1. Medical management after PCI Ma Hong 1 st affiliated hospital of Sun Yat-sen University

2. Successful PCI is just the beginning of another long journey

3. Goals of medical management after PCI To prevent acute/sub-acute stent thrombosis To prevent other coronary events (improve survival) To improve symptoms

4. Medical management after PCI Antiplatelet therapy Beta-blocade ACEI / ARB Statins others

6. After PCI, aspirin should be continued indefinitely. Postprocedural Antiplatelet Therapy I IIaIIbIII 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, JACC 2011:58(24) After PCI, it is reasonable to use 81 mg per day of aspirin in preference to higher maintenance doses. I IIaIIbIII

7. Postprocedural Antiplatelet Therapy The duration of P2Y 12 inhibitor therapy after stent implantation should generally be as follows: a)In patients receiving a stent (BMS or DES) during PCI for ACS, P2Y 12 inhibitor therapy should be given for at least 12 months (clopidogrel 75 mg daily); prasugrel 10 mg daily; and ticagrelor 90 mg twice daily. b)In patients receiving a DES for a non–ACS indication, clopidogrel 75 mg daily should be given for at least 12 months if patients are not at high risk of bleeding. c)In patients receiving a BMS for a non-ACS indication, clopidogrel should be given for a minimum of 1 month and ideally up to 12 months (unless the patient is at increased risk of bleeding; then it should be given for a minimum of 2 weeks). I IIaIIbIII 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, JACC 2011:58(24)

8. Continuation of clopidogrel, prasugrel or ticagrelor beyond 12 months may be considered in patients undergoing DES placement. Postprocedural Antiplatelet Therapy I IIaIIbIII If the risk of morbidity from bleeding outweighs the anticipated benefit afforded by a recommended duration of P2Y 12 inhibitor therapy after stent implantation, earlier discontinuation (e.g., <12 months) of P2Y 12 inhibitor therapy is reasonable. I IIaIIbIII 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, JACC 2011:58(24)

9. New P2Y 12 inhibitor -- prasugrel, ticagrelor Prasugrel –Phase 2 PCI: JUMBO – TIMI 26 –Phase 3 PCI in ACS: TRITON – TIMI 38 –TRIGGER-PCI – …… Ticagrelor –PLATO –PLATO-INVASIVE –……

10. N S O ClO CH 3 C Clopidogrel Prodrug Prasugrel N S O C O F O CH 3 85% Inactive MetaboliteshCE1Liver Hydrolysis (Esterases) N S O F O hCE2Gut HOOC * HS N O F CYPs: 3A4/5 2B6 2C9 2C19 Gut and Liver Oxidation (Cytochrome P450) Active Metabolite CYPs: 1A2 2B6 2C19 Liver HOOC * HS N O Cl OCH 3 CYPs: 3A4/5 2B6 2C9 2C19 Liver ClopidogrelPrasugrel

11. Wiviott SD et al. NEJM 2007; 357: 2001-2015 TRITON Efficacy and Safety in Patients with ACS ≥ 60 kg, < 75 years, no previous stroke/ TIA 0 2 4 6 8 10 12 14 16 03090180 270360450 Endpoint (%) Hazard Ratio, 1.240 (95% CI, 0.91 - 1.69) P = 0.17 Hazard Ratio, 0.75 (95% CI, 0.66 - 0.84) P < 0.001 Clopidogrel 11.0% Prasugrel 8.3% Clopidogrel 1.50% Prasugrel 2.0% Days Cardiovascular Death, MI, Stroke Major Bleeding ITT= 13,608 LTFU = 14 (0.1%)

12. Ticagrelor - An Oral Reversible P2Y12 Antagonist Ticagrelor is a cyclo-pentyl- triazolo-pyrimidine (CPTP) OH OH O OH N F S N H N N N N F n Direct acting l Not a prodrug; does not require metabolic activation l Rapid onset of inhibitory effect on the P2Y 12 receptor l Greater inhibition of platelet aggregation than clopidogrel n Reversibly bound l Degree of inhibition reflects plasma concentration l Faster offset of effect than clopidogrel l Functional recovery of all circulating platelets

13. PLATO study design Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding 6–12-month exposure Clopidogrel If pre-treated, no additional loading dose; if naive, standard 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) NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack

14. PLATO – INVASIVE study design 6–12 months treatment PCI = percutaneous coronary intervention; CV = cardiovascular; PI = principal investigator NSTEMI ACS (moderate-to-high risk) STEMI (if primary PCI) (N=18,624) Clopidogrel-treated or -naive; randomized <24 hours of index event At randomization, 13,408 (72%) of patients were specified by the Investigator: intent for invasive strategy Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding Clopidogrel (n=6,676) If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre-PCI) Ticagrelor (n=6,732) 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-PCI)

15. Primary endpoint: CV death, MI or stroke 0 0 5 10 15 60120180240 300360 Days after randomization K-M estimated rate (% per year) HR: 0.84 (95% CI = 0.75–0.94), p=0.0025 9.02 10.65 Clopidogrel Ticagrelor No. at risk Clopidogrel Ticagrelor 6,676 6,732 6,129 6,236 6,034 6,134 5,8814,815 4,889 3,680 3,735 2,965 3,0485,972 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

