1. Up-to-date : Antiplatelet Therapy for Acute Coronary Syndrome นพ. ภาวิทย์ เพียรวิจิตร หน่วยโรคหัวใจ คณะแพทยศาสตร์ โรงพยาบาลรามาธิบดี มหาวิทยาลัยมหิดล

2. Acute Coronary Syndrome and ER Management นพ. ภาวิทย์ เพียรวิจิตร หน่วยโรคหัวใจ คณะแพทยศาสตร์ โรงพยาบาลรามาธิบดี มหาวิทยาลัยมหิดล

3. Increasing CV Mortality Bureau of Health Policy and Plan and Division of Epidemiology, MOPH

4. Top Ten Causes of Death in Thailand Per 100,000 population Bureau of Health Policy and Plan and Division of Epidemiology, MOPH

7. CAD: 2 Major Presentations Stable angina Stable angina Unstable angina / ACS Unstable angina / ACS

8. Age: 55 Age: 55 Sex: Male Sex: Male Past History: HTN Past History: HTN Occupation: High stress Occupation: High stress Complaint: Complaint: Chest pain when he runs about 500 meters. Chest pain when he runs about 500 meters. Relieved with rest in 3 minutes. Relieved with rest in 3 minutes. Occasional chest pain with stress Occasional chest pain with stress Case # 1: อาการคงที่ (stable angina)

9. ไขมัน พังผืด เซล ‘Stable’ Angina: Predictable Disease

10. Age: 50 Age: 50 Sex: Male Sex: Male Habit: non-smoker Habit: non-smoker Past History: - Past History: - Complaint: Complaint: Sudden onset of chest pain while resting Sudden onset of chest pain while resting No improvement after 15minutes No improvement after 15minutes

11. What causes ‘unstable’ symptom? ?

12. Acute Coronary Syndrome

13. Plaque Rupture

14. Scanning electron micrograph of dormant platelets Activated, aggregating platelets with fibrin strands ‘Active’ Platelet Lip GYH et al. Circulation 1996; 94: 425-431. Lip GYH et al. Am Heart J 1996; 131: 724-730.

15. ลิ่ม เลือด

16. Truths about Plaque Rupture No warning. No warning. Can occur after ‘normal’ EST. Can occur after ‘normal’ EST. No precipitating cause: ?↑BP, ?activitiy No precipitating cause: ?↑BP, ?activitiy

17. Spectrum of ACS Accelerating/ New onset Angina Unstable Angina, EKG-, Trop- UA with Trop+NSTEMI / NQWMI UA with Trop+ / NSTEMI / NQWMI STEMI / QWMI

18. Non ST Elevation MI ST Elevation MI

19. Difference in Mortality

20. แนวทางการรักษาคนไข้ ACS Prevent plaque rupture Prevent plaque rupture Statins Statins Decrease O 2 need Decrease O 2 need Decrease platelet activation and aggregation Decrease platelet activation and aggregation Open blocked vessel Open blocked vessel

21. ยาต้านเกล็ดเลือด ยาต้านเกล็ดเลือด B-blockers* (? mode of administration) B-blockers* (? mode of administration) Ca blockers as alternatives Ca blockers as alternatives Nitrates Nitrates O 2 O 2 Morphine Morphine Anti-coagulation Anti-coagulation ACEI* ACEI* ยาที่ควรให้ใน ACS (NSTEMI and STEMI) Class I Recommendation If no contra-indications!

23. Aspirin Mechanism of action: Mechanism of action: COX inhibitor Irreversible COX inhibitor Prevents thromboxane A 2 formation Diminishing platelet aggregation Indication: Class IA Indication: Class IA Dosage: 160-300mg Dosage: 160-300mg

24. Efficacy of ASA: Reduction of Death or MI in Unstable Angina Wallentin LC et al JACC 1991;18:1587–1593 0.00 0.05 0.10 0.15 0.20 0.25 036912 Months Probability of death or MI Placebo ASA 75 mg Risk ratio after 1 year 0.52 95% Cl 0.37–0.72 (p=0.0001)

25. Lytics & ASA in STEMI: ISIS-2 1. ISIS-2 Collaborative Group. Lancet 1988; 2: 349  360. 12.0% 9.2% 9.4% 11.8% 13.2% 8.0% Placebo versus streptokinase Placebo versus ASA 162 mg Neither versus both 5-week mortality (%) 25%* p <0.00001 23%* p <0.00001 42%* p <0.00001 *Odds reduction 0 2 4 6 8 10 12 14

