Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב ,  בי " ח וולפסו...
Acute Coronary Syndromes  Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q...
Initial Treatment Strategy   ACS ST Elevation  Non ST Elevation <ul><li>Anti-thrombotic Rx ( +  Fibrinolysis) </li></ul><u...
Goals of Peri – PCI Medical Treatment  (short and long term) <ul><li>Minimize peri-procedural complications (related to th...
The Clinical Questions Combination Rx. (ASA + Clopidogrel) <ul><li>When angiography / PCI is planned in a patient already ...
<ul><li>Goals of therapy </li></ul><ul><ul><li>Prevent ischemic events until coronary angiography / PCI </li></ul></ul><ul...
Clopidogrel before coronary angiography -   Patients with ACS   <ul><li>ST Elevation </li></ul><ul><ul><li>CLARITY </li></...
<ul><li>ST Elevation </li></ul><ul><ul><li>CLARITY </li></ul></ul><ul><li>Non ST Elevation </li></ul><ul><ul><li>CURE </li...
Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd  Coronary Angiogram (2-8 days) Primary endpoint: Occ...
Primary Endpoint: Occluded Artery  (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.5...
Primary & Angiographic Outcomes  (median 3.5 days) 50.8 51.2 60.8 0.73 1.21 1.36 <0.001 0.008 <0.001 55.8 TIMI Myocardial ...
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...
CV Death, MI, RI    Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ra...
CLARITY: Patient Management <ul><li>Clopidogrel Placebo </li></ul><ul><li>Parameter  (n=1,752) (n=1,739) </li></ul><ul><li...
PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15...
PCI-CLARITY: MI, Stroke, or  CV Death Events pre and post PCI ***MI or Stroke  M Sabatine, et al.  JAMA 2005,  Patients wi...
Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulan...
Substudy Sites and  Patient Numbers <ul><li>France: 172 patients </li></ul><ul><li>L Soulat: 57 </li></ul><ul><li>Y Lamber...
Angiographic & ECG Parameters: Ambulance  vs.  Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p valu...
Primary Endpoint of  TIMI Flow Grade 0/1, MI or Death 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better...
<ul><li>ST Elevation </li></ul><ul><ul><li>CLARITY </li></ul></ul><ul><li>Non ST Elevation </li></ul><ul><ul><li>CURE </li...
Study Design Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.*  (6259 patients) Placebo + ASA  75-325 mg q.d.* (6303 patients) D...
Primary End Point - MI/Stroke/CV Death Clopidogrel  + ASA* 3 6 9 Placebo  + ASA* Months of Follow-Up 11.4% 9.3% 20%  RRR P...
MI/Stroke/CV Death within 30 Days Clopidogrel  + ASA* 10 20 30 Placebo  + ASA* Days of Follow-Up 0 21%  RRR P  = 0.003 N =...
MI/Stroke/CV Death or severe Ischemia at 24 hours CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM ...
Need for Additional Anti-Thrombotic After Randomization % patients requiring thrombolytic therapy 43% % patients requiring...
Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? <ul><li>GP ...
Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? <ul><li>Is ...
The Role of Platelets in Atherothrombosis Adhesion Aggregation 3 Reproduced with permission from Cannon CP.  Atherothrombo...
 
 
Conclusions: Early Clopidogrel Therapy <ul><li>Treatment with clopidogrel is indicated as soon as possible in patients wit...
Conclusions: Early Clopidogrel Therapy <ul><li>Loading dose should be 600mg to achieve early optimal antiplatelet effect  ...
Goals of Peri – PCI Medical Treatment  (short and long term) <ul><li>Minimize peri-procedural complications (related to th...
The Clinical Questions Combination Rx. (ASA + Clopidogrel) <ul><li>When PCI is planned in a patient already treated with A...
Discharge/Post-Discharge Medications - Guidelines <ul><li>ASA, if not contraindicated </li></ul><ul><li>Clopidogrel, when ...
Initial Treatment Strategy   ACS ST Elevation  Non ST Elevation <ul><li>Anti-thrombotic Rx ( +  Fibrinolysis) </li></ul><u...
Overall Study Design: PCI-CURE PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months a...
Overall Study Design: CREDO  Clopidogrel Arm Placebo  Arm PCI* 28 Days Placebo +  ASA †  (325 mg) Randomization - Pre-trea...
Methodological Pitfall <ul><li>Can a study with a single randomization provide an answer to two questions? </li></ul><ul><...
Study Design single randomization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 month...
Alternative Study Design two randomizations PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment...
Is it just methodology? <ul><li>Can we really expect long term benefit from early antiplatelet therapy? </li></ul>
Adjunct antiplatelet therapy for PCI <ul><li>EPISTENT </li></ul><ul><ul><li>Randomized study  designed to determine the ef...
Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Absolute reduction of Death or...
