Introduction to Aspirin Resistance.

May 10, 2004

Steven R. Steinhubl, MD

Aspirin History

First synthesized in pure form by Felix Hoffman of Friedr. Bayer &

Co. in 1897.

(From the German (From the German aacetylcetylspirspirsaure + chemical suffix – saure + chemical suffix – inin))

Aspirin History

Due to problems with the original Aspirin powder being counterfeited, it became the first pharmaceutical agent ever sold

in pill form in early 1900’s.

First pill in USA was 5 grains (~325 mg).

Metabolic Pathways ofArachadonic Acid

Membrane Phospholipids

ARACHIDONIC ACID

Prostaglandin H2

COX-1

Thromboxane A2 Platelet Aggregation

- Vasoconstriction

Prostacyclin Platelet Aggregation

- Vasodilitation

AspirinAspirin

Aspirin in the Treatment of ACS

Wallentin LC, et al. JACC 1991;18:1587-93.

0.00

0.05

0.10

0.15

0.20

0.25

0 3 6 9 12Months

Pro

bab

ilit

yo

f D

eath

or

MI

Placebo

Aspirin 75 mg

Risk ratio 0.5295% CL 0.37-0.72

Aspirin in Acute Myocardial Infarction: ISIS-2

100

200

300

400

500

600

0 7 14 21 28 35

Placebo alone:568/4300 (13.2%)

Aspirin alone:461/4295 (10.7%)

Streptokinase alone:448/4300 (10.4%)

Streptokinase plus aspirin:343/4292 (8.0%)

Cu

mu

lati

ve N

um

ber

of

Vas

cula

r D

eath

s

Days From Randomization

Randomized Trials of Aspirin in PTCA

Schwartz, N Engl J Med 1988;318:1714 White, Coronary Artery Disease 1991;2:757

0

4

8

12

Schwartz et alN=376

White et alN=337

% Major Ischemic Complications

6.9

12.6

Heparin 10,000 units

2.4

Ticlopidine + Heparin

1.6

ASA / Dipyridamole + Heparin

77%P=0.0113 3.2

75%P<0.001

What is “Aspirin Resistance?”

Inability of ASA to prevent treated patients from having thrombotic events.

Inability of ASA therapy to prolong bleeding time. Inability of treatment with ASA to prevent

thromboxane biosynthesis. Inability of ASA to achieve a pre-defined effect

on an ex vivo or in vitro measure of platelet function.

Patrono C. J Thromb Haemost 2003;1:1710-3

Inter-Individual Variability in Response to Aspirin

Quick AJ. American Journal of Medical Science

Sept 1966:265-9

N=10

Interpatient Variability in Aspirin Response - Bleeding Time

Aspirin, 325 mg daily in 40 CABG patients

Buchanan,Can J Cardiol 1995;11(3):221

100 300 500 700 900

100

300

500

700

900

Bleeding Time, Pre-ASA

BleedingTime

Post-ASA

Responders (58%)Mean BT 58 + 10 %

Non-responders(42%)Mean BT 2 + 4 %

Aspirin Responsiveness and Clinical Outcome

181 patients, following CVA. Aspirin 500 mg TID.Followed-up for 24 months.

100

75

506 12 18 24

% of Patients Without Event

Months of Observation

Aspirin RespondersN=114

Aspirin Non-respondersN=60

60%

95%

P<0.0001

Grotemeyer, Thrombosis Research 1993;71:397

Thromboxane Biosynthesis on Aspirin and CV Events

1.0

1.31.4

1.8

0

1

2

< 15.1 15.1 - 21.8 21.9 - 33.8 > 33.8

Uninary 11-dehydro thromboxane B2(ng/mmole creatinine)

Odds Ratio for MI, Stroke or CV Death

Eikelboom Circ 2002;105:1650 HOPE Trial N=488, with 5 yr f/u

Aspirin Responsiveness By PFA-100 and Aggregometry

23.8%

5.5%

70.7%Aspirin Sensitive

Resistant

Partial Responders

9.5%

90.5%Aspirin Sensitive

325 patients with stable ASCAD

AggregometryResponse to ADP and AA

PFA-100

Gum P. Am J Cardiol 2001;88:230-235

Clinical Outcomes: Aspirin Responsive-ness by Aggregometry And PFA-100

0

20

40

00 200200 400400 600600 800800

Days after Treatment

Not Aspirin Resistant, N = 309

Aspirin Resistant, N = 17

% Death, MI, CVA% Death, MI, CVA

Log rank Log rank 22=5.05, =5.05, p=0.03p=0.03

Gum, P. JACC 2003;41:961-5

0

5

10

15

20

ASA Responder

N=294

ASA Non-Responder

N=32

12.9

15.1

% Death, MI, CVA% Death, MI, CVA

P=0.4Clinical Outcomes based on

PFA-100 Results

Possible Mechanisms for Variability in Response to Aspirin

Decreased bioavailability Non-compliance Concomitant NSAIDs

Platelet function Accelerated platelet turnover Increased platelet COX-2

Platelet Receptor Polymorphisms Other factors

DeGaetano G. J Thromb Haemost 2003;1:2048-50

Metabolic Pathways of Arachadonic Acid

Membrane Phospholipids

ARACHIDONIC ACID

Prostaglandin H2

COX-1

Thromboxane A2 Platelet Aggregation

- Vasoconstriction

Prostacyclin Platelet Aggregation

- Vasodilitation

12-Lipoxygenase

12-HETE, 12-HPETE- Platelet Adhesivity

Non-EnzymaticLipid Peroxidation Catalyzed by Free

Radicals

Isoprostanes- Amplifies platelet response to other agonists. - Vasoconstrictor- Plasma levels 1-2 orders of magnitude > COX -derived metabolites.

Aspirin

PlA2 Polymorphism and Aspirin Resistance

0

20

40

60

80

0.1 1 10 100

% Aggregation

Aspirin µmol/L

P=0.02

P=0.01

PlA1/A1

PlA1/A2

Cooke, Lancet 1998;351:

PlA2 Polymorphism

Single nucleotide polymorphism -Proline for a leucine at position 33 of 3

subunit.

~25% of individuals of N. European ancestry are PlA2 +.

Aspirin Resistance: Role of COX-2 ?

Weber A-A Lancet 1999;353:900

• Aspirin is 170-fold more potent inhibitor of COX-1 than COX-2.

• Platelets from 20 different donors were COX-2 positive.

• COX-2 expression in platelets increased 16-fold in 9 post-CABG patients. (Zimmermann AHA 1999)

Conclusions

Every study that has ever evaluated individual responsiveness to ASA has found marked variability.

Most studies have been able to correlate this variability with a clinically significant increase in thrombotic events.

The ability to identify the substantial proportion of patients who are unable to achieve an adequate response to ASA has the potential to dramatically improve their antithrombotic regimen and with it, long-term outcomes.