1. Gender Differences in Long-Term Outcomes Following PCI of Patients with Non-ST Elevation ACS: Results from the ACUITY Trial Alexandra J. Lansky on behalf of the ACUITY Investigators

2. Disclosures  Alexandra J. Lansky Insert disclosures here  Alexandra J. Lansky Insert disclosures here

3. 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* *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

4. 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)

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

6. UF HeparinEnoxaparinBivalirudin U/Kgmg/Kgmg/kg Bolus601.0 sc bid0.1 iv Infusion/h12 1 0.25 iv PCI ACT 200-250s 0.30 iv bolus 2 0.75 iv bolus 3 0.50 bolus iv 1.75/h infusion iv 4 CABGPer institution Per institution 5 Medical mgtNone 6 Study Medications  Anti-thrombin agents (started pre angiography) 1 Target aPTT 50-75 seconds 2 If last enoxaparin dose ≥8h - <16h before PCI; 3 If maintenance dose discontinued or ≥16h from last dose 4 Discontinued at end of PCI with option to continue at 0.25mg/kg for 4-12h if GPIIb/IIIa inhibitor not used 5 Bivalirudin option for off-pump same as PCI dose. For on-pump bivalirudin discontinued 2 hours before 6 Option to continue with pre-PCI anti-thrombotic regimen at physician discretion

7. 3 Primary Endpoints (at 30 Days)  Composite ischemia  Death, MI, or unplanned revascularization for ischemia  Major bleeding (non-CABG)  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  Net clinical outcome  composite ischemia or major bleeding  Composite ischemia  Death, MI, or unplanned revascularization for ischemia  Major bleeding (non-CABG)  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  Net clinical outcome  composite ischemia or major bleeding

8. Background  Women with non-ST elevation acute coronary syndromes are at increased risk for ischemic and bleeding complications compared to men, especially among those undergoing PCI.  In the ACUITY Trial, women undergoing PCI had similar ischemic event rates but significantly higher major bleeding complications compared to men at 30 days.  Among women, treatment with bivalirudin resulted in significantly less major bleeding and similar ischemic outcomes at 30 days compared with heparin + GP IIb/IIIa inhibitors  Women with non-ST elevation acute coronary syndromes are at increased risk for ischemic and bleeding complications compared to men, especially among those undergoing PCI.  In the ACUITY Trial, women undergoing PCI had similar ischemic event rates but significantly higher major bleeding complications compared to men at 30 days.  Among women, treatment with bivalirudin resulted in significantly less major bleeding and similar ischemic outcomes at 30 days compared with heparin + GP IIb/IIIa inhibitors

9. Objectives  To examine the impact of gender and antithrombotic therapy on early and late outcomes in patients with moderate and high risk ACS undergoing PCI in the ACUITY Trial  We evaluated 30-day non-CABG Major Bleeding and 1-year Composite Ischemia and Mortality among:  Male vs female patients undergoing PCI  Female patients undergoing PCI and being treated with bivalirudin ± GP IIb/IIIa inhibition vs heparin plus GP IIb/IIIa inhibition  To examine the impact of gender and antithrombotic therapy on early and late outcomes in patients with moderate and high risk ACS undergoing PCI in the ACUITY Trial  We evaluated 30-day non-CABG Major Bleeding and 1-year Composite Ischemia and Mortality among:  Male vs female patients undergoing PCI  Female patients undergoing PCI and being treated with bivalirudin ± GP IIb/IIIa inhibition vs heparin plus GP IIb/IIIa inhibition

10. Baseline Characteristics by Gender Males vs. Females Women (N=2091) Men (N=5698) P-value Age (median [range], yrs) 67 (25-95)61 (20-93) <0.0001 Weight (median [IQR], kg) 75 (65, 87)86 (78, 98)<0.0001 Diabetes34.5%25.1%<0.0001 Hypertension74.8%62.1%<0.0001 Hyperlipidemia59.1%55.0%0.002 Current smoker26.9%32.4%<0.0001 Prior MI26.2%32.0%<0.0001 Prior PCI37.7%39.0% 0.27 Prior CABG13.1%19.1%<0.0001 Renal insufficiency*31.0%13.9%<0.0001 Anemia † 19.5%14.4%<0.0001 *Calculated creatinine clearance <60 mL/min using the Cockcroft-Gault equation. † Anemia was defined using the World Health Organization criteria (Hemoglobin ≤13 g/dL for men and ≤12 g/dL for women).

11. Clinical Outcomes by Gender Males vs. Females Women (N=2091) Men (N=5698) P-value 30-Day Major Bleeding 10.7%4.2%<0.0001 1-Year Composite Ischemia 19.6%18.5%0.27 1-Year Mortality3.5%3.1%0.31

12. Baseline Characteristics – Female PCI pts Heparin + IIb/IIIa (N=701) Bivalirudin + IIb/IIIa (N=690) Bivalirudin alone (N=700) Age (median [range], yrs) 68 [25, 91]67 [37, 95]66 [34, 92] Weight (median [IQR], kg) 74 [64, 88]74 [65, 86]76 [65, 88] Diabetes36.1%33.2%34.1% Hypertension73.7%77.7%73.1% Hyperlipidemia57.6%62.9%56.8% Current smoker27.4%26.7%26.5% Prior MI23.9%28.9%25.8% Prior PCI36.3%38.0%38.6% Prior CABG13.3% 12.8% Renal insufficiency*5.5%5.6%5.5% Anemia † 17.8%18.3%18.9% *Calculated creatinine clearance <60 mL/min using the Cockcroft-Gault equation. † Anemia was defined using the World Health Organization criteria (Hemoglobin ≤13 g/dL for men and ≤12 g/dL for women).

