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CURRENT OASIS 7: A 2X2 Factorial Randomized Trial of Optimal Clopidogrel and Aspirin Dosing in Patients with ACS Undergoing an Early Invasive Strategy.

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Presentation on theme: "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:

1 CURRENT 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 PCI OASIS-7 Shamir R. Mehta on behalf of the CURRENT Investigators Disclosures: 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.

2 Background Clopidogrel Clopidogrel 300 mg followed by 75 mg daily reduces major CV events across the spectrum of ACS and PCI Recent data suggest that doubling the loading and maintenance doses of clopidogrel results in a higher and more rapid antiplatelet effect Aspirin Dose of ASA varies between Europe and North America No large-scale RCTs have compared high (300-325 mg) versus low (75-100) dose aspirin in patients with ACS undergoing PCI

3 Relative Risk Reduction PCINo PCI CURE: Clopidogrel 300/75 mg v Placebo (CVD/MI) 30% 1 19% 2 STEMI: Clopidogrel 300/75 mg v Placebo (CVD/MI) 46% 3 9% 4 TRITON: Prasugrel v clopidogrel 300/75mg (CVD/MI/Stroke) 19% 5 Not evaluated Benefits of Antiplatelet Therapy in ACS are Greater in Patients Undergoing PCI 1. Mehta SR, et al. Lancet 2001; 358(9281):527-33. 2. Fox KAA, et al. Circulation 2004;110:1202-8 3. Sabatine MS, et al. JAMA 2005; 294(10):1224-32. 4. Chen ZM Lancet 2005;366:1607-21 4. Boersma E et al. Lancet 2002; 359:189 5. Wiviott S et al. N Engl J Med 2007; 357: 2001–15.

4 Study Design, Flow and Compliance 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG Δ (80.8%) or cardiac biomarker (42%) 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG Δ (80.8%) or cardiac biomarker (42%) PCI 17,232 (70%) Angio 24,769 (99%) Angio 24,769 (99%) No PCI 7,855 (30%) No Sig. CAD 3,616CABG 1,809CAD 2,430 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 (300-325 mg/d) vs Low dose (75-100 mg/d) Efficacy Outcomes:CV Death, MI or stroke at day 30 Stent Thrombosis at day 30 Safety Outcomes:Bleeding (CURRENT defined Major/Severe and TIMI Major) Key Subgroup: PCI v No PCI Clop in 1st 7d (median) 7d 7 d 2 d 7d Complete Followup 99.8% Compliance:

5 ASA Dose Comparison Primary Outcome and Bleeding ASA 75-100 mg ASA 300-325 mg HR95% CIP CV Death/MI/Stroke PCI (2N=17,232)4.24.10.980.84-1.130.76 No PCI (2N=7855)4.74.40.920.75-1.140.44 Overall (2N=25,087) 4.44.20.960.85-1.08 0.47 Stent Thrombosis2.11.90.910.73-1.120.37 TIMI Major Bleed1.030.970.940.73-1.210.71 CURRENT Major Bleed2.3 0.990.84-1.170.90 CURRENT Severe Bleed1.7 1.000.83-1.211.00 No other significant differences between ASA dose groups GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051

6 Clopidogrel Dose Comparison 2 Significant Interactions: 1. PCI v No PCI (P=0.016) 2. ASA dose (P=0.043)

7 Clopidogrel: Double vs Standard Dose Primary Outcome and Components StandardDoubleHR95% CIPIntn P CV Death/MI/Stroke PCI (2N=17,232)4.53.90.850.74-0.990.036 0.016 No PCI (2N=7855)4.24.91.170.95-1.440.14 Overall (2N=25,087)4.44.20.950.84-1.070.370 MI PCI (2N=17,232)2.62.00.780.64-0.950.012 0.025 No PCI (2N=7855)1.41.71.250.87-1.790.23 Overall (2N=25,087)2.21.90.860.73-1.030.097 CV Death PCI (2N=17,232)1.9 0.960.77-1.190.68 1.0 No PCI (2N=7855)2.82.70.960.74-1.260.77 Overall (2N=25,087)2.22.10.960.81-1.140.628 Stroke PCI (2N=17,232)0.4 0.880.55-1.410.59 0.50 No PCI (2N=7855)0.80.91.110.68-1.820.67 Overall (2N=25,087)0.5 0.990.70-1.390.950