26. Category of trial Prior MI Acute MI Prior stroke/TIA Other high risk All high risk (all the above) All low risk (primary prevention) All trials 119 18 104 142 3 145 MI/Stroke or Vascular Death Anti-platelet adjusted controls 13.5 % 17.1% 10.6 % 14.4% 18.4% 22.2% 6.9% 9.2% 4,183/36 536 5,400/36 711 (11.4%) (14.7%) 652/14,608 708/14,604 (4.46%) (4.85%) 4 835/51,144 6,108/51,315 (9.5%) (11.19%) 0 0.5 1.0 1.5 2.0 25(4) 29(4) 22(4) 32(4) 27(2) 10(6) 25(2) %OR (SD) OR&CI Antiplatelet Trialist Collaboration BMJ. 1994 Antiplatelet and Cardiovascular Events Antiplatelet and Cardiovascular Events better worse 2p <0.00001 No.of trials

27. ADP Antagonist Thienopyridine derivative Thienopyridine derivative Mechanism of action: Mechanism of action: ADP receptor antagonist ADP receptor antagonist

28. Mode of Action COX, cyclooxygenase; ADP, adenosine diphosphate; TxA 2, thromboxane A 2 Schafer AI Am J Med 1996;101:199–209

29. PLAVIX is a selective and potent inhibitor of platelet aggregation PLAVIX is a selective and potent inhibitor of platelet aggregation PLAVIX binds to a receptor and blocks ADP-induced aggregation PLAVIX binds to a receptor and blocks ADP-induced aggregation Blocking ADP binding results in a coupled biochemical reaction that inhibits binding of fibrinogen to the GPIIb/IIIa receptor on the platelet surface Blocking ADP binding results in a coupled biochemical reaction that inhibits binding of fibrinogen to the GPIIb/IIIa receptor on the platelet surface The end result is an irreversible modification of the platelet, rendering it unable to aggregate The end result is an irreversible modification of the platelet, rendering it unable to aggregate

30. Clopidogrel in Atherosclerotic Disease (CAPRIE) Patient population: Recent ischemic stroke Recent MI Symptomatic peripheral arterial disease ASA 325mg vs Clopidogrel 75mg Follow-up: 1 to 3 years

31. >> Confidential <<

32. Clopidogrel in Unstable Angina to Prevent Recurrent Events : CURE Design Double-blind treatment 3 to 12 months ASA 75–325 mg Clopidogrel 75 mg o.d. (~6250 patients) Placebo 1 tab o.d. (~6250 patients) ASA 75–325 mg 6 month visit 9 month visit 12 month or final visit 3 month visit Discharge visit 1 month visit ACS without ST elevation R N  12 500 28 countries Double-blind treatment 3 to 12 months Day 1 Clopidogrel 300 mg loading dose R Placebo loading dose CURE Study Investigators Eur Heart J 2000;21:2033–2041 Presented within 24hrs Clinical symptoms Ischemic EKG change

33. CURE : Primary Endpoint 20% RRR p=0.00009 n=12,562 Benefits were seen within hours and continued to increase over the 12 months 0123456789101112 Months of follow-up % of patients with recurrent ischemic event (cardiovascular death, MI, or stroke) * 0 10 14 12 4 8 6 2 Standard therapy ‡ Clopidogrel + standard therapy ‡ The CURE Investigators. N Eng J Med August 2001 ‡ including ASA 9.3% 11.4%

34. Overall12 56211.49.3 ST deviation +627514.311.5 ST deviation -62878.67.0 Entry enzymes elevated +317613.010.9 Entry enzymes elevated -938610.98.8 Diabetes +284016.714.2 Diabetes -97229.97.9 RiskLow41876.75.1 Intermediate41859.46.5 High418418.016.3 Rev after randomization +457713.911.5 Rev after randomization -798510.08.1 History of rev + 224614.48.4 History of rev -10 31610.79.5 Patient characteristics 0.40.60.81.01.2 RR (95% CI) + with condition - without condition Rev, revascularization The CURE Investigators. N Eng J Med August 2001 Primary Outcome : Subgroups ‡ including ASA 2N % events Standard therapy ‡ Clopidogrel + Standard therapy ‡

