lopidogrel in nstable Anginato Preventecurrentvents

CURE

DisclaimerThis slide kit presents new data to support the rationale for the use of ADP receptor antagonists for approved and unapproved indications. The slide kit has been prepared for medical and scientific purposes. It contains information on a use that is not approved by the FDA and should not be construed as an inducement to use clopidogrel for unapproved indications. Neither Sanofi-Synthelabo Inc., Bristol-Myers Squibb nor the partnership recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

CURE

RationaleDespite treatment with aspirin and heparin, the incidence of MI and CV death during hospitalization remains high, 6-8% Long term, the incidence of these events remain high at 6-8% per year The majority of patients (80%) who enter the hospital with acute coronary syndrome (ACS) are already on aspirin therapyThe negative findings of the oral GP IIb/IIIas underscores the need for alternative strategies to treat ACS CURE Study Investigators. Eur Heart J. 2000;21:2033-2041.PURSUIT Investigators. Am J Cardiol. 1999;83:1147-1151.

CURE

Study ObjectivesPrimaryEvaluate the early and long-term efficacy of clopidogrel vs placebo, both given in addition to aspirin and other standard therapy in preventing ischemic complications in patients with ACS without ST-segment elevation (unstable angina or non-ST-segment elevation MI) SecondaryEvaluate the safety of clopidogrel in combination with ASA therapy in patients with ACSCURE Study Investigators. Eur Heart J. 2000; 21:2033-2041.

CURE

Study DesignClopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients)Placebo + ASA 75-325 mg q.d.*(6303 patients)Day 16 m. Visit9 m. Visit12 m. or Final Visit3 m. VisitDischarge Visit1 m. VisitPatients withAcute Coronary Syndrome(unstable angina or non-ST-segment elevation MI)RPlacebo loading doseR = Randomization * In combination with other standard therapyThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.3 months double-blind treatment 12 monthsClopidogrel 300 mg loading dose

CURE

Key Inclusion Criteria

Age 21 years1Suspected UA or NSTEMI (no ST 1.0 mm)2Presentation 24 hours after onset of symptoms2 ECG changes compatible with ischemia or elevated cardiac enzymes or troponin I or T 2 x ULN21 CURE Study Protocol (Data on file, Sanofi-Synthelabo, Inc.)2 CURE Study Investigators. Eur Heart J. 2000; 21:2033-2041.

CURE

Key Exclusion CriteriaNYHA Class IV heart failure1Uncontrolled hypertension2Current use of anticoagulants1, clopidogrel, ticlopidine, or NSAIDS2, or GP IIb/IIIa inhibitor within 3 days1PCI or CABG within 3 months1History of severe thrombocytopenia or neutropenia2At high risk for bleeding1Contraindications to antithrombotic or antiplatelet therapy11 CURE Study Investigators. Eur Heart J. 2000; 21:2033-2041.2 CURE Study Protocol (Data on file, Sanofi-Synthelabo, Inc.)

CURE

Outcome Definitions MI: At least two of the following criteria: chest pain, ECG changes, elevation of cardiac markers or enzymes (Troponin, CK, CK-MB)Stroke: Neurological deficit 24 hrs (CT/MRI encouraged)CV Death: Excludes any death for which there was no clearly documented non-CV causeRefractory Ischemia: In-hosp: recurrent ischemia on max med Rx + ECG changes + intervention 1 day After discharge: Rehosp for UA with ECG changesSevere Ischemia: Changes similar to in-hospital refractory ischemia, but no interventionRecurrent Angina: All other ischemic chest pain in hospitalThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

CURE

Efficacy AnalysesFirst Primary End Point First occurrence of any component of the cluster of:Myocardial InfarctionStroke (ischemic, hemorrhagic, or of uncertain type)Cardiovascular deathSecond Primary End Point First occurrence of any component of the cluster of:Myocardial InfarctionStroke (ischemic, hemorrhagic, or of uncertain type)Cardiovascular deathRefractory ischemiaThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

CURE

Baseline CharacteristicsAge (mean) 64.264.2Mean time from pain onset to randomization (hrs)14.114.2Mean heart rate (beats/min)73.073.2 Mean systolic BP (mm Hg)134.1134.4 Female (%)38.338.7Diagnosis at EntryUnstable Angina (%)74.974.9NonST-segment elevation MI (%)25.125.1ECG abnormalities (%)93.993.7PlaceboN = 6303ClopidogrelN = 6259The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

