1. Aspirin Resistance: Significance, Detection and Clinical Management of This Real Phenomenon Webcast May 10 th, 2004 Sponsored by

2. Educational Objectives Define Aspirin Resistance, Incidence and Prevalence in the Population Describe the Mechanisms for Aspirin Resistance and Reduced Platelet Inhibition Understand the Importance of Aspirin Resistance Testing, Methods of Detection Understand Clinical Implication and Clinical Decisions in Aspirin Resistant Patients

3. Faculty Steven Steinhubl, M.D. Director of Cardiovascular Research and Education Associate Professor of Medicine University of Kentucky, Lexington, Kentucky Daniel I. Simon, M.D. Associate Professor of Medicine Harvard Medical School Associate Director, Interventional Cardiology Brigham and Women’s Hospital, Boston, Massachusetts Christopher Cannon, M.D. Associate Professor Of Medicine, Harvard Medical School Senior Investigator, TIMI Study Group Associate Physician, Brigham and Women’s Hospital Boston, Massachusetts

4. Aspirin in Cardiovascular Disease Christopher Cannon, M.D. Brigham and Women’s Hospital Boston, MA

5. Vascular Disease in the U.S. 1.American Heart Association. 2004 Heart Disease and Stroke Statistics. 2.Brown et al. Amer. Stroke Assoc. 25th Int. Stroke Conference. 2000. 3.National Stroke Association Press Release. April 25, 2000. 4.Hirsch AT et al. JAMA. 2001;286:11:1317-1324. TIA = transient ischemic attack. ACS = acute coronary syndrome. PAD = peripheral arterial disease. Annual Incidence (Millions) Prevalence (Millions) Stroke0.70 1 4.7 1 TIA0.50 2 4.9 3 ACS1.7 1 *14.2 1† PAD  8–12 4

6. 0 5 10 15 20 25 30 197019801990200020102020203020402050 Number of Patients (Millions) ACC/AHA Guidelines 2001, NHLBI Chartbook 2000 and Foot et al (JACC 2000) 12.4 24.6 U.S. Heart Disease Doubles in the Next Half Century

7. Estimated Direct and Indirect Costs of Cardiovascular Diseases and Stroke $214 $111.8 $49.4 $47.2 $23.2 $329.2 0 $50 $100 $150 $200 $250 $300 $350 Heart disease Coronary Heart disease Stroke Hypertensive disease Congestive heart failure Total CVD 3 Billions 2 1 2002 estimates (USA) 2 American Heart Association. 2002 Heart and Stroke Statistical Update. 2001 3 CVD = cardiovascular disease

8. Aspirin Usage In the US Percentage of Use 37.6 23.3 13.8 12.2 14.1 0 10% 20% 30% 40% Heart Disease ArthritisHeadacheBody Ache Other 26,000,000 Americans receive chronic aspirin therapy for cardioprotection.

9. Antithrombotic Trialists’ Collaboration (ATC): Efficacy of Antiplatelet Therapy on Vascular Events Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86. *Vascular events = myocardial infarction, stroke or vascular death Category% Odds Reduction Acute myocardial infarction Acute stroke Prior myocardial infarction Prior stroke/transient ischemic attack Other high risk Coronary artery disease (e.g. unstable angina, heart failure) Peripheral arterial disease (e.g. intermittent claudication) High risk of embolism (e.g. atrial fibrillation) Other (e.g. diabetes mellitus) All trials 1.00.50.01.52.0 Control better Antiplatelet better

10. 11.8 9.4 Plac.ASA 0 5 10 15 Acute Myocardial Infarction RISC Group. Lancet 1990;336:827-30. Roux etal.JACC 1992;19:671-7. ISIS-2.Lancet 1988;2:349-60. ISIS-2.Lancet 1988;2:349-60. Aspirin in Acute Coronary Syndromes

11. Primary Prevention Stable Angina PHS.NEJM 1989;321:129-35 Ridker etal.AJC 1991;114:835-9. Theroux, etal.NEJM 1988;319:1105-11. Cairns, etal.NEJM 1985;313:1369-75.

12. Indirect Comparisons of ASA Doses on Vascular Events in High-Risk Patients *Odds reduction. Treatment effect P<.0001. ASA, acetylsalicylic acid. Adapted with permission from BMJ Publishing Group. Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71-86. 0.51.01.52.0 500-1500 mg34 19 160-325 mg19 26 75-150 mg12 32 <75 mg 3 13 Any aspirin65 23 Antiplatelet BetterAntiplatelet Worse Aspirin DoseNo. of Trials (%) Odds Ratio 0 OR*

13. Clopidogrel + ASA (N=6259) ASA (N=6303) ASA Dose: <100 mg (N=1927) 1.9% 3.0% 0.53 100-200 mg (N=7428) 2.8% 3.4% >200 mg (N=2301) 3.7% 4.9% Major Bleeding at 1 year by ASA Dose CURE P-Value Peters RJG, et al. Circulation 2003;108:1682-1687

14. BRAVO: Bleeding By ASA dose Topol EJ, et al. Circulation. 2003;108:399-406. Outcomes by Aspirin Dose in Placebo Study Drug Patients Low Dose, 75-162 mg/d (n=2410) Higher Dose, 162-326 mg/d (n=2179) Primary end point16.418.6 Death, MI, stroke6.26.1 Death2.81.7 MI2.02.1 Stroke2.12.8 Internal bleeding2.43.3 Any bleeding11.115.4 Transfusion1.02.0

15. Aspirin in Cardiovascular Disease Aspirin is proven to reduce death, MI, stroke in patients with all types of cardiovascular disease Inexpensive, widely available Dosing now focused on low-dose (75-81 mg) for optimal efficacy / safety balance However… Does one dose fit all? Is there Aspirin resistance? Are their clinical consequences of Aspirin resistance?