Gregg W. Stone MD for the ACUITY Investigators Gregg W. Stone MD for the ACUITY Investigators A Prospective, Randomized Trial of Bivalirudin in Acute Coronary Syndromes Final One-Year Results from the ACUITY Trial

Moderate and high risk ACS (n=13,819) Study Design – First Randomization Angiography within 72h Aspirin in all Clopidogrel dosing and timing per local practice Aspirin in all Clopidogrel dosing and timing per local practice UFH/Enox + GP IIb/IIIa (n=4,603) Bivalirudin + GP IIb/IIIa (n=4,604) Bivalirudin Alone (n=4,612) R*R* *Stratified by pre-angiography thienopyridine use or administration Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) Medical management PCI CABG 56% 11% 33%

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

3 Primary Endpoints (at 30 Days) 1. Composite net clinical benefit = 2. Ischemic composite 3. Major bleeding or  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

3 Primary Endpoints (at 30 Days) 1. Composite net clinical benefit = 2. Ischemic composite 3. Major bleeding or  Non CABG related bleeding - Intracranial bleeding or intraocular bleeding - Retroperitoneal bleeding -Access site bleed requiring intervention/surgery - Hematoma ≥5 cm - Hgb  ≥3g/dL with an overt source or  ≥4g/dL w/o overt source - Blood product transfusion  Reoperation for bleeding

Baseline Characteristics UFH/Enoxaparin + GP IIb/IIIa (N=4,603) Bivalirudin + GP IIb/IIIa (N=4,604) Bivalirudin alone (N=4,612) Age (median [range], yrs) 63 [23-91]63 [21-95]63 [20-92] Male70.6%69.9%69.3% Weight (median [IQR], kg) 83 [73-95] 84 [73-96] Diabetes28.5%27.8%28.1% - Insulin requiring8.5%8.7%8.9% Hypertension66.8%67.2%67.1% Hyperlipidemia57.2%57.4%57.0% Current smoker29.0%29.3%29.0% Prior MI31.6%30.5%31.8% Prior PCI38.9%37.8%39.9% Prior CABG18.2%17.4%18.1% Renal insufficiency*19.2% 18.9% * creatinine clearance <60 mL/min

Baseline High Risk Features UFH/Enoxaparin + GP IIb/IIIa (N=4,603) Bivalirudin + GP IIb/IIIa (N=4,604) Bivalirudin alone (N=4,612) Biomarker or ST  73.1%71.6%72.4% - Biomarker +59.4%58.6%60.3% - Troponin +58.3%57.2%59.2% - ST-segment  35.2%35.4%34.3% TIMI Risk Score † - 0-2*16.1%15.4%15.6% %55.5%54.5% %29.1%29.9% *80.1% were biomarker+ or had baseline STΔ † 97% were TIMI intermediate or high risk, or biomarker+, or +STΔ

11.7%11.8%1.01 ( ) < Risk ratio ±95% CI Risk ratio ±95% CI Primary endpoint Primary Endpoint Measures (ITT) – 30 Days UFH/Enoxaparin + GPI vs. Bivalirudin + GPI Net clinical outcome Ischemic composite Major bleeding Bivalirudin + IIb/IIIa better UFH/Enox + IIb/IIIa better Bival + IIb/IIIa UFH/Enox + IIb/IIIa RR (95% CI) p value (non inferior) (superior) 7.3%7.7%1.07 ( ) %5.3%0.93 ( ) < Upper boundary non-inferiority Stone GW et al. NEJM 2006;355:

Primary Endpoint Measures (ITT) – 30 Days Bivalirudin alone better UFH/Enox + IIb/IIIa better Risk ratio ±95% CI Risk ratio ±95% CI Primary endpoint Bival alone UFH/Enox + IIb/IIIa RR (95% CI) Net clinical outcome Ischemic composite Major bleeding Upper boundary non-inferiority 11.7%10.1%0.86 ( ) < %7.8%1.08 ( ) %3.0%0.53 ( ) <0.001 p value (non inferior) (superior) UFH/Enoxaparin + GPI vs. Bivalirudin Alone Stone GW et al. NEJM 2006;355:

Medication Compliance: Anti-platelet agents UFH/Enoxaparin + GP IIb/IIIa (N=4,603) Bivalirudin + GP IIb/IIIa (N=4,604) Bivalirudin alone (N=4,612) Aspirin use - Before angio/PCI98.0%97.8%97.9% - Hospital discharge94.5%95.1%94.6% - 30 day follow-up*92.6%92.8%93.1% - 1 year follow-up*87.6%88.3%88.1% Thienopyridine use - Before angio/PCI62.8%64.7%64.2% - Hospital discharge71.6%72.7%73.0% - 30 day follow-up*66.7%68.7% - 1 year follow-up*44.8%44.3%44.1% *Greater than 50% of days since last visit