8 Clopidogrel Double vs Standard Dose Bleeding Overall Population Clopidogrel Standard N=12579 Double N=12508 Hazard Ratio 95% CIP TIMI Major 1 0.951.041.090.85-1.400.50 CURRENT Major 2 2.02.51.251.05-1.470.01 CURRENT Severe 3 1.51.91.231.02-1.490.03 Fatal0.110.13 1.150.56-2.350.71 ICH0.050.03 0.670.19-2.370.53 RBC transfusion 2U 1.76 2.211.261.06-1.510.01 CABG-related Major0.91.01.100.85-1.420.48 1 ICH, Hb drop 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal 2 Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units 3 Fatal or Hb 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of 4 units

9 Days Cumulative Hazard 0.0 0.004 0.008 0.012 036912151821242730 Clopidogrel Standard Dose Clopidogrel Double Dose 42% RRR HR 0.58 95% CI 0.42-0.79 P=0.001 Clopidogrel: Double vs Standard Dose Definite Stent Thrombosis (Angio confirmed)

10 Clopidogrel: Double vs Standard Dose Major Efficacy Outcomes in PCI Patients Day 30Clopidogrel Standard N=8684 % Double N=8548 % Hazard Ratio 95% CIP value Stent Thrombosis 2.31.60.710.57-0.890.002 Definite Definite1.20.70.580.42-0.790.001 MI2.62.00.780.64-0.950.012 MI or stent thrombosis 3.73.00.800.68-0.940.008 CV Death 1.91.90.960.77-1.190.68 Stroke0.40.40.880.55-1.410.59 CV Death/MI/Stroke 4.53.90.850.74-0.990.036

11 Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 036912151821242730 Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients Clopidogrel Standard Clopidogrel Double HR 0.85 95% CI 0.74-0.99 P=0.036 15% RRR CV Death, MI or Stroke

12 Clopidogrel Double vs Standard Dose Bleeding PCI Population Clopidogrel Standard N= 8684 Double N=8548 Hazard Ratio 95% CIP TIMI Major 1 0.5 1.060.70-1.610.79 CURRENT Major 2 1.11.61.441.11-1.860.006 CURRENT Severe 3 0.81.11.391.02-1.900.034 Fatal0.150.070.470.18-1.230.125 ICH0.0350.0461.350.30-6.040.69 RBC transfusion 2U 0.911.351.491.11-1.980.007 CABG-related Major0.1 1.690.61-4.70.31 1 ICH, Hb drop 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal 2 Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units 3 Fatal or Hb 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of 4 units

13 0.501.50 Overall NSTEMI/UA STEMI Male Female Age <= 65 yrs Age > 65 yrs Non-Diabetic Prev Diabetic No Inhosp GPIIb/IIIa GPIIb in hosp No Prot Pump Inhib Prot Pump Inhib Non-smoker Current Smoker ASA Low ASA High 17232 10886 6346 13009 4223 10975 6257 13400 3831 12288 4936 7675 5557 10845 6380 8620 8612 4.5 4.2 5.0 4.1 5.8 3.0 7.1 4.2 5.6 3.9 6.0 3.8 5.7 4.9 3.8 4.2 4.8 3.9 3.6 4.2 3.6 4.6 2.7 6.0 3.6 4.9 3.5 4.7 3.2 4.2 4.6 2.6 4.3 3.5 0.805 0.419 0.702 0.836 0.465 0.408 0.045 0.024 0.501.50 3.7 3.6 4.0 3.5 4.6 2.9 5.2 3.6 4.1 3.1 5.2 3.1 4.8 3.9 3.4 3.6 3.8 3.0 3.1 2.8 3.0 2.2 4.4 2.8 3.6 2.5 4.1 2.3 3.3 3.5 2.1 3.2 2.7 0.248 0.148 0.418 0.567 0.894 0.613 0.050 0.191 CV Death, MI or StrokeMI or Stent Thrombosis Clopidogrel: Double v Standard Dose PCI Cohort Subgroups Std %Double %Std %Double %Intxn P Double Dose Better Std Dose Better 2N

