Clopidogrel for the Reduction of Events During Observation Multicenter Multinational (USA, Canada) Prospective Randomized Double Blind Placebo Controlled Trial From Steinhubl et al, JAMA 2002;228:2411-20
Aim of the Study Safety and efficacy of a loading dose of Clopidogrel prior to elective PCI Safety and efficacy of 1 Year vs 1 Month combined treatment with Clopidogrel 75 mg + ASA after elective PCI
Inclusion Criteria Pts with symptomatic CAD scheduled for PCI without contraindications to antithrombotic or antiplatelet treatment or stent implantation and with no ST segment elevation within 24 hrs or planned staged procedures or recent (<7 days) administration of GP IIb-IIIa inhibitors, clopidogrel or thrombolytics
3-24 hrs before PCI 300 mg Clopidogrel Loading Dose + ASA 325 mg Placebo + ASA 325 mg GP IIb-IIIa Inhib. (mainly Abciximab) on prespecified or Bail-out Indications Clopidogrel 75 mg + ASA 325 mg for 1 Month 75 mg Clopidogrel + ASA 325 mg for 1 Year Placebo + ASA 325 mg for 1 Year 28 Days and 1 Year Clinical Follow-Up
Outcomes At 28 Days Death, MI, Urgent TVR in the per protocol population (all pts undergoing PCI) with prespecified secondary analysis of pts receiving clopidogrel loading dose or placebo <6 hrs or >6 hrs before PCI At 1 Year Death, MI, Stroke with prespecified secondary endpoints of TVR
Power Calculation based on a Retrospective Analysis of 2450 Pts in the EPISTENT trial: 28 Days Events 13.4% P<0.01 8.9% 7.5% No Ticlopidine Ticlopidine Expected Pre-PTCA Pre-PTCA for Clopid. Loading (expected placebo) Dose + 1 Year From Steinhubl et al, JACC 1998;32:1366-70
Clinical Characteristics (I) Clopidogrel Loading Dose + Clopidogrel 1 Year N= 1053 Placebo Loading Dose + Clopidogrel 1 Mo N= 1063 Age (yrs) 61+5 62+7 NS Male Sex (%) 70.7% 72.1% NS Diabetes (%) 27.5% 25.4% NS Statins (%) 53.6% 57.5% p=0.07 Ca ++ Chan. Block. (%) 25.5% 29.4% p=0.08 MI 14.3 13.1 Indication (%) UAP 52.5 53.1 NS SA 32.8 32.8 PTCA 85.6 86.2 Treatment (%) Medical 8.3 7.6 NS CABG 3.9 4.0
Clinical Characteristics (II) Clopidogrel Loading Dose + Clopidogrel 1 Year N= 900 Placebo Loading Dose + Clopidogrel 1 Mo N= 915 Received >1 Stent (%) 89.7 88.3 NS Total Stent Length (mm) 24.4 23.5 NS GP IIb-IIIa Antag. (%) 47.4% 43.3% p=0.08
Death, MI and Urgent TVR at 28 Days 10 8 6 4 2 0 NS -18.5% Clopid. No Loading Clopid. Loading 8.3% 6.8% 0 Days 7 14 21 28
Death, MI and Urgent TVR at 28 Days 10 8 6 4 2 0 P=0.051-38.6% Clopid. No Loading Clopid. < 6 Hrs Loading Clopid. > 6 Hrs 0 Days 7 14 21 28
Death, MI, Urgent TVR at 28 Days
15 10 5 0 Death, MI and Stroke at 1 Year P=.02 10.5% 8.5% -26% Clopid. 1 Mth Clopid. 1 Year 0 3 6 9 12 Mths
Death, MI, Stroke at 1 Year in Key Subgroups 0 1/2 4 24 48 Hrs
1 Year Primary and Secondary Prespecified EndPoints 1 Year Clopidogrel 1 Month Clopidogrel 13.1 13.6 6.7 8.4 1.7 2.3 0.9 0.9 Death MI Stroke TVR
Loading Dose-1 Year Clopidogrel Major Bleedings 1 Month Clopidogrel P = 0.24 8.8 P = 0.07 6.7 4.8 3.8 28 Days 1 Year More than ½ of major procedural bleedings due to CABG
Conclusions Prolongation of treatment with an ADP inhibitor such as clopidogrel beyond 1 month after PCIreduces the incidence of death/mi at 1 year There is a strong trend to reduction of death/mi/urgent TVR at 28 days after a loading dose of 300 mg of clopidogrel administered at least 6 hrs before PCI
Questions and Criticisms Did pretreatment interfere with long-term results? Did the poor compliance to long-term treatment with clopidogrel (only 63/61% of pts took the study drug) modify results? Can we improve it? Can we reduce the excess of bleeding?
Aspirin Dose and Bleeding Events in CURE 12563 Pts with non-st Elevation ACS Aspirin Alone (p=0.057) Aspirin/Clopidogrel (p=0.042) Major or Life Threatening Bleeding Events 4.63 4.64 1.92 2.82 2.24 3.19 3.32 3.77 ASA <100 mg 100-150 mg 150-300 mg >300 mg From Peters et al EHJ 2002;Suppl.4:510
Will a higher loading dose help? 10 + 10 Pts pretreated with 200 mg Aspirin 90 80 70 60 50 40 30 300 + 75 600 + 150 20 10 0 0 1/2 4 24 48 Hrs From Muller et al, Heart 2001;85:92-93
Do we still need IIb-IIIa inhibitors in pts with effective clopidogrel pretreatment? ISAR- REACT: after 600 mg loading dose Clopidogrel: Randomization to Abciximab or Placebo
TOPSTAR Study 109 Pts with 375 mg Clopidogrel and 500 mg ASA 24 Hrs before PCI Tirofiban 10 μg + 18 Hrs Infusion Placebo bolus + 18 Hrs infusion 100 100 128 108 87 98 10 14 Prior 30 min 12 Hrs 48 Hrs From Bonz et al, JACC 2002;40:662-8
TOPSTAR Study 109 Pts with 375 mg Clopidogrel and 500 mg ASA 24 Hrs before PCI Tirofiban 10 μg + 18 Hrs Infusion 40% Placebo bolus + 18 Hrs infusion 63% Positive Troponin T (>0.01 μg/ml) From Bonz et al, JACC 2002;40:662-8
Is 1 Year Treatment Enough? CHARISMA: 15000 Stable Angina Pts with 42 Mths F-Up From Metha et al, Lancet 2001;358:527-33 2658 Pts undergoing PCI in the CURE trial
Questions and Criticisms What about cost-effectiveness? Mechanism of clinical benefit? prevention of periprocedural damage, TVR late events and non TVR late events Long-term treatment with clopidogrel advised for pts who receive drug eluting stents (3 mths SIRIUS, 6 mths TAXUS)