Patient Follow-up at 1-Year* Heparin + IIb/IIIa 4,603 Bivalirudin + IIb/IIIa 4,604 Bivalirudin alone 4,612 All patients N = 13, Withdrawn 62 Lost to follow-up Heparin + IIb/IIIa 4,516 (98.1%) 1-year FU Bivalirudin + IIb/IIIa 4,502 (97.8%) 1-year FU Bivalirudin alone 4,521 (98.0%) 1-year FU 33 Withdrawn 69 Lost to follow-up 25 Withdrawn 66 Lost to follow-up R *Endpoints adjudicated: Composite ischemia (death, MI, unplanned revasc) and stent thrombosis

Composite ischemia (%) Days from Randomization UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone Estimate P (log rank) 30 day 7.4% % % — Estimate P (log rank) 16.3% % % 1 year — p=0.55 Bivalirudin alone vs. Hep+GPI HR [95% CI] = 1.05 ( ) Bivalirudin+GPI vs. Hep+GPI HR [95% CI] = 1.05 ( ) Ischemic Composite Endpoint (Death, MI, unplanned revascularization for ischemia) UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone

Composite ischemia (%) Days from Randomization Routine upstream IIb/IIIa Deferred selective IIb/IIIa Estimate P (log rank) 30 day 7.1% % Estimate P (log rank) 15.7% 17.2% 1 year Ischemic Composite Endpoint – GPIIb/IIIa Inhibitor Timing Randomization 0.15 Routine Upstream GPI vs. Deferred Selective GPI

Composite ischemia (%) Days from Randomization Routine upstream IIb/IIIa Deferred selective IIb/IIIa Bivalirudin alone Estimate P (log rank) 30 day 7.1% % %— Estimate P (log rank) 15.7% % % 1 year — p=0.30 Ischemic Composite Endpoint – GPIIb/IIIa Inhibitor Timing Randomization GPI Strategies vs. Bivalirudin Alone

Composite Ischemia at 1-year Hazard ratio ±95% CI Hazard ratio ±95% CI Bival alone UFH/Enox + IIb/IIIa HR (95% CI)P int 0.67 Bivalirudin alone better UFH/Enox + IIb/IIIa better 19.8%19.2%1.09 ( ) 21.1%20.7%1.04 ( ) 9.0%9.6%0.97 ( ) Actual Treatment PCI (n=5179) CABG (n=1040) Medical (n=2994) 17.7% 14.6% 16.4% 16.1% 1.14 ( ) 0.95 ( ) 0.11 Biomarkers (CK/Trop) Elevated (n=5072) Normal (n=3402) 16.2% 16.4% 17.2% 14.3% 0.97 ( ) 1.20 ( ) 0.07 Pre Thienopyridine Yes (n=5751) No (n=3305) UFH/Enoxaparin + GPIIb/IIIa vs. Bivalirudin alone 1 yr KM estimate

Stent Thrombosis (Protocol): Definite/Probable UFH/Enoxaparin + GP IIb/IIIa (N=2348) Bivalirudin + GP IIb/IIIa (N=2403) Bivalirudin alone (N=2407) P 1 Value P 2 Value Total-all stent pts2.3%2.4%1.9%  0 – 30 days1.3%1.6%1.3%  30 days – 1 year1.0%0.8%0.5% Total – at least one DES implanted 2.5%2.4%1.8% – 30 days 1.2%1.6%1.2% days – 1 year 1.3%0.7%0.6% Total – only BMS implanted 2.3%2.6%2.0% – 30 days 1.6% 1.5%> days – 1 year 0.6%1.0%0.5% P 1 = Bivalirudin+GPI vs. UFH/Enox+GPI; P 2 = Bivalirudin alone vs. UFH/Enox+GPI

Mortality (%) Days from Randomization 2 1 Mortality: 524 total deaths at 1-year UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone Estimate P (log rank) 1.4% % % — Estimate P (log rank) 4.4% % % 1 year — p=0.90 Bivalirudin+GPI vs. Hep+GPI HR [95% CI] = 0.99 ( ) 30 day 3 Bivalirudin alone vs. Hep+GPI HR [95% CI] = 0.95 ( )

Early and Late Mortality Landmark analysis UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone 30 day Estimate P (log rank) 1.4% % % — Estimate P (log rank) 3.1% % % 30d - 1 year — p=0.45 Mortality (%) Days from Randomization

Early and Late Mortality – PCI Subgroup Landmark analysis UFH/Enoxaparin + IIb/IIIa (N=2560) Bivalirudin + IIb/IIIa (N=2606) Bivalirudin alone (N=2619) Estimate P (log rank) 30 day 0.9% % % — Estimate P (log rank) 3.1% % % 1 year — p=0.78 Mortality (%) Days from Randomization

Mortality (%) Days from Randomization 2 1 Mortality – GPIIb/IIIa Inhibitor Timing Randomization Routine Upstream GPI vs. Deferred Selective GPI Estimate P (log rank) 30 day Estimate P (log rank) Routine upstream IIb/IIIa Deferred selective IIb/IIIa 1.4% % 4.3% 1 year 0.66

