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

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

5. 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 Heart Disease and Stroke Statistics.
Brown et al. Amer. Stroke Assoc. 25th Int. Stroke Conference
National Stroke Association Press Release. April 25, 2000.
Hirsch AT et al. JAMA. 2001;286:11:
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:
American Heart Association. Heart Disease and Stroke Statistics —2003 Update
Brown et al. American Stroke Association. 25th Int. Stroke Conference
NSA Press Release, April 25, 2000.
Dennis M et al. Prognosis of transient ischemic attacks in the Oxfordshire community stroke project. Stroke. 1990;21:
Hirsch AT et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA. 2001;286:11:
Dormandy JA et al. The fate of the claudicant—A prospective study of 1969 claudicants. Eur J Vasc Surg. 1991;5:
Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med. 2001;344:

6. U.S. Heart Disease Doubles in the Next Half Century30
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)

7. 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
estimates (USA)
2 American Heart Association 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
10%
20%
30%
40%
Heart
Disease
Arthritis
Headache
Body
Ache
Other
26,000,000 Americans receive chronic aspirin therapy for cardioprotection.

9. 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.

10. 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:
1992;19:671-7.
1988;2:
1988;2:

11. 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:
1988;319:

12. Indirect Comparisons of ASA Doses on Vascular Events in High-Risk Patients
OR*
Aspirin Dose No. of Trials (%)
Odds Ratio mg mg mg
<75 mg
Any aspirin
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 ( 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.

13. 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) % %
mg (N=7428) % % >200 mg (N=2301) % %
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:

14. BRAVO: Bleeding By ASA dose
Outcomes by Aspirin Dose in Placebo Study Drug Patients
Low Dose, mg/d (n=2410)
Higher Dose, mg/d (n=2179)
Primary end point
Death, MI, stroke
Death MI
Stroke
Internal bleeding
Any bleeding
Transfusion
Topol EJ, et al. Circulation. 2003;108:

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?