Insight into the Gauging Responsiveness with A VerifyNow Assay - Impact on Thrombosis And Safety (GRAVITS) Trial Peter Berger, MD Director, Center for Clinical Studies Interventional Cardiologist Geisinger Clinic CRT Feb. 2011

Potential Conflicts of Interest Consultant to Boehringer Ingelheim, Eli Lilly/Daiichi-Sankyo, AstraZeneca (each for less than $10,000). Executive Steering Committee for the GRAVITAS trial for Acumetrics (Unpaid). Equity in Lumen, Inc. (greater than $10,000). Research funding to institution for which I am the PI: Thrombovision, Helena, Accumetrics, AstraZeneca, Haemoscope, The Medicines Company, Corgenix/Aspirinworks, Lilly/Daiichi-Sankyo (each for more than $10,000).

Point-of-Care Platelet Function Testing Current Status At least 7 studies involving more than 3,000 patients reveal that high residual (on- clopidogrel) platelet reactivity measured by the VerifyNow P2Y12 test is associated with poor clinical outcomes after PCI. A treatment strategy for patients with high residual platelet reactivity has not been tested in a large, randomized, clinical trial. 3

GRAVITAS: Primary Hypothesis High-dose clopidogrel for 6 months is superior to standard-dose clopidogrel for the prevention of adverse CV events after PCI in patients with high residual reactivity. 4

GRAVITAS Study Design R Elective or Urgent PCI with DES* VerifyNow P2Y12 Test 12-24 hours post-PCI PRU ≥ 230 R High-Dose Clopidogrel† clopidogrel 600-mg, then clopidogrel 150-mg daily X 6 months Standard-Dose Clopidogrel† clopidogrel 75-mg daily X 6 months Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 mo Key Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo Pharmacodynamics: Repeat VerifyNow P2Y12 at 1 and 6 months *Peri-PCI clopidogrel protocol-mandated to ensure steady-state at 12-24 hrs †Placebo-controlled All patients received aspirin (81-162mg daily) 5

GRAVITAS Study Design Was GRAVITAS really designed to answer the question of whether platelet function testing provides clinically useful information? Not ideally. Couldn’t the study have been positive because 150 mg outperformed 75 in all pts regardless of responsiveness on the VerifyNow? Yes it could have been. A positive study would not necessarily have proven the role of platelet function testing. 6

DES for the treatment of stable or unstable CAD* Inclusion and Exclusion Criteria DES for the treatment of stable or unstable CAD* Major Inclusion Criteria Major Exclusion Criteria Bleeding event or other major complication prior to platelet function testing Recent glycoprotein IIb/IIIa inhibitor * STEMI pts permitted after a protocol modification during the trial 7

50% risk reduction with high-dose clopidogrel* Power Analysis: Sample Size Estimate Assumptions: An event rate of 5% in patients on standard-dose clopidogrel at 6-months 50% risk reduction with high-dose clopidogrel* 2200 patients needed to provide 80% power at a two-sided 0.05 significance level 8

GRAVITAS Sample Size Estimate Why was a 5% 6 mo event rate anticipated in pts on standard-dose clopidogrel? Why was a 50% risk reduction anticipated? STARS: 30-day event rate 3.6% in BMS pts on aspirin vs. 0.5% in pts on DAP Buonamici et al: 6 mo death/stent thrombosis rate 10.5% in clopidogrel non-responders vs 2.7% in responders Price et al: 6 mo event rate 6.5% in pts with high post- treatment reactivity vs 1.0% in those without it Large txmt effect anticipated since only pts identified to have biological potential for a large drug effect were enrolled 9

GRAVITAS Patient Flow 5429 patients screened with VerifyNow P2Y12 12-24 hours post-PCI 2214 (41%) with high residual platelet reactivity (PRU ≥ 230) 3215 (59%) without high residual platelet reactivity (PRU < 230) Clopidogrel High Dose N=1109 Clopidogrel Standard Dose N=1105 10

GRAVITAS Study Design Why was a PRU >230 selected as the cut-off distinguishing responders from hyporesponders? Reactivity above this threshold (~1/3 of pts on clopidogrel) is associated with ischemic events after PCI. This PRU level are generally consistent with other definitions of clopidogrel non-responsiveness that are associated with poor outcomes using other measurement techniques Gurbel PA et al. JACC 2005;46:1827-32 Hochholzer W et al. JACC 2006;48:1742-50 Bliden KP et al. JACC 2007;49:657-66 Price MJ et al. EHJ 2008;29(8):992-1000 Matetzky S et al. Circulation 2004;109(25):3171-5 11

Why was clopidogrel 150 mg chosen as the active treatment? GRAVITAS Study Design Why was clopidogrel 150 mg chosen as the active treatment? At least 5 studies in differing populations (stable CAD, diabetics, hyporesponders, etc.) revealed that 150 mg is associated with significantly greater levels of inhibition of aggregation than 75 mg. Prasugrel was not available at the time the study was designed or launched. 12

