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Resistance to Anti-Platelet Therapy in CAD

Resistance to Anti-Platelet Therapy in CAD. Rabih R. Azar, MD, MSc, FACC Associate Professor of Medicine Director of Cardiovascular Research Division of Cardiology Hotel Dieu de France Hospital. Resistance to Anti-Platelet Therapy in CAD. Role of platelets in coronary artery disease

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Resistance to Anti-Platelet Therapy in CAD

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  1. Resistance to Anti-Platelet Therapy in CAD Rabih R. Azar, MD, MSc, FACC Associate Professor of Medicine Director of Cardiovascular Research Division of Cardiology Hotel Dieu de France Hospital

  2. Resistance to Anti-Platelet Therapy in CAD • Role of platelets in coronary artery disease • Aspirin resistance • Clopidogrel resistance • New anti-platelet drugs • How to detect resistance to anti-platelet agents • How to manage resistant patients

  3. Role of the Platelets in Thrombosis ST  MI:occlusive thrombus (platelets, red blood cells, and fibrin) UA/NQMI:Partially-occlusive thrombus (primarily platelets) Intra-plaque thrombus (platelet dominated) Plaque core Intra-plaque thrombus (platelet dominated) Plaque core SUDDEN DEATH Adapted from Davies MJ. Circulation. 1990; 82 (supl II): 30-46.

  4. Aspirin is as important as streptokinase in AMI ISIS 2: Lancet 1988;2:349

  5. Aspirin in Primary and Secondary Prevention Trials

  6. Currently Available Antiplatelet Agents Mechanismof Action Significant Side Effects Efficacy TXA2 GI bleeding, Aspirin 25%1 GI intolerance3 ADP binding to receptor Severe neutropenia, Ticlopidine/ clopidogrel 33%1 rash, diarrhea4 GI distress, headache4 cAMP Dipyridamole 16%2 1Antiplatelet Trialists’ Collaboration. BMJ. 1994;308:81–106.2Diener HC et al. J Neurol Sci. 1996;143:1–13. 3Schafer AI. In: Smith TW, ed. Cardiovascular Therapeutics. Philadelphia, PA: WB Saunders; 1996:chap 27. 4Schafer AI. Am J Med. 1996;101:199–209.

  7. 8.7% 16 Overall RiskReduction 12 8 4 0 CAPRIE StudyMI, Ischemic Stroke, or Vascular Death Aspirin Event Rate per Year Clopidogrel 5.83% Cumulative Event Rate, % 5.33% P = 0.045 0 3 6 9 12 15 18 21 24 27 30 33 36 Months of Follow-Up

  8. CURE Study: Clopidogrel on the top of aspirinPrimary End Point - MI/Stroke/CV Death 11.4% Placebo + ASA* 9.3% Clopidogrel + ASA* 20% RRR P < 0.001 N = 12,562 0 3 6 9 12 Months of Follow-Up * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  9. Resistance to Anti-Platelet Therapy in CAD • Role of platelets in coronary artery disease • Aspirin resistance • Clopidogrel resistance • New anti-platelet drugs • How to detect resistance to anti-platelet agents • How to manage resistant patients

  10. 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

  11. 26,000,000 Americans receive chronic aspirin therapy for cardioprotection. 40% 37.6 30% 23.3 20% 14.1 13.8 12.2 10% 0 Heart Disease Arthritis Headache Body Ache Other Aspirin Usage In the US Percentage of Use

  12. Definitions of Aspirin and Clopidogrel Resistance • Clinical: • Failure to prevent clinical events • Biological: • Failure to adequately inhibit platelet aggregation • Aspirin: • Aggregation > 70% on 5 µmol/L ADP • Aggregation > 70% on 10 µmol/L ADP • Aggregation > 20% on 0.5mg/mL arachidonic acid • Clopidogrel: • Baseline – post-treatment ADP aggregation < 10% • ADP aggregation < 14% (Plateletworks) J Am Coll Cardiol 2006;47:27-33

  13. 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

  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. 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

  16. Non-Enzymatic Lipid Peroxidation Catalyzed by Free Radicals 12-Lipoxygenase 12-HETE, 12-HPETE -  Platelet Adhesivity • Isoprostanes • Amplifies platelet response • to other agonists. • Vasoconstrictor • Plasma levels 1-2 orders • of magnitude > COX • -derived metabolites. Metabolic Pathways of Arachidonic Acid Membrane Phospholipids ARACHIDONIC ACID COX-1 Aspirin Prostaglandin H2 • Thromboxane A2 •  Platelet Aggregation • Vasoconstriction • Prostacyclin •  Platelet Aggregation • Vasodilitation

  17. Resistance to Anti-Platelet Therapy in CAD • Role of platelets in coronary artery disease • Aspirin resistance • Clopidogrel resistance • New anti-platelet drugs • How to detect resistance to anti-platelet agents • How to manage resistant patients

  18. ACC/AHA Guidelines (2005)Percutaneous Coronary Interventions: Oral Antiplatelet Therapy Prevalence of inadequate response to clopidogrel 4% to 30% Nguyen et al. J Am Coll Cardiol 2005;45:1157-64

