Dr. Harvey White on behalf of the ACUITY investigators ACUITY PCI A Prospective Trial of Patients with ACS Undergoing PCI after Randomization to Heparin plus GP IIb/IIIa Inhibitors vs. Bivalirudin With or Without GP IIb/IIIa Inhibitors Dr. Harvey White on behalf of the ACUITY investigators

Disclosure Harvey D. White Research Grants: Alexion, Fournier Laboratories, Sanofi Aventis, Johnson & Johnson, Eli Lilly, Proctor & Gamble, Merck Sharpe & Dohme, Schering Plough, Roche, The Medicines Company, Glaxo Smith Kline, Pfizer, Neuren Pharmaceuticals, NIH Consultant: Sanofi Aventis, The Medicines Company

Study Design – First Randomization Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N=13,819) UFH/Enox + GP IIb/IIIa (n=4,603) Medical management PCI Moderate and high risk ACS (n=13,819) Bivalirudin + GP IIb/IIIa (n=4,604) Angiography within 72h R* Aspirin in all Clopidogrel dosing and timing per local practice Bivalirudin Alone (n=4,612) CABG *Stratified by pre-angiography thienopyridine use or administration

Study Design – Second Randomization Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy UFH/Enox + GP IIb/IIIa (n=4,603) GP IIb/IIIa upstream (N=2294) GP IIb/IIIa CCL for PCI (N=2309) Moderate and high risk ACS (n=13,819) Bivalirudin + GP IIb/IIIa (n=4,604) GP IIb/IIIa upstream (N=2311) R* GP IIb/IIIa CCL for PCI (N=2293) Aspirin in all Clopidogrel dosing and timing per local practice Bivalirudin Alone (n=4,612) *Stratified by pre-angiography thienopyridine use or administration

ACUITY Primary Endpoints Net Clinical Outcome (Composite Ischemia, Non-CABG Major Bleeding) Composite Ischemia: Death from any cause Myocardial infarction During medical Rx: Any biomarker elevation >ULN Post PCI: CKMB >ULN with new Q waves or >3x ULN w/o Q waves Post CABG: CKMB >5x ULN with new Q waves, >10x ULN w/o Q waves Unplanned revascularization for ischemia Non-CABG Major Bleeding Intracranial bleeding or intraocular bleeding Retroperitoneal bleeding Access site bleed requiring intervention/surgery Hematoma ≥5 cm Hgb  ≥ 3 g/dL with , or  ≥ 4 g/dL without overt source Blood product transfusion Reoperation for bleeding

ACUITY: Primary results – 30 days UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone PNI <0.001 PSup = 0.015 PNI = 0.011 PSup = 0.32 PSup <0.001 Stone GW et al. NEJM 2006;355:2203-16

Ischemic Composite Endpoint (Death, MI, unplanned revascularization for ischemia) UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 25 Estimate P (log rank) 30 day 7.4% 0.36 7.8% 0.34 7.9% — Estimate P (log rank) 16.3% 0.38 16.5% 0.31 16.4% 1 year — 20 UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone p=0.55 15 Ischemic Composite (%) 10 Bivalirudin+GPI vs. Hep+GPI HR [95% CI] = 1.05 (0.94-1.16) 5 Bivalirudin alone vs. Hep+GPI HR [95% CI] = 1.05 (0.95-1.17) 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization Stone GW. ACC 2007 presentation

Mortality: 524 total deaths at 1-year UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 5 Bivalirudin+GPI vs. Hep+GPI HR [95% CI] = 0.99 (0.80-1.22) p=0.90 4 Bivalirudin alone vs. Hep+GPI HR [95% CI] = 0.95 (0.77-1.18) 3 Mortality (%) 2 Estimate P (log rank) 1.4% 0.53 1.6% 0.39 — 30 day Estimate P (log rank) 4.4% 0.93 4.2% 0.66 3.8% 1 year — 1 UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization Stone GW. ACC 2007 presentation

Goals of the present analysis To examine the long-term outcomes of bivalirudin ± GP IIb/IIIa inhibition compared to UFH/Enoxaparin + GP IIb/IIIa inhibition in moderate and high risk ACS patients undergoing PCI Overall primary clinical endpoints at 1 year Outcomes in patients switched to bivalirudin monotherapy from UFH or enoxaparin Analysis of the relative impact of iatrogenic bleeding complications on long-term outcome

