CURRENT OASIS 7: A 2X2 Factorial Randomized Trial of Optimal Clopidogrel and Aspirin Dosing in Patients with ACS Undergoing an Early Invasive Strategy.
Post on 26-Mar-2015
229 Views
Preview:
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
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 InvestigatorsShamir 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.
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 RCT’s have compared high (300-325 mg) versus low (75-100) dose aspirin in patients with ACS undergoing PCI
Relative Risk Reduction
PCI No PCI
CURE: Clopidogrel 300/75 mg v Placebo (CVD/MI)CURE: Clopidogrel 300/75 mg v Placebo (CVD/MI) 30%30%11 1919%%22
STEMI: Clopidogrel 300/75 mg v Placebo (CVD/MI)STEMI: Clopidogrel 300/75 mg v Placebo (CVD/MI) 46%46%33 9%9%44
TRITON: Prasugrel v clopidogrel 300/75mg TRITON: Prasugrel v clopidogrel 300/75mg (CVD/MI/Stroke)(CVD/MI/Stroke)
19%19%55 Not evaluatedNot 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;110:1202-83. Sabatine MS, et al. JAMA 2005; 294(10):1224-32.4. Chen ZM Lancet 2005;366:1607-214. Boersma E et al. Lancet 2002; 359:1895. 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 PCIIschemic 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 PCIIschemic 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 3,616 CABG 1,809 CAD 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 30Stent Thrombosis at day 30
Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCI
Efficacy Outcomes: CV Death, MI or stroke at day 30Stent 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%
Complete Followup
99.8%
Compliance:Compliance:
ASA Dose ComparisonPrimary Outcome and Bleeding
ASA
75-100 mg
ASA
300-325 mg
HR 95% CI P
CV Death/MI/Stroke
PCI (2N=17,232) 4.2 4.1 0.98 0.84-1.13 0.76
No PCI (2N=7855) 4.7 4.4 0.92 0.75-1.14 0.44
Overall (2N=25,087) 4.4 4.2 0.96 0.85-1.08 0.47
Stent Thrombosis 2.1 1.9 0.91 0.73-1.12 0.37
TIMI Major Bleed 1.03 0.97 0.94 0.73-1.21 0.71
CURRENT Major Bleed 2.3 2.3 0.99 0.84-1.17 0.90
CURRENT Severe Bleed 1.7 1.7 1.00 0.83-1.21 1.00
No other significant differences between ASA dose groupsNo other significant differences between ASA dose groups
GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051GI 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 DosePrimary Outcome and Components
Standard Double HR 95% CI P Intn P
CV Death/MI/Stroke
PCI (2N=17,232) 4.5 3.9 0.85 0.74-0.99 0.0360.016
No PCI (2N=7855) 4.2 4.9 1.17 0.95-1.44 0.14
Overall (2N=25,087) 4.4 4.2 0.95 0.84-1.07 0.370
MI
PCI (2N=17,232) 2.6 2.0 0.78 0.64-0.95 0.0120.025
No PCI (2N=7855) 1.4 1.7 1.25 0.87-1.79 0.23
Overall (2N=25,087) 2.2 1.9 0.86 0.73-1.03 0.097
CV Death
PCI (2N=17,232) 1.9 1.9 0.96 0.77-1.19 0.681.0
No PCI (2N=7855) 2.8 2.7 0.96 0.74-1.26 0.77
Overall (2N=25,087) 2.2 2.1 0.96 0.81-1.14 0.628
Stroke
PCI (2N=17,232) 0.4 0.4 0.88 0.55-1.41 0.590.50
No PCI (2N=7855) 0.8 0.9 1.11 0.68-1.82 0.67
Overall (2N=25,087) 0.5 0.5 0.99 0.70-1.39 0.950
Clopidogrel Double vs Standard DoseBleeding Overall Population
Clopidogrel
Standard
N=12579
Double
N=12508
Hazard
Ratio
95% CI P
TIMI Major1 0.95 1.04 1.09 0.85-1.40 0.50
CURRENT Major2 2.0 2.5 1.25 1.05-1.47 0.01
CURRENT Severe3 1.5 1.9 1.23 1.02-1.49 0.03
Fatal 0.11 0.13 1.15 0.56-2.35 0.71
ICH 0.05 0.03 0.67 0.19-2.37 0.53
RBC transfusion ≥ 2U 1.76 2.21 1.26 1.06-1.51 0.01
CABG-related Major 0.9 1.0 1.10 0.85-1.42 0.48
1ICH, 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
1ICH, 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
Days
Cu
mu
lati
ve H
azar
d
0.0
0.00
40.