CURE

Patient HistoryHistory of MI32.032.4CABG Surgery/PTCA18.117.7Stroke3.74.4Heart Failure7.87.4Hypertension57.859.9Diabetes22.822.4Current or former smoker60.960.6Placebo N = 6303 (%)Clopidogrel N = 6259 (%)The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

CURE

ECG Abnormality Type History Abnormal ECG93.993.7ST-segment Dep > 1 mm 42.042.2ST-segment elevation < 1 mm 3.23.2Major T-wave inversion25.925.4Other T-wave inversion11.311.5Other abnormalities10.910.7Placebo (%)Clopidogrel (%)The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

CURE

Primary End Point - MI/Stroke/CV DeathClopidogrel + ASA*369Placebo + ASA*Months of Follow-Up11.4%9.3%20% RRRP < 0.001N = 12,562012* In combination with standard therapyThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

CURE

MI/Stroke/CV Death within 30 DaysClopidogrel + ASA*102030Placebo + ASA*Days of Follow-Up021% RRRP = 0.003N = 12,562* In combination with standard therapyThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

CURE

Main Efficacy Results - Primary EndpointCV death, MI, stroke (Primary11.4%9.3%20%< 0.001 end point)MI6.7%5.2%23%Stroke1.4%1.2%14%CV death5.5%5.1%7%Relative Risk ReductionP valueOutcomePlacebo + ASA* N = 6303Clopidogrel + ASA* N = 6259* In combination with standard therapyThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

CURE

Main Efficacy Results - Second Primary End PointRRRP value End PointPlacebo + ASA*Clopidogrel + ASA** In combination with standard therapy ** Not significant Heart failure was a secondary end pointSecond Primary End Point18.8%16.5%14%< 0.001Refractory Ischemia9.3%8.7%7%NS**Refractory Ischemia in hospital2.0%1.4%32%P < 0.001Refractory Ischemia after discharge7.6%7.6%1%NS**Severe Ischemia3.8%2.8%26%P = 0.003Recurrent Ischemia22.9%20.9%9%P = 0.01Heart Failure4.4%3.7%18%P = 0.03The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

CURE

Beneficial Outcomes with Clopidogrel in Various SubgroupsOverall125629.311.4Associated MI328311.313.7 No associated MI92798.610.6Male sex77269.111.9 Female sex48369.510.765 yr old63545.47.6 > 65 yr old620813.315.3ST-segment deviation627511.514.3 No ST-segment deviation62877.08.6Enzymes elevated at entry317610.713.0 Enzymes not elevated at entry93868.810.9Diabetes284014.216.7 No diabetes97227.99.9Low risk41875.16.7 Intermediate risk41856.59.4 High risk418416.318.0History of revascularization22468.414.4 No history of revascularization103169.510.7Revascularization after randomization457711.513.9 No revascularization after randomization79858.110.0Placebo + ASA*CharacteristicNo. of PatientsClopidogrel + ASA*Percentage of Patients with EventPlacebo BetterClopidogrel BetterRelative Risk (95% CI)1.21.00.80.60.4* In combination with standard therapyThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

CURE

Thrombolytic and IV GP IIb/IIIa Inhibitor Use After RandomizationRelative Risk ReductionP valuePlacebo + ASA* N = 6303Clopidogrel + ASA* N = 6259Thrombolytics2.0%1.1%43% 0.43-0.76< 0.001IV GP IIb/IIIa Inhib7.2%5.9%18% 0.72-0.930.003CI* As part of standard therapyThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

CURE

Definition of BleedingBleeding was defined as Major and MinorMajor bleeding was defined as follows:life threatening: fatal, symptomatic intracranial hemorrhage, leading to a drop in hemoglobin of at least 5 g/dL, significant hypotention requiring IV inotropes, requiring surgical intervention, or requiring transfusion of 4 or more units of bloodnon-life-threatening: substantially disabling, intraocular bleeding leading to vision loss, or requiring at least 2 units of bloodMinor any other bleeds that led to interruption of study medicationThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