35. PCI-CURE CV death, MI or urgent TVR at 30d post PCI 30% risk reduction Absolute reduction 1.9% P=0.03

36. PCI-CURE : Long-term Efficacy 0.15 0.10 0.05 0.0 010010 0 40 100200300400 Cumulative hazard rates 31% RRR p=0.002n=2658 Days of follow-up ab Placebo ‡ Clopidogrel ‡ The CURE Investigators. Lancet August 2001 a = median time from randomization to PCI (10 days) b = 30 days after median time of PCI †up to 12 months ‡on top of standard therapy including ASA 12.6% 8.8% Composite of CV-death or MI from randomization to end of follow-up†

38. Peters RJ et al. Circulation 2003;108:1682 CURE: Major Bleeding by ASA Dose

39. 2002 ACC/AHA UA/NSTEMI Guidelines Update Class I: Class I: ASA should be administered as soon as possible after presentation and continued indefinitely (IA)ASA should be administered as soon as possible after presentation and continued indefinitely (IA) Clopidogrel 75 mg daily (in the absence of contraindications) when ASA is not tolerated (IA)Clopidogrel 75 mg daily (in the absence of contraindications) when ASA is not tolerated (IA) If early non-interventional approach is planned, clopidogrel should be added to ASA as soon as possible on admission and administered for at least 1 month (IA) and for up to 9 months (IB)If early non-interventional approach is planned, clopidogrel should be added to ASA as soon as possible on admission and administered for at least 1 month (IA) and for up to 9 months (IB) If PCI planned, clopidogrel should be started and continued for at least 1 month (IA) and up to 9 months in patients who are not at high risk for bleeding (IB)If PCI planned, clopidogrel should be started and continued for at least 1 month (IA) and up to 9 months in patients who are not at high risk for bleeding (IB) 1. Braunwald E et al. FOR INTERNAL USE ONLY

40. Class I: Class I: In patients taking clopidogrel in whom elective CABG is planned, the drug should be withheld for 5  7 days (IB)In patients taking clopidogrel in whom elective CABG is planned, the drug should be withheld for 5  7 days (IB) Anticoagulation with subcutaneous low molecular weight heparin (LMWH) or intravenous (iv) unfractionated heparin (UFH) should be added to antiplatelet therapy with ASA and/or clopidogrel (IA)Anticoagulation with subcutaneous low molecular weight heparin (LMWH) or intravenous (iv) unfractionated heparin (UFH) should be added to antiplatelet therapy with ASA and/or clopidogrel (IA) A platelet GPIIb/IIIa antagonist should be administered, in addition to ASA and heparin, to patients in whom catheterization and PCI are planned. The GPIIb/IIIa antagonist may also be administered just prior to PCI (IA)A platelet GPIIb/IIIa antagonist should be administered, in addition to ASA and heparin, to patients in whom catheterization and PCI are planned. The GPIIb/IIIa antagonist may also be administered just prior to PCI (IA) 1. Braunwald E et al. *Also known as non-Q-wave MI FOR INTERNAL USE ONLY 2002 ACC/AHA UA/NSTEMI Guidelines Update

41. Class I: Class I: For long-term medical therapy, the combination of ASA and clopidogrel is recommended for 9 months after UA/NSTEMI (B)For long-term medical therapy, the combination of ASA and clopidogrel is recommended for 9 months after UA/NSTEMI (B) 1. Braunwald E et al. *Also known as non-Q-wave MI FOR INTERNAL USE ONLY 2002 ACC/AHA UA/NSTEMI Guidelines Update

42. ALBION Assessment of best Loading dose of clopidogrel to Blunt platelet activation, Inflammation and Ongoing Necrosis 103 patients aged 18 to 85 years 103 patients aged 18 to 85 years UA NSTEMI within the 48 hours prior to randomisation. UA NSTEMI within the 48 hours prior to randomisation. 300mg, 600mg and 900mg 300mg, 600mg and 900mg Blood monitored every hour during the first 6 hours then at 24 hours to determine the kinetics of inhibition of platelet aggregation. Blood monitored every hour during the first 6 hours then at 24 hours to determine the kinetics of inhibition of platelet aggregation. Within the first 24 hours, higher loading doses of clopidogrel induced faster onset of action and higher levels of inhibition of platelet aggregation than the indicated loading dose of 300mg, in patients with ACS Within the first 24 hours, higher loading doses of clopidogrel induced faster onset of action and higher levels of inhibition of platelet aggregation than the indicated loading dose of 300mg, in patients with ACS Similar safety profile among different dosage groups. Similar safety profile among different dosage groups. EuroPCR Congress in Paris on May 24

