1. Duration Safety and Efficacy of Bivalirudin in patients undergoing PCI: The impact of duration of infusion in ACUITY trial Dr. David Cox Lehigh Valley Hospital Allentown, PA Dr. David Cox Lehigh Valley Hospital Allentown, PA Duration Duration

2. Duration Presenter Disclosure  Consultant, lecture fees from The Medicines Company

3. Duration Bivalirudin as an Alternative to UFH/LMWH  Advantages of the direct thrombin inhibitor bivalirudin  No requirement for anti-thrombin III  Effective on clot-bound thrombin  Inhibits thrombin-mediated platelet activation  No interactions with PF-4  Plasma half-life 25 minutes  No requirement for anticoagulant monitoring  Clinical results with bivalirudin in PCI  Similar protection from ischemic events as UFH + GP IIb/IIIa inhibitors, with markedly reduced bleeding1  Advantages of the direct thrombin inhibitor bivalirudin  No requirement for anti-thrombin III  Effective on clot-bound thrombin  Inhibits thrombin-mediated platelet activation  No interactions with PF-4  Plasma half-life 25 minutes  No requirement for anticoagulant monitoring  Clinical results with bivalirudin in PCI  Similar protection from ischemic events as UFH + GP IIb/IIIa inhibitors, with markedly reduced bleeding1 REPLACE 2. Lincoff AM et al. JAMA 2003;289:853-863

4. Duration Moderate- high risk ACS Study Design  Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) Angiography within 72h Aspirin in all Clopidogrel dosing and timing per local practice UFH or Enoxaparin + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin Alone R* *Stratified by pre-angiography thienopyridine use or administration ACUITY Design. Stone GW et al. AHJ 2004;148:764–75 Medical management PCI CABG

5. Duration Major Entry Criteria  Moderate-high risk unstable angina or NSTEMI ACUITY Design. Stone GW et al. AHJ 2004;148:764–75 Inclusion Criteria  Age ≥18 years  Chest pain ≥10’ within 24h  At least one of:  New ST depression or transient ST elevation ≥1 mm  Troponin I, T, or CKMB   Documented CAD  All other 4 TIMI risk criteria - Age ≥65 years - Aspirin within 7 days - ≥2 angina episodes w/i 24h - ≥3 cardiac risk factors  Written informed consent Exclusion Criteria  No angiography within 72h  Acute STEMI or shock  Bleeding diathesis or major bleed within 2 weeks  Platelet count ≤100,000/mm 3  INR >1.5 control  CrCl ≤30 ml/min  Abcx or ≥2 prior LMWH doses  Prior UFH, LMWH (1 dose), eptifibatide and tirofiban were allowed  Allergy to drugs, contrast

6. Duration Primary Endpoints (30 day)  Net Clinical Outcome  Death, MI, unplanned revascularization for ischemia or non-CABG major bleeding  Composite Ischemic  Death, MI or unplanned revascularization for ischemia  Non-CABG Major Bleeding Endpoint  Intracranial, intraocular, or retroperitoneal bleeding  Access site bleed requiring intervention/surgery  Hematoma ≥5 cm  Hgb  ≥4g/dL w/o overt source  Hgb  ≥3g/dL with an overt source  Reoperation for bleeding  Any blood transfusion  Net Clinical Outcome  Death, MI, unplanned revascularization for ischemia or non-CABG major bleeding  Composite Ischemic  Death, MI or unplanned revascularization for ischemia  Non-CABG Major Bleeding Endpoint  Intracranial, intraocular, or retroperitoneal bleeding  Access site bleed requiring intervention/surgery  Hematoma ≥5 cm  Hgb  ≥4g/dL w/o overt source  Hgb  ≥3g/dL with an overt source  Reoperation for bleeding  Any blood transfusion

7. Duration ACUITY Primary Results (ITT)  Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone P NI <0.001 P Sup = 0.015 P NI = 0.011 P Sup = 0.32 P NI <0.001 P Sup <0.001 *Heparin=unfractionated or enoxaparin

8. Duration ACUITY Major Bleeding Endpoints  Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone *Heparin=unfractionated or enoxaparin All Major Bleeding (All, including CABG) Major Bleeding (Non-CABG related) P Sup =0.38P Sup <0.001P Sup =0.31P Sup 0.001

9. Duration Median Time Intervals: PCI patients Time in hours (interquartile range) Heparin + IIb/IIIa N =2561 Bivalirudin + IIb/IIIa N =2609 Bivalirudin alone N =2619 Admission to start of first PCI 19.7 [6.3-30.5]19.3 [6.3-29.2]19.6 [6.3-30.7] Randomization to first PCI 4.92 [2.0 – 21.2]4.92[ 2.0 – 20.6]5.08 [2.1-21.5] Antithrombin study drug to PCI 4.05 [1.4-18.7]3.85 [1.2-18.7]3.98 [1.4-19.7] Duration of PCI (min)25 [16-41]25 [15-40]25 [15-42]

