Gregg W. Stone MD for 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 Gregg W. Stone MD for the ACUITY Investigators

Disclosure Gregg W. Stone Consultant to The Medicines Company and Bristol Myers Squibb Imaging Lecture fees from The Medicines Company and Nycomed

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) Bivalirudin (n=4,604) Alone (n=4,612) R* Angiography within 72h Medical management PCI CABG Moderate and high risk ACS (n=13,819) Aspirin in all Clopidogrel dosing and timing per local practice *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) Bivalirudin (N=4,604) Alone (N=4,612) R* GPI upstream (N=2294) GPI CCL for PCI (N=2309) GPI upstream (N=2311) GPI CCL for PCI (N=2293) Moderate and high risk ACS (n=13,819 Aspirin in all Clopidogrel dosing and timing per local practice *Stratified by pre-angiography thienopyridine use or administration

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

Composite Ischemia – All pts UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 15 Estimate P (log rank) UFH/Enoxaparin + IIb/IIIa (N=4603) 7.4% Bivalirudin + IIb/IIIa (N=4604) 7.9% 0.37 10 Bivalirudin alone (N=4612) 8.0% 0.30 Cumulative Events (%) 5 5 10 15 20 25 30 35 Days from Randomization

Major Bleeding (Non CABG) – All pts UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 5 10 15 20 25 30 35 Estimate P (log rank) 5.7% UFH/Enoxaparin + IIb/IIIa (N=4603) Bivalirudin + IIb/IIIa (N=4604) 5.3% 0.41 Bivalirudin alone (N=4612) 3.1% <0.0001 Cumulative Events (%) Days from Randomization

Net Clinical Outcomes – All pts UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 15 10 Cumulative Events (%) Estimate P (log rank) 11.9% UFH/Enoxaparin + IIb/IIIa (N=4603) Bivalirudin + IIb/IIIa (N=4604) 0.89 Bivalirudin alone (N=4612) 0.014 10.3% 5 5 10 15 20 25 30 35 Days from Randomization

Goals of the ACUITY PCI Sub-study To examine the outcomes of bivalirudin ± GPIIb/IIIa inhibitors compared to heparin (unfractionated or enoxaparin) + GPIIb/IIIa inhibitors in pts with moderate and high risk ACS undergoing PCI 3 primary clinical endpoints at 30 days Angiographic outcomes from a large independent blinded core lab analysis Specific subgroups and analyses of interest: Troponin positive pts Impact of pre-PCI thienopyridine use “ISAR-REACT-2 like” cohort Angiographic thrombus

Management Strategy (N=13,819) Medical Rx (n=4,491) CABG (n=1,539) 32.2% 11.4% 56.4% PCI (n=7,789) Heparin + IIb/IIIa N = 2,561 Bivalirudin + IIb/IIIa N = 2,609 Bivalirudin alone N = 2,619

Baseline Characteristics – PCI pts Heparin + IIb/IIIa (N=2561) Bivalirudin + IIb/IIIa (N=2609) Bivalirudin alone (N=2619) Age (median [range], yrs) 63 [25-91] 62 [21-95] 63 [30-92] Male 72.6% 73.6% 73.3% Weight (median [IQR], kg) 84 [73,96] 84 [74,96] 84 [75,95] Diabetes 27.5% 27.3% - Insulin requiring 8.0% 8.6% Hypertension 65.3% 64.8% 65.4% Hyperlipidemia 55.0% 55.2% 54.9% Current smoker 30.1% 30.6% 30.4% Prior MI 29.7% 29.1% 30.5% Prior PCI 38.2% 37.5% 39.3% Prior CABG 17.3% 17.9% Renal insufficiency* 19.0% 18.4% 17.8% * creatinine clearance <60 mL/min

Baseline High Risk Features – PCI pts Heparin + IIb/IIIa (N=2561) Bivalirudin + IIb/IIIa (N=2609) Bivalirudin alone (N=2619) Cardiac biomarker  (MB or trop) 65.1% 63.7% 66.4% - Troponin  64.8% 62.6% 66.2% ST-segment  ≥1mm 35.4% 36.7% 35.3% Cardiac biomarker  or ST-segments  76.8% 75.3% 77.0% TIMI Risk Score 0-2* 16.7% 15.3% 16.0% 3-4 52.1% 54.6% 53.2% 5-7 31.2% 30.0% 30.8% 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

Antiplatelet Medications – PCI pts Heparin + IIb/IIIa (N=2561) Bivalirudin + IIb/IIIa (N=2609) Bivalirudin alone (N=2619) Aspirin use or administration pre-angiography or PCI - Yes 98.0% 97.7% Thienopyridine use or administration pre PCI 68.0% 67.4% 69.0% - Clopidogrel 67.5% 67.7% 68.7% - Ticlopidine 1.0% 0.7% -