43. Faster Onset of Action and Higher Level of Platelet Inhibition  p< 0.05 vs. 300 mg LD Shortened time to reach the highest level of inhibition of the 300 mg LD

44. Faster Onset of Action and Higher Level of Platelet Inhibition  p< 0.05 vs. 300 mg LD

45. Major Adverse Cardiac Events 300 mg n = 35 600 mg n = 34 900 mg n = 34 Death (n) Non-fatal MI*(n) Unplanned PCI (n) Hospitalization for recurrent angina (n) 011202000000 TOTAL – n (%) 4 (11.4) 2 (5.9) 0 * New Q wave or CK > 3 times the ULN

46. Safety 300 mg n = 35 600 mg n = 34 900 mg n = 34 Bleeding* Day 1- Discharge (n) Severe Severe Moderate Moderate Mild MildTOTAL011011001010011314 *GUSTO Classification

47. Summary In patients with NSTEMI, 600 and 900 mg LDs compared to 300-mg LD provided: More rapid and higher levels of IPA during the first 24 h Potential favorable trends on ischemic events and troponin release Greater reductions in some markers of platelet activation (PAC-1 and VASP) during the first 24 hours Comparable safety profiles IPA: Inhibition of Platelet Aggregation

48. Study Design *ASA=150–325 mg (if no ASA within prior 24 hours) as loading dose. Patients received heparin if they received a fibrin specific thrombolytic † All patients received ASA 75–162 mg/day plus other standard care Study treatment until angiography (2  8 days) or hospital discharge (maximum 8 days) n=1752 n=1739 Thrombolysis, heparin and ASA* Clopidogrel 300 mg loading dose / 75 mg QD † Placebo † R Double-blind, randomized, placebo-controlled trial in patients aged 18  75 years with STEMI ≤12 hours Clinical Follow-up at 30 days Primary endpoint: occluded artery (TIMI flow grade [TFG] 0/1), death/MI by time of angiography 1. Sabatine MS et al. New Engl J Med 2005; 352 (available at www.nejm.org)

49. Inclusion criteriaInclusion criteria Age 18  75 yearsAge 18  75 years STEMI within 12 hoursSTEMI within 12 hours Planned treatment with fibrinolyticPlanned treatment with fibrinolytic Major exclusion criteriaMajor exclusion criteria Clopidogrel within 7 daysClopidogrel within 7 days Planned clopidogrel or GPIIb/IIIa before angiographyPlanned clopidogrel or GPIIb/IIIa before angiography Contraindications to thrombolysis (stroke, ICH, brain tumor)Contraindications to thrombolysis (stroke, ICH, brain tumor) Cardiogenic shockCardiogenic shock Intention of angiography within 48 hoursIntention of angiography within 48 hours CABG, creatinine >2.5 mg/dL, hepatic insufficiency,  plateletsCABG, creatinine >2.5 mg/dL, hepatic insufficiency,  platelets  67 kg and >4000 U bolus UFH; >67 kg and >5000 U bolus >1.1 mg/kg subcutaneous of enoxaparin  67 kg and >4000 U bolus UFH; >67 kg and >5000 U bolus >1.1 mg/kg subcutaneous of enoxaparin Inclusion/Exclusion Criteria FOR INTERNAL USE ONLY

50. Angiographic Outcomes and Long-term Mortality 1. Gibson CM et al. Circulation 2002; 105: 1909  1913. TFG 0/1 2-year mortality (%) 14.5% TFG 2/3TMPG 0/1TMPG 2/3 6.4% 4.8% 9.1% HR: 0.41 (p=0.001)HR: 0.51 (p=0.038) TIMI flow grade TIMI myocardial perfusion grade* *90 minute angiogram in TIMI 10b trial; HR=hazard ratio

51. Primary endpoint: Primary endpoint: CompositeComposite % of occluded infarct related artery (TFG 0/1) on pre- discharge angiogram% of occluded infarct related artery (TFG 0/1) on pre- discharge angiogram Death or MI before CAGDeath or MI before CAG Death or MI by hospital discharge (maximum 8 days) if no angiography performedDeath or MI by hospital discharge (maximum 8 days) if no angiography performed Study Endpoints *CV death, MI, stroke or recurrent ischemia leading to urgent target vessel revascularization FOR INTERNAL USE ONLY 1. Sabatine MS et al. New Engl J Med 2005; 352