  19. Importance of clopidogrel resistance in ST elevation MI • Patients with ST elevation MI were divided in 4 quartile according to their response to clopidogrel compared to baseline • First quartile = Poor responder • 4th quartile = Excellent responder • Cardiovascular event rate was higher in the first quartile

  20. Clopidogrel resistance is associated with increased recurrent atherothrombotic events in patient with acute MI(Circulation 2004;109:3171-3175) % % Quartiles of mean platelet aggregationRecurrent cardiovascular events as compared to baseline

  21. Clopidogrel Metabolism • Clopidogrel is a prodrug • It requires oxidation by the hepatic cytochrome P450 to generate the active metabolite • Only a small proportion of clopidogrel undergoes metabolism by CYP450 • Clopidogrel is mostly hydrolyzed by esterases to an inactive carboxylic acid derivative that accounts for 85% of clopidogrel-related circulating compounds • Any drugs that affects CYP450 may affect the efficacy of clopidogrel

  22. Resistance to Anti-Platelet Therapy in CAD • Role of platelets in coronary artery disease • Aspirin resistance • Clopidogrel resistance • New anti-platelet drugs • How to detect resistance to anti-platelet agents • How to manage resistant patients

  23. Resistance to Anti-Platelet Therapy in CAD • Role of platelets in coronary artery disease • Aspirin resistance • Clopidogrel resistance • New anti-platelet drugs • How to detect resistance to anti-platelet agents • How to manage resistant patients

  24. How to Measure Platelets Aggregation? • Platelets function is measured in vitro by light transmission aggregometry • This method is considered the gold standard • Disadvantages: • Limited reproducibility • Complex sample preparation • Cannot be routinely performed

  25. WHAT ARE THE ALTERNATIVES TO LIGHT TRANSMISSION AGGREGOMETRY?

  26. 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

  27. Plateletworks: Kit for measurement of platelets aggregation Photo-optical (turbidometric) platelet aggregometry

  28. Excellent Correlation Between Light Transmission Aggregometry and Plateletworks Test (Cathet Cardiovasc Intervent 2001;53:346-351)

  29. PlateletWorks: Values in Healthy Patients* Agonist % aggregation % inhibtion Collagen > 70% < 30% ADP > 86% < 14% Arach. Acid > 60% < 40% Healthy patients = patients with normal platelets and not on anti-platelet therapy

  30. Resistance to Anti-Platelet Therapy in CAD • Role of platelets in coronary artery disease • Aspirin resistance • Clopidogrel resistance • New anti-platelet drugs • How to detect resistance to anti-platelet agents • How to manage resistant patients

  31. How to Manage Aspirin Resistant Patients • Assess compliance with treatment • Eliminate drugs that interfere with aspirin (NSAID) • Increase the dose of aspirin? • May increase toxicity without improving response • Add clopidogrel

  32. How to Manage Clopidogrel Resistant Patients • Assess compliance with treatment • Eliminate drugs that interfere with the metabolism of clopidogrel (Cytochrome P 450 inhibitors) • Increase the dose of clopidogrel

  33. Dual Resistance to Aspirin and Clopidogrel in Patients Undergoing PCI • 150 patients referred for elective PCI • All were on aspirin 81 to 325 mg/day for > 1 week • Clopidogrel was given immediately following PCI • The response to clopidogrel was tested at 24 hours post loading dose • 12.7% resistant to aspirin • 24% resistant to clopidogrel • 47% of aspirin resistant patients were also resistant to clopidogrel J Am Coll Cardiol 2006;47:27-33

  34. ACC/AHA Guidelines (2005)Percutaneous Coronary Interventions: Oral Antiplatelet Therapy CLASS I: - After the PCI procedure, in patients with neither aspirin resistance, allergy, nor increased risk of bleeding, aspirin 325 mg daily should be given for at least 1 month after BMS implantation, 3 months after sirolimus-eluting stent implantation, and 6 months after paclitaxel-eluting stent implantation, after which daily chronic aspirin use should be continued indefinitely at a dose of 75 to 162 mg. CLASS IIb: - In patients in whom subacute thrombosis may be catastrophic or lethal, platelet aggregation studies may be considered and the dose of clopidogrel increased to 150 mg per day if less than 50% inhibition of platelet aggregation is demonstrated.

  35. Aspirin and Clopidogrel Effects Should Be Monitored • 75 year old male • HTN, treated with ramipril BP: 120/70 mm Hg • Diabetes, treated with insuline HbA1c: 6.8% • Hyperlipidemia, treated with atorvastatin LDL: 88 mg/dL • S/P stent, aspirin and clopidogrel ???????????? Do you want to be sure that aspirin and clopidogrel are working?

  36. Aspirin and Clopidogrel Effects Should Be Monitored • 75 year old male • HTN, treated with ramipril BP: 120/70 mm Hg • Diabetes, treated with insuline HbA1c: 6.8% • Hyperlipidemia, treated with atorvastatin LDL: 88 mg/dL • S/P stent, aspirin and clopidogrel ???????????? Do you want to be sure that aspirin and clopidogrel are working?

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