GP IIb/IIIa Inhibitor Administration – PCI pts Heparin + IIb/IIIa (N=2561) Bivalirudin (N=2609) Bivalirudin alone (N=2619) GPI initiated pre angio 50.7% 50.9% 0.7% - Eptifibatide 31.8% 32.2% 0.4% - Tirofiban 18.5% 18.2% 0.2% - Abciximab 0.5% 0.1% GPI inhibitor during PCI 96.6% 96.7% 9.1%* 59.6% 60.9% 4.5% 19.2% 19.7% 0.8% 17.8% 16.3% 3.8% IIb/IIIa inhib * For ischemic complications per protocol in 6.5% of pts

Procedural Characteristics – PCI pts Heparin + IIb/IIIa (N=2561) Bivalirudin + IIb/IIIa (N=2609) Bivalirudin alone (N=2619) Attempted lesions per pt 1.50 ± 0.83 1.49 ± 0.82 1.51 ± 1.93 - 1 65.2% 64.7% 66.3% - 2 24.4% 25.3% 23.2% - ≥3 10.4% 10.0% 10.6% Attempted vessels per pt 1.18 ± 0.44 1.18 ± 0.43 1.18 ± 0.42 - ≥2 16.3% 16.9% 16.0% Target Vessel - Left main 1.7% 1.5% - LAD 41.2% 44.0% 43.5% - LCX 34.7% 34.4% 35.7% - RCA 38.4% 36.7% 35.4% - Bypass graft conduit 7.2% 7.5% 7.0% 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%)

Bivalirudin + IIb/IIIa Device Use – PCI pts Heparin + IIb/IIIa (N=2561) Bivalirudin + IIb/IIIa (N=2609) Bivalirudin alone (N=2619) Stent implanted 92.7% 93.1% Drug-eluting stents 60.9% 59.7% 59.6% - ≥1 Cypher implanted 26.5% 25.8% 24.8% - ≥1 Taxus implanted 31.3% 30.4% 31.1% - ≥1 other DES implanted 5.4% 5.1% 5.6% Non-drug-eluting stent 36.2% 37.6% 37.7% Thrombectomy 1.7% 1.5% 1.8% Distal Protection 1.3% Atherectomy 0.7% 0.6% 0.5% Cutting Balloon 2.9% 3.2%

Composite Ischemia – PCI pts Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone 15 10 P=0.36 Event Rate (%) 5 Estimate P (log rank) 8.4% Heparin* + IIb/IIIa (N=2561) Bivalirudin + IIb/IIIa (N=2609) 0.15 9.4% Bivalirudin alone (N=2619) 0.45 8.9% 5 10 15 20 25 30 35 Days from Randomization *Heparin=unfractionated or enoxaparin

Components of Ischemia – PCI pts Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone p=0.16 p=0.45 p=0.37 p=0.53 p=0.19 p=0.31 P=0.87 *Heparin=unfractionated or enoxaparin

Adjudicated Stent Thrombosis PCI Patients With ≥1 Stent Implanted (N=7,211) RR 1.00 [0.61-1.64] p=0.99 RR 0.82 [0.51-1.30] p=0.39 RR 1.23 [0.77-1.96] p=0.39

Major Bleeding (Non-CABG) – PCI pts Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone 15 Estimate P (log rank) 6.8% Heparin* + IIb/IIIa (N=2561) Bivalirudin + IIb/IIIa (N=2609) 0.31 7.6% Bivalirudin alone (N=2619) <0.001 3.5% 10 Event Rate (%) P<0.0001 5 5 10 15 20 25 30 35 Days from Randomization *Heparin=unfractionated or enoxaparin

Major Bleeding (non-CABG) – PCI pts Heparin + IIb/IIIa (N=2561) Bivalirudin + IIb/IIIa (N=2609) Bivalirudin alone (N=2619) P value* Major bleeding 6.8% 7.5% 3.5% <0.001 Intracranial 0% (1) 1.00 Retroperitoneal 0.7% 0.9% 0.2% 0.006 Access site 3.3% 3.6% 1.0% - req interv/surgery 0.6% 0.8% 0.3% 0.13 - hematoma ≥5 cm 2.9% 3.1% Hgb  ≥3 g/dL with overt source 2.8% 1.2% Hgb  ≥4 g/dL with no overt source 1.1% 0.82 Blood transfusion 3.0% 3.9% 1.7% 0.002 Reoperation for bleed 0.2% (5) 0.1% (3) 0.33 *P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor

