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:
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.
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 ( mg) versus low (75-100) dose aspirin in patients with ACS undergoing PCI
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): Fox KAA, et al. Circulation 2004;110: Sabatine MS, et al. JAMA 2005; 294(10): Chen ZM Lancet 2005;366: Boersma E et al. Lancet 2002; 359: Wiviott S et al. N Engl J Med 2007; 357: 2001–15.
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 ( mg/d) vs Low dose ( 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:
ASA Dose Comparison Primary Outcome and Bleeding ASA mg ASA mg HR95% CIP CV Death/MI/Stroke PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087) Stent Thrombosis TIMI Major Bleed CURRENT Major Bleed CURRENT Severe Bleed No other significant differences between ASA dose groups GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051
Clopidogrel Dose Comparison 2 Significant Interactions: 1. PCI v No PCI (P=0.016) 2. ASA dose (P=0.043)
Clopidogrel: Double vs Standard Dose Primary Outcome and Components StandardDoubleHR95% CIPIntn P CV Death/MI/Stroke PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087) MI PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087) CV Death PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087) Stroke PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087)
Clopidogrel Double vs Standard Dose Bleeding Overall Population Clopidogrel Standard N=12579 Double N=12508 Hazard Ratio 95% CIP TIMI Major CURRENT Major CURRENT Severe Fatal ICH RBC transfusion 2U CABG-related Major 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
Days Cumulative Hazard Clopidogrel Standard Dose Clopidogrel Double Dose 42% RRR HR % CI P=0.001 Clopidogrel: Double vs Standard Dose Definite Stent Thrombosis (Angio confirmed)
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 Definite Definite MI MI or stent thrombosis CV Death Stroke CV Death/MI/Stroke
Days Cumulative Hazard Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients Clopidogrel Standard Clopidogrel Double HR % CI P= % RRR CV Death, MI or Stroke
Clopidogrel Double vs Standard Dose Bleeding PCI Population Clopidogrel Standard N= 8684 Double N=8548 Hazard Ratio 95% CIP TIMI Major CURRENT Major CURRENT Severe Fatal ICH RBC transfusion 2U CABG-related Major 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
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 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
ClopidogrelHR95% CI PP intn StandardDouble CV Death/MI/Stroke (Overall) ASA High ASA Low MI/Stent Thrombosis (PCI pts) ASA High ASA Low Major Bleed (Overall) ASA High ASA Low Clopidogrel: Double vs Standard Dose by ASA Factorial
Definite Stent Thrombosis in 4 Groups (Angiographically Proven) Days Cumulative Hazard 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 ASA Low ASA
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.
Conclusions ASA Dose Comparison No significant difference in efficacy or bleeding between ASA mg and ASA mg.
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 Patients not undergoing PCI should continue to use the standard dose regimen of clopidogrel.
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
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 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
Days Cumulative Hazard 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 mg ASA mg Clopidogrel: Double vs Standard Dose Primary Outcome
ASA Dose Comparison Death/MI/Stroke at 30 days Days Cumulative Hazard HR 0.96 ( ) P = ASA mg ASA mg