Management Strategy (N=13,819) Medical Rx (n=4,491) CABG (n=1,539) 32.5% 11.1% 56.4% PCI (n=7,789) UFH/Enox + GP IIb/IIIa N = 2,561 Bivalirudin + GP IIb/IIIa N = 2,609 Bivalirudin alone N = 2,619

ACUITY PCI: Baseline Characteristics UFH/Enox + GP IIb/IIIa (N=2561) Bivalirudin + GP IIb/IIIa (N=2609) Bivalirudin alone (N=2619) Age (median [range], yrs) 63 [25-91] 62 [21-95] 63 [30-92] Male 73% 74% Weight (median [IQR], kg) 84 [73,96] 84 [74,96] 84 [75,95] Diabetes 28% 27% - Insulin requiring 8% 9% Hypertension 66% 65% Hyperlipidemia 56% Current smoker 31% Prior MI 30% Prior PCI 38% 40% Prior CABG 17% 18% Renal insufficiency* 19% * creatinine clearance <60 mL/min Stone GW et al. Lancet 2007;369:907-19

ACUITY PCI: Baseline High Risk Features UFH/Enox + GP IIb/IIIa (N=2561) Bivalirudin + GP IIb/IIIa (N=2609) Bivalirudin alone (N=2619) Cardiac biomarker  (CK-MB or trop) 65% 64% 66% - Troponin  63% ST-segment  ≥1mm 35% 37% Cardiac biomarker  or ST-segments  77% 75% TIMI Risk Score 0-2* 17% 15% 16% 3-4 52% 55% 53% 5-7 31% 30% Non-ST-segment elevation MI (elevated baseline CKMB or troponin) was present in 59 percent of patients, whereas 41 percent had unstable angina. Baseline ST-segment deviation or cardiac biomarker elevation 3171/4340 (73.1%)3119/4362 (71.5%)3173/4385 (72.4%) * 84.0% had +biomarkers or baseline ST 97% of all pts had +biomarkers or baseline ST, or were TIMI Int/High risk Stone GW et al. Lancet 2007;369:907-19

ACUITY PCI: Primary results – 30 days UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone P=0.10 P=0.057 P=0.16 P=0.45 P=0.32 <0.0001 Stone GW et al. Lancet 2007;369:907-19

ACUITY PCI: Bleeding – 30 days UFH/Enox + GP IIb/IIIa (N=2561) Bivalirudin + GP IIb/IIIa (N=2609) Bivalirudin alone (N=2619) P Value* ACUITY Scale - Major Bleed, all 7.3% 8.0% 4.2% <0.0001 - Major, non-CABG 7% 8% 4% - Minor, non-CABG 26% 28% 15% TIMI Scale - Any 9% 5% - Major 2% 0.8% - Minor Transfusions, non-CABG 3% 0.002 *P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor Stone GW et al. Lancet 2007;369:907-19

ACUITY PCI: Primary Results – 1 Year Hazard Ratio ±95% CI HR (95% CI) Composite Ischemia 1.09 (0.96-1.23) Mortality 0.95 (0.70-1.30) Bivalirudin Better UFH/Enox+ IIb/IIIa Better

ACUITY PCI: Early and Late Mortality UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone 30 day Estimate P (log rank) 0.9% 0.45 1.2% 0.63 1.1% — 3.1% 0.70 2.4% 0.48 2.2% 1 year Mortality (%) p=0.78 Days from Randomization

ACUITY PCI: Influence of 30 day Major Bleeding and MI on Late Mortality Hazard Ratio ±95% CI HR (95% CI) P-Value 30 Day Major Bleed 3.16 (2.25-4.42) <0.0001 30 Day Myocardial Infarction 2.30 (1.57-3.36) <0.0001 Cox model adjusted for baseline predictors, with non-CABG major bleeding and MI as time-updated covariates

ACUITY PCI: Impact of Bleeding on LOS Patients with Bleeding Event N=459 Patients without Bleeding Event N=7318 P Value Hospital length of stay, median days 5.0 3.0 <0.0001