Long Term Clopidogrel Post PCI <ul><li>Clinical guidelines : 9 months to 1 year in patients with ACS </li></ul><ul><li>How...
Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary
Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time
Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk
Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low ri...
Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding
Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1...
Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1...
Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? <ul><li>Long term clo...
Who is ”High Risk” Patients in whom long term clopidogrel should be considered <ul><li>The vulnerable patient </li></ul><u...
Who is ”High Risk” Patients in whom long term clopidogrel should be considered <ul><li>The vulnerable patient </li></ul><u...
ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipi...
Atherosclerotic Plaques - Terminology <ul><li>Culprit </li></ul><ul><ul><li>Responsible for the clinical event  </li></ul>...
Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable...
N Engl J Med 2000;343:915-22 <ul><li>Angiograms of 253 patients with acute MI </li></ul><ul><li>Complex Plaques: </li></ul...
Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques <ul><li>Similar results when analysis was restricted to p...
Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina   Multivariate analysis : UA and CRP >3 mg...
Vulnerable Patient – at high risk for vascular event coronary elsewhere
Who is the vulnerable patient? <ul><li>Patient with current multiple complex plaques </li></ul><ul><ul><li>Coronary, carot...
Vulnerability cutoff value ?
 
Who is ”High Risk” Patients in whom long term clopidogrel should be considered <ul><li>The vulnerable patient </li></ul><u...
TIMI Risk Score and Outcome Budaj et al. circulation 2002 Excess major bleeding risk with clopidogrel is independent of th...
TIMI Risk Score and Absolute Reduction of death/MI/Stroke with Clopidogrel TIMI Risk Score N=  752  2524  3730  3567  1593...
Who is ”High Risk” Patients in whom long term clopidogrel should be considered <ul><li>The vulnerable patient </li></ul><u...
Aspirin Failure – Patient with acute vascular event (coronary, cerebral) while being treated with aspirin <ul><li>Aspirin ...
Aspirin Resistance Cellular Factors Insufficient suppression  of COX-1 Overexpression  of COX-2 mRNA Erythrocyte-induced  ...
Unfortunately (surprisingly) there is no subgroup analysis of CAPRIE or CURE for patients who were on prior aspirin  Howev...
Clopidogrel in patients with prior CABG  CAPRIE substudy ( N=1480) Vascular death Combined endpoint:  Vascular death, MI, ...
Clopidogrel in patients with history of prior ischemic event -  CAPRIE substudy ( N=4496) Ringleb, P. A. et al. Stroke 200...
Beneficial Outcomes with Clopidogrel in Various Subgroups Overall 12562 9.3 11.4 Associated MI 3283 11.3 13.7 No associate...
CURE: Impact of History of Revascularization 6.0% 1.2% Percent of Patients with an Event History of Revascularization (N=2...
Conclusions – early treatment <ul><li>Clopidogrel loading should be given to patients with ACS (both STE and Non-STE) as s...
<ul><li>Clinical guidelines recommend 9-12 months clopidogrel to  all  patients with non-STE ACS </li></ul><ul><li>Treatme...
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  • The mean time to fibrinolytic administration following the onset of symptoms was 2.65 hours with a mean time of 10 minutes to study drug administration (clopidogrel 300 mg loading dose followed by 75 mg once daily versus placebo) 1 Patients received a median of four doses of study medication 1 Angiography was performed in 94% of patients at a mean time of 84 hours (3.5 days) following randomization 1 Coronary revascularization (PCI or CABG) was performed in 63% of patients 1 Reference 1. Sabatine M et al. New Engl J Med 2005; 352: 1179 – 1189.
  • Inspection of the Kaplan-Meier estimated event rates for cardiovascular death, recurrent myocardial infarction, or stroke over time reveals that the incidence curves separated soon after PCI and continued to diverge over time. Sabatine M, et al. JAMA 2005, in press.
  • Overall, when the events before and after PCI are considered as a whole, pretreatment with clopidogrel significantly reduced the rate of the composite of cardiovascular death, recurrent myocardial infarction, or stroke through 30 days by 41% (7.5% vs. 12.0%, adjusted OR 0.59, 95% CI 0.43-0.81, P=.001) This represents a NNT of 23 patients treated to prevent 1 serious vascular event. Sabatine M, et al. JAMA 2005, in press.
  • In CLARITY, the addition of clopidogrel to aspirin in fibrinolytic therapy for ST-elevation MI improved coronary patency and reduced ischemic events. As just presented, early clopidogrel treatment was also associated with improved clinical outcomes in patients undergoing PCI after the initial lytic therapy. In CLARITY, a subgroup of patients was randomized in the ambulance and treated earlier than the other patients; we present here the analysis of this subgroup
  • Eleven centers in 3 countries participated into this substudy and recruited a total of 217 patients
  • TFG which was evaluated on average 3.5 days after erollment did not differ between the 2 groups In contrast, the early evaluation of reperfusion with ST segment resolution showed a significant advantage in the ambulance group
  • The magnitude of the clopidogrel effect on the primary EP of the study was at least as important in the ambulance group as in the non ambulance group.