52. Clopidogrel Improved Perfusion *Based on odds of an occluded infarct-related artery (TFG 0/1), death or MI by angiography for clopidogrel versus placebo (OR: 0.64 [0.53 to 0.76]; p <0.001) Placebo (n=1739) Clopidogrel (n=1752) 21.7 15.0 5 10 15 20 25 Primary endpoint* (%) 36% reduction* p <0.001 1. Sabatine MS et al. New Engl J Med 2005; 352 (available at www.nejm.org)

53. CLARITY: Reduction of Primary Endpoint by 36% ClopidogrelPlaceboOdds ratio (n=1752) (n=1739) (95% CI) p value Primary endpoint (%) Primary endpoint (%) TFG 0/1, MI/death15.021.70.64 (0.53  0.76)<0.001 TFG 0/1, MI/death15.021.70.64 (0.53  0.76)<0.001 Components (%) Components (%) TFG 0/111.718.40.59 (0.48  0.72)<0.001 TFG 0/111.718.40.59 (0.48  0.72)<0.001 Recurrent MI2.53.60.70 (0.47  1.04)0.08 Recurrent MI2.53.60.70 (0.47  1.04)0.08 Death2.62.21.17 (0.75  1.82)0.49 Death2.62.21.17 (0.75  1.82)0.49 FOR INTERNAL USE ONLY 1. Sabatine MS et al. New Engl J Med 2005; 352

54. Number ofOdds Event rates (%) CharacteristicpatientsreductionClopidogrelPlacebo OVERALL34913615.021.7 Age <65 years24664213.221.0  65 years10152219.023.1 Gender Male27963514.520.8 Female6853816.924.7 Infarct location Anterior14163315.020.7 Non-anterior20653815.022.2 Fibrinolytic Fibrin-specific23973114.720.1 Non-fibrin specific10844415.724.9 Predominant heparin LMWH14293111.415.7 UFH14314217.827.1 None6212617.121.9 1.00.40.60.81.21.6 Clopidogrel betterPlacebo better Primary Endpoint: Subgroups 1. Sabatine MS et al. New Engl J Med 2005; 352

55. Clopidogrel Improved Angiographic Outcomes 1 ClopidogrelPlaceboOdds ratio ClopidogrelPlaceboOdds ratio (n=1752) (n=1739) (95% CI) p value (n=1752) (n=1739) (95% CI) p value Angiographic outcomes (%) Angiographic outcomes (%) TFG 3*67.860.81.36 (1.18  1.57)<0.001 TFG 3*67.860.81.36 (1.18  1.57)<0.001 TMPG 3 † 55.851.21.21 (1.05  1.40)0.008 TMPG 3 † 55.851.21.21 (1.05  1.40)0.008 Thrombus43.050.80.73 (0.64  0.84)<0.001 Thrombus43.050.80.73 (0.64  0.84)<0.001 FOR INTERNAL USE ONLY *TFG= TIMI Flow Grade † TPMG= TIMI Myocardial Perfusion Grade 1. Sabatine MS et al. New Engl J Med 2005; 352 (available at www.nejm.org)

56. CLARITY : Clinical Events at 30 Days CV death, MI or recurrent ischemia leading to urgent revascularization Time (days) Incidence of clinical endpoints (%) 0 5 10 15 051015202530 Placebo Clopidogrel 20%* p=0.03 1. Sabatine MS et al. New Engl J Med 2005

57. Endpoints at 30-Day Endpoints at 30-Day Odds reduction ClopidogrelPlacebo CV death3 4.44.5 Recurrent MI 31 4.15.9 Recurrent ischemia leading to urgent 24 3.54.5 revascularization Stroke 46 0.91.7 CV death or MI 17 8.49.9 CV death, MI or stroke 18 9.110.9 CV death, MI or recurrent ischemia leading to urgent 20 11.614.1 revascularization CV death, MI, stroke or recurrent ischemia leading 21 12.315.0 to urgent revascularization Percentage of patients with event Endpoint Odds ratio (95% CI) 1.00.40.60.81.2 Clopidogrel betterPlacebo better 1.6 1. Sabatine MS et al. New Engl J Med 2005; 352 (available at www.nejm.org)