008
0.01
2
0 3 6 9 12 15 18 21 24 27 30
Clopidogrel Standard Dose
Clopidogrel Double Dose
42% RRR
HR 0.5895% CI 0.42-0.79
P=0.001
Clopidogrel: Double vs Standard DoseDefinite Stent Thrombosis (Angio confirmed)
Clopidogrel: Double vs Standard DoseMajor Efficacy Outcomes in PCI Patients
Day 30 Clopidogrel
StandardN=8684
%
Double N=8548
%
Hazard Ratio
95% CI P value
Stent ThrombosisStent Thrombosis 2.32.3 1.61.6 0.710.71 0.57-0.890.57-0.89 0.0020.002
DefiniteDefinite 1.21.2 0.70.7 0.580.58 0.42-0.790.42-0.79 0.0010.001
MIMI 2.62.6 2.02.0 0.780.78 0.64-0.950.64-0.95 0.0120.012
MI or stent thrombosisMI or stent thrombosis 3.73.7 3.03.0 0.800.80 0.68-0.940.68-0.94 0.0080.008
CV DeathCV Death 1.91.9 1.91.9 0.960.96 0.77-1.190.77-1.19 0.680.68
StrokeStroke 0.40.4 0.40.4 0.880.88 0.55-1.410.55-1.41 0.590.59
CV Death/MI/StrokeCV Death/MI/Stroke 4.54.5 3.93.9 0.850.85 0.74-0.990.74-0.99 0.0360.036
Days
Cu
mu
lati
ve H
azar
d
0.0
0.01
0.02
0.03
0.04
0 3 6 9 12 15 18 21 24 27 30
Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients
Clopidogrel Standard
Clopidogrel Double
HR 0.8595% CI 0.74-0.99
P=0.036
15% RRR15% RRR
CV Death, MI or StrokeCV Death, MI or Stroke
Clopidogrel Double vs Standard DoseBleeding PCI Population
Clopidogrel
Standard
N= 8684
Double
N=8548
Hazard
Ratio
95% CI P
TIMI Major1 0.5 0.5 1.06 0.70-1.61 0.79
CURRENT Major2 1.1 1.6 1.44 1.11-1.86 0.006
CURRENT Severe3 0.8 1.1 1.39 1.02-1.90 0.034
Fatal 0.15 0.07 0.47 0.18-1.23 0.125
ICH 0.035 0.046 1.35 0.30-6.04 0.69
RBC transfusion ≥ 2U 0.91 1.35 1.49 1.11-1.98 0.007
CABG-related Major 0.1 0.1 1.69 0.61-4.7 0.31
1ICH, 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
1ICH, 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
0.50 1.50
Overall
NSTEMI/UA STEMI
MaleFemale
Age <= 65 yrsAge > 65 yrs
Non-DiabeticPrev Diabetic
No Inhosp GPIIb/IIIaGPIIb in hosp
No Prot Pump InhibProt Pump Inhib
Non-smokerCurrent Smoker
ASA LowASA High
17232
10886 6346
13009 4223
10975 6257
13400 3831
12288 4936
7675 5557
10845 6380
8620 8612
4.5
4.25.0
4.15.8
3.07.1
4.25.6
3.96.0
3.85.7
4.93.8
4.24.8
3.9
3.64.2
3.64.6
2.76.0
3.64.9
3.54.7
3.24.2
4.62.6
4.33.5
0.805
0.419
0.702
0.836
0.465
0.408
0.045
0.024
0.50 1.50
3.7
3.64.0
3.54.6
2.95.2
3.64.1
3.15.2
3.14.8
3.93.4
3.63.8
3.0
3.12.8
3.03.0
2.24.4
2.83.6
2.54.1
2.33.3
3.52.1
3.22.7
0.248
0.148
0.418
0.567
0.894
0.613
0.050
0.191
CV Death, MI or StrokeCV Death, MI or Stroke MI or Stent ThrombosisMI or Stent Thrombosis
Clopidogrel: Double v Standard DosePCI Cohort Subgroups
Std %Std % Double %Double % Std %Std % Double %Double %Intxn PIntxn P Intxn PIntxn P
Double Dose Better
Double Dose Better
Double Dose Better
Double Dose Better
Std Dose Better
Std Dose Better
Std Dose Better
Std Dose Better
2N2N
Clopidogrel HR 95% CI P P int’n
Standard Double
CV Death/MI/Stroke (Overall)
ASA High 4.6 3.8 0.83 0.70-0.99 0.0360.043ASA Low 4.2 4.5 1.07 0.91-1.27 0.42
MI/Stent Thrombosis (PCI pts)
ASA High 3.8 2.7 0.71 0.56-0.90 0.005 0.19
ASA Low 3.6 3.2 0.89 0.71-1.12 0.32
Major Bleed (Overall)
ASA High 2.2 2.4 1.08 0.86-1.37 0.510.099
ASA Low 1.9 2.7 1.43 1.13-1.81 0.003
Clopidogrel: Double vs Standard Dose by ASA Factorial
Definite Stent Thrombosis in 4 Groups (Angiographically Proven)
Days
Cu
mu
lati
ve H
azar
d
0.0
0.00
40.