  • Patients were eligible for CURE if they were admitted to the hospital within 24 hours of an episode of chest pain suggestive of unstable angina or non–ST-segment elevation MI. The average time between onset of pain and admission was 14 hours. Patients were randomized to one of two treatment arms: either clopidogrel (300 mg loading dose followed by 75 mg/day) or placebo, both in addition to aspirin (75-325 mg/day) and other standard therapy. Medications at time of randomization may include heparin or low–molecular weight heparin, beta-blockers, ACE inhibitors, lipid-lowering agents, calcium channel blockers, and/or other therapies or interventions (PTCA, CABG) at physician’s discretion. Treatment duration was for up to 1 year. The average duration of treatment was 9 months. Follow-up assessments were conducted at 1 and 3 months for all patients and at 6, 9 and 12 months for patients randomized early in the study.
  • Clopidogrel provided a 20% relative risk reduction in the composite outcome of MI, stroke or CV death (95% CI 0.72-0.90, P &lt; 0.001). Overall there were 719 (11.4%) first events in the placebo group and 582 (9.3%) in the clopidogrel group. The hazard rate curves began to separate within the first few hours after therapy initiation and continued to diverge over the remainder of the trial.
  • Clopidogrel provided a 21% relative risk reduction in the primary end point of MI, stroke or CV death within 30 days (95% CI 0.67-0.92, P = 0.003). Beneficial effects were reported within a few hours, with the rate of cardiovascular death, nonfatal stroke, or refractory or severe ischemia significantly reduced by 24 hours in the clopidogrel treated group vs the placebo group (1.4% vs 2.1%, RRR 34% 95% CI of 0.51 to 0.86).
  • Scanning electron microscope photographs showing platelet adhesion and activation (left photo) and early platelet aggregation (right photo)
  • The mechanism of action of clopidogrel is similar to that of ticlopidine but different from that of aspirin.[1] Both clopidogrel and ticlopidine require biotransformation for their pharmacologic activity. Clopidogrel is a potent, noncompetitive inhibitor of ADP-induced platelet aggregation. Clopidogrel inhibits the binding of ADP to platelet membrane receptors. The effect of clopidogrel on ADP binding is irreversible[2] and lasts for the duration of platelet life, about 7 to 10 days. The inhibition is also specific and does not significantly affect cyclooxygenase or arachidonic acid metabolism.[1] Both low- and high-affinity ADP receptors are present on platelets, and the active metabolite of clopidogrel binds to the low-affinity receptors.[1] ADP binding to this site is necessary for activation of the GP IIb/IIIa receptor, which is the binding site for fibrinogen. Fibrinogen links different platelets together to form the platelet aggregate.[3] Clopidogrel thus ultimately inhibits the activation of the GP IIb/IIIa receptor and its binding with fibrinogen.[3] Aspirin inhibits the cyclooxygenase enzyme, preventing the production of prostaglandin and thromboxane A 2 (TXA 2 ) from arachidonic acid.[3] TXA 2 activates the GP IIb/IIIa binding site on the platelet, allowing fibrinogen to bind. Aspirin also exerts its effects on other parts of the body system.[3] Paradoxically, aspirin blocks synthesis of prostacyclin by endothelial cells, resulting in an effect that promotes platelet aggregation.[3] Dipyridamole has been suggested to act as an antiplatelet drug by several possible mechanisms. It directly stimulates prostacyclin synthesis, potentiates the platelet inhibitory actions of prostacyclin, and inhibits phosphodiesterase to raise platelet cyclic AMP (cAMP) levels. However, these effects may not occur at therapeutic levels of the drug; hence the mechanism of action of dipyridamole remains to be elucidated.[3] Schrör K. The basic pharmacology of ticlopidine and clopidogrel. Platelets . 1993;4:252-261. Plavix ® (clopidogrel bisulfate) Prescribing Information. Schafer AI. Antiplatelet therapy. Am J Med . 1996;101:199-209.
  • Inflammation promotes thrombus formation by mediating endothelial cell function.[1] Platelets contribute to thrombus formation by producing inflammatory modulators and responding to thrombotic stimuli. Inflammatory modulators produced by platelets include platelet-derived growth factor, platelet factor 4, CD 154 (CD40 ligand), RANTES (regulated on activation, normal T expressed and secreted), thrombospondin, transforming growth factor-β, and nitric oxide. These modulators contribute to thrombus formation through a number of mechanisms. For example, platelet-derived growth factor increases interleukin 6 (IL6) production, which in turn, increases the production of the procoagulants fibrinogen and plasminogen activator inhibitor-1 (PAI-1); platelet factor 4 is a chemokine; CD154 is a cell surface-based signaling system that induces tissue factor expression and subsequent thrombus formation; and RANTES contributes to macrophage adhesion to endothelial cells by acting as a bridge.   Libby P, Simon DI. Inflammation and thrombosis: the clot thickens. Circulation. 2001;103:1718-1720. Editorial.