CURE

Bleeding ResultsPlacebo + ASA* N = 6303Clopidogrel + ASA* N = 6259Major bleeding2.7%3.7%**Life-threatening bleeding1.8%2.2% Non-life-threatening bleeding0.9%1.5% Minor bleeding2.4%5.1% End Point* In combination with standard therapy** P = 0.001; P = NS; P = 0.002; P < 0.001.The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

CURE

Life-Threatening BleedingLife-Threatening1.82.2Fatal0.20.25 g/dL drop hemoglobin0.90.9Hypotension-inotropic therapy0.50.5Surgery required0.70.7Hemorrhagic stroke0.10.1 4 Blood units1.01.2Placebo + ASA* N = 6303(%)Clopidogrel + ASA* N = 6259(%)* In combination with standard therapyThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

CURE

Major Bleeding in IV GP IIb/IIIa Antagonists ACS Trials vs CURE: within 30 DaysActive*DiffTrialNPlacebo*CURE:125621.5%2.0%+0.5%IV GP IIb/ IIIa Trials:PRISM-PLUS19150.8%1.4%+0.6%PURSUIT93759.1%10.6%+1.5% excluding CABG1.3%3.0%+1.7%CAPTURE12651.9%3.8%+1.9%* In addition to standard therapy including aspirin and heparinPRISM-PLUS Investigators. N Engl J Med. 1998;338:1488-97. PURSUIT Investigators. N Engl J Med. 1998;339:436-43. CAPTURE Investigators. Lancet. 1997;349 (9063):1429-1435.The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

CURE

ConclusionsIn the CURE study of 12,562 patients with ACS without ST-segment elevation:clopidogrel demonstrated a 20% relative risk reduction in MI, stroke or cardiovascular death with long-term use (P 24 hours. Stroke was further classified as due to intracranial hemorrhage, ischemia, or of uncertain originCardiovascular death included all deaths for which there was no clearly documented non-vascular cause (eg, car accident).Refractory ischemia was defined in two ways:Refractory ischemia in hospital was defined as recurrent chest pain lasting more than 5 minutes with new ECG changes indicative of myocardial ischemia while on optimal medical therapy (2 antianginal medications, one of which was IV nitrates unless contraindicated) and leading to additional intervention (thrombolytics, cardiac catheterization, insertion of intra-aortic balloon pump, revascularization or transfer to a referral hospital for an invasive procedure) by midnight of the next calendar day.Refractory ischemia after discharge was defined as rehospitalization lasting > 24 hours for unstable angina with ECG changes consistent with ischemia. Severe ischemia was defined as similar to in-hospital refractory ischemia, but for which no urgent intervention was performed.Recurrent angina was also defined as in-hospital refractory ischemia, without the ECG changes.For Educational Purposes Only. Not For Distribution.The primary analysis was based on intention-to-treat population and captured the occurrence of the first ischemic event.The primary end point of CURE was the composite of MI, stroke or cardiovascular death.MI was defined as presence of at least two of the following criteria: (1) ischemic chest pain, (2) elevation of cardiac markers to at least twice the upper limit of normal, and (3) ECG changes compatible with infarctionStroke was defined as new focal neurologic deficit of vascular origin; lasting > 24 hours. Stroke was further classified as due to intracranial hemorrhage, ischemia, or uncertainCardiovascular death included all deaths for which there was no clearly documented non-vascular causeThe second primary end point was the above plus refractory ischemia.Refractory ischemia was defined in two ways:Refractory ischemia in hospital was defined as recurrent chest pain lasting more than 5 minutes with new ECG changes indicative of myocardial ischemia while on optimal medical therapy (2 antianginal medications, one of which was IV nitrates unless contraindicated) and leading to additional intervention (thrombolytics, cardiac catheterization, insertion of intra-aortic balloon pump , revascularization or transfer to a referral hospital for an invasive procedure) by midnight the next calendar day.Refractory ischemia after discharge was defined as rehospitalization lasting > 24 hours for unstable angina with ECG changes consistent with ischemia.For Educational Purposes Only. Not For Distribution.NEJMThe baseline patient characteristics, seen above, were comparable between the two treatment groups. Approximately 38% were female and the mean age was 64 years. Seventy-five percent had unstable angina, while 25% had an acute MI without ST-segment elevation. Approximately 94% of patients had ECG abnormalities. For Educational Purposes Only. Not For Distribution.NEJMThe two groups had similar patient histories. Thirty-two percent had a previous MI,18% had either CABG or PTCA, 4% had a previous stroke, and approximately 7% had heart failure. Note that 22% of the total population had diabetes.For Educational Purposes Only. Not For Distribution.NEJMNearly 94% of patients had an abnormal ECG at study entry, with ST-segment depression 1 mm being the most common abnormality. Overall, the baseline demographic data indicate that this is at least an intermediate risk group of patients with unstable angina or nonST-segment elevation MI.For Educational Purposes Only. Not For Distribution.Clopidogrel provided a 20% relative risk reduction in the composite outcome of MI, stroke or CV death (95% CI 0.72-0.90, P < 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.For Educational Purposes Only. Not For Distribution.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).For Educational Purposes Only. Not For Distribution.NEJMClopidogrel in addition to aspirin provided a 20% relative risk reduction in the composite end point of CV death, MI, and stroke (11.4% vs 9.3%, 95% CI 0.72-0.90, P < 0.001).Each component of the composite outcome was reduced with the greatest benefit seen in the MI outcome (RRR 23%). There was also a 14% relative risk reduction in strokes and a 7% relative risk reduction in cardiovascular death.TO BE RESOLVEDFor Educational Purposes Only. Not For Distribution.NEJMThis slide summarizes the other efficacy results. The addition of clopidogrel significantly reduced the second primary end point of MI, stroke, cardiovascular death or refractory ischemia (16.5% vs 18.8%, RR 0.86, 95% CI 0.79-0.94, P < 0.001). Clopidogrel also provided a 32% relative risk reduction of in hospital refractory ischemia. The addition of clopidogrel reduced the risk of severe ischemia during the initial hospital visit by 26% (2.8% vs 3.8%, P = 0.003), and the risk of heart failure based on radiologic evidence during the initial hospital stay by 18% (3.7% vs 4.4%, P = 0.03).For Educational Purposes Only. Not For Distribution.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.For Educational Purposes Only. Not For Distribution.NEJMThe clopidogrel group reported a 43% relative risk reduction of thrombolytic use (1.1% vs 2.0%, P < 0.001) and a 18% relative risk reduction in the use of IV GP IIb/IIIa inhibitors (5.9% vs 7.2%, P = 0.003) For Educational Purposes Only. Not For Distribution.Bleeding was divided into Major and Minor Bleeding.Major bleeding was further subdivided into life-threatening bleeds and nonlife threatening bleeds. Life threatening was defined as fatal or leading to a drop in hemoglobin of at least 5 g/dL, significant hypotension requiring IV inotropes, surgical intervention, symptomatic intracranial hemorrhage or transfusion of 4 or more units of blood. Nonlife-threatening was defined as disabling, intraocular leading to vision loss or requiring at least 2 units of blood.Minor bleeds were any other bleed that led to interruption of study medication.The definition of bleeding was conservatively defined in the CURE trial.

