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 1.Role of platelets in coronary artery disease 2.Aspirin resistance 3.Clopidogrel resistance 4.New anti-platelet drugs 5.How to detect resistance to anti-platelet agents 6.How to manage resistant patients

3. Role of the Platelets in Thrombosis UA/NQMI: Partially-occlusive thrombus (primarily platelets) Intra-plaque thrombus (platelet dominated) Plaque core ST  MI: occlusive thrombus (platelets, red blood cells, and fibrin) 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 1 Antiplatelet Trialists’ Collaboration. BMJ. 1994;308:81–106. 2 Diener HC et al. J Neurol Sci. 1996;143:1–13. 3 Schafer AI. In: Smith TW, ed. Cardiovascular Therapeutics. Philadelphia, PA: WB Saunders; 1996:chap 27. 4 Schafer AI. Am J Med. 1996;101:199–209. Aspirin Ticlopidine/clopidogrel Dipyridamole Mechanism of Action  TXA 2  ADP binding to receptor  cAMP Efficacy 25% 1 33% 1 16% 2 Significant Side Effects GI bleeding, GI intolerance 3 Severe neutropenia, rash, diarrhea 4 GI distress, headache 4

7. CAPRIE Study MI, Ischemic Stroke, or Vascular Death Months of Follow-Up Cumulative Event Rate, % 0 4 8 12160369121518212427303336 5.83% Clopidogrel Aspirin 5.33% Overall Risk Reduction 8.7% Event Rate per Year P = 0.045

8. Clopidogrel + ASA* 369 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. CURE Study: Clopidogrel on the top of aspirin Primary End Point - MI/Stroke/CV Death

9. Resistance to Anti-Platelet Therapy in CAD 1.Role of platelets in coronary artery disease 2.Aspirin resistance 3.Clopidogrel resistance 4.New anti-platelet drugs 5.How to detect resistance to anti-platelet agents 6.How to manage resistant patients

10. Prevalence of ASA Resistance Gum PA et al. Am J Cardiol 2001;88:230-235 ASA-R: mean aggregation ≥70% with µM 10 ADP & ≥20% with 0.5 mg/ml AA 325 patients with stable CVD taking ASA 325 mg >7days

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

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 Gum PA, et al. J Am Coll Cardiol 2003; 41:961-965 ASA-R: mean aggregation ≥70% with 10 µM ADP & ≥20% with 0.5 mg/ml AA 326 CVD patients on ASA 325 mg > 7 days p=0.03

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

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

17. Resistance to Anti-Platelet Therapy in CAD 1.Role of platelets in coronary artery disease 2.Aspirin resistance 3.Clopidogrel resistance 4.New anti-platelet drugs 5.How to detect resistance to anti-platelet agents 6.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

21. 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 4 th quartile = Excellent responder Cardiovascular event rate was higher in the first quartile

22. 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

24. 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

25. Resistance to Anti-Platelet Therapy in CAD 1.Role of platelets in coronary artery disease 2.Aspirin resistance 3.Clopidogrel resistance 4.New anti-platelet drugs 5.How to detect resistance to anti-platelet agents 6.How to manage resistant patients

29. Resistance to Anti-Platelet Therapy in CAD 1.Role of platelets in coronary artery disease 2.Aspirin resistance 3.Clopidogrel resistance 4.New anti-platelet drugs 5.How to detect resistance to anti-platelet agents 6.How to manage resistant patients

30. 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

31. WHAT ARE THE ALTERNATIVES TO LIGHT TRANSMISSION AGGREGOMETRY?

32. Newer Platelet Function Tests (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 Analyzeraggregation 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 Harrison P. Br J Hematology 2000;111:733-744 Mukherjee D & Moliterno DJ. Clin Pharmacokinet 2000;39(6): 445-458 Flow cytometry Whole blood - Platelet GP, Flexible & powerful. Requires activation markers, specialized operator. Expensive Platelet function AssaySubstrate BedsidePrincipleComments

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

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

36. 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

37. Resistance to Anti-Platelet Therapy in CAD 1.Role of platelets in coronary artery disease 2.Aspirin resistance 3.Clopidogrel resistance 4.New anti-platelet drugs 5.How to detect resistance to anti-platelet agents 6.How to manage resistant patients

38. 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

39. 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

42. 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

43. 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.

44. Aspirin and Clopidogrel Effects Should Be Monitored 75 year old male HTN, treated with ramipril BP: 120/70 mm Hg Diabetes, treated with insulineHbA1c: 6.8% Hyperlipidemia, treated with atorvastatinLDL: 88 mg/dL S/P stent, aspirin and clopidogrel???????????? Do you want to be sure that aspirin and clopidogrel are working?

45. Aspirin and Clopidogrel Effects Should Be Monitored 75 year old male HTN, treated with ramipril BP: 120/70 mm Hg Diabetes, treated with insulineHbA1c: 6.8% Hyperlipidemia, treated with atorvastatinLDL: 88 mg/dL S/P stent, aspirin and clopidogrel???????????? Do you want to be sure that aspirin and clopidogrel are working?