  • None
  • This slide summarizes the PCI-CURE design. A total of 2658 patients with non-ST-segment elevation MI undergoing PCI had been randomized to receive clopidogrel or placebo. The majority of patients received an intracoronary stent (81% in the placebo group and 82% in the clopidogrel group). Patients were treated with the blinded study drug for a median of 6 days prior to the procedure. After the procedure, the majority (&gt; 80%) received open-label thienopyridine (either clopidogrel or ticlopidine) for approximately 4 weeks; then, the blinded study drug was continued until the end of follow-up (average duration of 8 months). Medications at time of randomization may include heparin or low–molecular weight heparin, beta-blockers, ACE inhibitors, lipid-lowering agents, calcium channel blockers, and/or other therapies or interventions (PTCA, CABG) at physician’s discretion.. The primary end point was the composite of myocardial infarction, cardiovascular death or urgent target vessel revascularization within 30 days of PCI.
  • Following randomization, patients entered in CREDO received either a 300 mg loading dose of clopidogrel, or matching placebo, 3-24 hours prior to PCI. In addition, all patients also received a 325 mg dose of ASA at this point. Both arms then received clopidogrel 75 mg daily from the time of PCI up to 28 days, on top of standard therapy including a daily dose of 325 mg ASA. Thus, at the end of 28 days, the only difference between the two groups was the use of a 300 mg loading dose of clopidogrel before the PCI. From day 29 to 1 year, the group initially randomized to pre-treatment with clopidogrel received a 75 mg daily dose of clopidogrel, whilst the no-pre-treatment arm received a matching placebo. Both groups continued to receive ASA (81 mg to 325 mg daily dose, left at the investigator’s discretion) and other standard therapy until the end of the 1 year period. The medications that encompassed post-randomized concomitant therapy were left to the discretion of the investigator with the exception of ASA, which was mandated by the protocol for every patient. Reference: Steinhubl S, Berger P, Tift Mann III J, et al. JAMA . 2002;Vol 288,No 19:2411-2420.
  • This slide summarizes the PCI-CURE design. A total of 2658 patients with non-ST-segment elevation MI undergoing PCI had been randomized to receive clopidogrel or placebo. The majority of patients received an intracoronary stent (81% in the placebo group and 82% in the clopidogrel group). Patients were treated with the blinded study drug for a median of 6 days prior to the procedure. After the procedure, the majority (&gt; 80%) received open-label thienopyridine (either clopidogrel or ticlopidine) for approximately 4 weeks; then, the blinded study drug was continued until the end of follow-up (average duration of 8 months). Medications at time of randomization may include heparin or low–molecular weight heparin, beta-blockers, ACE inhibitors, lipid-lowering agents, calcium channel blockers, and/or other therapies or interventions (PTCA, CABG) at physician’s discretion.. The primary end point was the composite of myocardial infarction, cardiovascular death or urgent target vessel revascularization within 30 days of PCI.
  • This slide summarizes the PCI-CURE design. A total of 2658 patients with non-ST-segment elevation MI undergoing PCI had been randomized to receive clopidogrel or placebo. The majority of patients received an intracoronary stent (81% in the placebo group and 82% in the clopidogrel group). Patients were treated with the blinded study drug for a median of 6 days prior to the procedure. After the procedure, the majority (&gt; 80%) received open-label thienopyridine (either clopidogrel or ticlopidine) for approximately 4 weeks; then, the blinded study drug was continued until the end of follow-up (average duration of 8 months). Medications at time of randomization may include heparin or low–molecular weight heparin, beta-blockers, ACE inhibitors, lipid-lowering agents, calcium channel blockers, and/or other therapies or interventions (PTCA, CABG) at physician’s discretion.. The primary end point was the composite of myocardial infarction, cardiovascular death or urgent target vessel revascularization within 30 days of PCI.
  • Figure 13 Atherothrombosis: a variable mix of chronic atherosclerosis and acute thrombosis. Cross-sectioned arterial bifurcation illustrating a collagen-rich (blue-stained) plaque in the circumflex branch (left) and a lipid-rich and ruptured plaque with a non-occlusive thrombosis superimposed in the obtuse branch (right) . C = contrast in the lumen; Ca = calcification; T = thrombosis. Adapted from Falk E, Prediman S, Fuster V. Coronary plaque disruption. Circulation 1995;92:657–71.
  • Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina   N Engl J Med  1994;331:417-424. Biasucci LM, Vitelli A, Liuzzo G, et al.  Elevated levels of interleukin-6 in unstable angina.   Circulation  1996;94:874-877. Buffon A, Biasucci LM, Liuzzo G, et al.  Widespread coronary inflammation in unstable angina.  N Engl J Med  2002;347:5-12. Lombardo A, Coli S, Natale L, Crea F.  Carotid plaque inflammation in a patient with unstable angina.  Ital Heart J  2003;4:125-8. Lombardo A, Biasucci LM, Lanza GA, et al. Inflammation as a possible link between coronary and carotid plaque instability.  Circulation  2004;109:-63. Monaco C, Rossi E, Milazzo D, et.  Persistent systemic inflammation in unstable angina is largely unrelated to the atherothrombotic burden.   J Am Coll Cardiol  2005;45:238-43.
  • There were over 30 subgroup analyses conducted which were remarkably consistent in showing the benefit of clopidogrel plus aspirin. This next slide summarizes some of those results. Note five of the key subgroup analyses: 1. Patients with or without an associated MI, 2. Patients with or without elevation of enzymes, 3. Patients with or without type 2 diabetes, 4. Patients at low, intermediate or high risk, 5. Patients with or without a history of a revascularization. Although the study was not powered to look at individual subgroups, there was a beneficial trend seen across all subgroups analyzed. A total of 2838 patients with diabetes were enrolled into the CURE trial. In this subgroup of patients, there was nearly a twofold increase in event rates. The addition of clopidogrel to standard therapy, including aspirin, resulted in a 17% relative risk reduction, a benefit consistent with the primary end point.
  • Early And Long Term Treatment With Clopidogrel In Coronary ...

    1. 1. Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב , בי &quot; ח וולפסון דצמבר 2005
    2. 2. Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST 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. 3. Initial Treatment Strategy ACS ST Elevation Non ST Elevation <ul><li>Anti-thrombotic Rx ( + Fibrinolysis) </li></ul><ul><li>2. Early / Primary PCI </li></ul><ul><li>Anti-thrombotic Rx </li></ul><ul><li>Early PCI </li></ul>Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization
    4. 4. Goals of Peri – PCI Medical Treatment (short and long term) <ul><li>Minimize peri-procedural complications (related to the treated plaque) </li></ul><ul><ul><li>Thrombosis etc </li></ul></ul><ul><li>Stabilize the rest of the non-occlusive narrowings </li></ul><ul><ul><li>Prevent progression </li></ul></ul><ul><ul><li>Prevent atherothrombosis </li></ul></ul>1 2
    5. 5. The Clinical Questions Combination Rx. (ASA + Clopidogrel) <ul><li>When angiography / PCI is planned in a patient already treated with ASA: </li></ul><ul><li>Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) </li></ul><ul><li>Is continuation of clopidogrel beyond 1 month improving long-term outcome </li></ul>1 2
    6. 6. <ul><li>Goals of therapy </li></ul><ul><ul><li>Prevent ischemic events until coronary angiography / PCI </li></ul></ul><ul><ul><ul><li>Before plaque stabilization was achieved </li></ul></ul></ul><ul><ul><li>Prevent PCI / stent related ischemic complications </li></ul></ul>Clopidogrel before coronary angiography - Patients with ACS 1
    7. 7. Clopidogrel before coronary angiography - Patients with ACS <ul><li>ST Elevation </li></ul><ul><ul><li>CLARITY </li></ul></ul><ul><li>Non ST Elevation </li></ul><ul><ul><li>CURE </li></ul></ul>1
    8. 8. <ul><li>ST Elevation </li></ul><ul><ul><li>CLARITY </li></ul></ul><ul><li>Non ST Elevation </li></ul><ul><ul><li>CURE </li></ul></ul>Clopidogrel before coronary angiography - Patients with ACS 1
    9. 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. 10. Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction
    11. 11. Primary & Angiographic Outcomes (median 3.5 days) 50.8 51.2 60.8 0.73 1.21 1.36 <0.001 0.008 <0.001 55.8 TIMI Myocardial Perfusion 3 43.0 67.8 Angiographic (%) TIMI Flow Grade 3 Thrombus 0.08 0.70 3.6 2.5 MI <0.001 0.59 18.4 11.7 TIMI Flow Grade 0/1 2.2 21.7 Placebo 1.17 0.64 Odds Ratio 0.49 <0.001 P value 2.6 15.0 Clopidogrel Death Primary End Point (%) Outcome
    12. 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. 13. CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1
    14. 14. CLARITY: Patient Management <ul><li>Clopidogrel Placebo </li></ul><ul><li>Parameter (n=1,752) (n=1,739) </li></ul><ul><li>Symptom onset to fibrinolytic (hours) 2.7 2.6 </li></ul><ul><li>Fibrinolytic to study drug (minutes) 10 10 </li></ul><ul><li>Median doses of study medication 4 4 </li></ul><ul><li>Angiography performed (%) 94 94 </li></ul><ul><li>Study drug to angiography (hours) 84 84 </li></ul><ul><li>Coronary revascularization (%): 63 63 </li></ul><ul><li>PCI 57.2 56.6 </li></ul><ul><li>CABG 5.9 6.0 </li></ul>Sabatine M et al. New Engl J Med 2005; 352: 1179 – 1189.
