Presentation on theme: "OASIS-7 CURRENT OASIS 7: A 2X2 Factorial Randomized Trial of Optimal Clopidogrel and Aspirin Dosing in Patients with ACS Undergoing an Early Invasive Strategy."— Presentation transcript:
1OASIS-7CURRENT OASIS 7: A 2X2 Factorial Randomized Trial of Optimal Clopidogrel and Aspirin Dosing in Patients with ACS Undergoing an Early Invasive Strategy with Intent For PCIShamir R. Mehta on behalf of the CURRENT InvestigatorsDisclosures: CURRENT OASIS 7 was funded by a grant from sanofi-aventis and Bristol Myers Squibb. All data were managed independently of the sponsor at the PHRI, McMaster University and the trial was overseen by an international steering committee of experts.
2Background Clopidogrel Clopidogrel 300 mg followed by 75 mg daily reduces major CV events across the spectrum of ACS and PCIRecent data suggest that doubling the loading and maintenance doses of clopidogrel results in a higher and more rapid antiplatelet effectAspirinDose of ASA varies between Europe and North AmericaNo large-scale RCT’s have compared high ( mg) versus low (75-100) dose aspirin in patients with ACS undergoing PCI
3Relative Risk Reduction Benefits of Antiplatelet Therapy in ACS are Greater in Patients Undergoing PCIRelative Risk ReductionPCINo PCICURE: Clopidogrel 300/75 mg v Placebo (CVD/MI)30%119%2STEMI: Clopidogrel 300/75 mg v Placebo (CVD/MI)46%39%4TRITON: Prasugrel v clopidogrel 300/75mg (CVD/MI/Stroke)19%5Not evaluated1. Mehta SR, et al. Lancet 2001; 358(9281):2. Fox KAA, et al. Circulation 2004;110:1202-83. Sabatine MS, et al. JAMA 2005; 294(10):4. Chen ZM Lancet 2005;366:4. Boersma E et al. Lancet 2002; 359:1895. Wiviott S et al. N Engl J Med 2007; 357: 2001–15.
4Study Design, Flow and Compliance 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (<24 h) Invasive Management with intended PCIIschemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)Randomized to receive (2 X 2 factorial):CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d)ASA: High Dose ( mg/d) vs Low dose ( mg/d)Angio 24,769(99%)PCI 17,232(70%)No PCI 7,855 (30%)No Sig. CAD 3,616CABG 1,809CAD 2,430Compliance:Clop in 1st 7d (median) 7d d d dEfficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCIComplete Followup 99.8%
5ASA Dose Comparison Primary Outcome and Bleeding mgmgHR95% CIPCV Death/MI/StrokePCI (2N=17,232)18.104.22.1680.76No PCI (2N=7855)22.214.171.1240.44Overall (2N=25,087)0.960.47Stent Thrombosis126.96.36.1990.37TIMI Major Bleed1.030.970.940.71CURRENT Major Bleed2.30.990.90CURRENT Severe Bleed1.71.00GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051No other significant differences between ASA dose groups
6Clopidogrel Dose Comparison 2 Significant Interactions:PCI v No PCI (P=0.016)ASA dose (P=0.043)
7Clopidogrel: Double vs Standard Dose Primary Outcome and Components HR95% CIPIntn PCV Death/MI/StrokePCI (2N=17,232)188.8.131.520.0360.016No PCI (2N=7855)184.108.40.206.14Overall (2N=25,087)4.40.950.370MI2.62.00.780.0120.0251.41.71.250.220.127.116.110.097CV Death0.960.681.02.82.70.772.10.628Stroke0.40.880.590.500.80.91.110.670.50.990.950
8Clopidogrel Double vs Standard Dose Bleeding Overall Population HazardRatio95% CIPTIMI Major10.951.041.090.50CURRENT Major22.02.51.250.01CURRENT Severe18.104.22.168.03Fatal0.110.131.150.71ICH0.050.670.53RBC transfusion ≥ 2U1.762.211.26CABG-related Major0.91.01.100.481ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units
9Clopidogrel: Double vs Standard Dose Definite Stent Thrombosis (Angio confirmed)Clopidogrel Standard Dose0.01242%RRR0.008Cumulative HazardClopidogrel Double Dose0.004HR 0.5895% CIP=0.0010.036912151821242730Days
10Clopidogrel: Double vs Standard Dose Major Efficacy Outcomes in PCI Patients Day 30ClopidogrelStandardN=8684%Double N=8548Hazard Ratio95% CIP valueStent Thrombosis22.214.171.1240.002Definite126.96.36.1990.001MI2.62.00.780.012MI or stent thrombosis3.73.00.800.008CV Death1.90.960.68Stroke0.40.880.59CV Death/MI/Stroke188.8.131.520.036
11Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients CV Death, MI or StrokeClopidogrel Standard15% RRR0.04Clopidogrel Double0.03Cumulative Hazard0.02HR 0.8595% CIP=0.0360.010.036912151821242730Days
12Clopidogrel Double vs Standard Dose Bleeding PCI Population HazardRatio95% CIPTIMI Major10.51.060.79CURRENT Major184.108.40.2060.006CURRENT Severe30.81.390.034Fatal0.150.070.470.125ICH0.0350.0461.350.69RBC transfusion ≥ 2U0.911.490.007CABG-related Major0.11.690.311ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units
13Clopidogrel: Double v Standard Dose PCI Cohort Subgroups CV Death, MI or StrokeMI or Stent Thrombosis2NStd %Double %Intxn PStd %Double %Intxn POverall1723220.127.116.11.0NSTEMI/UA108818.104.22.168.10.8050.248STEMI63465.04.24.02.8Male130094.13.63.53.00.4190.148Female4222.214.171.124.0Age <= 65 yrs109753.02.72.92.20.7020.418Age > 65 yrs62577.16.05.24.4Non-Diabetic134004.23.63.62.80.8360.567Prev Diabetic383126.96.36.199.6No Inhosp GPIIb/IIIa1228188.8.131.52.50.4650.894GPIIb in hosp49366.04.75.24.1No Prot Pump Inhib767184.108.40.206.30.4080.613Prot Pump Inhib555220.127.116.11.3Non-smoker108418.104.22.168.50.0450.050Current Smoker63803.82.63.42.1ASA Low8622.214.171.124.20.0240.191ASA High86126.96.36.199.7Double Dose BetterStd Dose BetterDouble Dose BetterStd Dose Better0.501.500.501.50
14Clopidogrel: Double vs Standard Dose by ASA Factorial HR95% CIPP int’nStandardDoubleCV Death/MI/Stroke (Overall)ASA High188.8.131.520.0360.043ASA Low4.24.51.070.42MI/Stent Thrombosis (PCI pts)2.70.710.0050.193.63.20.890.32Major Bleed (Overall)2.22.41.080.510.0991.91.430.003
15Definite Stent Thrombosis in 4 Groups (Angiographically Proven) C Standard, A Low0.012C Standard, A HighC Double, A Low0.008Cumulative HazardC Double, A High0.004Standard ClopDouble ClopHRPIntnHigh ASA184.108.40.2060.003Low ASA0.80.0580.350.036912151821242730Days
16Conclusions Clopidogrel Dose Comparison Double-dose clopidogrel significantly reduced stent thrombosis and major CV events (CV death, MI or stroke) in PCI.In patients not undergoing PCI, double dose clopidogrel was not significantly different from standard dose (70% had no significant CAD or stopped study drug early for CABG).There was a modest excess in CURRENT-defined major bleeds but no difference in TIMI major bleeds, ICH, fatal bleeds or CABG-related bleeds.
17Conclusions ASA Dose Comparison No significant difference in efficacy or bleeding between ASA mg and ASA mg.
18Clinical Implications For every 1,000 patients with ACS receiving PCI, using double-dose clopidogrel for 7 days instead of standard dose will prevent an additional 6 MI’s and 7 stent thromboses with an excess of 3 severe bleeds and no increase in fatal, CABG-related or TIMI major bleeds.Patients not undergoing PCI should continue to use the standard dose regimen of clopidogrel.
21Comparison of CURRENT and TRITON CURRENT PCIN=17,232TRITONN=13,608CV Death, MI or Stroke↓ 15%↓ 21% (w high dose ASA)↓ 19%Definite Stent Thrombosis↓ 42%↓ 51% (w high dose ASA)↓ 58%TIMI Major BleedNo increase↑ 32%CABG-related Bleeding↑ 4-foldFatal bleeding
22Baseline Characteristics and In Hospital Meds Meds After RandAge (y)61.4GP IIb/IIIa inhibitor31.8Female27.4%Statin87.2UA/NSTEMI70.8%Beta Blocker82.5Rand to Angio3.4 hACE/ARB75.7STEMI29.2%PPI40*0.5 hH2 Blocker11.3Diabetes23.4Prior Stroke4.1Ischemic ECG Δ80.8↑ Biomarker42Variables equally balanced among the randomized groups*38.6% low dose ASA v 41.4% high dose ASA and 40% standard dose Clop v 40% high dose Clop
23Clopidogrel: Double vs Standard Dose Primary Outcome 0.05C Std, A HiC Double, A LoC Std, A Lo0.04C Double, A Hi0.03Cumulative Hazard0.02Clop StandardClop DoubleHRPIntnASA mg220.127.116.110.0360.043ASA mg4.24.51.070.430.010.036912151821242730Days
24Death/MI/Stroke at 30 days ASA Dose ComparisonDeath/MI/Stroke at 30 daysDaysCumulative Hazard0.00.010.020.030.0436912151821242730HR 0.96 ( ) P = 0.489ASA mgASA mg