For Educational Purposes Only. Not For Distribution.NEJMThere was a significant difference in major and minor bleeding between the clopidogrel and aspirin group compared to the aspirin group alone. However, there was no statistically significant difference in life-threatening bleeding between the two treatment arms, which included fatal bleeding, drop in hemoglobin of at least 5 g/dL, significant hypotension requiring IV inotropes, bleeds requiring surgical interventions, intracranial hemorrhage, or transfusion of 4 or more units of blood. Major bleeds were increased both early (< 30 days) and late (> 30 days). The principal sites for major bleeding included gastrointestinal and at arterial puncture sites.There was a statistically significant difference in minor bleeding in the clopidogrel plus aspirin group (2.4% vs 5.1%, P < 0.001).The number of patients receiving transfusions of 2 or more units of blood was higher in the clopidogrel plus aspirin group (2.8% vs 2.2%, P = 0.02).Overall, there was no significant excess in major bleeds after coronary bypass graft surgery with clopidogrel plus aspirin vs aspirin. However, in most patients scheduled for CABG, study medication were discontinued prior to procedure (median time of stopping before procedure was 5 days). For Educational Purposes Only. Not For Distribution.NEJMThere was no significant difference between the two treatment arms in life-threatening bleeds, which included fatal bleeding, drops in hemoglobin of 5 g/dL or more, bleeds requiring inotropic therapy surgical interventions, intracranial hemorrhage or a transfusion of 4 or more units of blood (P = 0.13).For Educational Purposes Only. Not For Distribution.NEJMThe bleeding rate seen in CURE was comparable to that seen with the IV GP IIb/IIIa inhibitor clinical trials. The above data for the IV GP IIb/IIIa inhibitor trials are a summary of the 30-day results based on the TIMI definition, which is less conservative than the CURE definition.Due to differences in study design, direct comparisons of bleeding rates for the study drugs cannot be made.