    15. 15. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005
    16. 16. PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, 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*
    17. 17. Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy
    18. 18. Substudy Sites and Patient Numbers <ul><li>France: 172 patients </li></ul><ul><li>L Soulat: 57 </li></ul><ul><li>Y Lambert: 48 </li></ul><ul><li>F Lapostolle: 28 </li></ul><ul><li>F Thieuleux: 21 </li></ul><ul><li>C Gully: 10 </li></ul><ul><li>D Pollet: 5 </li></ul><ul><li>D Galley: 2 </li></ul><ul><li>L Olliver: 1 </li></ul>UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total
    19. 19. Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 37.0 52.7 64.4 0.02 0.05 47.2 63.2 <ul><li>Complete* ST resolution at ECG </li></ul><ul><ul><li>90 min </li></ul></ul><ul><ul><li>180 min </li></ul></ul>NS 64.4 TFG 3 0.5 0 1.0 1.5 2.0 2.5 3.0
    20. 20. Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) 0.60 (0.30  1.17) 0.64 (0.53  0.76) 0.65 (0.54  0.77)
    21. 21. <ul><li>ST Elevation </li></ul><ul><ul><li>CLARITY </li></ul></ul><ul><li>Non ST Elevation </li></ul><ul><ul><li>CURE </li></ul></ul>Clopidogrel before coronary angiography - Patients with ACS 1
    22. 22. Study Design 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 . N Engl J Med. 2001;345:494-502. 3 months  double-blind treatment  12 months Clopidogrel 300 mg loading dose CURE
    23. 23. Primary End Point - MI/Stroke/CV Death Clopidogrel + ASA* 3 6 9 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 . N Engl J Med. 2001;345:494-502. CURE
    24. 24. MI/Stroke/CV Death within 30 Days Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators . N Engl J Med. 2001;345:494-502. CURE 1
    25. 25. MI/Stroke/CV Death or severe Ischemia at 24 hours CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 CURE 1
    26. 26. Need for Additional Anti-Thrombotic After Randomization % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1
    27. 27. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? <ul><li>GP IIb/IIIa receptor is the final common pathway in platelet aggregation. </li></ul><ul><li>GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. </li></ul><ul><li>Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. </li></ul><ul><li>Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. </li></ul>
    28. 28. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? <ul><li>Is there additional benefit to clopidogrel that would justify: </li></ul><ul><ul><li>Increased CABG bleeding </li></ul></ul><ul><ul><ul><li>or alternatively </li></ul></ul></ul><ul><ul><li>Need to postpone CABG for 3-5 days </li></ul></ul>No data in the literature however
    29. 29. The Role of Platelets in Atherothrombosis Adhesion Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2
    30. 32. Conclusions: Early Clopidogrel Therapy <ul><li>Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome </li></ul><ul><ul><li>ST elevation and non ST elevation </li></ul></ul><ul><li>Treatment is effective to reduce ischemic complications </li></ul><ul><ul><li>Before coronay angiography </li></ul></ul><ul><ul><li>During and after PCI </li></ul></ul>1
    31. 33. Conclusions: Early Clopidogrel Therapy <ul><li>Loading dose should be 600mg to achieve early optimal antiplatelet effect </li></ul><ul><ul><li>?? 300mg in patients after fibrinolytic therapy </li></ul></ul><ul><li>It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists </li></ul><ul><ul><li>Especially in high risk patients in whom the likelihood for CABG is high </li></ul></ul>1
    32. 34. Goals of Peri – PCI Medical Treatment (short and long term) <ul><li>Minimize peri-procedural complications (related to the treated plaque) </li></ul><ul><ul><li>Thrombosis etc </li></ul></ul><ul><li>Stabilize the rest of the non-occlusive narrowings </li></ul><ul><ul><li>Prevent progression </li></ul></ul><ul><ul><li>Prevent atherothrombosis </li></ul></ul>1 2
    33. 35. The Clinical Questions Combination Rx. (ASA + Clopidogrel) <ul><li>When PCI is planned in a patient already treated with ASA: </li></ul><ul><li>Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) </li></ul><ul><li>Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome </li></ul>1 2
    34. 36. Discharge/Post-Discharge Medications - Guidelines <ul><li>ASA, if not contraindicated </li></ul><ul><li>Clopidogrel, when ASA contraindicated </li></ul><ul><li>Aspirin + Clopidogrel for up to 9 months </li></ul><ul><li> -blocker, if not contraindicated </li></ul><ul><li>Lipid  agents + diet, if LDL >130 mg/dL </li></ul><ul><li>ACE Inhibitor: CHF, EF < 40%, DM, or HTN </li></ul>2 I IIa IIb III
    35. 37. Initial Treatment Strategy ACS ST Elevation Non ST Elevation <ul><li>Anti-thrombotic Rx ( + Fibrinolysis) </li></ul><ul><li>2. Early / Primary PCI </li></ul><ul><li>Anti-thrombotic Rx </li></ul><ul><li>Early PCI </li></ul>Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization
    36. 38. Overall Study Design: PCI-CURE 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 R Mehta, SR. et al for the CURE Trial Investigators . N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2