008
0.01
2
0 3 6 9 12 15 18 21 24 27 30
C Standard, A Low
C Standard, A High
C Double, A Low
C Double, A High
Standard Clop
Double Clop
HR PP
Intn
High ASA 1.2 0.6 0.49 0.003
Low ASA 1.2 0.8 0.6 0.058 0.35
ConclusionsClopidogrel Dose Comparison
1.1. Double-dose clopidogrel significantly reduced stent Double-dose clopidogrel significantly reduced stent thrombosis and major CV events (CV death, MI or stroke) thrombosis and major CV events (CV death, MI or stroke) in PCI.in PCI.
2.2. In patients not undergoing PCI, double dose clopidogrel In patients not undergoing PCI, double dose clopidogrel was not significantly different from standard dose (70% had was not significantly different from standard dose (70% had no significant CAD or stopped study drug early for CABG).no significant CAD or stopped study drug early for CABG).
3.3. There was a modest excess in CURRENT-defined major There was a modest excess in CURRENT-defined major bleeds but no difference in TIMI major bleeds, ICH, fatal bleeds but no difference in TIMI major bleeds, ICH, fatal bleeds or CABG-related bleeds.bleeds or CABG-related bleeds.
ConclusionsASA Dose Comparison
No significant difference in efficacy or No significant difference in efficacy or bleeding between ASA 300-325 mg and bleeding between ASA 300-325 mg and ASA 75-100 mg.ASA 75-100 mg.
Clinical Implications
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 MI’s and 7 stent thromboses with an excess of 3 severe bleeds and no increase in fatal, CABG-related or TIMI major bleeds.
2. 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. Franzosi R.J.G. Peters
S. Chrolavicius C.B. Granger L. Piegas
A. Ajani M. Gupta J. Probstfield A. Avezum S. Jolly J. RankinJ.P. Bassand C. Joyner M. Ruda W.E. Boden N. Karatzas Z. Rumboldt A. Budaj A. Kastrati H.J. RupprechtE. Cardona J.H. Kim P.G. Steg S. Chrolavicius T.H. Koh J-F. Tanguay J. Col F. Lanas V. Valentin P. Commerford B. Lewis J. Varigos G. Di Pasquale C. Macaya H. WhiteR. Diaz T. Moccetti P. WidimskyJ. Eha G. Montalescot D. Xavier J.W. Eikelboom K. Niemela J. Zhu D.P. Faxon Z. Ongen J-R Zhu M. Flather A. Orlandini
P. Sleight (Chair)J.L. AndersonD.L. DeMetsJ. HirshD.R. Holmes JrD.E. Johnstone
S. ChrolaviciusS.R. MehtaA. RobinsonB. Jedrzejowski J. PogueR. AfzalL. BlakeW. Chen S. Di DiodatoM. LawrenceR. ManojlovicL. MastrangeloA. MeadE. PasadynT. SovereignL. 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
Sponsors Project Office
Consultant: R. Peto
CURRENT Investigators from 597 sites in 39 countries
Supplementary Slides
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 Bleed No increase ↑ 32%
CABG-related Bleeding No increase ↑ 4-fold
Fatal bleeding No increase ↑ 4-fold
Comparison of CURRENT and TRITON
22
Baseline Characteristics and In Hospital Meds