Baseline Characteristics of the Randomized Groups High-Dose Clopidogrel (N=1109) Standard-Dose Clopidogrel (N=1105) Residual platelet reactivity, median (IQR) 282 PRU (255 - 320) 283 PRU (255 - 321) Age, mean ± SD 64 ± 11 Male sex 65% Diabetes Mellitus 44% 47% Hx of MI 30% 29% STEMI .5% .2% NSTEMI 10% ACS with STE depression 5.0% 5.3% Stable 85% 13

High risk pts were eligible. Were high risk pts enrolled? GRAVITAS Study Design High risk pts were eligible. Were high risk pts enrolled? The study population generally consisted of low risk patients. The result of the trial (or any trial) should generally only be applied to patients who resemble patients enrolled in the trial. *Large since the trial only enrolls individuals identified to have biological potential for a large drug effect. 14

Pharmacodynamics: Effect of SD vs HD Clopidogrel Standard-Dose High-Dose 500 P = 0.98 P < 0.001 400 Persistently high reactivity @ 30 days: 62% vs 40%, p<0.001 PRU value 300 200 100 N=1105 N=1013 N=940 N=1109 N=1012 N=944 Post-PCI 30 d 6 mo Post-PCI 30 d 6 mo 15

Pharmacodynamics: Effect of SD vs HD Clopidogrel Standard-Dose High-Dose 500 P = 0.98 P < 0.001 400 The difference in aggregability was significant but modest, and the variability in both groups was large Persistently high reactivity @ 30 days: 62% vs 40%, p<0.001 PRU value 300 200 100 N=1105 N=1013 N=940 N=1109 N=1012 N=944 Post-PCI 30 d 6 mo Post-PCI 30 d 6 mo 16

Primary Endpoint: CV Death, MI, Stent Thrombosis Observed event rates are listed; P value by log rank test. 17

Bleeding Events: Safety Population Severe or life-threatening: Fatal bleeding, intracranial hemorrhage, or bleeding causing hemodynamic compromise requiring blood or fluid replacement, inotropic support, or surgical intervention Moderate: Bleeding that leads to transfusion but does not meet criteria for severe bleeding P by log rank test; observed event rates listed. HD, high-dose; SD, standard dose 18

GRAVITAS Patient Flow: Secondary Analysis 5429 patients screened with VerifyNow P2Y12 12-24 hours post-PCI 2214 (41%) with high residual platelet reactivity (PRU ≥ 230) 3215 (59%) without high residual platelet reactivity (PRU < 230) Random selection Clopidogrel High Dose N=1109 Clopidogrel Standard Dose N=1105 Clopidogrel Standard Dose N=586 Non-Randomized Comparison 19

Baseline Characteristics: Non-Randomized Comparison SD – High RPR N=1105 SD – Not High RPR N=586 p Residual platelet reactivity, median (IQR) 283 PRU (255 - 321) 151 PRU (105 - 191) <0.001 Age, years 64 ± 11 62 ± 10 Male sex 65% 80% Diabetes Mellitus 47% 29% Body mass index (median) 31 29 Cr Cl < 60 ml/min 42% 27% Proton pump inhibitor 30% 20% Indication for PCI 0.41 Stable angina or ischemia 60% 56% UA, no ST depression 24% 28% NSTE-ACS UA, ST-dep, biomarker (-) 5% Cardiac biomarker (+) 10% 11% 20

2o Comparison: High vs. Not High Reactivity 2o Comparison: High vs. Not High Reactivity Treated with Clopidogrel 75-mg Daily Observed event rates are listed. P value by log-rank test. 21

Post Hoc Analysis: CV Events and PRU In Pts With and Without High Reactivity Trxted With Clopidogrel 75 mg Daily 500 Red dots: patients with CV death, MI, or ST 400 PRU 12 - 24 hrs post-PCI 300 230 PRU 200 100 N=1105 N= 586 High Residual Reactivity Not High Residual Reactivity ITT population 22

GRAVITAS: Summary Compared with standard-dose therapy, high-dose clopidogrel achieved a modest pharmacodynamic effect in patients with high residual reactivity. In patients with high residual reactivity measured after PCI, 6-months of high-dose clopidogrel did not reduce the rate of cardiovascular death, non- fatal MI, or stent thrombosis and did not increase GUSTO severe or moderate bleeding. 23

GRAVITAS: Possible Explanations Underpowered: patients low-risk, low event rates? Given HR of 1.01 with more than 2,200 patients, unlikely that a clinically meaningful benefit would have been present even if a much larger trial identified modest clinical benefit. Pharmacodynamic effect of the intervention was too weak? A stronger intervention, or goal-directed therapy with serial measurements, might well have made a difference (TRIGGER-PCI; ARCTIC; TARGET-PCI) 24

GRAVITAS does not support a treatment strategy of high-dose clopidogrel in low-risk patients with high residual reactivity identified by a single platelet function test after PCI. 25