to Risk of AF Correlation with hypertension, heart failure, diabetes mellitus, metabolic syndrome Left atrial diameter Obstructive sleep apnea Epicardial/pericardial fat-secretion of adipokines:? role of inflammation (IL-6, TNFα, CRP) on cardiac contractile and vascular dysfunction

Epicardial and Perivascular Fat Ouwens DM, et al. The role of epicardial and perivascular adipose tissue in the pathophysiology of cardiovascular disease. J Cell Mol Med. 2010 Aug 16. Thanassoulis G, et al. Pericardial fat is associated with prevalent atrial fibrillation. Circ Arrhythm Electrophysiol. 2010 Aug 1;3. Batal O, et al. Left atrial epicardial adiposity and atrial fibrillation. Circ Arrhythm Electrophysiol. 2010 Aug 1;3.? local effect of adipose tissue perhaps mediated by secretion of cytokines??? atrial tissue

? Role of Inflammation Bruins P, et al. Circulation. 1997;96:3542-8. Noted that levels of IL-6 rose sharply and peaked within 6 hours of cardiac surgery. CRP peaked on second post-op day CRP-complement complexes peaked 2 nd to 3 rd post-operative day Atrial arrhythmias also peak within 2-3 days

Role of Inflammatory Cells (Nat Med 2010) Neutrophil Azurophilic primary granules contain myeloperoxidase (MPO). MPO is released by activated neutrophils generating HOCl. MPO also generates reactive nitrogen intermediates (NOx) deleterious to endothelium.

Myeloperoxidase Deficient Mice (mpo / ) Wild Type (control): MPO Knockout: Marked decrease in atrial fibrosis, reduced matrix metalloproteinase activity, and decreased susceptibility to AF. Rudolph V. Nat Med. 2010 April ; 16(4): 470 474

Inflammatory Infiltrate in Atrium Activated Neutrophils Myeloperoxidase HOCl + Reactive Nitrogen Intermediates Endothelial damage, MMP, Fibrosis Tissue conducive to AF

Association of left atrial fibrosis detected by delayedenhancement MRI and risk of stroke in patients with atrial fibrillation Daccarett M, et al. JACC 2011 Feb 15;57(7):831-8

Ramoni R, et al. Stroke 2009;40 Ramoni R, et al. Stroke 2009;40 STROKE GENOMICS

Challenges for Further Refinement of Risk Prediction Tools Universal application Practical Cost Clinical endpoints and incremental benefit? Applicable to all AF types: Inheritable AF, Focal, Complex, Post-operative AF [Pathophysiological classification for AF type: Kirchhof P, Lip GYH, et al. 3 rd AF Competence NETwork/EHRA consensus conference. Europace. 2011 Jul 26]

Cumulative Incidence of Major Bleeding in the First Year Among Patients Newly Starting Warfarin by Age 0.00 0.02 0.04 0.06 0.08 0.10 0 100 200 300 400 Days on Warfarin Age <80 Age >=80 Hylek EM et al, Circulation 2007;115(21):2689-2696. Hylek EM et al, Circulation 2007;115(21):2689-2696.

Age and Gastrointestinal Hemorrhage THE FACTS: Incidence of UGIB and LGIB increase with age. 70% of acute UGIB occur > 60 years of age. Incidence of LGIB increases 200-fold from the 3 rd to 9 th decade of life..

46% mortality 17% major deficit 2/3 occur with an INR in 2.0-3.0 range OR 80 years of age 2.8 (1.3 to 5.8) p<0.001 Hylek EM, Singer DE. Ann Intern Med 1994

Risk of Stopping Therapy in the First Year Among Patients Newly Starting Warfarin by Age 0.0005.001.0015.002 0 100 200 300 400 Days on Warfarin Age <80 Age >=80 Hylek EM et al, Circulation 2007;115(21):2689-2696.

Risk Stratification for Major Hemorrhage HASBLED Score Points Hypertension (SBP >160mmHG) = 1 Abnormal renal or liver fxn = 1 or 2 Stroke = 1 Bleeding tendency = 1 Labile INRs (if on warfarin) = 1 Elderly (e.g. age >65 ) = 1 Drugs (e.g. NSAIDs, aspirin) or = 1 or 2 alcohol abuse Lip, GYH, et al. (J Am Coll Cardiol 2011;57:000 00)

How Would you Use this Information? Address modifiable risk factors Follow high risk patients more closely Reinforce early warning signs of bleeding Reconsider risk/benefit for those patients with high bleeding risk and low risk of stroke

CONCLUSION Our current risk stratification tools for ischemic stroke work modestly well. Incorporation of biomarkers, genomics, radiologic imaging will be challenged by cost, availability, and their added incremental value. Ris k factors for stroke overlap significantly with risk factors for hemorrhage making it difficult to discriminate risk in clinical practice. Risk of both ischemic stroke and major hemorrhage increase with increasing number of risk factors. More research is needed to better refine risk, explore temporal associations with risk, determine applicability to different AF types.