58. Safety ClopidogrelPlacebo (n=1733) (n=1719) p value Primary bleeding endpoint (%) Primary bleeding endpoint (%) TIMI major 23 (1.3)19 (1.1)0.64 TIMI major 23 (1.3)19 (1.1)0.64 Secondary bleeding endpoints (%) Secondary bleeding endpoints (%) TIMI minor 17 (1.0)9 (0.5)0.17 TIMI minor 17 (1.0)9 (0.5)0.17 TIMI major or minor 40 (2.3)28 (1.6)0.18 TIMI major or minor 40 (2.3)28 (1.6)0.18 Intracranial hemorrhage8 (0.5)12 (0.7)0.38 Intracranial hemorrhage8 (0.5)12 (0.7)0.38 Bleeding through 30 days (%) Bleeding through 30 days (%) TIMI major 33 (1.9)30 (1.7)0.80 TIMI major 33 (1.9)30 (1.7)0.80 TIMI minor 27 (1.6)16 (0.9)0.12 TIMI minor 27 (1.6)16 (0.9)0.12 TIMI major or minor 59 (3.4)46 (2.7)0.24 TIMI major or minor 59 (3.4)46 (2.7)0.24 FOR INTERNAL USE ONLY 1. Sabatine MS et al. New Engl J Med 2005; 352

59. CLARITY: Summary For STEMI, ASA + Lytics + loading dose (300mg) clopidogrel followed by 75mg OD:For STEMI, ASA + Lytics + loading dose (300mg) clopidogrel followed by 75mg OD: 36% reduction in the odds of an occluded infarct- related artery, or death or MI by time of pre-discharge angiography or hospital discharge (maximum 8 days)36% reduction in the odds of an occluded infarct- related artery, or death or MI by time of pre-discharge angiography or hospital discharge (maximum 8 days) Consistent across all major subgroupsConsistent across all major subgroups At 30 days, a 20% reduction (p=0.03) in CV death, MI or recurrent ischemia leading to urgent revascularizationAt 30 days, a 20% reduction (p=0.03) in CV death, MI or recurrent ischemia leading to urgent revascularization No significant excess in TIMI major bleeding or ICHNo significant excess in TIMI major bleeding or ICH FOR INTERNAL USE ONLY

60. TIMI 1 APRICOTClarity 47%RR; P<0.001 36%RR; P<0.001 22%RR; P=0.25

61. 1. Chen ZM et al. ACC 2005. COMMIT/CCS-2: ClOpidogrel and Metoprolol in Myocardial Infarction Trial

62. Double-blind treatment until hospital discharge or for a maximum of 4 weeks (n ~ 23,000) n=~46,000 R Patients with acute STEMI  24 hours * All patients received a background of ASA 162mg/day during the study (2  2 Factorial with metoprolol) Study Design Clopidogrel 75 mg QD* Placebo* (n ~ 23,000) 1. Chen ZM et al. ACC 2005.

63. Inclusion/Exclusion Criteria  Inclusion Criteria: Suspected acute MI (with definite ECG changes: ST Elevation or LBBB) Suspected acute MI (with definite ECG changes: ST Elevation or LBBB) 24 h since the onset of symptoms 24 h since the onset of symptoms No clear indication/contraindication to trial treatments No clear indication/contraindication to trial treatments  Exclusion Criteria: High risk of adverse drug reactions: High risk of adverse drug reactions: – Allergy to aspirin or any trial drug – Active bleeding or haematologic disorder – Persistent hypotension or bradycardia – High-degree AV block, pacemaker, cardiogenic shock Small likelihood of potential benefits: Small likelihood of potential benefits: – Low risk of MI death (non-typical MI, primary PCI) FOR INTERNAL USE ONLY 1. Chen ZM et al. ACC 2005.

64. ClopidogrelPlacebo Characteristic (n=22,960)(n=22,891) Characteristic (n=22,960)(n=22,891) Female (%)27.727.9 Female (%)27.727.9 Mean age (yrs) 61.361.4 Mean age (yrs) 61.361.4 Age >70 (%) 26.026.0 Age >70 (%) 26.026.0 Time from symptom onset Time from symptom onset to randomization (hrs)10.310.3 to randomization (hrs)10.310.3 Time from symptom onset <6 h (%) Time from symptom onset <6 h (%) 33.833.7 33.833.7 Killip class II/III (%) 24.124.0 Killip class II/III (%) 24.124.0 STEMI/LBBB93.193.1 STEMI/LBBB93.193.1 Prior MI history (%) 8.68.1 Prior MI history (%) 8.68.1 Fibrinolytic (%)49.749.8 Fibrinolytic (%)49.749.8 Patient characteristics FOR INTERNAL USE ONLY 1. Chen ZM et al. ACC 2005.