Bleeding Endpoints – PCI pts Heparin + IIb/IIIa (N=2561) Bivalirudin + IIb/IIIa (N=2609) Bivalirudin alone (N=2619) P Value ACUITY Scale - Major Bleed, all 7.3% 8.0% 4.2% <0.001 - Major, non-CABG 6.8% 7.5% 3.5% - Minor, non-CABG 26.0% 28.4% 14.9% TIMI Scale - Any 7.8% 8.5% 4.5% - Major 2.3% 2.4% 0.8% - Minor 8.2% Transfusions, non-CABG 3.0% 3.9% 1.7% 0.002 *P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor

Net Clinical Outcomes – PCI pts Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone 15 P=0.001 10 Event Rate (%) 5 Estimate P (log rank) 13.5% Heparin* + IIb/IIIa (N=2561) Bivalirudin + IIb/IIIa (N=2609) 0.10 15.1% Bivalirudin alone (N=2619) 0.049 11.7% 5 10 15 20 25 30 35 Days from Randomization *Heparin=unfractionated or enoxaparin

Impact of Baseline Troponins – PCI pts UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone RR [95%CI] 0.93 [0.77-1.12] RR [95%CI] 1.12 [0.88-1.42] RR [95%CI] 0.59 [0.44-0.80] RR [95%CI] 0.75 [0.57-0.99] RR [95%CI] 1.02 [0.74—1.42] RR [95%CI] 0.36 [0.22-0.61] Troponin + Troponin - Interaction P values = 0.46, 0.86 and 0.28 respectively

Thienopyridine Exposed* Not Thienopyridine Exposed Influence of Thienopyridine Exposure – PCI pts 30 Day Primary Endpoint Adverse Events RR [95%CI] 0.81 (0.68-0.96) RR [95%CI] 0.96 (0.77-1.20) RR [95%CI] 0.50 (0.37-0.67) RR [95%CI] 1.07 (0.83-1.39) RR [95%CI] 1.37 (1.00-1.88) RR [95%CI] 0.61 (0.39-0.97) Thienopyridine Exposed* Not Thienopyridine Exposed *Thienopyridine at any time, any dose, up to time of PCI Interaction P values = 0.17, 0.19 and 0.65 respectively

“ISAR-REACT-2 Like” Patients (N=1,358) Troponin+ PCI pts, Thienopyridine use prior to PCI, GPI started after angiography but before PCI RR [95%CI] 0.84 [0.62-0.1.13] RR [95%CI] 1.00 [0.67-1.49] RR [95%CI] 0.53 [0.34-0.83]

Core Lab Analysis: Patient Flow All patients N = 13,819 US patients, total and PCI N = 7,851 and 4,254 Goals: 7,000 acquired 6,300 interpretable US core lab analysis, total and PCI N = 6,921 (88.2%) and 3,664 (86.1%) PCI core lab analysis Heparin + IIb/IIIa 1,190 pts, 1,616 lsns Bivalirudin + IIb/IIIa 1,254 pts, 1,680 lsns Bivalirudin alone 1,220 pts, 1,617 lsns

Procedural Events – PCI pts Any adverse angiographic event (core lab) Heparin + IIb/IIIa (N=1190) Bivalirudin + IIb/IIIa (N=1254) Bivalirudin alone (N=1220) P value 3-way New or ↑ thrombus 13.7% 13.6% 16.2% 0.12 Abrupt closure 1.1% 0.6% 0.28 No reflow 0.3% 0.7% 0.24 Distal embolization 1.3% 1.2% 0.26 Spasm 2.8% 2.4% 2.9% 0.74 Dissection 5.1% 5.6% 4.3% 0.36 Perforation 0.2% 0.1% 0.39

Bivalirudin + IIb/IIIa Procedural Events – PCI pts Final adverse angiographic events (core lab) Heparin + IIb/IIIa (N=1190) Bivalirudin + IIb/IIIa (N=1254) Bivalirudin alone (N=1220) P value 3-way New or ↑ thrombus 1.5% 0.9% 0.7% 0.13 Abrupt closure 0.2% 0.1% 0.62 No reflow 0% 0.25 Distal embolization 0.8% 0.4% 1.0% 0.21 Spasm 0.5% 0.6% 1.1% 0.19 Dissection 0.84 Perforation 0.61

TIMI Flows – PCI pts Core lab vessel analysis Heparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone P1 value P2 Baseline TIMI Flow (N=1389) (N=1467) (N=1421) - 0/1 13.3% 12.4% 13.6% 0.47 0.84 - 2 9.6% 9.5% 10.1% 0.92 0.71 - 3 77.0% 78.1% 76.4% 0.52 0.67 Final TIMI Flow (N=1384) (N=1461) (N=1419) 1.5% 1.0% 2.0% 0.24 0.29 1.7% 1.4% 2.6% 0.53 0.11 96.7% 97.5% 95.3% 0.21 0.06 P1 = H+GPI vs. Biv+GPI; P2 = H+GPI vs. Biv alone

