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

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?

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;111:733-744

Newer Platelet Function Tests Assay Substrate Bedside Principle Comments (PFA)-100 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;111:733-744 Mukherjee D & Moliterno DJ. Clin Pharmacokinet 2000;39(6): 445-458

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;88:230-235

Prevalence of Aspirin Resistance 422 patients presenting to cardiac cath lab on ASA 81-325 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 1.189-3.411, p=0.009) No association with gender, DM, smoking, ASA dose Wang JC et al. Amer J Cardiol 2003;92:1492-4

Clinical Studies

ASA Resistance: Long-term Clinical Studies Pts ASA dose Test F/U End-point Results Stroke1 1500 mg Plt Reactivity 24 m Stroke/MI/ 10-fold lower (n=180) Vascular death risk in ASA responders PVD2 100 mg Whole blood 18 m Arterial 87% higher risk (n=100) aggregometry Occlusion in ASA-R CVD/CVA3 100 mg PFA-10 >60 m Recurrent CVA/ Recurrent CVA 34% (n=53) TIA TIA ASA-R vs. 0% no recurrent events Subgroup 75-325 mg Urinary 11-dehydro 5 yrs MI/Stroke/ 1.8 times HOPE4 TX B2 CVDeath higher risk in (n=967) upper vs. lower quartile CVD5 325 mg Optical platelet 679±185 Death/MI/CVA 24% ASA-R vs. (n=326) aggregation days 10% ASA-S [HR 3.12 (95% CI 1.1- 8.9, p=0.03) Grotemeyer KH, et al. Thromb Res 1993; 71:397-403 Mueller MR, et al. Thromb Haemost 1997; 78:1003-1007 Grundmann K, et al. J Neurol 2003; 250: 63-66 Eikelboom JW, et al. Circulation 2002; 105:1650-1655 Gum PA, et al. J Am Coll Cardiol 2003; 41:961-965

ASA Resistance and Clinical Outcome in CAD Patients HOPE Trial Substudy: ASA 75-325 mg Eikelboom JW, et al. Circulation 2002; 105:1650-1655

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; 41:961-965

ASA Resistance and Clinical Outcome in PVD Patients Mueller MR et al. Thromb Haemost 1997; 78:1003-1007

ASA Resistance and Clinical Outcome in Stroke Patients Grotemeyer KH et al. Thromb Res 1993; 71:397-403

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

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

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.

Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events loading dose 300mg Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Aspirin 75-325mg Patients with Non-ST elevation Acute Coronary Syndrome R 3 months £ double-blind treatment £ 12 months Aspirin 75-325mg 1 3 6 9 12 Months Placebo Placebo + ASA 75-325 mg q.d.* (6303 patients) The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

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 0.72-0.90, 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;345:494-502.

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

CREDO: Primary Endpoint 26.9% relative risk reduction (CI 3.9-44.4%; P=0.02) Absolute reduction = 3% Steinhubl et al. JAMA 2002

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.

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