Estimate P (log rank) 30 day Estimate P (log rank) Routine upstream IIb/IIIa Deferred selective IIb/IIIa 1.4% 1.6% 4.3% 1 year Bivalirudin alone 1.6%—3.8%— p=0.82 Mortality – GPIIb/IIIa Inhibitor Timing Randomization GPI Strategies vs. Bivalirudin Alone Mortality (%) Days from Randomization

Death at 1-year UFH/Enoxaparin + GPIIb/IIIa vs. Bivalirudin alone Hazard ratio ±95% CI Hazard ratio ±95% CI Bival alone UFH/Enox + IIb/IIIa HR (95% CI)P int 0.96 Bivalirudin alone better UFH/Enox + IIb/IIIa better 3.2%4.0%0.95 ( ) 6.8%6.7%1.03 ( ) 4.0%4.3%0.95 ( ) Actual Treatment PCI (n=5179) CABG (n=1040) Medical (n=2994) 4.8% 2.4% 5.0% 3.6% 1.04 ( ) 0.84 ( ) 0.40 Biomarkers (CK/Trop) Elevated (n=5072) Normal (n=3402) 3.5% 4.0% 4.2% 4.4% 0.90 ( ) 1.05 ( ) 0.52 Pre Thienopyridine Yes (n=5751) No (n=3305) 1 yr KM estimate

Mortality (%) Days from Randomization 2 1 UFH/Enoxaparin + IIb/IIIa Bivalirudin alone Estimate P (log rank) 3.9% % 1 year — REPLACE-2 + ACUITY-PCI: Mortality UFH/Enoxaparin + GPI vs. Bivalirudin Alone

Mortality (%) Days from Randomization 2 1 REPLACE-2 + ACUITY-PCI: Mortality UFH/Enoxaparin + GPI vs. Bivalirudin Alone UFH/Enoxaparin + IIb/IIIa (n=5568) Bivalirudin alone (n=5613) Estimate P (log rank) 0.7% % 30 day — Estimate P (log rank) 3.0% % 30d - 1 year —

Mortality (%) Days from Randomization Estimate Patients with MI (N=705) 11.4% 1 year Patients with Major Bleed (N=645) 14.9% Patients w/o Major Bleed (N=13,168) 3.6% Patients w/o MI (N=13,108) 3.8% Pts with vs. without MI and Major Bleeding within 30d Impact of Major Adverse Events Within 30 Days on Subsequent Mortality

Mortality (%) Days from Randomization p= year Estimate Major Bleed only (without MI) (N=551)12.5% 28.9%Both MI and Major Bleed (N=94) 3.4%No MI or Major Bleed (N=12,557) MI only (without Major Bleed) (N=611)8.6% Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year

Cox model adjusted for baseline predictors, with non- CABG major bleeding and MI as time-updated covariates Influence of Major Bleeding and MI in the First 30 Days on Risk of Death Over 1 Year Major bleeding 2.89 ( ) < Myocardial Infarction 2.47 ( ) < HR ± 95% CI P-value HR (95% CI)

Day 0 – 2 after MI 12.6 ( ) 29 (37.6) < Day 3 – 7 after MI 5.3 ( ) 11 (14.3) < Day 8 – 35 after MI 1.6 ( ) 12 (15.6) 0.18 Day > 35 after MI 1.2( ) 25 (32.5) 0.34 Day 0 – 2 after Major Bleed 3.0 ( ) 12 (12.9) Day 3 – 7 after Major Bleed 4.0 ( ) 15 (16.1) < Day 8 – 35 after Major Bleed 4.5 ( ) 25 (26.9) < Day > 35 after Major Bleed 2.2 ( ) 41 (44.1) < P-value Influence of Non-CABG Major Bleeding and MI in the First 30 Days on the Risk of Death Over 1 Year Deaths (n/%) HR ± 95% CI HR (CI)

Conclusions  In patients with moderate and high risk ACS undergoing an early invasive strategy with the use of GP IIb/IIIa inhibitors  Bivalirudin is an acceptable substitute for either unfractionated heparin or enoxaparin  Compared to either UFH/enoxaparin with GP IIb/IIIa inhibition or bivalirudin with GP IIb/IIIa inhibition  A bivalirudin alone strategy results in marked reduction of bleeding at 30 days, and similar rates of mortality and composite ischemia at 1-year  The results of this study further establish the important relationship between iatrogenic bleeding complications and the long-term prognosis in patients with ACS  In patients with moderate and high risk ACS undergoing an early invasive strategy with the use of GP IIb/IIIa inhibitors  Bivalirudin is an acceptable substitute for either unfractionated heparin or enoxaparin  Compared to either UFH/enoxaparin with GP IIb/IIIa inhibition or bivalirudin with GP IIb/IIIa inhibition  A bivalirudin alone strategy results in marked reduction of bleeding at 30 days, and similar rates of mortality and composite ischemia at 1-year  The results of this study further establish the important relationship between iatrogenic bleeding complications and the long-term prognosis in patients with ACS