最新CURE Clinical Trial Results The International Leader in 治疗的临床试验的的结果的国际领先-PPT文档.ppt

Disclaimer,This 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 Study Investigators. Eur Heart J. 2000;21:2033-2041. PURSUIT Investigators. Am J Cardiol. 1999;83:1147-1151.,Rationale,Despite 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 therapy The 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.,Study Objectives,Primary Evaluate 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) Secondary Evaluate the safety of clopidogrel in combination with ASA therapy in patients with ACS,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.,Study Design,3 months £ double-blind treatment £ 12 months,Clopidogrel 300 mg loading dose,1 CURE Study Protocol (Data on file, Sanofi-Synthelabo, Inc.) 2 CURE Study Investigators. Eur Heart J. 2000; 21:2033-2041.,Key Inclusion Criteria,Age ³ 21 years1 Suspected UA or NSTEMI (no ST ³ 1.0 mm)2 Presentation £ 24 hours after onset of symptoms2 ECG changes compatible with ischemia or elevated cardiac enzymes or troponin I or T ³ 2 x ULN2,1 CURE Study Investigators. Eur Heart J. 2000; 21:2033-2041. 2 CURE Study Protocol (Data on file, Sanofi-Synthelabo, Inc.),Key Exclusion Criteria,NYHA Class IV heart failure1 Uncontrolled hypertension2 Current use of anticoagulants1, clopidogrel, ticlopidine, or NSAIDS2, or GP IIb/IIIa inhibitor within 3 days1 PCI or CABG within 3 months1 History of severe thrombocytopenia or neutropenia2 At high risk for bleeding1 Contraindications to antithrombotic or antiplatelet therapy1,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 ³ 24 hrs (CT/MRI encouraged) CV Death: Excludes any death for which there was no clearly documented non-CV cause Refractory Ischemia: In-hosp: recurrent ischemia on max med Rx + ECG changes + intervention £ 1 day After discharge: Rehosp for UA with ECG changes Severe Ischemia: Changes similar to in-hospital refractory ischemia, but no intervention Recurrent Angina: All other ischemic chest pain in hospital,The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.,Efficacy Analyses,First Primary End Point First occurrence of any component of the cluster of: Myocardial Infarction Stroke (ischemic, hemorrhagic, or of uncertain type) Cardiovascular death Second Primary End Point First occurrence of any component of the cluster of: Myocardial Infarction Stroke (ischemic, hemorrhagic, or of uncertain type) Cardiovascular death Refractory ischemia,The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.,Age (mean) 64.2 64.2 Mean time from pain onset to randomization (hrs) 14.1 14.2 Mean heart rate (beats/min) 73.0 73.2 Mean systolic BP (mm Hg) 134.1 134.4 Female (%) 38.3 38.7 Diagnosis at Entry Unstable Angina (%) 74.9 74.9 NonST-segment elevation MI (%) 25.1 25.1 ECG abnormalities (%) 93.9 93.7,Placebo N = 6303,Clopidogrel N = 6259,Baseline Characteristics,The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.,History of MI 32.0 32.4 CABG Surgery/PTCA 18.1 17.7 Stroke 3.7 4.4 Heart Failure 7.8 7.4 Hypertension 57.8 59.9 Diabetes 22.8 22.4 Current or former smoker 60.9 60.6,Placebo N = 6303 (%),Clopidogrel N = 6259 (%),The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.,Patient History,History Abnormal ECG 93.9 93.7 ST-segment Dep 1 mm 42.0 42.2 ST-segment elevation 1 mm 3.2 3.2 Major T-wave inversion 25.9 25.4 Other T-wave inversion 11.3 11.5 Other abnormalities 10.9 10.7,Placebo (%),Clopidogrel (%),The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.,ECG Abnormality Type,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.,Primary End Point - MI/Stroke/CV Death,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.,MI/Stroke/CV Death within 30 Days,CV death, MI, stroke (Primary 11.4% 9.3% 20% 0.001 end point) MI 6.7% 5.2% 23% Stroke 1.4% 1.2% 14% CV death 5.5% 5.1% 7%,Relative Risk Reduction,P value,Outcome,Placebo + ASA* N = 6303,Clopidogrel + ASA* N = 6259,* In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.,Main Efficacy Results - Primary Endpoint,RRR,P value,End Point,Placebo + ASA*,Clopidogrel + ASA*,Main Efficacy Results - Second Primary End Point,* In combination with standard therapy * Not significant Heart failure was a secondary end point,Second Primary End Point 18.8% 16.5% 14% 0.001 Refractory Ischemia 9.3% 8.7% 7% NS* Refractory Ischemia in hospital 2.0% 1.4% 32% P 0.001 Refractory Ischemia after discharge 7.6% 7.6% 1% NS* Severe Ischemia 3.8% 2.8% 26% P = 0.003 Recurrent Ischemia 22.9% 20.9% 9% P = 0.01 Heart Failure 4.4% 3.7% 18% P = 0.03,The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.,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.,Beneficial Outcomes with Clopidogrel in Various Subgroups,Relative Risk Reduction,P value,Placebo + ASA* N = 6303,Clopidogrel + ASA* N = 6259,Thrombolytics 2.0% 1.1% 43% 0.43-0.76 0.001 IV GP IIb/IIIa Inhib 7.2% 5.9% 18% 0.72-0.93 0.003,CI,* As part of standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.,Thrombolytic and IV GP IIb/IIIa Inhibitor Use After Randomization,The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.,Definition of Bleeding,Bleeding was defined as “Major” and “Minor” Major 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 blood non-life-threatening: substantially disabling, intraocular bleeding leading to vision loss, or requiring at least 2 units of blood Minor any other bleeds that led to interruption of study medication,Placebo + ASA* N = 6303,Clopidogrel + ASA* N = 6259,Major bleeding 