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Dominick J. Angiolillo, MD, PhD, FACC, FESC Director of Cardiovascular Research Assistant Professor of Medicine

CRT 2008 Wednesday February 13 th , 2008. Antiplatelet Resistance: What Does it Mean and What Should/Can we do About it?. Dominick J. Angiolillo, MD, PhD, FACC, FESC Director of Cardiovascular Research Assistant Professor of Medicine. Presenter Disclosure Information

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Dominick J. Angiolillo, MD, PhD, FACC, FESC Director of Cardiovascular Research Assistant Professor of Medicine

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  1. CRT 2008 Wednesday February 13th, 2008 Antiplatelet Resistance: What Does it Mean and What Should/Can we do About it? Dominick J. Angiolillo, MD, PhD, FACC, FESC Director of Cardiovascular Research Assistant Professor of Medicine

  2. Presenter Disclosure Information Name: Dominick J Angiolillo Within the past 12 months, the presenter or their spouse/partner have had a financial interest/arrangement or affiliation with the organization listed below. Company Name: Relationship: Bristol Myers Squibb Consultant/Speaker bureau Sanofi-Aventis Consultant/Speaker bureau Eli Lilly Consultant/Speaker bureau Daiichi Sankyo Consultant/Speaker bureau Portola Consultant GSK Educational Grant

  3. Antiplatelet Resistance • - What does it mean? • - What should/can we do?

  4. Antiplatelet Resistance • - What does it mean? • - What should/can we do?

  5. ? Long-term Efficacy of ASA in Reducing Death or MI in Patients with Unstable Angina Probabilityof death or MI 0.25 Placebo 0.20 Risk ratio after 1 year 0.5295% Cl 0.37–0.72 (p=0.0001) 0.15 0.10 ASA 75 mg 0.05 0.00 0 3 6 9 12 Months Wallentin LC et al JACC 1991;18:1587–1593

  6. Definition(s) of “APT Resistance?” The fact that some patients may experience recurrent vascular events despite the use of APT should be properly defined as “treatment failure” rather than “APT resistance” (multiple pathways mediate thrombotic events). APT Resistance/Non-responsiveness = Failure to inhibit the target APT Resistance/Non-responsiveness ≠ Clinical failure

  7. ASPECT study: Individual platelet aggregation data measured after stimuli by 3 concentrations of AA by LTA at 3 different doses of aspirin Gurbel, P. A. et al. Circulation 2007;115:3156-3164

  8. ASPECT study: Effects of Assay and Dose on Measurement of Aspirin Resistance Gurbel, P. A. et al. Circulation 2007;115:3156-3164

  9. Clinical Outcomes: Aspirin Responsiveness % Death, MI, CVA Not Aspirin Resistant, N = 309 40 Aspirin Resistant, N = 17 ASA-R: mean aggregation ≥70% with 10 µM ADP & ≥20% with 0.5 mg/ml AA Log rank 2=5.05, p=0.03 20 0 0 200 400 600 800 0 200 400 600 800 Days after Treatment Gum, P. JACC 2003;41:961-5

  10. OCH3 CH3 O O O C N HOOC N * HS Cl S 15% active metabolite Cl Gi Gs AC Clopidogrel ATP ADP P2X1 P2Y1 Gastro-intestinal absorption Gq G12 “Rho” Ca2+ flux Shape change PIP2 P2Y12 PLCβ Shape change + DAG IP3 Hepatic CYP Biotransformation PKC αi βγ Ca2+ mobilization MLCK-P AC PI3K 85% inactive metabolites (Esterases in blood) GP IIb/IIIa receptor activation Granule secretion PKB/Akt Rap1b GP IIb/IIIa receptor activation Initiation of Platelet Aggregation cAMP Stabilization of Platelet Aggregation VASP VASP-P PGE1 cAMP GP IIb/IIIa receptor activation Angiolillo DJ et al JACC 2007

  11. Individual Response Variability to Dual Antiplatelet Therapy in the Steady State Phase of Treatment 20 Bleeding risk Ischemic risk 15 Number of Patients 10 5 0 2.5 12.5 22.5 32.5 42.5 52.5 62.5 72.5 82.5 92.5 7.5 17.5 27.5 37.5 47.5 57.5 67.5 77.5 87.5 97.5 % Platelet Aggregation (LTA-ADP 20mmol/L) Adapted from Angiolillo DJ et al. Am J Cardiol. 2006;97:38-43.

  12. Clinical Relevance of Clopidogrel Non-responsiveness Post-Stent Ischemic Events and Periprocedural Infarction adapted from Angiolillo DJ et al. Am J Cardiov Drugs. 2007.

  13. Clinical Relevance of Clopidogrel Non-responsiveness Stent Thrombosis adapted from Angiolillo DJ et al. Am J Cardiov Drugs. 2007.