Baseline N=25,088 Meds After Rand N=25,088
Age (y) 61.4 GP IIb/IIIa inhibitor 31.8
Female 27.4% Statin 87.2
UA/NSTEMI 70.8% Beta Blocker 82.5
Rand to Angio 3.4 h ACE/ARB 75.7
STEMI 29.2% PPI 40*
Rand to Angio 0.5 h H2 Blocker 11.3
Diabetes 23.4
Prior Stroke 4.1
Ischemic ECG Δ 80.8
↑ Biomarker 42
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
Cu
mu
lati
ve H
azar
d
0.0
0.01
0.02
0.03
0.04
0.05
0 3 6 9 12 15 18 21 24 27 30
C Std, A Lo
C Std, A Hi
C Double, A Lo
C Double, A Hi
Clop Standard
Clop Double
HR PP
Intn
ASA 300-325 mg 4.6 3.8 0.83 0.0360.043
ASA 75-100 mg 4.2 4.5 1.07 0.43
Clopidogrel: Double vs Standard Dose Primary Outcome
ASA Dose Comparison Death/MI/Stroke at 30 days
Days
Cu
mu
lati
ve H
azar
d
0.0
0.01
0.02
0.03
0.04
0 3 6 9 12 15 18 21 24 27 30
HR 0.96 (0.85-HR 0.96 (0.85-1.08)1.08)
P = 0.489P = 0.489
HR 0.96 (0.85-HR 0.96 (0.85-1.08)1.08)
P = 0.489P = 0.489
ASA 81-100 mgASA 300-325 mg
ASA Dose ComparisonPrimary Outcome
ASA Hazard P
81-100 mg 300-325 mg Ratio 95% CI value
% %
Primary Outcome
CV Death/MI/Stroke 4.4 4.2 0.96 0.85-1.08 0.489
Components
CV Death 2.3 2.0 0.88 0.74-1.04 0.134
MI 2.1 2.0 0.97 0.82-1.15 0.726
Stroke 0.5 0.6 1.18 0.84-1.67 0.330
Cu
mu
lati
ve H
azar
d
0.0
0.00
50.
015
0.02
5
0 3 6 9 12 15 18 21 24 27 30
ASA Dose ComparisonDeath at 30 days
HR 0.86 (0.73-HR 0.86 (0.73-1.02)1.02)
P = 0.077P = 0.077
HR 0.86 (0.73-HR 0.86 (0.73-1.02)1.02)
P = 0.077P = 0.077
ASA 81-100 mgASA 300-325 mg
Secondary Outcomes (ASA)
ASA Hazard P
< 100 mg > 300 mg Ratio 95% CI value
% %
CV Death/MI/Stroke + RI 4.8 4.5 0.93 0.83-1.04 0.206
Total Death 2.5 2.2 0.86 0.73-1.02 0.077
Stent Thrombosis 1.4 1.3 0.90 0.73-1.12 0.347
Definite 0.7 0.6 0.89 0.66-1.21 0.458
Probable 0.8 0.7 0.90 0.67-1.20 0.471
Major Bleeding at 30 Days (ASA)
ASA Hazard P
< 100 mg > 300 mg Ratio 95% CI value% %
All Major Bleeding 2.3 2.3 0.99 0.84-1.17 0.904
Severe Bleeding 1.7 1.7 1.00 0.83-1.21 1.000
Other Major Bleeding 0.6 0.6 1.00 0.73-1.38 0.985
Minor Bleeding 4.4 4.9 1.12 1.00-1.25 0.059
ASA Dose ComparisonMajor Bleeding at 30 days
Days
Cu
mu
lati
ve H
azar
d
0.0
0.00
50.
010
0.01
50.
020
0 3 6 9 12 15 18 21 24 27 30
ASA < 100 mgASA > 300 mg
HR 0.99 (0.84-1.17)HR 0.99 (0.84-1.17)P = 0.904P = 0.904
HR 0.99 (0.84-1.17)HR 0.99 (0.84-1.17)P = 0.904P = 0.904
Details of Major Bleeding
ASA
81-100 mg
300-325 mg
No. of Major Bleeds 287 283
Fatal 16 15
Symptomatic ICH 5 6
Surgical Intervention 49 45
Significant hypotension (inotropes)
56 58
Hemoglobin drop > 5 g/dL 232 240
Transfusions 258 255
Sites of Major Bleeding
ASA
81-100 mg 300-325 mg
No. of Major Bleeds 287 283
Cardiac Tamponade 27 20
Surgical 115 107
Intracranial 6 6
Retroperitoneal 11 14
Gastrointestinal 30 47*
Puncture Site 40 46
*P=0.051
top related