65. 07142128 0 1 2 3 4 5 6 7 8 9 10 Days since randomization (up to 28 days) Clopidogrel (9.3%) Placebo (10.1%) Events (%) RRR=9% P=0.002 COMMIT: Composite Endpoint (Death, MI, or Stroke) FOR INTERNAL USE ONLY 1. Chen ZM et al. ACC 2005.

66. 07142128 0 1 2 3 4 5 6 7 8 9 Days since randomization (up to 28 days) Clopidogrel (7.5%) Placebo (8.1%) RRR=7% p=0.03 Mortality (%) COMMIT: Mortality 1. Chen ZM et al. ACC 2005.

67. Clopidogrel Decreased Re- Infarction Odds ratio & 95% CI Clopi betterPlacebo better Outcome Clopidogrel Placebo after Re-MI (n=22,958) (n=22,891) Fatal MI209 (0.9%) 223 (1.0%) Non-Fatal MI273 (1.2%)330 (1.4%) ALL 482 (2.1%)553 (2.4%) 13% SE 6 Reduction p=0.02 0.40.60.81.01.21.41.6 FOR INTERNAL USE ONLY 1. Chen ZM et al. ACC 2005.

68. Effects of Clopidogrel on Stroke Odds ratio & 95% CI Clopi betterPlacebo better Clopidogrel Placebo Type (n=22,958) (n=22,891) Ischemic162 (0.7%) 192 (0.8%) Hemorrhagic55 (0.2%)55 (0.2%) ALL216 (0.9%)249 (1.1%) 14% SE 9 Reduction P>0.1, NS 0.40.60.81.01.21.41.6 FOR INTERNAL USE ONLY 1. Chen ZM et al. ACC 2005.

69. Effects of Clopidogrel on Non- Cerebral Bleeding Odds ratio & 95% CI Clopi betterPlacebo better Clopidogrel Placebo Type (n=22,958) (n=22,891) Major Bleed*82 (0.4%) 73 (0.3%) Other Bleed831 (3.6%)721 (3.1%) ALL896 (3.9%)777 (3.4%) 16% SE 5 Increase P=0.004 0.40.60.81.01.21.41.6 *Fatal or transfused FOR INTERNAL USE ONLY 1. Chen ZM et al. ACC 2005.

70. Consistent Effects of Clopidogrel on Death, Re-MI or Stroke by Age and Gender Odds ratio & 95% CI Clopi betterPlacebo better BaselineClopidogrel Placebo Features(n=22,958) (n=22,891) Gender Male1276 (7.7%)1416 (8.6%) Female849 (13.3%)895 (14.0%) Age <60487 (5.1%)513 (5.4%) 60-69747 (10.2%) 835 (11.2%) 70+891 (14.9%)963 (16.2%) ALL2125 (9.3%)2311 (10.1%) 9% SE 3 Reduction P=0.002 0.40.60.81.01.21.41.6 FOR INTERNAL USE ONLY 1. Chen ZM et al. ACC 2005.

71. Outcomes by Time Delay and Fibrinolytic Use Odds ratio & 95% CI Clopi betterPlacebo better BaselineClopidogrel Placebo Features(n=22,958) (n=22,891) Time Delay (hrs) 0-6776 (9.3%)904 (10.9%) 7-12672 (9.7%)735 (10.7%) 13-24666 (8.8%)666 (8.7%) Lytic Given Yes1005 (8.8%)1123 (9.9%) No1120 (9.7%) 1188 (10.3%) ALL2125 (9.3%)2311 (10.1%) 9% SE 3 Reduction P=0.002 0.40.60.81.01.21.41.6 1. Chen ZM et al. ACC 2005.

72. COMMIT: Summary For STEMI, ASA + clopidogrel 75mg OD + Lytic:For STEMI, ASA + clopidogrel 75mg OD + Lytic: 7% reduction mortality7% reduction mortality No significant excess in TIMI major bleeding or ICHNo significant excess in TIMI major bleeding or ICH FOR INTERNAL USE ONLY

73. GP IIb/IIIa Receptor Antagonists Eptifibatide Eptifibatide Tirofiban Tirofiban Abciximab Abciximab

76. A murine monoclonal antibody that completely blocks the binding of fibrinogen to platelets produces a thrombasthenic-like state in normal platelets and binds to glycoproteins IIb and/or IIIa. J Clin Invest 1983 Coller BS, Peerschke EI, Scudder LE, Sullivan CA. Fc fragment of murine monoclonal antibody against Gp2b3a, 7E3, was removed to prevent immunogenicity and Fab fragments joined with the constant regions of human immunoglobulin, forming a chimeric compound (abciximab, or c7E3).

