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ASA Resistance and Clinical Outcomes

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?

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ASA Resistance and Clinical Outcomes

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  1. ASA Resistance andClinical 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. Advantages Disadvantages Assay Plt Function Test Platelet Function Test Bleeding time Aggregometry-turbidometric methods Aggregometry-impedance methods Aggregometry & luminescence Adenine nucleotides Thromboelastography (TEG) Glass filterometer Platelet release 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 In Vivo screening test Responsiveness to panel agonists Responsiveness to panel agonists Combined aggregation and ADP release Stored and released ADP Global Hemostasis High shear platelet function In vivo platelet activation markers Established Platelet Function Tests Harrison P. Br J Hematology 2000;111:733-744

  4. 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 cytometryWhole 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

  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;88:230-235

  6. 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

  7. Clinical Studies

  8. 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

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

  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; 41:961-965

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

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

  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. 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. Oral Antiplatelet Agents clopidogrel bisulfate Dipyridamole ADP ticlopidine HCl Phosphodiesterase ADP ADP CollagenThrombinTXA2 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 Clopidogrel 300mg loading dose Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Aspirin 75-325mg Patients with Non-ST elevation Acute CoronarySyndrome 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.

  17. 11.4% Placebo + ASA* 0.12 9.3% 0.10 0.08 Clopidogrel + ASA* Cumulative Hazard Rate 0.06 0.04 20% RRR P < 0.001 N = 12,562 0.02 0.00 0 3 6 9 12 Months of Follow-Up Primary Endpoint: MI/Stroke/CV Death 0.14 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  18. 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 PCI 30 days post PCI R 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 3.9-44.4%; 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

  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

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