TIMI Definition of major bleeding: Severe or life-threatening bleeding was defined as Intracranial hemorrhage or bleeding associated with severe hemodynamic compromise. Major bleeding was defined as that which was associated with >15% absolute reduction in hematocrit or requiring a blood transfusion

CURE Definition of major bleeding: Life-threatening bleeding which was defined as fatal or leading to one of the following intracranial hemmorhage, drop in hemoglobin of 5 g/dL, substantial hypotension requiring inotropic therapy, surgical intervention, or transfusion of 4 or more units of blood.Non-life threatening bleeding was defined as substantially disabling bleeding, intraocular bleeding leading to the loss of vision or bleeding necessitating the transfusion of at least 2 units of blood.

For Educational Purposes Only. Not For Distribution.Clopidogrel in addition to aspirin and other standard therapy provided a 20% risk reduction in the composite outcome of MI, stroke and cardiovascular death (P < 0.001). This reduction was seen as early as a few hours and continued over the course of 12 months.The clopidogrel group also provided a 14% relative risk reduction in the second primary endpoint of MI, stroke, CV death or refractory ischemia (P80% of patients in each arm received open-label thienopyridine post-PCI. Follow-up ranged from 312 months.For Educational Purposes Only. Not For Distribution.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 (> 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 lowmolecular weight heparin, beta-blockers, ACE inhibitors, lipid-lowering agents, calcium channel blockers, and/or other therapies or interventions (PTCA, CABG) at physicians discretion.. The primary end point was the composite of myocardial infarction, cardiovascular death or urgent target vessel revascularization within 30 days of PCI.For Educational Purposes Only. Not For Distribution.The end points were:within 30 days of PCI: the composite of myocardial infarction (MI), urgent target-vessel revascularization or cardiovascular deathfrom PCI to end of follow-up: the composite of myocardial infarction or cardiovascular death.MI was defined as the presence of 2 or more of the following:ischemic symptomscardiac enzyme elevations to at least 3 times the upper limit of normal (ULN) within 48 hours of PCI and 2 times the ULN thereafternew ECG changes compatible with MI.Urgent target vessel revascularization was defined as either a second PCI or any CABG procedure performed on a non-elective basis in the target vessel due to recurrent ischemia.Cardiovascular death included all deaths (including deaths that were sudden, of unknown cause or secondary to complications of a cardiac procedure) unless there was documented evidence of a clear noncardiovascular cause.For Educational Purposes Only. Not For Distribution.The two study groups were well balanced at the start of the study with respect to age, gender, ECG abnormalities and cardiovascular history.