    37. 39. Overall Study Design: CREDO Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA † (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA † (325 mg) Clopidogrel 75 mg QD + ASA † 325 mg QD 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 Question 1 Question 2 1 2 Open label clopidogrel continuation
    38. 40. Methodological Pitfall <ul><li>Can a study with a single randomization provide an answer to two questions? </li></ul><ul><ul><li>Alternatively </li></ul></ul><ul><li>Should a second randomization be done in order to answer the second question? </li></ul>
    39. 41. Study Design single randomization 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 R Mehta, SR. et al for the CURE Trial Investigators . N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation
    40. 42. Alternative Study Design two randomizations PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE R1 Mehta, SR. et al for the CURE Trial Investigators . N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2
    41. 43. Is it just methodology? <ul><li>Can we really expect long term benefit from early antiplatelet therapy? </li></ul>
    42. 44. Adjunct antiplatelet therapy for PCI <ul><li>EPISTENT </li></ul><ul><ul><li>Randomized study designed to determine the effect of treatment with abciximab </li></ul></ul><ul><li>TARGET </li></ul><ul><ul><li>Randomized study designed to show that tirofiban is not inferior to abciximab </li></ul></ul><ul><ul><li>Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel </li></ul></ul><ul><li>PCI-CURE </li></ul><ul><ul><li>Subgroup of CURE patients who underwent PCI </li></ul></ul><ul><ul><li>Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo </li></ul></ul>
    43. 45. Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Absolute reduction of Death or MI at 1 month and 1 year <ul><li>Abciximab </li></ul><ul><li>Early clopidogrel </li></ul><ul><li>Early and continued </li></ul><ul><li>clopidogrel </li></ul>% reduction * * 6 month data in TARGET
    44. 46. Long Term Clopidogrel Post PCI <ul><li>Clinical guidelines : 9 months to 1 year in patients with ACS </li></ul><ul><li>However, current data does not fully support this recommendation </li></ul><ul><li>What should we do? </li></ul>2
    45. 47. Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary
    46. 48. Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time
    47. 49. Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk
    48. 50. Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk <ul><li>Fixed, except for the initial few days </li></ul><ul><ul><li>heparin, catheterization </li></ul></ul>
    49. 51. Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding
    50. 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
    51. 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
    52. 54. Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? <ul><li>Long term clopidogrel for patients with </li></ul><ul><ul><li>High risk for vascular event </li></ul></ul><ul><ul><li>Low bleeding risk </li></ul></ul><ul><li>Short term clopidogrel for patients with </li></ul><ul><ul><li>Low risk for vascular event </li></ul></ul><ul><ul><li>High bleeding risk </li></ul></ul>vascular bleeding
    53. 55. Who is ”High Risk” Patients in whom long term clopidogrel should be considered <ul><li>The vulnerable patient </li></ul><ul><li>TIMI risk score </li></ul><ul><li>Aspirin Failure </li></ul><ul><li>Others </li></ul>
    54. 56. Who is ”High Risk” Patients in whom long term clopidogrel should be considered <ul><li>The vulnerable patient </li></ul><ul><li>TIMI risk score </li></ul><ul><li>Aspirin Failure </li></ul><ul><li>Others </li></ul>
    55. 57. 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 Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli
    56. 58. Atherosclerotic Plaques - Terminology <ul><li>Culprit </li></ul><ul><ul><li>Responsible for the clinical event </li></ul></ul><ul><li>Vulnerable </li></ul><ul><ul><li>High risk to become culprit (cause clinical event) </li></ul></ul><ul><li>Quiescent ( Stable) </li></ul><ul><ul><li>Primary or healed (vulnerable or culprit) </li></ul></ul>
    57. 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
    58. 60. N Engl J Med 2000;343:915-22 <ul><li>Angiograms of 253 patients with acute MI </li></ul><ul><li>Complex Plaques: </li></ul><ul><ul><li>Single: 153 - 60.5% </li></ul></ul><ul><ul><li>Multiple: 100 – 39.5% </li></ul></ul>
    59. 61. Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques <ul><li>Similar results when analysis was restricted to patients with multivessel coronary disease: </li></ul><ul><li>74.5% of single </li></ul><ul><li>91.0% of multiple </li></ul>
    60. 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
    61. 63. Vulnerable Patient – at high risk for vascular event coronary elsewhere
    62. 64. Who is the vulnerable patient? <ul><li>Patient with current multiple complex plaques </li></ul><ul><ul><li>Coronary, carotid etc </li></ul></ul><ul><li>Patient with multiple uncontrolled risk factors </li></ul><ul><ul><li>At risk to develop new complex plaques </li></ul></ul>
    63. 65. Vulnerability cutoff value ?
