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Up-to-date : Antiplatelet Therapy for Acute Coronary Syndrome

Up-to-date : Antiplatelet Therapy for Acute Coronary Syndrome. นพ. ภาวิทย์ เพียรวิจิตร หน่วยโรคหัวใจ คณะแพทยศาสตร์โรงพยาบาลรามาธิบดี มหาวิทยาลัยมหิดล. Increasing CV Mortality. Bureau of Health Policy and Plan and Division of Epidemiology, MOPH. CAD: 2 Major Presentations. Stable angina

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Up-to-date : Antiplatelet Therapy for Acute Coronary Syndrome

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

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

  3. CAD: 2 Major Presentations • Stable angina • Unstable angina / ACS

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

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

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

  7. What causes ‘unstable’ symptom? ?

  8. Acute Coronary Syndrome

  9. ลิ่มเลือด

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

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

  12. Non ST Elevation MI ST Elevation MI

  13. แนวทางการรักษาคนไข้ ACS • Prevent plaque rupture • Statins • Decrease O2 need • Decrease platelet activation and aggregation • Open blocked vessel

  14. ยาที่ควรให้ในACS (NSTEMI and STEMI) • ยาต้านเกล็ดเลือด • B-blockers* (? mode of administration) • Ca blockers as alternatives • Nitrates • O2 • Morphine • Anti-coagulation • ACEI* Class I Recommendation If no contra-indications!

  15. Aspirin • Mechanism of action: • Irreversible COX inhibitor • Prevents thromboxane A2 formation • Diminishing platelet aggregation • Indication: Class IA • Dosage: 160-300mg

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

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

  18. ADP Antagonist • Thienopyridine derivative • Mechanism of action: • ADP receptor antagonist

  19. Mode of Action COX, cyclooxygenase; ADP, adenosine diphosphate; TxA2, thromboxane A2 Schafer AI Am J Med 1996;101:199–209

  20. Clopidogrel in Unstable Angina to Prevent Recurrent Events : CURE Design N 12 500 28 countries Clopidogrel 300 mg loading dose Clopidogrel75 mg o.d.(~6250 patients) ASA 75–325 mg ACS without ST elevation R R Double-blind treatment 3 to 12 months Double-blind treatment 3 to 12 months • Presented within 24hrs • Clinical symptoms • Ischemic EKG change ASA 75–325 mg Placebo 1 tab o.d.(~6250 patients) 12 monthor final visit 3 month visit 1 month visit 6 month visit 9 month visit Day 1 Discharge visit Placebo loading dose CURE Study Investigators Eur Heart J 2000;21:2033–2041

  21. CURE : Primary Endpoint % of patients with recurrent ischemic event (cardiovascular death, MI, or stroke) * 14 11.4% Benefits were seen within hours and continued to increase over the 12 months 12 9.3% 10 20% RRR p=0.00009 n=12,562 8 6 4 Standard therapy‡ Clopidogrel + standard therapy‡ 2 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Months of follow-up ‡including ASA The CURE Investigators. N Eng J Med August 2001

  22. Primary Outcome : Subgroups % events 2N Standard therapy‡ Clopidogrel + Standard therapy‡ RR (95% CI) Patient characteristics Overall 12 562 11.4 9.3 ST deviation + 6275 14.3 11.5 ST deviation - 6287 8.6 7.0 Entry enzymes elevated + 3176 13.0 10.9 Entry enzymes elevated - 9386 10.9 8.8 Diabetes + 2840 16.7 14.2 Diabetes - 9722 9.9 7.9 Risk Low 4187 6.7 5.1 Intermediate 4185 9.4 6.5 High 4184 18.0 16.3 Rev after randomization + 4577 13.9 11.5 Rev after randomization - 7985 10.0 8.1 History of rev + 2246 14.4 8.4 History of rev - 10 316 10.7 9.5 + with condition - without condition Rev, revascularization 0.4 0.6 0.8 1.0 1.2 ‡including ASA The CURE Investigators. N Eng J Med August 2001

  23. PCI-CURE :Long-term Efficacy Composite of CV-death or MI from randomization to end of follow-up† 12.6% Placebo‡ Clopidogrel‡ 0.15 31% RRR p=0.002 n=2658 8.8% Cumulative hazard rates 0.10 0.05 0.0 0 100 200 300 400 10 40 Days of follow-up a b 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 The CURE Investigators. Lancet August 2001

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

  25. 2002 ACC/AHA UA/NSTEMI Guidelines Update • Class I: • 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) • 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) 1. BraunwaldE et al. FOR INTERNAL USE ONLY

  26. ALBIONAssessment of best Loading dose of clopidogrel to Blunt platelet activation, Inflammation and Ongoing Necrosis • 103 patients aged 18 to 85 years • UA NSTEMI within the 48 hours prior to randomisation. • 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. • 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. EuroPCR Congress in Paris on May 24

