1. Antiplatelet Controversies: Clopidogrel Dose Following OASIS-7 (CURRENT)
Robert A. Harrington, MD
Professor of Medicine
Director, Duke Clinical Research Institute
Duke University Medical Center

2. Robert A. Harrington, MD DISCLOSURES Consulting Fees
AstraZeneca, Novartis, Portola Pharmaceuticals, Inc., Schering-Plough Corp./Merck & Co., Inc.
Grants/Contracted Research
AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, The Medicines Company, Portola Pharmaceuticals, Inc., Schering-Plough Corp./ Merck & Co., Inc.
Honoraria
The Medicines Company supported Theheart.org program
I intend to reference unlabeled/ unapproved uses of drugs or devices in my presentation.
I intend to reference antiplatelet agents and therapy, guidelines for ACS & AMI, STEMI timing for treatment and other general discussion of clinical trials in ACS and AMI management.

3. Conflict of Interest Reporting: Relationships with Industry Relevant to Presentation
Research grants/contracts with DCRI
Sanofi Aventis; Lilly; Daiichi-Sankyo; BMS; Astra Zeneca; Portola; Novartis
Consulting
BMS; Astra Zeneca; Portola; Novartis
Full industry relationship disclosure
Chairperson of ACC Science and Clinical Policy Committee (oversees policy for ACC documents)

4. Should We Change Clopidogrel Dosing Following OASIS-7 (CURRENT)?
A quick overview of clopidogrel
Variability in response to clopidogrel
OASIS-7 key findings
An interpretation of the totality of the data

5. Clopidogrel: An Overview of Use in CV Disease
Clopidogrel is an excellent drug
Well studied in large RCTs; benefits and risks have been carefully quantified
ACS (NSTE and STE MI); PCI (stents); chronic vascular disease (for some); AF (when no oral VKA)
Long and extensive clinical experience
Class I Guideline recommendations
Clopidogrel has well known limitations
Rapidity, predictability and variability of effect
Genetic and drug interactions

6. Variability in Individual Clopidogrel Response
Hochholzer Circulation. 2005;111:

7. Variability in Clopidogrel Responsiveness in a Diverse Population of 544
Serebruany VL, et al. JACC 2005; 45:246 –51.

8. Clopidogrel Response and Clinical Outcomes
New
797 patients undergoing PCI
1-year f/u
ADP-induced (5 µM) platelet aggregation (RPA) was assessed after 600 mg load/ 75 mg a day of clopidogrel
Pre-discharge RPA >14% was associated with a hazard ratio for death and MI of 3.0 (95% CI: ; P=0.004)
Trenk.J Am Coll Cardiol.May.2008/p1925/ lines A7-A9, p1926/c1/lines 52-54
RPA >14% 8
Trenk.J Am Coll Cardiol.May.2008/ p1932/c1/figure 3
RPA ≤14% 6
Log-rank P=0.004
Trenk.J Am Coll Cardiol.May.2008/p1929/c1/ lines 44-50
Death or MI (%) 4
Trenk.J Am Coll Cardiol.May.2008/p1930/c1/ lines 27-33 2
120
240
360
Trenk and colleagues examined 797 patients from the EXCELSIOR cohort undergoing PCI to determine whether the loss-of-function CYP2C19 681G>A *2 polymorphism was associated with high residual platelet aggregation while being treated with clopidogrel. In the study, ADP-induced residual platelet aggregation (RPA) was assessed after a 600 mg loading dose and the first 75 mg maintenance dose of clopidogrel before discharge. Patients were followed for 1 year.
Carriers of the 2C19*2 allele were significantly more likely than wild type individuals to have an RPA >14% (defined as high on-treatment platelet reactivity).
Predischarge RPA >14% was associated with a hazard ratio for death and MI of 3.0 (95% CI: ; P=0.004)
Trenk.J Am Coll Cardiol.May.2008/p1925/ lines A1-A3, p1926/c1/lines
Days after PCI
No. at risk RPA >14%
RPA ≤14%
Trenk.J Am Coll Cardiol.May.2008/p1929/c1/lines
Trenk.J Am Coll Cardiol.May.2008/p1930/c1/ lines 27-33
-Trenk D et al. JACC. 2008;51:1925
Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol. 2008;51: 8

9. Increasing the Dose May Influence Response3 6 9 12 15 18 21 24 27 30 33
<-30
(-30,-20]
(-20,-10]
(-10,0]
(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
(60,70]
>70
Post Treatment Platelet Reactivity
5 µM ADP-induced Platelet Aggregation at 24 hours
Patients (%)
Resistance = 28% (300 mg)
Resistance = 8% (600 mg)
300 mg Clopidogrel
600 mg Clopidogrel
N = 194
Clopidogrel nonresponsiveness, or decreased platelet inhibition to clopidogrel treatment, may in part be overcome with a higher dose of clopidogrel.
Gurbel P J Am Coll Cardiol. 2005;45:1392 9

10. Clopidogrel: Pro-drug to Active Metabolite Formation
Esterases (1o Hepatic)
Clopidogrel N S Cl
COOCH3
Inactive Metabolites
carboxylic acid derivative
(85% of ingested clopidogrel)
CH3 O N S Cl C
2-oxo Compound
CYP 1A2
CYP 2B6
CYP 2C19
1o Hepatic
Metabolism
Active Metabolite
HOOC
* HS N O Cl
OCH3
CYP 3A4
CYP 2C9
CYP 2C19
CYP 2B6
1o Hepatic
Metabolism

