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

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

Faculty Steven Steinhubl, M.D. Daniel I. Simon, M.D. Director of Cardiovascular Research and Education Associate Professor of Medicine University of Kentucky, Lexington, Kentucky Daniel I. Simon, M.D. 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

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

Vascular Disease in the U.S. Annual Incidence (Millions) Prevalence (Millions) Stroke 0.701 4.71 TIA 0.502 4.93 ACS 1.71* 14.21† PAD  8–124 Despite the improvement in the diagnosis and treatment of vascular disease (stroke, MI, and peripheral arterial disease [PAD]), the incidence of these conditions still remains high. Each year about 700,000 Americans have a new or recurrent stroke, and 24% die from stroke each year, making stroke the third leading cause of death.[1,2] In the United States, 4.7 million people have survived a stroke (2.3 million men and 2.3 million women), but 20% require help caring for themselves.[2] Latest data from the Mayo Clinic report that approximately 500,000 TIAs have occurred in the US in 1999.[3] And, according to a recent survey of 10,112 people conducted by the National Stroke Association and Roper Search Worldwide, 4.9 million of all adults age 18 and older (2.9%) have been diagnosed with TIA. Of those surveyed adults 65 years of age and older, 8.5% (or 2.6 million) reported that they had been diagnosed with a TIA.[4] The average risk for death following a TIA is approximately 6.3% per year.[5] MI is the largest single cause of death in the United States. An estimated 1.1 million Americans will have a new or recurrent MI this year, and more than 45% who experience a coronary attack will die within 1 year. Another 550,000 cases of angina will occur each year. Today, an estimated 12.9 million Americans have a history of MI, stable/unstable angina or both, and are at risk for developing subsequent ischemic events.[2,4] The prevalence of PAD is thought to be even higher than that of MI and stroke. It is estimated that PAD affects approximately 8 to 12 million Americans.[6] The mortality rate for established PAD is estimated to be approximately 4% per year.[7] Patients with critical limb ischemia who have the lowest ankle-brachial index have an annual mortality of 25%.[8] TIA = transient ischemic attack. ACS = acute coronary syndrome. PAD = peripheral arterial disease. American Heart Association. 2004 Heart Disease and Stroke Statistics. Brown et al. Amer. Stroke Assoc. 25th Int. Stroke Conference. 2000. National Stroke Association Press Release. April 25, 2000. Hirsch AT et al. JAMA. 2001;286:11:1317-1324. References Broderick J et al. The greater Cincinnati/Northern Kentucky stroke study. Preliminary first-ever and total incidence rates of stroke among blacks. Stroke. 1998;29:415-421. American Heart Association. Heart Disease and Stroke Statistics —2003 Update. 2002. Brown et al. American Stroke Association. 25th Int. Stroke Conference. 2000. NSA Press Release, April 25, 2000. Dennis M et al. Prognosis of transient ischemic attacks in the Oxfordshire community stroke project. Stroke. 1990;21:848-853. Hirsch AT et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA. 2001;286:11:1317-1324. Dormandy JA et al. The fate of the claudicant—A prospective study of 1969 claudicants. Eur J Vasc Surg. 1991;5:132-133. Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med. 2001;344: 1608-1621.

U.S. Heart Disease Doubles in the Next Half Century 30 24.6 25 20 Number of 15 Patients 12.4 (Millions) 10 5 1970 1980 1990 2000 2010 2020 2030 2040 2050 ACC/AHA Guidelines 2001, NHLBI Chartbook 2000 and Foot et al (JACC 2000)

Estimated Direct and Indirect Costs of Cardiovascular Diseases and Stroke $350 $329.2 $300 $250 $214 $200 Billions2 $150 $111.8 $100 $49.4 $47.2 $50 $23.2 Heart disease Stroke Hypertensive disease Total CVD3 Coronary Heart disease Congestive heart failure 1 2002 estimates (USA) 2 American Heart Association. 2002 Heart and Stroke Statistical Update. 2001 3 CVD = cardiovascular disease

