1. Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005

2. Acute Coronary Syndromes Acute Coronary Syndrome No ST ElevationST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062.

3. Initial Treatment Strategy ACS ST Elevation Non ST Elevation 1.Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI 1.Anti-thrombotic Rx 2.Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization

4. Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non- occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term)

5. The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2

6.  Goals of therapy 1.Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved 2.Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1

7. ST Elevation –CLARITY Non ST Elevation –CURE 1

8. ST Elevation –CLARITY Non ST Elevation –CURE 1 Clopidogrel before coronary angiography - Patients with ACS

9. Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups

10. Primary Endpoint: Occluded Artery (or D/MI by time of angio) PlaceboClopidogrel P=0.00000036P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.00.40.60.81.21.6 Clopidogrelbetter Placebobetter n=1752n=1739 36% Odds Reduction 36% Odds Reduction

11. Angiographic (%) TIMI Flow Grade 3 67.860.81.36<0.001 TIMI Myocardial Perfusion 3 55.851.21.210.008 Thrombus43.050.80.73<0.001 Primary & Angiographic Outcomes (median 3.5 days) OutcomeClopidogrelPlacebo Odds Ratio P value Primary End Point (%) 15.021.70.64<0.001 TIMI Flow Grade 0/1 11.718.40.59<0.001 MI2.53.60.700.08 Death2.62.21.170.49

12. Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI

13. CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 051015202530 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20%20% 1

14. CLARITY: Patient Management ClopidogrelPlacebo Parameter (n=1,752)(n=1,739) Symptom onset to fibrinolytic (hours)2.72.6 Fibrinolytic to study drug (minutes)1010 Median doses of study medication44 Angiography performed (%)9494 Study drug to angiography (hours)8484 Coronary revascularization (%):6363 PCI57.256.6 CABG5.96.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189.

15. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 051015202530 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005

16. PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke Patients with endpoint (%) 0 5 10 15 7.5 12.0 Clopidogrel Pretreatment (n=933) No Pretreatment (n=930) 41% p=0.001 Overall Events* Pre-PCI Events** 4.0 6.2 38% p=0.03 3.6 6.2 46% p=0.008 Post-PCI Events* M Sabatine, et al. JAMA 2005,

17. Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy

18. Montalescot G. ESC, September 2005 Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total

19. Montalescot G. ESC, September 2005 Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance TFG 364.4 NS Complete* ST resolution at ECG 90 min 180 min 47.2 63.2 37.0 52.7 0.02 0.05 *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) AmbulanceNon- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0.501.01.52.0 2.5 3.0

20. Montalescot G. ESC, September 2005 00.51.01.52.0 Ambulance Non-ambulance Overall Clopidogrel betterPlacebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.30  1.17) 0.64 (0.53  0.76) 0.65 (0.54  0.77)

21. ST Elevation –CLARITY Non ST Elevation –CURE 1 Clopidogrel before coronary angiography - Patients with ACS

22. Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months  double-blind treatment  12 months Clopidogrel 300 mg loading dose CURE

23. Clopidogrel + ASA* 369 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE

24. Clopidogrel + ASA* 102030 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1

25. CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1

26. % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization 0.001 P< 0.001 0.003 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1

27. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ?  GP IIb/IIIa receptor is the final common pathway in platelet aggregation.  GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy.  Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG.  Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG.

28. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ?  Is there additional benefit to clopidogrel that would justify:  Increased CABG bleeding or alternatively  Need to postpone CABG for 3-5 days No data in the literature however

29. Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2

32. Conclusions: Early Clopidogrel Therapy  Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome  ST elevation and non ST elevation  Treatment is effective to reduce ischemic complications  Before coronay angiography  During and after PCI 1

33. Conclusions: Early Clopidogrel Therapy  Loading dose should be 600mg to achieve early optimal antiplatelet effect  ?? 300mg in patients after fibrinolytic therapy  It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists  Especially in high risk patients in whom the likelihood for CABG is high 1

34. Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non- occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term)

35. The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2

36. Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months  -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months  -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I I IIa IIb III 2

37. Initial Treatment Strategy ACS ST Elevation Non ST Elevation 1.Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI 1.Anti-thrombotic Rx 2.Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization

38. PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R CURE Trial Investigators Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI- CURE Question 1 Question 2

39. Clopidogrel Arm PlaceboArm PCI* 28 Days Placebo + ASA † (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA † (325 mg) Clopidogrel 75 mg QD + ASA † 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA † (81-325 mg) QD Clopidogrel 75 mg QD + ASA † (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation

40. Methodological Pitfall  Can a study with a single randomization provide an answer to two questions? Alternatively  Should a second randomization be done in order to answer the second question?

41. PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R CURE Trial Investigators Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI- CURE Continuation

42. PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 CURE Trial Investigators Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI- CURE R2 Clop. Placebo Continuation Question 2 2

43. Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy?