14 ClopidogrelHR95% CI PP intn StandardDouble CV Death/MI/Stroke (Overall) ASA High4.63.80.830.70-0.990.036 0.043 ASA Low4.24.51.070.91-1.270.42 MI/Stent Thrombosis (PCI pts) ASA High3.82.70.710.56-0.900.005 0.19 ASA Low3.63.20.890.71-1.120.32 Major Bleed (Overall) ASA High2.22.41.080.86-1.370.51 0.099 ASA Low1.92.71.431.13-1.810.003 Clopidogrel: Double vs Standard Dose by ASA Factorial

15 Definite Stent Thrombosis in 4 Groups (Angiographically Proven) Days Cumulative Hazard 0.0 0.004 0.008 0.012 036912151821242730 C Standard, A Low C Standard, A High C Double, A Low C Double, A High Standard Clop Double Clop HRP P Int n High ASA1.20.60.490.003 Low ASA1.20.80.60.0580.35

16 Conclusions Clopidogrel Dose Comparison 1.Double-dose clopidogrel significantly reduced stent thrombosis and major CV events (CV death, MI or stroke) in PCI. 2.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). 3.There was a modest excess in CURRENT-defined major bleeds but no difference in TIMI major bleeds, ICH, fatal bleeds or CABG-related bleeds.

17 Conclusions ASA Dose Comparison No significant difference in efficacy or bleeding between ASA 300-325 mg and ASA 75-100 mg.

18 Clinical Implications 1. 1.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 MIs and 7 stent thromboses with an excess of 3 severe bleeds and no increase in fatal, CABG-related or TIMI major bleeds. 2. 2.Patients not undergoing PCI should continue to use the standard dose regimen of clopidogrel.

19 Acknowledgements S. Yusuf (Chair) D. Foley P. Pais S.R. Mehta (P.I.) M.G. FranzosiR.J.G. Peters S. Chrolavicius C.B. GrangerL. Piegas A. AjaniM. GuptaJ. Probstfield A. AvezumS. JollyJ. Rankin J.P. BassandC. JoynerM. Ruda W.E. BodenN. KaratzasZ. Rumboldt A. BudajA. KastratiH.J. Rupprecht E. CardonaJ.H. KimP.G. Steg S. ChrolaviciusT.H. KohJ-F. Tanguay J. ColF. LanasV. Valentin P. CommerfordB. LewisJ. Varigos G. Di PasqualeC. MacayaH. White R. DiazT. MoccettiP. Widimsky J. EhaG. MontalescotD. Xavier J.W. EikelboomK. NiemelaJ. Zhu D.P. FaxonZ. OngenJ-R Zhu M. FlatherA. Orlandini P. Sleight (Chair) J.L. Anderson D.L. DeMets J. Hirsh D.R. Holmes Jr D.E. Johnstone S. Chrolavicius S.R. Mehta A. Robinson B. Jedrzejowski J. Pogue R. Afzal L. Blake W. Chen S. Di Diodato M. Lawrence R. Manojlovic L. Mastrangelo A. Mead E. Pasadyn T. Sovereign L. Wasala M. Blumenthal (Bristol-Myers Squibb) C. Gaudin (Sanofi-Aventis) C. Marchese (Sanofi- Aventis) P. Hornick (Bristol-Myers Squibb) C. Joyner (Chair) M. Lawrence (Coordinator) Steering Committee DSMB Adjudication Committee SponsorsProject Office Consultant: R. Peto CURRENT Investigators from 597 sites in 39 countries

20 Supplementary Slides

21 CURRENT PCI N=17,232 TRITON N=13,608 CV 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 BleedingNo increase 4-fold Fatal bleedingNo increase 4-fold Comparison of CURRENT and TRITON

