1. ASA Resistance and Clinical Outcomes
Daniel I. Simon, M.D.
Associate Director, Interventional Cardiology
Brigham and Women’s Hospital
Associate Professor of Medicine
Harvard Medical School
Boston, MA USA

2. ASA Resistance: Key Questions
Does a standardized definition exist?
Are there reliable tests to diagnose this phenomenon?
What are the possible mechanisms and future implications?
Does it have any clinical significance?
How do we manage patients with Aspirin resistance?

3. Established Platelet Function Tests
Bleeding time
Aggregometry-turbidometric methods
Aggregometry-impedance methods
Aggregometry & luminescence
Adenine nucleotides
Thromboelastography (TEG)
Glass filterometer
Platelet release markers
In Vivo screening test
Responsiveness to panel agonists
Combined aggregation and ADP release
Stored and released ADP
Global Hemostasis
High shear platelet function
In vivo platelet activation markers
Advantages
Physiological
Diagnostic
Whole blood test
More information
Sensitive
Predicts bleeding
Simple
Simple, systemic
measure of platelet
activation
Disadvantages
Insensitive, invasive & high variability
Labor intensive & non-physiological
Insensitive
Semi-quantitative
Specialized equipment
Measures clot properties
only, insensitive to ASA
Requires blood counter
Prone to artifact
Plt Function Test
Assay
Harrison P. Br J Hematology 2000;111:

4. Newer Platelet Function Tests
Assay Substrate Bedside Principle Comments
(PFA) Whole blood Primary Limited range-most pts
hemostasis after GP IIb/IIIa inhibitors have
(high shear closure times >300 sec, so may
adhes/aggreg) not be able to discern diff. Used to assay ADP antagonist
Clot Signature Whole blood Adhesion, Large instrument for routine use
Analyzer aggregation and interpretation of results is
complex
Rapid platelet Whole blood Aggregation GP IIb/IIa: baseline sample req.
function assay Clinical outcome data (GOLD)
Aspirin: AA-like agonist
Flow cytometry Whole blood Platelet GP, Flexible & powerful. Requires
activation markers, specialized operator. Expensive
Platelet function
Harrison P. Br J Hematology 2000;111:
Mukherjee D & Moliterno DJ. Clin Pharmacokinet 2000;39(6):

5. Prevalence of ASA Resistance
325 patients with stable CVD taking ASA 325 mg >7days
ASA-R: mean aggregation ≥70% with µM 10 ADP & ≥20% with 0.5 mg/ml AA
Gum PA et al. Am J Cardiol 2001;88:

6. Prevalence of Aspirin Resistance
422 patients presenting to cardiac cath lab on ASA mg >7d
23.4% Aspirin non-responsive
Accumetrics VerifyNow Aspirin
Definition: ARU > 550
Multivariate analysis: history of CAD associated with twice the odds of being ASA non-responder (odds ratio 2.09, 95% CI , p=0.009)
No association with gender, DM, smoking, ASA dose
Wang JC et al. Amer J Cardiol 2003;92:1492-4

7. Clinical Studies

8. ASA Resistance: Long-term Clinical Studies
Pts ASA dose Test F/U End-point Results
Stroke mg Plt Reactivity m Stroke/MI/ fold lower
(n=180) Vascular death risk in ASA responders
PVD mg Whole blood m Arterial % higher risk (n=100) aggregometry Occlusion in ASA-R
CVD/CVA mg PFA-10 >60 m Recurrent CVA/ Recurrent CVA 34%
(n=53) TIA TIA ASA-R vs. 0% no
recurrent events
Subgroup mg Urinary 11-dehydro 5 yrs MI/Stroke/ times
HOPE TX B CVDeath higher risk in (n=967) upper vs. lower quartile
CVD mg Optical platelet ±185 Death/MI/CVA 24% ASA-R vs.
(n=326) aggregation days % ASA-S [HR (95% CI , p=0.03)
Grotemeyer KH, et al. Thromb Res 1993; 71:
Mueller MR, et al. Thromb Haemost 1997; 78:
Grundmann K, et al. J Neurol 2003; 250: 63-66
Eikelboom JW, et al. Circulation 2002; 105:
Gum PA, et al. J Am Coll Cardiol 2003; 41:

9. ASA Resistance and Clinical Outcome in CAD Patients
HOPE Trial Substudy: ASA mg
Eikelboom JW, et al. Circulation 2002; 105:

10. ASA Resistance and Clinical Outcome in CVD Patients
326 CVD patients on ASA 325 mg > 7 days
p=0.03
ASA-R: mean aggregation ≥70% with 10 µM ADP & ≥20% with 0.5 mg/ml AA
Gum PA, et al. J Am Coll Cardiol 2003; 41:

11. ASA Resistance and Clinical Outcome in PVD Patients
Mueller MR et al. Thromb Haemost 1997; 78:

12. ASA Resistance and Clinical Outcome in Stroke Patients
Grotemeyer KH et al. Thromb Res 1993; 71:

13. ASA Resistance and Clinical Outcome in Stroke Patients
53 CVA pts on ASA 100 mg for secondary prevention > 60 months
Grundmann K et al. J Neurol 2003; 250: 63-66

14. RPFA-ASA, ASA/clopidogrel (n=151), 19.2% ASA resistant
ASA Resistance in PCI
RPFA-ASA, ASA/clopidogrel (n=151), 19.2% ASA resistant
Chen et al. J Amer Coll Cardiol 2004;43:1122-6

15. clopidogrel bisulfate
Oral Antiplatelet Agents
clopidogrel bisulfate
Dipyridamole
ticlopidine HCl
ADP
Phosphodiesterase
ADP
ADP
Collagen Thrombin TXA2
Gp IIb/IIIa
Activation
(Fibrinogen
Receptor)
COX
TXA2
Aspirin
ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase.
Schafer AI. Am J Med 1996;101:199–209.

16. Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events
loading dose
300mg
Clopidogrel 75mg q.d. + ASA mg q.d.*
(6259 patients)
Aspirin mg
Patients with
Non-ST elevation
Acute Coronary Syndrome R
3 months £ double-blind treatment £ 12 months
Aspirin mg
Months
Placebo
Placebo + ASA mg q.d.*
(6303 patients)
The CURE Trial Investigators. N Engl J Med. 2001;345:

17. Primary Endpoint: MI/Stroke/CV Death
0.14
0.00
0.02
0.04
0.06
0.08
0.10
0.12
Cumulative Hazard Rate
Clopidogrel + ASA* 3 6 9
Placebo + ASA*
Months of Follow-Up
11.4%
9.3%
20% RRR
P < 0.001
N = 12,562 12
Clopidogrel provided a 20% relative risk reduction in the composite outcome of MI, stroke or CV death (95% CI , P < 0.001). Overall there were 719 (11.4%) first events in the placebo group and 582 (9.3%) in the clopidogrel group. The hazard rate curves began to separate within the first few hours after therapy initiation and continued to diverge over the remainder of the trial.
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:

18. N = 2,116 patients undergoing elective PCI
CREDO
N = 2,116 patients undergoing elective PCI
Pretreatment
Clopidogrel 75 QD
PLACEBO
+ ASA *
N = 1345
End of follow-up
Up to 12 months
after randomization R
PCI
30 days post PCI
This slide summarizes the PCI-CURE design. A total of 2658 patients with non-ST-segment elevation MI undergoing PCI had been randomized to receive clopidogrel or placebo. The majority of patients received an intracoronary stent (81% in the placebo group and 82% in the clopidogrel group).
Patients were treated with the blinded study drug for a median of 6 days prior to the procedure. After the procedure, the majority (> 80%) received open-label thienopyridine (either clopidogrel or ticlopidine) for approximately 4 weeks; then, the blinded study drug was continued until the end of follow-up (average duration of 8 months).
Medications at time of randomization may include heparin or low–molecular weight heparin, beta-blockers, ACE inhibitors, lipid-lowering agents, calcium channel blockers, and/or other therapies or interventions (PTCA, CABG) at physician’s discretion..
The primary end point was the composite of myocardial infarction, cardiovascular death or urgent target vessel revascularization within 30 days of PCI.
Clopidogrel 75 QD
CLOPIDOGREL
300 mg
3-24h pre-PCI
+ ASA *
N = 1313
Pretreatment
* In combination with standard therapy

19. CREDO: Primary Endpoint
26.9% relative risk reduction
(CI %; P=0.02)
Absolute reduction = 3%
Steinhubl et al. JAMA 2002

20. Aspirin Resistant Patient Management
Eliminate interfering substances (ibuprofen)
Increase aspirin dose
Use other anti-platelet medications such as clopidogrel to prevent recurrent ischemic events
Educate patient on importance of compliance
It is very important to the physician that something can be done for the patient as a result of determining that a patient is a non-responder to aspirin therapy. In this case there are several courses of action that can address the problem, including:
Determining that the patient is actually taking their aspirin regularly. Surprisingly, even though aspirin has profound benefits, many patients do not always take their aspirin. Once a patient is found to be a non-responder, most will admit to the doctor that they may not have been compliant, which serves as an key way to reinforce the importance and reinitiate consistent therapy.
There many other medications that can interfere with the effectiveness of aspirin therapy that need to be changed or eliminated to ensure that a patient is receiving the full benefit of aspirin therapy. One very common medication, ibuprofen, the active ingredient in Advil, Motrin and other commonly used pain relievers, interferes with aspirin. Changing the type of pain reliever used, can eliminate this source of interference with aspirin effectiveness.
Even though it is desirable to use the lowest possible dose of aspirin to minimize bleeding risk, often times the standard 81 mg dose of aspirin is not sufficient to produce the desired antiplatelet effects. In many cases, simply increasing the dose can produce that effect.
Lastly, there is Plavix therapy. If a patient does not respond to aspirin, the alternative of choice is Plavix. However, because Plavix at $3 per table is considerably more expensive than aspirin, it is important to first determine if aspirin is working.

21. Conclusions
ASA use associated with 23% reduction in the odds of vascular events
Beneficial anti-thrombotic effect of ASA mediated by irreversible acetylation of COX-1
ASA resistance 5-60%
ASA resistance associated with increased risk of major adverse cardiovascular events