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

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

  29. Major Adverse Cardiac Events * New Q wave or CK > 3 times the ULN

  30. Safety *GUSTO Classification

  31. Study Design Double-blind, randomized, placebo-controlled trial inpatients aged 1875 years with STEMI ≤12 hours Clopidogrel 300 mg loading dose / 75 mg QD† n=1752 Thrombolysis, heparin and ASA* Study treatment until angiography (28 days) or hospital discharge (maximum 8 days) Clinical Follow-up at 30 days R n=1739 Placebo† Primary endpoint: occluded artery (TIMI flow grade [TFG] 0/1), death/MI by time of angiography *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 1. Sabatine MS et al. New Engl J Med 2005; 352 (available at www.nejm.org)

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

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

  34. Clopidogrel Improved Perfusion 25 36% reduction* p <0.001 21.7 20 15.0 15 Primary endpoint* (%) 10 5 Placebo (n=1739) Clopidogrel (n=1752) *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) 1. Sabatine MS et al. New Engl J Med 2005; 352 (available at www.nejm.org)

  35. CLARITY: Reduction of Primary Endpoint by 36% Clopidogrel PlaceboOdds ratio (n=1752) (n=1739)(95% CI) p value • Primary endpoint (%) • TFG 0/1, MI/death 15.021.7 0.64 (0.530.76) <0.001 • Components (%) • TFG 0/1 11.718.4 0.59 (0.480.72) <0.001 • Recurrent MI 2.53.6 0.70 (0.471.04) 0.08 • Death 2.62.2 1.17 (0.751.82) 0.49 1. Sabatine MS et al. New Engl J Med 2005; 352 FOR INTERNAL USE ONLY

  36. Primary Endpoint: Subgroups Number of Odds Event rates (%) Characteristic patients reduction Clopidogrel Placebo OVERALL 3491 36 15.0 21.7 Age <65 years 2466 42 13.2 21.0 65 years 1015 22 19.0 23.1 Gender Male 2796 35 14.5 20.8 Female 685 38 16.9 24.7 Infarct location Anterior 1416 33 15.0 20.7 Non-anterior 2065 38 15.0 22.2 Fibrinolytic Fibrin-specific 2397 31 14.7 20.1 Non-fibrin specific 1084 44 15.7 24.9 Predominant heparin LMWH 1429 31 11.4 15.7 UFH 1431 42 17.8 27.1 None 621 26 17.1 21.9 0.4 0.6 0.8 1.0 1.2 1.6 Clopidogrel better Placebo better 1. Sabatine MS et al. New Engl J Med 2005; 352

  37. CLARITY : Clinical Events at 30 Days 15 Placebo 20%* p=0.03 Clopidogrel 10 CV death, MI or recurrent ischemia leading to urgent revascularization Incidence of clinical endpoints (%) 5 0 0 5 10 15 20 25 30 Time (days) 1. Sabatine MS et al. New Engl J Med 2005

  38. Safety Clopidogrel Placebo (n=1733) (n=1719)p value • Primary bleeding endpoint (%) • TIMI major 23 (1.3)19 (1.1) 0.64 • Secondary bleeding endpoints (%) • TIMI minor 17 (1.0)9 (0.5) 0.17 • TIMI major or minor 40 (2.3)28 (1.6) 0.18 • Intracranial hemorrhage 8 (0.5)12 (0.7) 0.38 • Bleeding through 30 days (%) • TIMI major 33 (1.9)30 (1.7) 0.80 • TIMI minor 27 (1.6)16 (0.9) 0.12 • TIMI major or minor 59 (3.4)46 (2.7) 0.24 1. Sabatine MS et al. New Engl J Med 2005; 352 FOR INTERNAL USE ONLY

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

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

  41. COMMIT: Composite Endpoint(Death, MI, or Stroke) Placebo (10.1%) RRR=9% P=0.002 10 9 Clopidogrel (9.3%) 8 7 6 Events (%) 5 4 3 2 1 0 0 7 14 21 28 Days since randomization(up to 28 days) FOR INTERNAL USE ONLY 1. Chen ZM et al. ACC 2005.

  42. COMMIT: Mortality Placebo (8.1%) 9 RRR=7% p=0.03 8 7 Clopidogrel (7.5%) 6 5 Mortality (%) 4 3 2 1 0 0 7 14 21 28 Days since randomization (up to 28 days) 1. Chen ZM et al. ACC 2005.

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

  44. GP IIb/IIIa Receptor Antagonists • Eptifibatide • Tirofiban • Abciximab

  45. A murine monoclonalantibody that completely blocks the binding of fibrinogen to platelets producesa thrombasthenic-like state in normal platelets and binds to glycoproteinsIIb and/or IIIa. J Clin Invest 1983Coller 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).

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