77. RGD sequence

78. Gp IIb/IIIa in ACS

79. Gp IIb/IIIa blockers are recommended (Class I) for UA/NSTEMI treated with interventional approach. For non-interventional patients with ongoing ischemia (Class II)

80. ISAR-REACT: 30-d adverse reactions in low-to-moderate risk undergoing PCI after 600mg Clopidogrel loading dose

81. Medical solution Mechanical solution เมื่อหลอด เลือดตัน …

82. Percutaneous Coronary Intervention (PCI)

83. Angioplasty Volume in Thailand (Approximate figures) 27 Cath Labs * Projected for 2004

84. Problems with Angioplasty Balloon-induced Dissection/ Plaque rupture Blood-Exposed Non- Intimal Surface (BENIS)

85. Efficacy of Drug Regimens in Coronary Stenting Event rates (% death, MI, revasc.) 0 4 8 12 ISAR N=517 FANTASTIC N=485 STARS N=1653 MATTIS N=350 Ticlopidine + ASACoumadin + ASA 6.2 1.6 8.3 5.7 2.7 0.5 11 5.6 3.6 ASA CLASSICS N=1020 1.5 1.20.9 Clopidogrel + ASA Clopidogrel LD + ASA

86. 28 (8.2%) 17 (5.1%) 7 (2%) Early Discontinuation of Study Drug No. of patients discontinuing

87. CREDO JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420 Symptomatic CAD with objective evidence of ischemia Symptomatic CAD with objective evidence of ischemia symptoms of angina pectoris symptoms of angina pectoris positive stress test positive stress test dynamic ECG changes dynamic ECG changes referred for elective or urgent PCI referred for elective or urgent PCI Randomized to clopidogrel loading (300mg) and long term maintenance. Randomized to clopidogrel loading (300mg) and long term maintenance.

88. 6-24 h before PTCA ± stent Double-blind, comparison between two regimens 2000 patients, 100 centres in the US CREDO 1 MONTH 1 YEAR Placebo + aspirin Clopidogrel 75 mg + aspirin Placebo + aspirin Clopidogrel 75 mg + aspirin Clopidogrel 300 mg LD + aspirin Group 1 Group 2 PTCA ± stent

89. CREDO 300mg clopidogrel vs placebo 3-24hr prior to PCI 300mg clopidogrel vs placebo 3-24hr prior to PCI From day 29 to 12months randomized to long term clopidogrel vs placebo From day 29 to 12months randomized to long term clopidogrel vs placebo 1 year result : 29% reduction in death, MI, stroke with loading and long-term clopidogrel. 1 year result : 29% reduction in death, MI, stroke with loading and long-term clopidogrel. Gp IIb/IIIa antagonist had relative benefits in the group with >6-24hr of clopidogrel pretreatment. Gp IIb/IIIa antagonist had relative benefits in the group with >6-24hr of clopidogrel pretreatment.

90. Long-term Benefits of Clopidogrel in PCI Patients 27% RRR p = 0.02 11.5% (MI, Stroke, or Death) 1 year results * Standard therapy including ASA JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420

91. 0.60.81.01.2 GPIIb/IIIa Inhibitor Yes(N=826) No(N=1289) ACS Yes(N=1407) No(N=694) Diabetes Yes(N=560) No(N=1556) Stent Yes(N=1616) No(N=500) Male(N=1510) Female(N=606) Overall(N=2116) 28.8 26.5 27.6 22.7 11.2 32.8 28.8 19.0 24.5 32.1 26.9 0.4 Hazard ratio (95% CI) Placebo Better Clopidogrel Better RRR (MI, Stroke, or Death at 1 year) JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420 CREDO: Results by Subgroups

92. Antiplatelet therapy is essential in the management of patients with ACS Antiplatelet therapy is essential in the management of patients with ACS Medically treated Medically treated Percutaneous intervention Percutaneous intervention New studies support expanding role of ADP antagonists in the management of STEMI New studies support expanding role of ADP antagonists in the management of STEMI Conclusions FOR INTERNAL USE ONLY 1. Chen ZM et al. ACC 2005.

93. Thank you for your attention.