Myocardial Blush – PCI pts Core lab vessel analysis Heparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone P1 value P2 Baseline Blush (N=1211) (N=1304) (N=1239) - 0/1 17.0% 15.0% 16.9% 0.18 0.93 - 2 15.4% 16.8% 0.97 0.34 - 3 67.6% 69.6% 66.3% 0.30 0.50 Final Blush (N=1145) (N=1252) (N=1168) 2.8% 1.8% 2.7% 0.12 0.84 10.0% 10.8% 12.0% 0.51 87.2% 87.4% 85.4% 0.92 0.19 P1 = H+GPI vs. Biv+GPI; P2 = H+GPI vs. Biv alone

Primary Endpoint Measures Patients with ≥1 PCI Thrombotic Lesion at Baseline (n=712) *Heparin=unfractionated or enoxaparin

Bivalirudin + IIb/IIIa Angiographic Outcomes (core lab analysis) Pts with ≥1 PCI Thrombotic Lesions at Baseline (n=712) Heparin + IIb/IIIa (N=222) Bivalirudin + IIb/IIIa (N=241) Bivalirudin alone (N=249) P value 3-way Any thrombotic compl* post PCI 8.6% 3.7% 5.6% 0.09 Final TIMI flow 3 90.5% 93.7% 90.7% 0.37 Final blush grade 3 81.5% 79.0% 79.5% 0.78 * New or ↑ thrombus, abrupt closure, no reflow, or distal embolization

Composite Ischemia – PCI pts All sub randomized groups 8.5% Bivalirudin + IIb/IIIa Upstream (N=1341) Bivalirudin + IIb/IIIa CCL for PCI (N=1268) 10.4% Bivalirudin alone (N=2619) 9.0% 9.1% UFH/Enox + IIb/IIIa CCl for PCI (N=1289) 7.7% UFH/Enox + IIb/IIIa Upstream (N=1272) KM Estimate P value (vs Biv) 0.71 0.14 0.97 0.20 5 10 15 20 25 30 35 Cumulative Events (%) Days from Randomization P=0.20 *Heparin=unfractionated or enoxaparin

Major Bleeding (Non-CABG) – PCI pts All sub randomized groups 5 10 15 20 25 30 35 Cumulative Events (%) Days from Randomization KM Estimate P value (vs Biv) Bivalirudin + IIb/IIIa Upstream (N=1341) 8.5% <0.001 UFH/Enox + IIb/IIIa CCl for PCI (N=1289) 6.6% <0.001 UFH/Enox + IIb/IIIa Upstream (N=1272) 7.0% <0.001 Bivalirudin + IIb/IIIa CCL for PCI (N=1268) 6.5% <0.001 Bivalirudin alone (N=2619) 3.5% P<0.0001 *Heparin=unfractionated or enoxaparin

Net Clinical Outcomes – PCI pts All sub randomized groups 15 P=0.006 10 Cumulative Events (%) Bivalirudin + IIb/IIIa Upstream (N=1341) Bivalirudin + IIb/IIIa CCL for PCI (N=1268) Bivalirudin alone (N=2619) UFH/Enox + IIb/IIIa CCl for PCI (N=1289) UFH/Enox + IIb/IIIa Upstream (N=1272) KM Estimate P value (vs Biv) 0.003 0.002 0.03 0.31 5 14.9% 15.3% 11.7% 14.2% 12.7% 5 10 15 20 25 30 35 Days from Randomization *Heparin=unfractionated or enoxaparin

REPLACE-2 vs. ACUITY PCI REPLACE-2 (PCI) ACUITY PCI p = 0.40 * R2 major bleeding definition applied to both

Study Limitations Even though the baseline characteristics of the 3 groups were well matched, the ACUITY PCI sub-study is not technically a randomized trial The ACUITY PCI sub-study was under-powered for non-inferiority testing and subgroups All analyses should be considered hypothesis generating Given the complexity of the trial, the study design was open label, and as such bias cannot be excluded The rate of provisional IIb/IIIa inhibitor use for ischemic complications was almost identical to that in the blinded REPLACE-2 trial Use of blinded CECs and core labs reduces but does not eliminate the potential for bias

Conclusions and Clinical Implications In patients with moderate and high risk ACS undergoing PCI Replacing upstream heparin with bivalirudin in pts treated with GP IIb/IIIa inhibitors provides similar clinical and angiographic outcomes Replacing heparin and GP IIb/IIIa inhibitors with bivalirudin alone (with provisional IIb/IIIa inhibitor use in <10% of pts) results in similar rates of ischemia with markedly reduced hemorrhagic complications, thereby improving overall event-free survival