16. Stent thrombosis Ticagrelor (n=6,732) Clopidogrel (n=6,676) HR for ticagrelor (95% CI) p value* Stent thrombosis, % Definite Probable or definite Possible, probable, or definite 1.0 1.7 2.2 1.6 2.3 3.1 0.62 (0.45–0.85) 0.72 (0.56–0.93) 0.72 (0.58–0.90) 0.003 0.01 0.003 ¶ Evaluated in patients with any stent during the study Time-at-risk is calculated from the date of first stent insertion in the study or date of randomization * By univariate Cox model

17. Primary safety event: Major bleeding * No. at risk Clopidogrel Ticagrelor 6,585 6,651 5,215 5,235 4,984 4,947 4,786 Days after randomization 3,753 3,726 2,754 2,741 2,496 2,503 060120180240300360 10 5 0 15 Clopidogrel Ticagrelor 11.6 11.5 4,755 K-M estimated rate (% per year) HR 0.99 (95% CI = 0.89–1.10), p=0.88 * PLATO definitions

21. Before we have the new P2Y12 Inhibitors, what we can do for high risk patients ?

22. Low Dose ASA (75-100 mg) Low Dose ASA (75-100 mg) Mehta SR et al. Am Heart J 2008 25,000 ACS or STEMI Patients Angiography with intended PCI <72 hrs No restriction on use of GP IIb/IIIa inhibitors 25,000 ACS or STEMI Patients Angiography with intended PCI <72 hrs No restriction on use of GP IIb/IIIa inhibitors DOUBLE DOSE Clopidogrel 600mg then 150 mg OD x 6d then 75 mg OD DOUBLE DOSE Clopidogrel 600mg then 150 mg OD x 6d then 75 mg OD STANDARD DOSE Clopidogrel 300 mg followed by 75 mg daily STANDARD DOSE Clopidogrel 300 mg followed by 75 mg daily Randomized High Dose ASA (300-325 mg) High Dose ASA (300-325 mg) High Dose ASA (300-325 mg) High Dose ASA (300-325 mg) Low Dose ASA (75-100 mg) Low Dose ASA (75-100 mg) A Randomized, Double-Blind, 2X2 Factorial Trial of Clopidogrel Double vs. Standard Dose and High versus Low Dose ASA in ACS or STEMI with an Early Invasive Strategy and intent for PCI Primary Efficacy Outcome CV Death / MI /stroke at 30 days Secodary Outcome ARC defined STENT THROMBOSIS CVD/MI/Stroke + Rec Ischemia Rational for high dose clopidogrel therapy CURRENT -- OASIS 7

23. 23 Definite Stent Thrombosis in 4 Groups (Angiographically Proven) Days Cumulative Hazard 0.0 0.004 0.008 0.012 036912151821242730 C Standard, A Low C Standard, A High C Double, A Low C Double, A High Standar d Clop Double Clop HRP P Int n High ASA1.20.60.490.003 Low ASA1.20.80.60.0580.35

24. 24 Days Cumulative Hazard 0.0 0.005 0.010 0.015 036912151821242730 Clopidogrel Standard Clopidogrel Double HR 0.54 95% CI 0.35-0.84 P=0.006 STEMI-PCI: Definite Stent Thrombosis 46% RRR Mehta SR. TCT 2009 LBCT

25. DAPT – the longer the better ? Duration of DAPT after DES : at least 12 months, possibly longer await for RCT

27. Others – prevention of GIB Interaction of PPI and Clopidogrel : what we have known ?

28. Scientific Basis Juhász et al. Digestion 2010 ; Taubert D et al. Clin Pharmacol Ther 2006;80:486–501

29. Lab. result

30. Observational Data

31. Randomized Data

32. The Cogent Trial Randomized to Clopidogrel + Omeprazole (CGT 2168) or Clopidogrel + Placebo 3627 patients (above the initial target of 3200) 393 sites Median follow-up 133 days (maximum 362 days) 136 adjudicated cardiovascular events (preliminary) 105 adjudicated GI events (preliminary)

33. CONGENT – Primary Endpoint Bhatt DL. Presented at: NEJM OCTOBER 2010

34. Prevention of GIB -- guidelines PPI should be used in patients with history of prior GIB who require DAPT. PPI use is reasonable in patients with increased risk of gastrointestinal bleeding (advanced age, concomitant use of warfarin, steroids, nonsteroidal anti-inflammatory drugs, H pylori infection, etc.) who require DAPT. Routine use of a PPI is not recommended for patients at low risk of gastrointestinal bleeding, who have much less potential to benefit from prophylactic therapy. I IIaIIbIII I IIaIIbIII I IIaIIbIII 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, JACC 2011:58(24)

35. Second prevention 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, JACC 2011:58(24)

36. THANK YOU

37. Antiplatelet therapy for polymer- free stent and biodegenerable stents ? We are not clear need more trials

38. 38 1.Overall, the primary outcome was neutral between the clopidogrel and aspirin dose groups. 1 2.In patients undergoing PCI, the double-dose clopidogrel regimen reduced the primary outcome (CV death, MI or stroke) and stent thrombosis 3.The reduction in stent thrombosis was robust and observed in those receiving DES and BMS and in those presenting with STEMI 4.There was a modest excess in major bleeds, but no difference in ICH, fatal bleeds or CABG-related bleeds with the double-dose regimen. No difference in major bleeds between aspirin dose groups. 5.There was an interaction between clopidogrel and aspirin such that the lowest event rates were observed in those receiving double-dose clopidogrel and high-dose aspirin. 2. Mehta et al. Lancet 2010; Online First Sept 1 1. CURRENT Investigators. N Engl J Med 2010;363:930-42 Rational for high dose clopidogrel therapy CURRENT -- OASIS 7