  14. Antiplatelet Resistance • - What does it mean? • - What should/can we do?

  15. Aspirin Resistant Patient Management • - Educate patient on importance of compliance

  16. Overestimation of Aspirin Resistance: Key Role of Compliance Tantry U et al. JACC 2005

  17. Aspirin Resistant Patient Management • - Eliminate interfering substances (ibuprofen) • - Increase aspirin dose (?) (.....increasing the dose of aspirin does not enhance COX-1 inhibition) • - Switch to other anti-platelet medications (?) (.....no evidence that switching to alternative treatment strategies improves outcomes) • - Educate patient on importance of compliance

  18. Genetic Factors • Polymorphisms of CYP • Polymorphisms of GPIa • Polymorphisms of P2Y12 • Polymorphisms of GPIIIa • Cellular Factors • Accelerated platelet turnover • Reduced CYP3A metabolic activity • Increased ADP exposure • Up-regulation of the P2Y12 pathway • Up-regulation of the P2Y1 pathway • Up-regulation of P2Y–independent pathways • (collagen, epinephrine, TXA2, thrombin) • Clinical Factors • Failure to prescribe/poor compliance • Under-dosing • Poor absorption • Drug-drug interactions involving CYP3A4 • Acute coronary syndrome • Diabetes mellitus/insulin resistance • Elevated body mass index Clopidogrel Response Variability Angiolillo DJ et al. J Am Coll Cardiol. 2007; 49: 1505-1516 .

  19. In patients in whom subacute thrombosis may be catastrophic or lethal (unprotected left main, bifurcating left main, or last patent coronary vessel), 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. I IIa IIb III ACC/AHA/SCAI 2005 Guideline Update for PCIOral Antiplatelet Adjunctive Therapies C Adapted from Smith SC Jr, et al. Available at: www.acc.org/clinical/guidelines/percutaneous/update/index_rev.pdf

  20. 150 mg clopidogrel/day for 30 days (n=20) 75 mg clopidogrel/day for 30 days (n=20) OPTIMUS Study: (Optimizinganti-Platelet Therapy In diabetes MellitUS) Type 2 diabetes mellitus patients with coronary artery disease on aspirin (81 mg) + clopidogrel (75 mg) therapy for ≥1 month Inclusion Criteria Platelet function assessment to identify suboptimal and optimal responders Study Time Point 1 Optimal responders Suboptimal responders * Randomization Not eligible for randomization Study Time Point 2 Platelet function assessment 75 mg clopidogrel/day for 30 days Study Time Point 3 Platelet function assessment Angiolillo DJ et al. Circulation. 2007;115:708-16. * >50% ADP (20 mmol/L)-induced post-treatment platelet reactivity

  21. P=0.002 P<0.0001 P=0.32 P=0.5 63.1±7 52.3±13 OPTIMUS Study: (Optimizinganti-Platelet Therapy In diabetes MellitUS) Primary Endpoint: Maximal ADP (20 mmol/L) Platelet Aggregation 100 64.9±9 67.4±6 80 60 Maximal ADP (20 mmol/L) platelet aggregation (%) 40 20 0 T1 T1 T2 T2 75mg 150mg Angiolillo DJ et al. Circulation. 2007;115:708-16.

  22. 100% 40% 60% OPTIMUS Prevalence of Patients Reaching Therapeutic P2Y12 Target Levels (20 mmol/L-induced Aggmax≤50%) Aggmax >50% Aggmax≤50% 100 80 60 % 40 20 0 75 mg 150 mg Angiolillo DJ et al. Circulation. 2007;115:708-16.

  23. OPTIMUS-2 Impact of Cilostazol on P2Y12 inhibition in T2DM on aspirin and clopidogrel therapy (%) p<0.0001 P2Y12 reactivity index (PRI) CILOSTAZOL PLACEBO Angiolillo DJ et al. TCT 2007

  24. What’s in the pipeline????

  25. ASCET trial (ASpirin non-responsiveness and Clopidogrel Endpoint Trial)

  26. Tailoring Treatment with Tirofiban in patients showing Resistance to aspirin and/or Resistance to clopidogrel Patients with stable, unstable low risk CAD undergoing elective PCI being ASA and/or clopidogrel resistance using Verify Now 3T/2R 1:1 Double blind SHBD Tirofiban Placebo N=250 pts

  27. Design GRAVITAS 7800 Patients with successful implantation of DES at 50 sites in US and Canada DESIGN: Prospective, randomized, 3-arm, multi-center trial of tailored antiplatelet therapy after DES. OBJECTIVE: To evaluate whether clopidogrel dose-adjustment based on the VerifyNow P2Y12 assay reduces thrombotic events after DES implantation. PRINCIPAL INVESTIGATOR Matthew J. Price, MDScripps Clinic La Jolla, CA Pre-Discharge VerifyNow Platelet Function Assessment NonResp Resp R 150mg/day 75mg/day 75mg/day 30 day VerifyNow Assessment 150mg/day 75mg/day 75mg/day 30d, 6M, and 1 yr Clinical FU Primary Endpoint: 6-mo CV Death, Non-Fatal MI, ARC definite/prob ST

  28. Novel P2Y12 ADP receptor antagonist More potent and less variability!! Better Clinical Outcomes?? Angiolillo DJ et al. J Am Coll Cardiol. 2007.

  29. Take Home Messages • Variability in individual response to antiplatelet therapy is a true phenomenon and has clinical implications. UNSOLVED ISSUES • HOW and WHEN to measure antiplatelet drug responsiveness? • WHAT do we do with the results coming from the “test tube”? (No demonstration of an association with clinical events conditioning cost-effective changes in treatment).

  30. Conclusions Responsiveness to antiplatelet therapy should be evaluated for investigational purposes only!!!!!

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