13. Baseline High Risk Features – Female PCI pts Heparin + IIb/IIIa (N=701) Bivalirudin + IIb/IIIa (N=690) Bivalirudin alone (N=700)  Cardiac biomarker  (MB or trop) 62.6%61.7%64.5%  - Troponin  63.5%62.3%65.6% ST-segment  ≥1mm 74.1%68.3%72.9%  Cardiac biomarker  or ST-segments  75.2%71.6%74.4% TIMI Risk Score 0-211.9%11.1%10.2% 3-450.6%52.9%54.7% 5-737.5%36.0%35.1%

14. Antiplatelet Medications – Female PCI pts Heparin + IIb/IIIa (N=701) Bivalirudin + IIb/IIIa (N=690) Bivalirudin alone (N=700) Aspirin use or administration pre-angiography or PCI - Yes97.9%97.4%98.0% Thienopyridine use or administration pre PCI - Yes66.0%66.7%67.4% - Clopidogrel65.2%66.6%67.1% - Ticlopidine1.0%0.9%

15. Procedural Characteristics – Female PCI pts Heparin + IIb/IIIa (N=701) Bivalirudin + IIb/IIIa (N=690) Bivalirudin alone (N=700) Attempted lesions per pt 1.47 ± 0.811.43 ± 0.771.42 ± 0.71 - 1 65.7%67.3%68.8% - 225.2%25.8%22.4% - ≥39.1%6.8%8.9% Attempted vessels per pt1.18 ± 0.451.16 ± 0.411.15 ± 0.38 - ≥215.4%14.9%14.3% Target Vessel - Left main1.2%0.8%1.4% - LAD39.8%40.1%39.8% - LCX27.6%26.3%27.0% - RCA31.4%32.9%31.8%

16. Device Use – Female PCI pts   Heparin + IIb/IIIa (N=701) Bivalirudin + IIb/IIIa (N=690) Bivalirudin alone (N=700) Stent implanted94.7%95.8%95.3% Drug-eluting stents62.8%62.2%61.2% - ≥1 Cypher implanted42.5%43.2%41.5% - ≥1 Taxus implanted48.2%48.1%50.2% - ≥1 other DES implanted6.8%8.9%6.6% Non-drug-eluting stent31.9%33.6%34.1% Thrombectomy1.7%0.7%1.4% Distal Protection1.1%1.5%1.1% Atherectomy0.7%0.9%0.3% Cutting Balloon3.0%4.4%3.0%

17. 1-Year Composite Ischemia – Female PCI pts *Heparin=unfractionated or enoxaparin Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone 0306090120150180210240270300330360395 0 5 15 25 10 20 UFH/Enox + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin alone p=0.18 Mortality (%) Days from Randomization

18. 0306090120150180210240270300330360395 0 1 3 5 2 4 UFH/Enox + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin alone p=0.23 Mortality (%) Days from Randomization 1-Year Mortality – Female PCI pts *Heparin=unfractionated or enoxaparin Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone

19. 30-Day Major Bleeding (non-CABG) – Female PCI pts Heparin + IIb/IIIa (N=701) Bivalirudin + IIb/IIIa (N=690) Bivalirudin alone (N=700) P value* Major bleeding11.8%13.9%6.3% <0.001 Intracranial0%0% (1)0% 1.00 Retroperitoneal1.9% 0.3% 0.004 Access site5.7%5.9%1.9% <0.001 - req interv/surgery1.3%1.7%0.9% 0.44 - hematoma ≥5 cm5.0%4.8%1.6% <0.001 Hgb  ≥3 g/dL with overt source 5.6%5.4%1.7% <0.0001 Hgb  ≥4 g/dL with no overt source 1.4%2.5%1.7% 0.66 Blood transfusion6.1%8.1%3.7% 0.04 Reoperation for bleed0%0.1% 0.32 *P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor

20. Bleeding Endpoints – Female PCI pts Heparin + IIb/IIIa (N=701) Bivalirudin + IIb/IIIa (N=690) Bivalirudin alone (N=700) P Value ACUITY Scale - Major Bleed, all12.1%14.1%6.9% <0.001 - Major, non-CABG11.8%13.9%6.3% <0.001 - Minor, non-CABG32.5%34.2%17.1% <0.001 TIMI Scale - Any12.0%12.8%6.7% <0.001 - Major4.0%4.2%1.3% <0.001 - Minor11.8%12.3%6.3% <0.001 Transfusions, non-CABG 6.1%8.1%3.7% 0.04 *P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor

21. Study Limitations  Even though the baseline characteristics of the 3 groups were well matched, the ACUITY PCI Gender sub-study is not a randomized trial  The ACUITY PCI Gender 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  Even though the baseline characteristics of the 3 groups were well matched, the ACUITY PCI Gender sub-study is not a randomized trial  The ACUITY PCI Gender 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

22. Conclusions and Clinical Implications  In patients with moderate and high risk ACS undergoing PCI  Women undergoing PCI have similar long- term ischemia outcomes as men but with significantly increased major bleeding at 30 days.  Among women, treatment with bivalirudin alone resulted in significantly reduced 30 day major bleeding and similar rates of 1-year composite ischemia and mortality compared to heparin + GP IIb/IIIa inhibitors.  In patients with moderate and high risk ACS undergoing PCI  Women undergoing PCI have similar long- term ischemia outcomes as men but with significantly increased major bleeding at 30 days.  Among women, treatment with bivalirudin alone resulted in significantly reduced 30 day major bleeding and similar rates of 1-year composite ischemia and mortality compared to heparin + GP IIb/IIIa inhibitors.