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

Antithrombotic Trialists’ Collaboration (ATC): Efficacy of Antiplatelet Therapy on Vascular Events 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 1.0 0.5 0.0 1.5 2.0 This slide compares risk reduction in a number of high-risk subgroups to the overall result, which demonstrated a consistent benefit across all patient groups with a mean of 22%.1 Stratified odds ratio of an event in treatment groups to that in control groups were plotted for each group of trials (white diamond) – along with a 99% confidence interval (horizontal line). ‘Other’ high risk groups (total reduction 13% ±7) include hemodialysis (reduction 41% ±16), diabetes mellitus (reduction 7% ±8), carotid disease (reduction 19% ±22). Antiplatelet better Control better *Vascular events = myocardial infarction, stroke or vascular death Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86. Reference: 1. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high-risk patients. BMJ 2002; 324: 71–86.

Aspirin in Acute Coronary Syndromes 17.1 6.5 Plac. ASA 5 10 15 20 % of Patients Unstable Angina Acute Myocardial Infarction 25 11 Plac. ASA 10 20 30 3.3 1.9 Plac. ASA 1 2 3 4 15 11.8 9.4 10 5 Plac. ASA RISC Group. Lancet Roux etal. JACC ISIS-2. L ancet ISIS-2. L ancet 1990;336:827-30. 1992;19:671-7. 1988;2:349-60. 1988;2:349-60.

Aspirin in Acute Coronary Syndromes Primary 12.9 6.2 Plac. ASA 5 10 15 2.2 1.3 0.5 1 1.5 2 2.5 % of Patients Unstable Angina Stable Prevention Angina 12.9 3.9 Plac. ASA 5 10 15 11.9 3.3 Plac. ASA 5 10 15 PHS. NEJM Ridker etal. AJC Cairns, etal. NEJM Theroux, etal. NEJM 1989;321:129-35 1991;114:835-9. 1985;313:1369-75. 1988;319:1105-11.

Indirect Comparisons of ASA Doses on Vascular Events in High-Risk Patients OR* Aspirin Dose No. of Trials (%) Odds Ratio 500-1500 mg 34 19 160-325 mg 19 26 75-150 mg 12 32 <75 mg 3 13 Any aspirin 65 23 The Antithrombotic Trialists’ Collaboration compared data from 65 aspirin trials to examine the effects of aspirin dose on vascular events in high-risk patients (in some trials, the aspirin dose was used in more than one of the comparisons).1 Serious vascular events (the primary measure of outcome) included nonfatal myocardial infarction, nonfatal stroke, death from vascular causes, and death from unknown causes. They found that all doses of aspirin studied reduced the risk of vascular events. The greatest number of trials (34) examined high aspirin doses (500- 1500 mg) and revealed a proportional reduction in vascular events of 19%. Aspirin doses of 160 to 325 mg were associated with a 26% proportional reduction in vascular events, whereas 75 to 150 mg and <75 mg were associated with reductions of 32% and 13%, respectively. 0.5 1.0 1.5 2.0 * Odds reduction. Treatment effect P<.0001. ASA, acetylsalicylic acid. Adapted with permission from BMJ Publishing Group. Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71-86. Antiplatelet Better Antiplatelet Worse References 1 Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71-86.

Major Bleeding at 1 year by ASA Dose CURE Major Bleeding at 1 year by ASA Dose ASA (N=6303) Clopidogrel + ASA (N=6259) P-Value 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% NEJM The incidence of major bleeding increased according to the aspirin dose. The most important determinant of aspirin dose was the investigational site at which the patient was treated, and in general there were large differences based on country (P<0.0001). After adjusting for risk factors for bleeding including age, gender, serum creatinine, elevated enzymes, ST depression at baseline, weight and BMI, the odds ratio for major bleeding for 325 mg vs. 75 mg of ASA was 2.07 (P=0.0001) Peters RJG, et al. Circulation 2003;108:1682-1687

BRAVO: Bleeding By ASA dose 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 point 16.4 18.6 Death, MI, stroke 6.2 6.1 Death 2.8 1.7 MI 2.0 2.1 Stroke 2.1 2.8 Internal bleeding 2.4 3.3 Any bleeding 11.1 15.4 Transfusion 1.0 2.0 Topol EJ, et al. Circulation. 2003;108:399-406.

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?