    64. 67. Who is ”High Risk” Patients in whom long term clopidogrel should be considered <ul><li>The vulnerable patient </li></ul><ul><li>TIMI risk score </li></ul><ul><li>Aspirin Failure </li></ul><ul><li>Others </li></ul>
    65. 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%
    66. 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
    67. 70. Who is ”High Risk” Patients in whom long term clopidogrel should be considered <ul><li>The vulnerable patient </li></ul><ul><li>TIMI risk score </li></ul><ul><li>Aspirin Failure </li></ul><ul><li>Others </li></ul>
    68. 71. Aspirin Failure – Patient with acute vascular event (coronary, cerebral) while being treated with aspirin <ul><li>Aspirin was not enough to prevent the event </li></ul><ul><ul><li>Aspirin is ineffective as an antiplatelet agent – resistance? </li></ul></ul><ul><ul><li>Aspirin is effective as an antiplatelet agent but the disease risk is high and there is a need for more aggressive antiplatelet therapy </li></ul></ul>
    69. 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
    70. 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
    71. 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 10 1 2 3 4 9 5 6 7 8 0 0 6 12 18 24 30 36 9.7% 8.1% Aspirin Clopidogrel p = 0.03 Months of Follow-up 43% 50 15 5 10 20 25 45 30 35 40 0 0 6 12 18 24 30 36 Aspirin Clopidogrel 46.1% p = 0.001 36.7% Months of Follow-up 31%
    72. 75. Clopidogrel in patients with history of prior ischemic event - CAPRIE substudy ( N=4496) Ringleb, P. A. et al. Stroke 2004;35:528-532
    73. 76. Beneficial Outcomes with Clopidogrel in Various Subgroups Overall 12562 9.3 11.4 Associated MI 3283 11.3 13.7 No associated MI 9279 8.6 10.6 Male sex 7726 9.1 11.9 Female sex 4836 9.5 10.7  65 yr old 6354 5.4 7.6  65 yr old 6208 13.3 15.3 ST-segment deviation 6275 11.5 14.3 No ST-segment deviation 6287 7.0 8.6 Enzymes elevated at entry 3176 10.7 13.0 Enzymes not elevated at entry 9386 8.8 10.9 Diabetes 2840 14.2 16.7 No diabetes 9722 7.9 9.9 Low risk 4187 5.1 6.7 Intermediate risk 4185 6.5 9.4 High risk 4184 16.3 18.0 History of revascularization 2246 8.4 14.4 No history of revascularization 10316 9.5 10.7 Revascularization after randomization 4577 11.5 13.9 No revascularization after randomization 7985 8.1 10.0 Placebo + ASA* Characteristic No. of Patients Clopidogrel + ASA* Percentage of Patients with Event Placebo Better Clopidogrel Better Relative Risk (95% CI) 1.2 1.0 0.8 0.6 0.4 * In combination with standard therapy The CURE Trial Investigators . N Engl J Med. 2001;345:494-502. CURE
    74. 77. CURE: Impact of History of Revascularization 6.0% 1.2% Percent of Patients with an Event History of Revascularization (N=2246) (N=10316)
    75. 78. Conclusions – early treatment <ul><li>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 </li></ul><ul><ul><li>* 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). </li></ul></ul><ul><ul><ul><li>will be clarified by ongoing trial – “early ACS” </li></ul></ul></ul>
    76. 79. <ul><li>Clinical guidelines recommend 9-12 months clopidogrel to all patients with non-STE ACS </li></ul><ul><li>Treatment should be definitely continued as long as there is a risk for stent thrombosis </li></ul><ul><ul><li>Longer duration </li></ul></ul><ul><ul><ul><li>high risk subset (multiple complex plaques, TIMI risk score >5, continuously elevated CRP?) </li></ul></ul></ul><ul><ul><ul><li>Aspirin failure ? </li></ul></ul></ul><ul><ul><li>Shorter duration </li></ul></ul><ul><ul><ul><li>High bleeding risk (e.g. coumadin etc) </li></ul></ul></ul>Conclusions – long term treatment
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