ACUITY PCI: High Risk* patients 30 day Results 1 year Results Risk Ratio ±95% CI Hazard Ratio ±95% CI RR (95% CI) HR (95% CI) Composite ischemia 1.08 (0.88-1.32) Major bleeding 0.55 (0.42-0.72) Mortality 0.94 (0.67-1.31) Bivalirudin better UFH/Enox+ IIb/IIIa better Bivalirudin better UFH/Enox+ IIb/IIIa better * High risk = ↑Tn, CKMB or ECG Δ’s

ACUITY PCI: Impact of clopidogrel PCI patients 1-year Mortality Hazard Ratio ±95% CI HR (95% CI) Clopidogrel at any time prior to hospitalization, randomization or end of angiography (n=3,429) 1.02 (0.69-1.50) Clopidogrel after end of angiography to 30’ post PCI (n=1,044) 1.14 (0.89-2.03) Clopidogrel after 30’ post PCI (n=519) 0.43 (0.17-1.11) No clopidogrel (n=88) 3.20 (0.34-31.1) Bivalirudin better UFH/Enox + IIb/IIIa better Groups based on first exposure to clopidogrel; excludes patients who received ticlopidine

ACUITY PCI: Impact of clopidogrel PCI troponin+ patients 1-year Mortality Hazard Ratio ±95% CI HR (95% CI) Clopidogrel at any time prior to hospitalization, randomization or end of angiography (n=1,891) 1.07 (0.66-1.73) Clopidogrel after end of angiography to 30’ post PCI (n=649) 1.09 (0.46-2.58) Clopidogrel after 30’ post PCI (n=307) 0.56 (0.17-1.93) No clopidogrel (n=51) 3.07 (0.32-29.49) Bivalirudin better UFH/Enox + IIb/IIIa Better Groups based on first exposure to clopidogrel; excludes patients who received ticlopidine

ACUITY PCI: Switch from Prior Antithrombin 30 day Results 1 year Results Risk Ratio ±95% CI Hazard Ratio ±95% CI RR (95% CI) HR (95% CI) PCI (n=2528) Composite ischemia 1.10 (0.85-1.42) Major bleeding 0.52 (0.36-0.74) PCI (n=2528) Mortality 0.93 (0.58-1.48) PCI HIGH RISK* (n=1988) Composite ischemia 1.14 (0.86-1.52) Major bleeding 0.56 (0.38-0.81) PCI HIGH RISK* (n=1988) Mortality 0.99 (0.60-1.63) Switch to Bivalirudin better Switch to Bivalirudin better Consistent UFH/Enox + IIb/IIIa better Consistent UFH/Enox + IIb/IIIa better * High risk = ↑Tn, CKMB or ECG Δ’s

ACUITY PCI: Antithrombin Naïve Patients 30 day Results 1 year Results Risk Ratio ±95% CI Hazard Ratio ±95% CI RR (95% CI) HR (95% CI) PCI (n=1639) Composite ischemia 1.03 (0.72-1.47) Major bleeding 0.46 (0.28-0.75) PCI (n=1639) Mortality 1.08 (0.57-2.04) PCI HIGH RISK* (n=987) Composite ischemia 1.06 (0.68-1.65) Major bleeding 0.48 (0.26-0.86) PCI HIGH RISK* (n=987) Mortality 1.15 (0.54-2.45) UFH/Enox + IIb/IIIa better UFH/Enox + IIb/IIIa better Bivalirudin better Bivalirudin better * High risk = ↑Tn, CKMB or ECG Δ’s

This analysis is of post-randomization outcomes Study Limitations This analysis is of post-randomization outcomes The ACUITY PCI sub-study was under-powered for subgroup comparisons All analyses should be considered hypothesis generating

Conclusions and Clinical Implications In patients with moderate and high risk ACS undergoing PCI Bivalirudin alone results in similar 1 year mortality to UFH/enoxaparin plus GP IIb/IIIa inhibition regardless of patient risk, prior antithrombin therapy and clopidogrel exposure Switching from UFH or enoxaparin to bivalirudin enables patients to achieve significant reductions in bleeding at 30 days and similar mortality at 1 year These results substantiate the strong relationship between bleeding complications and late mortality in PCI patients