11. Determinants of Active Metabolite Formation
Cytochrome P450 2C19
*1  normal function
*2 loss of function (25% of European, 30% African, 50% Asian)
*3 - *7  rare, loss of function
Clopidogrel AM vs. genotype after 300mg single dose
ADP LTA vs. genotype with 75mg daily dosing, similar results seen in ACS patients, smaller but continued effect seen with 300mg loading doses (will review dose response later with genotypes later)
Brandt et al, J Thromb Haemost. 2007,
5(12):
Hulot et al, Blood, 2006, 108(7),

12. Meta-Analysis of Studies of CYP2C19 Variants and Outcome in Pts on Clopidogrel
Carriers vs Non-Carriers
Heterozygotes vs WT
Homozygotes vs WT
Major Adverse CV Events
Stent Thrombosis
Risk Ratio (95% Cl) P Value
1.61 ( ) <0.001
1.5 ( )
1.81 ( )
2.76 ( ) <0.001
2.51 ( ) <0.001
4.78 ( ) <0.001
Risk Lower with CYP2C19 Variant
Risk Higher with CYP2C19 Variant
0.5
1.0
15.0
Nine studies of association of CYP2C19 reduced-function genetic variants with MACE in pts treated with clopidogrel (N=9,684 subjects)
Mega JL et al. Circulation. 2009;120:S598-S599

13. Influence of Dosing in Carriers
Gladding JACC Cardiovasc Interv. 2008;1:620-7

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%)
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 3,616
CABG 1,809
CAD 2,430
Compliance:
Clop in 1st 7d (median) 7d d d 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

16. Clopidogrel: Double vs Standard Dose Primary Outcome16
Clopidogrel: Double vs Standard Dose Primary Outcome
0.05
C Std, A Hi
C Double, A Lo
C Std, A Lo
0.04
C Double, A Hi
0.03
Cumulative Hazard
0.02
Clop Standard
Clop Double HR P
Intn
ASA mg
4.6
3.8
0.83
0.036
0.043
ASA mg
4.2
4.5
1.07
0.43
0.01
0.0 3 6 9 12 15 18 21 24 27 30
Days

17. ASA Dose Comparison Primary Outcome and Bleedingmg mg HR
95% CI P
CV Death/MI/Stroke
PCI (2N=17,232)
4.2
4.1
0.98
0.76
No PCI (2N=7855)
4.7
4.4
0.92
0.44
Overall (2N=25,087)
0.96
0.47
Stent Thrombosis
2.1
1.9
0.91
0.37
TIMI Major Bleed
1.03
0.97
0.94
0.71
CURRENT Major Bleed
2.3
0.99
0.90
CURRENT Severe Bleed
1.7
1.00
GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051
No other significant differences between ASA dose groups

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

19. Clopidogrel: Double vs Standard Dose Primary Outcome and ComponentsHR
95% CI P
Intn P
CV Death/MI/Stroke
PCI (2N=17,232)
4.5
3.9
0.85
0.036
0.016
No PCI (2N=7855)
4.2
4.9
1.17
0.14
Overall (2N=25,087)
4.4
0.95
0.370 MI
2.6
2.0
0.78
0.012
0.025
1.4
1.7
1.25
0.23
2.2
1.9
0.86
0.097
CV Death
0.96
0.68
1.0
2.8
2.7
0.77
2.1
0.628
Stroke
0.4
0.88
0.59
0.50
0.8
0.9
1.11
0.67
0.5
0.99
0.950

20. Efficacy Outcomes: PCI Patients20
Efficacy Outcomes: PCI Patients
CV Death, MI, Stroke
Definite Stent Thrombosis
Clopidogrel Standard
Clopidogrel Standard
15% RRR
0.012
0.04
42%
RRR
Clopidogrel Double
0.03
0.008
Cumulative Hazard
Cumulative Hazard
Clopidogrel Double
0.02
HR 0.85
95% CI
P=0.036
0.004
HR 0.58
95% CI
P=0.001
0.01
0.0
0.0 3 6 9 12 15 18 21 24 27 30 3 6 9 12 15 18 21 24 27 30
Days
Days

21. Clopidogrel Double vs Standard Dose Bleeding PCI Population
Hazard
Ratio
95% CI P
TIMI Major1
0.5
1.06
0.79
CURRENT Major2
1.1
1.6
1.44
0.006
CURRENT Severe3
0.8
1.39
0.034
Fatal
0.15
0.07
0.47
0.125
ICH
0.035
0.046
1.35
0.69
RBC transfusion ≥ 2U
0.91
1.49
0.007
CABG-related Major
0.1
1.69
0.31
1ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal
2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units
3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

22. Definite Stent Thrombosis in 4 Groups (Angiographically Proven)
C Standard, A Low
0.012
C Standard, A High
C Double, A Low
0.008
Cumulative Hazard
C Double, A High
0.004
Standard Clop
Double Clop HR P
Intn
High ASA
1.2
0.6
0.49
0.003
Low ASA
0.8
0.058
0.35
0.0 3 6 9 12 15 18 21 24 27 30
Days

23. PCI Patients: CV Death, MI or Stroke23
PCI Patients: CV Death, MI or Stroke 2N
Std Dose %
Double Dose %
Hazard Ratio
95% CI
All PCI
17,232
4.5
3.9
P=0.036
UA/NSTEMI
10,886
4.2
3.6
Interaction P=0.81
STEMI
6,346
5.0
4.2
0.50
1.50
Double Dose Better
Std Dose Better