2.7% 3.7%* Life-threatening bleeding 1.8% 2.2% Non-life-threatening bleeding 0.9% 1.5% Minor bleeding 2.4% 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.,Bleeding Results,Life-Threatening 1.8 2.2 Fatal 0.2 0.2 5 g/dL drop hemoglobin 0.9 0.9 Hypotension-inotropic therapy 0.5 0.5 Surgery required 0.7 0.7 Hemorrhagic stroke 0.1 0.1 4 Blood units 1.0 1.2,Placebo + ASA* N = 6303 (%),Clopidogrel + ASA* N = 6259 (%),* In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.,Life-Threatening Bleeding,Active*,Diff,Trial,N,Placebo*,CURE: 12562 1.5% 2.0% +0.5% IV GP IIb/ IIIa Trials: PRISM-PLUS 1915 0.8% 1.4% +0.6% PURSUIT 9375 9.1% 10.6% +1.5% excluding CABG 1.3% 3.0% +1.7% CAPTURE 1265 1.9% 3.8% +1.9%,* In addition to standard therapy including aspirin and heparin,PRISM-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.,Major Bleeding in IV GP IIb/IIIa Antagonists ACS Trials vs CURE: within 30 Days, Up to 12 months,Conclusions,In 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 0.001) the Kaplan-Meier curves began to diverge within hours and continued to diverge over the course of 12 months clopidogrel also demonstrated a 14% relative risk reduction in MI, stroke, cardiovascular death or refractory ischemia (P 0.001) Clopidogrel in addition to aspirin and other standard therapy demonstrated an early effect (within hours) and sustained long-term benefit throughout the entire study period of 12 months,The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.,The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.,Conclusions,Minor bleeding was increased, but there was no increase in life-threatening bleeds (including intracranial bleeds) 18% Relative Risk Reduction in heart failure (P = 0.03) Significant reductions in the reported use of: IV GP IIb/IIIa inhibitor: 18% (P = 0.003) thrombolytics: 43% (P 0.001),Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.,Design,Prospectively designed study of patients undergoing PCI who were randomized to double-blind therapy with clopidogrel or placebo, both in addition to aspirin and other standard therapy in the CURE trial Objectives to test the hypothesis that pre-treatment with clopidogrel in addition to aspirin and other standard therapy would be more effective than aspirin and standard therapy alone in preventing major ischemic events within the first 30 days after PCI to determine if long-term treatment (up to 1 year) with clopidogrel in addition to aspirin and other standard therapy after PCI would provide additional clinical benefit,PCI-CURE,Study Design,Patients randomized to clopidogrel or placebo at CURE trial entry, both in addition to aspirin and standard therapy All patients undergoing PCI during the course of the CURE trial were included in PCI-CURE Timing of PCI was at the physicians discretion At time of PCI, study drug was interrupted and open-label therapy was initiated for 2-4 weeks During open-label therapy, thienopyridines in combination with ASA was permitted Follow-up ranged from 3-12 months,Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.,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,* In combination with standard therapy,N = 1345,N = 1313,CURE,PCI-CURE,Study Design,R,Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502.,PCI-CURE,End Points,Composite of the following within 30 days of PCI: myocardial infarction urgent target-vessel revascularization cardiovascular death Composite of the following from PCI to end of follow-up: myocardial infarction cardiovascular death,Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.,PCI-CURE,Baseline Characteristics,Age (mean, years) 61.4 61.6 Male (%) 69.9 69.7 Diabetes (%) 19.0 19.0 Previous MI (%) 26.0 27.3 Prior PCI (%) 13.8 13.4 Prior CABG (%) 13.0 12.0 ST-segment depression (%) 42.4 43.2 ST-segment elevation (%) 4.4 5.1,* In combination with standard therapy,Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.,PCI-CURE,Placebo Clopidogrel + ASA* + ASA* (N = 1345) (N = 1313),Interventional Characteristics,Placebo Clopidogrel + ASA* + ASA* (N = 1345) (N = 1313) Overall median days after randomization on which PCI was done 10 10 PCI during initial hospitalization 6 6 PCI after initial hospitalization 49 49 Stent use (%) 81.3 82.4 Use of open-label thienopyridine Before PCI (%) 24.7 26.4 Overall (%) 84.1 82.9,* In combination with standard therapy Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.,PCI-CURE,RRR,P value,Placebo + ASA* N = 1345,Clopidogrel + ASA* N = 1313,From PCI to 30 days MI, urgent revascularization or CV death 6.4% 4.5% 30% 0.03 From PCI to follow-up CV death or MI 8.0% 6.0% 25% 0.047,Efficacy Outcomes,* In combination with standard therapy Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.,PCI-CURE,0.15,0.10,0.05,0.0,0,100,200,300,400,Days of follow-up,12.6%,8.8%,31% RRR P = 0.002 N = 2658,Clopidogrel + ASA*,Placebo + ASA*,Cumulative Hazard Rate,* In combination with standard therapy Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001.,Composite of cardiovascular death or MI from randomization to end of follow-up,Overall Long-Term Results,PCI-CURE,30 Day Results,0,5,10,15,20,25,30,Days of follow-up,0.0,0.02,0.04,0.06,0.08,30% RRR P = 0.03 N = 2658,Cumulative Hazard Rate,* In combination with standard therapy Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.,6.4%,4.5%,Clopidogrel + ASA*,Placebo + ASA*,Composite of cardiovascular death, MI, or urgent revascularization,PCI-CURE,Overall 12.6% 8.8% 0.69 0.54-0.87 Stent 11.