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.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

Aspirin in Cardiovascular Disease

Christopher Cannon, M.D.

Brigham and Women’s Hospital

Boston, MA

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.

AnnualIncidence(Millions)

Prevalence(Millions)

Stroke 0.701 4.7

1

TIA 0.502

4.93

ACS 1.71* 14.2

1†

PAD 8–124

0

5

10

15

20

25

30

1970 1980 1990 2000 2010 2020 2030 2040 2050

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 Doublesin the Next Half Century

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 CoronaryHeart

disease

Stroke Hypertensive disease

Congestive heart failure

Total CVD3

Bil

lio

ns2

1 2002 estimates (USA)2 American Heart Association. 2002 Heart and Stroke Statistical Update. 20013 CVD = cardiovascular disease

Aspirin Usage In the US

Percentage of Use

37.6

23.3

13.812.2

14.1

0

10%

20%

30%

40%

Heart Disease

Arthritis Headache Body Ache

Other

26,000,000 Americans receive chronic aspirin therapy for

cardioprotection.

26,000,000 Americans receive chronic aspirin therapy for

cardioprotection.

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 riskCoronary 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

1.00.50.0 1.5 2.0Control betterAntiplatelet better

17.1

6.5

Plac. ASA0

5

10

15

20

% o

f P

atie

nts

Unstable Angina

25

11

Plac. ASA0

10

20

30

3.3

1.9

Plac. ASA0

1

2

3

4

11.8

9.4

Plac. ASA0

5

10

15

Acute Myocardial Infarction

RISC Group. Lancet 1990;336:827-30.

Roux etal. JACC1992;19:671-7.

ISIS-2. Lancet1988;2:349-60.

ISIS-2. Lancet1988;2:349-60.

Aspirin in Acute Coronary Syndromes

Aspirin in Acute Coronary Syndromes

12.9

3.9

Plac. ASA0

5

10

15

11.9

3.3

Plac. ASA0

5

10

15

12.9

6.2

Plac. ASA0

5

10

15

2.2

1.3

Plac. ASA0

0.5

1

1.5

2

2.5

% o

f P

atie

nts

Unstable AnginaPrimary Prevention

Stable Angina

PHS. NEJM 1989;321:129-35

Ridker etal. AJC 1991;114:835-9.

Theroux, etal. NEJM1988;319:1105-11.

Cairns, etal. NEJM1985;313:1369-75.

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.

0.5 1.0 1.5 2.0

500-1500 mg 34 19

160-325 mg 19 26

75-150 mg 12 32

<75 mg 3 13

Any aspirin 65 23

Antiplatelet Better Antiplatelet Worse

Aspirin Dose No. of Trials (%) Odds Ratio

0

OR*

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 DoseCURE

P-Value

Peters RJG, et al. Circulation 2003;108:1682-1687

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 point 16.4 18.6Death, MI, stroke 6.2 6.1Death 2.8 1.7MI 2.0 2.1Stroke 2.1 2.8

Internal bleeding 2.4 3.3Any bleeding 11.1 15.4Transfusion 1.0 2.0

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?