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

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.

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 http://www.dcri.duke.edu/research/coi.jsp Chairperson of ACC Science and Clinical Policy Committee (oversees policy for ACC documents)

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

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

Variability in Individual Clopidogrel Response Hochholzer Circulation. 2005;111:2560-2564.

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

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: 1.4-6.8; 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: 1.4-6.8; P=0.004) Trenk.J Am Coll Cardiol.May.2008/p1925/ lines A1-A3, p1926/c1/lines 52-54 Days after PCI No. at risk RPA >14% RPA ≤14% 217 548 211 540 205 537 200 520 Trenk.J Am Coll Cardiol.May.2008/p1929/c1/lines 44-50 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;51:1925-1934. 8

Increasing the Dose May Influence Response 3 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

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

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):2429-36 Hulot et al, Blood, 2006, 108(7), 2244-2247.

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 (1.28-2.02) <0.001 1.5 (1.08-2.08) 0.016 1.81 (1.21-2.71) 0.004 2.76 (1.77-4.30) <0.001 2.51 (1.59-3.98) <0.001 4.78 (2.01-11.39) <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

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

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 (300-325 mg/d) vs Low dose (75-100 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 7 d 2 d 7d 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

Clopidogrel: Double vs Standard Dose Primary Outcome 16 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 300-325 mg 4.6 3.8 0.83 0.036 0.043 ASA 75-100 mg 4.2 4.5 1.07 0.43 0.01 0.0 3 6 9 12 15 18 21 24 27 30 Days

ASA Dose Comparison Primary Outcome and Bleeding 75-100 mg 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) 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 0.99 0.84-1.17 0.90 CURRENT Severe Bleed 1.7 1.00 0.83-1.21 GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051 No other significant differences between ASA dose groups

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

Clopidogrel: Double vs Standard Dose Primary Outcome and Components HR 95% CI P Intn P CV Death/MI/Stroke PCI (2N=17,232) 4.5 3.9 0.85 0.74-0.99 0.036 0.016 No PCI (2N=7855) 4.2 4.9 1.17 0.95-1.44 0.14 Overall (2N=25,087) 4.4 0.95 0.84-1.07 0.370 MI 2.6 2.0 0.78 0.64-0.95 0.012 0.025 1.4 1.7 1.25 0.87-1.79 0.23 2.2 1.9 0.86 0.73-1.03 0.097 CV Death 0.96 0.77-1.19 0.68 1.0 2.8 2.7 0.74-1.26 0.77 2.1 0.81-1.14 0.628 Stroke 0.4 0.88 0.55-1.41 0.59 0.50 0.8 0.9 1.11 0.68-1.82 0.67 0.5 0.99 0.70-1.39 0.950

Efficacy Outcomes: PCI Patients 20 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 0.74-0.99 P=0.036 0.004 HR 0.58 95% CI 0.42-0.79 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

Clopidogrel Double vs Standard Dose Bleeding PCI Population Hazard Ratio 95% CI P TIMI Major1 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 1.39 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 1.49 1.11-1.98 0.007 CABG-related Major 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 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

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

PCI Patients: CV Death, MI or Stroke 23 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