For Educational Purposes Only. Not For Distribution.The two groups were well balanced with regard to the timing of intervention, cardiovascular medications used before and after procedure, and stent placement.Sixty-five percent (1730 procedures) of the interventions were performed during the initial hospitalization and 35% (928 procedures) were performed after the initial discharge.The two groups were also well balanced in the types of lesions that were treated:target vessels (clopidogrel vs. placebo): left main (1.8% vs.1.8%); proximal (28.5% vs. 26.1%); mid/distal (23.5% vs 22.3%), left anterior descending, circumflex (29.0% vs. 29.3%); right coronary (31.9% vs. 32.8%); saphenous vein graft (3.3% vs. 2.4%).Open-label thienopyridine use was >80% in both treatment arms after PCI.For Educational Purposes Only. Not For Distribution.NEJMClopidogrel provided a 25% relative risk reduction in the composite outcome of MI or CV death at follow-up (8.0% vs 6.0%, P = 0.047), with a 29% reduction in MI (6.4% vs 4.5%, P = 0.03). Cardiovascular death was similar between the two groups at follow-up.Within 30 days there was also a 30% relative risk reduction in the primary outcome of MI, target vessel revascularization or CV death (6.4% vs 4.5%, P = 0.03), with a significant reduction in MI (3.8% vs 2.1%, RRR 44%) and urgent revascularization (2.8% vs 1.9%, RRR 33%). The rate of CV death was similar between the two groups. The reduction in the primary end point was seen within 48 hours following PCI, with increasing benefit at 7 and 14 days which continued throughout the 30 days.The benefits seen with early and long-term clopidogrel in addition to aspirin and other standard therapy, illustrates the need for early and continued antiplatelet protection in these high-risk patients.For Educational Purposes Only. Not For Distribution.For the end point of MI or cardiovascular death from time of randomization to end of follow-up, treatment with clopidogrel in addition to aspirin and other standard therapy resulted in a 31% RRR (8.8% clopidogrel vs. 12.6% placebo, P = 0.002).The curves diverged early and continued to separate over the course of 12 months. This end point included events that were prevented prior to PCI, in addition to those following the procedure.There were consistent reductions in MI or cardiovascular death in almost every subgroup examinedFor Educational Purposes Only. Not For Distribution.Treatment with clopidogrel in addition to aspirin and other standard therapy resulted in a RRR of 30% (P = 0.03) compared with aspirin and standard therapy alone for the endpoint of cardiovascular death, MI, or urgent revascularization at 30 days post-PCI. The event curves separated early and continued to separate up to 30 days and beyond.A reduction in this endpoint was observed within 2 days, with continuing benefit throughout the study period (up to 1 year).The majority of patients (> 80% in both groups) received open-label ADP-receptor antagonist following PCI, suggesting the early benefit was mainly due to clopidogrel pre-treatment.An on-treatment analysis which excluded those patients that received open-label ADP-receptor antagonist prior to PCI (~25% in both groups) demonstrated a 42% RRR (P = 0.005) in this endpoint.

For Educational Purposes Only. Not For Distribution.Several subgroup analysis were performed and select results are summarized above. Although this study was not powered to look at individual subgroups, there was a beneficial trend seen across all subgroups analyzed. For Educational Purposes Only. Not For Distribution.NEJMUnless the patients developed refractory ischemia, the use of GP IIb/IIIa inhibitors was discouraged. The clopidogrel group reported a 21% relative risk reduction in GP IIb/IIIa inhibitor use (26.6% vs 20.9%, P = 0.001). There was also an 18% relative risk reduction in the need for a second revascularization (17.1% vs 14.2%, P = 0.049) in the clopidogrel plus aspirin group.For Educational Purposes Only. Not For Distribution.NEJMThere was no significant difference in major bleeding at 30 days or at end of follow-up (2.5% vs 2.7%, RR 1.12, P = 0.64). Similarly, there was no significant difference in life-threatening bleeding at 30 days (0.7% vs 0.7%) or at follow-up (1.3% vs. 1.2%). Minor bleeding was slightly increased in the clopidogrel group at 30 days (0.7% vs. 1.0%) and significantly increased at follow-up (2.1% vs. 3.5%, RR 1.68, P = 0.03).For Educational Purposes Only. Not For Distribution.In the 2658 patients who underwent percutaneous coronary intervention (PCI) in the CURE trial:clopidogrel demonstrated a 25% relative risk reduction in the composite of MI or cardiovascular death with long-term (up to 12 months) use from PCI to end of follow-up (P = 0.04)in the 30 days after PCI, clopidogrel reduced the incidence of MI, urgent revascularization or cardiovascular death by 30% (P = 0.03)clopidogrel in addition to aspirin and other standard therapy provides early beneficial effect and sustained long-term benefit.There was no significant difference in major (2.5% vs 2.7%, P = 0.64) or life-threatening bleeding (1.3% vs 1.2%, P = 0.78) from PCI to end of follow-up between the placebo plus aspirin and clopidogrel plus aspirin group, respectively. However, there was a significant increase in minor bleeding in the clopidogrel plus aspirin group (2.1% vs 3.5%, P = 0.03) from PCI to end of follow-up.

For Educational Purposes Only. Not For Distribution.Long-term administration (mean duration 8 months) resulted in an overall 26% relative risk reduction in CV death or MI. Pretreatment with clopidogrel, prior to PCI, resulted in a 30% relative risk reduction in CV death, MI and target vessel revascularization for 30 days post PCI. This benefit was seen as early as 2 days after the procedure.

For Educational Purposes Only. Not For Distribution.