14th Vietnam National Congress of Cardiology Da Nang City Vietnam 2014 Great Debates on Antiplatelet and Anticoagualant Therapies New P2Y12 Blockers is the Best Anti-platelet agent for Patients Undergoing PCI Dr Tan Huay Cheem MBBS, M Med(Int Med), FRCP(UK), FAMS, FACC, FSCAI Director, National University Heart Centre, Singapore (NUHCS) Associate Professor of Medicine, Yong Loo Lin School of Medicine National University of Singapore President, Asia Pacific Society of Interventional Cardioloogy Debate At Medical Meetings Humorous discussion for the entertainment of the audience with little or no significant scientific content Do Not Be Misled!! Do Not Turn blind eye to Current Evidence! Proper Interpretation of Trial Evidence Milestones in ACS Management Anti-thrombin Rx Heparin LMWH Bivalirudin Fondaparinux Antiplatelet Rx GP IIb/IIIa blockers Aspirin Clopidogrel Treatment Strategy Conservative Prasugrel Early invasive PRISM-PLUS PURSUIT ESSENCE PLATO REPLACE CURE HORIZON MI QASIS-5 SYNERGY TACTICS TIMI-18 Ticagrelor TRITON ACUITY 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2010 PCI Ischemic Risk Bleeding Risk  5% Stents  85% Stents Drug-Eluting Stents 2nd Gen DES Dual Antiplatelet Therapy is a Cornerstone of ACS Treatment • Dual antiplatelet therapy with ASA and P2Y12 inhibition has been shown to be effective for secondary prevention in ACS patients • Clopidogrel has been core of post-ACS treatment – CURE: NSTE-ACS (n=12,562) • Clopidogrel vs Placebo; on top of ASA • year follow-up • 20% RRR (2.1% ARR) in CV death/MI/stroke – COMMIT: STEMI (n=45,852) • Clopidogrel vs Placebo; on top of ASA • month follow-up • 9% RRR (0.9% ARR) in CV death/MI/stroke CURE Investigators N Engl J Med 2001; 345: 494-502 COMMIT Investigators Lancet 2005; 366: 1607-21 Current Dual Antiplatelet Regimen Why Not Clopidogrel? Variability in Clopidogrel Response Change in ADP-Induced platelet aggregation 75 mg chronic dosing N=544 Maximal aggregation 5µmol/L ADP (%) following 600 mg loading dose 100 80 N=1001 60 40 20 0 Time from loading dose to cath (h) Red dot: nonresponder Serebruany et al J Am Coll Cardiol 2005; 45:246 Hochholzer W et al Circulation 2005 10 PLATO: Primary Efficacy Endpoint Over Time (Composite of CV Death, MI or Stroke) 31-360 days 0-30 days Clopidogrel 5.4 4.8 Ticagrelor (HR, 0.88; 95% CI, 0.77-1.00; P=0.045) 0 10 20 30 Cumulative incidence (%) Cumulative incidence (%) 6.6 Clopidogrel 5.3 Ticagrelor (HR, 0.80; 95% CI, 0.70-0.91; P[...]... 361:1045-1057 Platelet Response to Clopidogrel Is Attenuated in Diabetic Patients Undergoing Coronary Stent Implantation ADP aggregation after a 600-mg clopidogrel loading dose Geisler T et al Diabetes Care 2007; 30: 372 - 37432 Increased Risk of Ischaemic Events in Diabetic Patients CV death, MI or stroke All-cause mortality MI 1.0 HR (95% CI) Decreased risk for diabetics Increased risk for diabetics... 13: 533-542 % Inhibition of Platelet Aggregation During PCI n = 48 60 Optimal Clopidogrel 300 mg 40.9(26.2) 40 % Sub-Optimal 25.6(22.3) 20 7.8(11.3) Median (SD) % 0 10 min Post -PCI 4 hrs post -PCI 24 hrs post -PCI ACS Diabetes Overweight Diffuse CAD Bad genes UFH 100 UI/kg baseline (ASA 200 mg/d) Angiolillo DJ et al Thromb Res 2005; 115: 101-8 New P2Y12 Receptor Antiplatelet Agents • Prasugrel • Ticagrelor... CYP2C19 Poor Metabolisers CYP2C19 Normal Metabolisers CYP2C19 Rapid Metaboliser Indians (n = 100) CYP2C19 *2 or *3 CYP2C19 WT or combination *2/*3 and *17 CYP2C19 *17 Mark Y Chan et al Pharmacogenomics 2012; 13: 533-542 CYP2C19 and Clopidogrel Response RM= rapid metaboliser NM= normal metaboliser PM= poor metaboliser CYP2C19 only accounts for 17% of variability in on-clopidogrel platelet reactivity... Receptor Antiplatelet Agents • Prasugrel • Ticagrelor Prasugrel vs Clopidogrel: More Effective Platelet P2Y12 Inhibition IPA in Healthy Subjects • More rapid • More potent • More consistent platelet inhibition • Less frequent “resistance” • More efficient generation of its active metabolite Inhibition of Platelet Aggregation (%) 100 90 80 70 60 50 40 30 Pras 60/10 20 Clop 600/75 Clop 300/75 10 0 -10... design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38) Am Heart J 2006 Oct;152(4):627-35 TRITON TIMI 38: Balance of Efficacy and Safety Wiviott SD et al N Engl J Med 2007; 357: 2001 15 TRITON TIMI 38 Bleeding Events (n=13 457) Clopidogrel Prasugrel ICH in patients with prior... 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre PCI) Ticagrelor 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre -PCI) 6–12-month exposure Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack Wallentin... genotype with a high prevalence of CYP2C19*2 and *3 loss-of-function polymorphisms and low prevalence of the CYP2C19*17 gain-of-function polymorphism In contrast, Indian subjects demonstrated a South Asian genotype, with a lower prevalence of loss-of-function polymorphisms but a higher prevalence of the *17 gain-of-function polymorphism Mark Y Chan et al Pharmacogenomics 2012; 13: 533-542 70 Clopidogrel... and planned PCI n = 13,608 ASA Double-blind Clopidogrel 300 mg LD/ 75 mg MD Prasugrel 60 mg LD/ 10 mg MD Duration of therapy: 6–15 months 1o endpoint: CV death, MI, stroke 2o endpoint: Stent thrombosis Safety endpoints: TIMI major bleeds, life-threatening bleeds Reprinted with permission from: Wiviott SD, Antman EM, Gibson CM, et al Evaluation of prasugrel compared with clopidogrel in patients with... Functional recovery of all circulating platelets Onset/Offset: Inhibition of Platelet Aggregation Ticagrelor IPA at day 3 (72hrs) post dosing was similar to clopidogrel IPA at day 5 (120hrs) post dosing Gurbel PA et al Circulation 2009; 120: 2577-2585 PLATO Study Design NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624)... N H N HO O N F N Ticagrelor F S OH • New chemical class of P2Y12 inhibitors - Cyclo-pentyl-triazole-pyrimidine (CPTP): not a thienopyridine or ATP analogue - Inhibits adenosine reuptake • Direct-acting - Not a prodrug; does not require metabolic activation - Onset (within 2 hours); peak plasma levels within 2-3 hours - Greater and more consistent inhibition of platelet aggregation vs clopidogrel •