22 22 Baseline Characteristics and In Hospital Meds Baseline N=25,088Meds After RandN=25,088 Age (y) 61.4GP IIb/IIIa inhibitor31.8 Female 27.4%Statin87.2 UA/NSTEMI 70.8%Beta Blocker82.5 Rand to Angio3.4 hACE/ARB75.7 STEMI29.2%PPI40* Rand to Angio0.5 hH2 Blocker11.3 Diabetes23.4 Prior Stroke4.1 Ischemic ECG Δ80.8 Biomarker42 Variables 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

23 Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 0.05 036912151821242730 C Std, A Lo C Std, A Hi C Double, A Lo C Double, A Hi Clop Standard Clop Double HRP P Int n ASA 300-325 mg4.63.80.830.036 0.043 ASA 75-100 mg4.24.51.070.43 Clopidogrel: Double vs Standard Dose Primary Outcome

24 ASA Dose Comparison Death/MI/Stroke at 30 days Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 036912151821242730 HR 0.96 (0.85- 1.08) P = 0.489 ASA 81-100 mg ASA 300-325 mg

25 ASA Dose Comparison Primary Outcome ASAHazardP 81-100 mg300-325 mg Ratio95% CIvalue % Primary Outcome CV Death/MI/Stroke4.44.20.960.85-1.080.489 Components CV Death2.32.00.880.74-1.040.134 MI2.12.00.970.82-1.150.726 Stroke0.50.61.180.84-1.670.330

26 Cumulative Hazard 0.0 0.005 0.015 0.025 036912151821242730 ASA Dose Comparison Death at 30 days HR 0.86 (0.73- 1.02) P = 0.077 ASA 81-100 mg ASA 300-325 mg

27 Secondary Outcomes (ASA) ASAHazardP < 100 mg> 300 mg Ratio95% CIvalue % CV Death/MI/Stroke + RI4.84.50.930.83-1.040.206 Total Death2.52.20.860.73-1.020.077 Stent Thrombosis1.41.30.900.73-1.120.347 Definite0.70.60.890.66-1.210.458 Probable0.80.70.900.67-1.200.471

28 Major Bleeding at 30 Days (ASA) ASAHazardP < 100 mg> 300 mgRatio95% CIvalue % All Major Bleeding2.3 0.990.84-1.170.904 Severe Bleeding1.7 1.000.83-1.211.000 Other Major Bleeding0.6 1.000.73-1.380.985 Minor Bleeding 4.44.91.121.00-1.250.059

29 ASA Dose Comparison Major Bleeding at 30 days Days Cumulative Hazard 0.0 0.005 0.010 0.015 0.020 036912151821242730 ASA < 100 mg ASA > 300 mg HR 0.99 (0.84-1.17) P = 0.904

30 Details of Major Bleeding ASA 81-100 mg 300-325 mg No. of Major Bleeds287283 Fatal1615 Symptomatic ICH56 Surgical Intervention4945 Significant hypotension (inotropes) 5658 Hemoglobin drop > 5 g/dL232240 Transfusions258255

31 Sites of Major Bleeding ASA 81-100 mg300-325 mg No. of Major Bleeds287283 Cardiac Tamponade2720 Surgical115107 Intracranial66 Retroperitoneal1114 Gastrointestinal3047* Puncture Site4046 *P=0.051

32 0.40.71.01.31.61.9 HR (95% CI) Primary Composite NSTEMI STEMI Non-Diabetic Prev Diabetic GRACE <140 GRACE >=140 Age <= 65 yrs Age > 65 yrs No Prot Pump Inhib Prot Pump Inhib Weight >= 60kg Weight < 60kg Non-smoker Current Smoker No PCI With PCI 2N 25087 17757 7321 19196 5870 13394 3516 15762 9316 15193 3204 22504 2358 16688 8369 7855 17232 81- 100 mg 4.4 4.2 4.8 4.0 5.6 3.0 8.3 3.1 6.6 4.3 4.2 4.1 5.7 4.9 3.3 4.7 4.2 300-325 mg 4.2 3.9 5.0 3.8 5.6 2.8 7.1 2.7 6.8 4.2 4.6 4.1 4.7 3.1 4.4 4.1 P interaction 0.446 0.585 0.575 0.145 0.483 0.339 0.977 0.724 ASA Dose Comparison: Subgroups


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