44. Adjunct antiplatelet therapy for PCI  EPISTENT –Randomized study designed to determine the effect of treatment with abciximab  TARGET –Randomized study designed to show that tirofiban is not inferior to abciximab –Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel  PCI-CURE –Subgroup of CURE patients who underwent PCI –Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo

45. Absolute reduction of Death or MI at 1 month and 1 year -Abciximab -Early clopidogrel -Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS

46. Long Term Clopidogrel Post PCI  Clinical guidelines: 9 months to 1 year in patients with ACS  However, current data does not fully support this recommendation  What should we do? 2

47. Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary

48. Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time

49. Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk

50. Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk  Fixed, except for the initial few days  heparin, catheterization

51. Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding

52. Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk

53. Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin

54. Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ??  Long term clopidogrel for patients with  High risk for vascular event  Low bleeding risk  Short term clopidogrel for patients with  Low risk for vascular event  High bleeding risk vascular bleeding

55. Who is ”High Risk” Patients in whom long term clopidogrel should be considered  The vulnerable patient  TIMI risk score  Aspirin Failure  Others

56. Who is ”High Risk” Patients in whom long term clopidogrel should be considered  The vulnerable patient  TIMI risk score  Aspirin Failure  Others

57. Inflammation, Plaque Rupture, Thrombosis, and Microembolization ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF Clotting Cascade TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli

58. Atherosclerotic Plaques - Terminology Culprit –Responsible for the clinical event Vulnerable –High risk to become culprit (cause clinical event) QuiescentQuiescent ( Stable) –Primary or healed (vulnerable or culprit)

59. Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation

60. N Engl J Med 2000;343:915-22  Angiograms of 253 patients with acute MI  Complex Plaques:  Single: 153 - 60.5%  Multiple: 100 – 39.5%

61. Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques Similar results when analysis was restricted to patients with multivessel coronary disease:  74.5% of single  91.0% of multiple

62. Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina Multivariate analysis: UA and CRP >3 mg/l were independently and strongly associated with complex carotid plaques

63. Vulnerable Patient – at high risk for vascular event coronaryelsewhere

64. Who is the vulnerable patient?  Patient with current multiple complex plaques –Coronary, carotid etc  Patient with multiple uncontrolled risk factors –At risk to develop new complex plaques

65. Vulnerability cutoff value ?

67. Who is ”High Risk” Patients in whom long term clopidogrel should be considered  The vulnerable patient  TIMI risk score  Aspirin Failure  Others

68. TIMI Risk Score and Outcome Budaj et al. circulation 2002 Excess major bleeding risk with clopidogrel is independent of the TIMI risk – it is 1%

69. TIMI Risk Score and Absolute Reduction of death/MI/Stroke with Clopidogrel TIMI Risk Score N= 752 2524 3730 3567 1593 396 Percent reduction Major bleeding – 1% Majority of patients

70. Who is ”High Risk” Patients in whom long term clopidogrel should be considered  The vulnerable patient  TIMI risk score  Aspirin Failure  Others

71. Aspirin Failure – Patient with acute vascular event (coronary, cerebral) while being treated with aspirin  Aspirin was not enough to prevent the event  Aspirin is ineffective as an antiplatelet agent – resistance?  Aspirin is effective as an antiplatelet agent but the disease risk is high and there is a need for more aggressive antiplatelet therapy

72. Aspirin Resistance Cellular Factors Insufficient suppression of COX-1 Overexpression of COX-2 mRNA Erythrocyte-induced platelet activation Increased norepinephrine Generation of 8-iso-PGF 2  Adapted with permission from Bhatt DL. J Am Coll Cardiol. 2004;43:1127-1129. Aspirin Resistance Genetic Polymorphisms COX-1 GP IIIa receptor Collagen receptor vWF receptor Clinical Factors Failure to prescribe Noncompliance Nonabsorption Interaction with ibuprofen Can be intermittent

73. Unfortunately (surprisingly) there is no subgroup analysis of CAPRIE or CURE for patients who were on prior aspirin However There are other subgroup analyses

74. Clopidogrel in patients with prior CABG CAPRIE substudy ( N=1480) Vascular death Combined endpoint: Vascular death, MI, stroke or hospitalization for ischemia or bleeding Circulation 2001; 103: 363-368

75. Ringleb, P. A. et al. Stroke 2004;35:528-532 Clopidogrel in patients with history of prior ischemic event - CAPRIE substudy (N=4496)

76. Overall125629.311.4 Associated MI328311.313.7 No associated MI92798.610.6 Male sex77269.111.9 Female sex48369.510.7  65 yr old63545.47.6  65 yr old620813.315.3 ST-segment deviation627511.514.3 No ST-segment deviation62877.08.6 Enzymes elevated at entry317610.713.0 Enzymes not elevated at entry93868.810.9 Diabetes284014.216.7 No diabetes97227.99.9 Low risk41875.16.7 Intermediate risk41856.59.4 High risk418416.318.0 History of revascularization22468.414.4 No history of revascularization103169.510.7 Revascularization after randomization457711.513.9 No revascularization after randomization79858.110.0 Placebo + ASA* Characteristic No. of Patients Clopidogrel + ASA* Percentage of Patients with Event Placebo BetterClopidogrel Better Relative Risk (95% CI) 1.21.00.80.60.4 * In combination with standard therapy The CURE Trial Investigators The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Beneficial Outcomes with Clopidogrel in Various Subgroups CURE

77. 6.0% 1.2% CURE: Impact of History of Revascularization Percent of Patients with an Event History of Revascularization (N=2246)(N=10316)

78. Conclusions – early treatment  Clopidogrel loading should be given to patients with ACS (both STE and Non- STE) as soon as possible regardless* of the timing of the planned coronary angiography –* It is still unclear whether treatment can be postponed when “upstream” GP IIb/IIIa is being used (especially when the likelihood of CABG is high). will be clarified by ongoing trial – “early ACS”

79.  Clinical guidelines recommend 9-12 months clopidogrel to all patients with non-STE ACS  Treatment should be definitely continued as long as there is a risk for stent thrombosis –Longer duration high risk subset (multiple complex plaques, TIMI risk score >5, continuously elevated CRP?) Aspirin failure ? –Shorter duration High bleeding risk (e.g. coumadin etc) Conclusions – long term treatment