10. Duration Current Analysis: Objective and Methods  Objective:  Examine the utility of bivalirudin monotheraphy as the antithrombotic regimen in patients with delay to PCI.  Methods:  Comparison of 30-day event rates for net clinical outcomes, ischemia and bleeding in patients undergoing PCI within 24 hours from randomization versus > 24 hours.  Objective:  Examine the utility of bivalirudin monotheraphy as the antithrombotic regimen in patients with delay to PCI.  Methods:  Comparison of 30-day event rates for net clinical outcomes, ischemia and bleeding in patients undergoing PCI within 24 hours from randomization versus > 24 hours.

11. Duration Baseline Characteristics: Patients undergoing PCI > 24 hours after randomization Heparin + IIb/IIIa (N=484) Bivalirudin alone (N=511) P-value Age (median [range], yrs) 65 [31, 91]64 [34, 92]0.60 Male (%) 73.6 0.99 Weight (median [IQR], kg) 83 [73, 94]82 [72, 94]0.82 Diabetes(%) 28.127.20.83 Hypertension (%) 64.760.90.38 Hyperlipidemia (%) 55.747.90.05 Current smoker (%) 30.430.30.30 Prior MI (%) 28.929.70.75 Prior PCI (%) 34.133.10.93 Prior CABG (%) 18.820.00.56 Thienopyridine exposure 80.579.60.71 Renal insufficiency* (%) 21.719.80.47 High Risk* (%) 78.081.10.23 * creatinine clearance <60 mL/min *Elevated cardiac markers and/or ST changes

12. Duration Procedural characteristics: Patients undergoing PCI > 24 hours after randomization Heparin + IIb/IIIa (N=484) Bivalirudin alone (N=511) P- value PCI immediately after angiography (%)78.780.20.554 Attempted vessels per patient (%) 182.682.80.96 214.915.30.86 >=32.31.80.56 Target Vessel LAD (%)41.445.10.250 RCA (%)37.432.00.074

13. Duration Baseline Comparisons Time to PCI 24 hours <= 24 hours (N=6321) > 24 hours (N=1453) P-value Age (median [range], yrs)62 [21, 95]64 [31, 92]<0.001 Male (%)73.173.40.789 Weight (median [IQR], kg)84 [74, 96]82 [72, 93]<0.001 Diabetes(%)27.727.20.700 Hypertension (%)66.361.90.001 Hyperlipidemia (%)57.052.40.002 Current smoker (%)31.030.50.695 Prior MI (%)30.430.60.895 Prior PCI (%)39.933.4<0.001 Prior CABG (%)17.119.20.063 Renal insufficiency* (%)17.920.70.013 Thienopyridine exposure65.580.5<0.001 High Risk* (%)75.380.4<0.001 * creatinine clearance <60 mL/min *Elevated cardiac markers and/or ST changes

14. Duration Primary Endpoint Measures by Duration  Heparin + IIb/IIIa vs. Bivalirudin Alone Time to PCI <= 24 hrsTime to PCI > 24 hrs Results persist after adjusting for differences in baseline characteristics 1.08(0.88-1.33)0.57(0.43-0.75)0.90(0.77-1.07)1.05(0.72-1.52)0.37(0.22-0.65) 0.77(0.57-1.04)

15. Duration Primary Endpoint Measures by Duration Ischemia and Bleeding  Heparin + IIb/IIIa vs. Bivalirudin Alone Results persist after adjusting for differences in baseline characteristics Time to PCI <= 24 hrsTime to PCI > 24 hrs 1.08 (0.88-1.33)0.57 (0.43-1.75)1.05(0.72-1.52)0.37 (0.22-0.65)

16. Duration Non-CABG Bleeding Patients undergoing PCI >24 hours of medical therapy  Heparin* + IIb/IIIa vs. Bivalirudin Alone *Heparin=unfractionated or enoxaparin P< 0.001P=0.008P<0.001P=0.06

17. Duration Primary Endpoint Measures by Duration Ischemia and Bleeding in HIGH Risk PCI*  Heparin + IIb/IIIa vs. Bivalirudin Alone *High Risk: elevated cardiac markers and/or ST changes Results persist after adjusting for differences in baseline characteristics Time to PCI <= 24 hrsTime to PCI > 24 hrs 1.08 (0.86-1.37)0.59 (0.43-0.80)1.10 (0.73-1.66)0.45 (0.26-0.79)

18. Duration 0.90 (0.75-1.09) RR (95% CI) Odds ratio ±95% CI Odds ratio ±95% CI Bivalirudin alone better Heparin + IIb/IIIa better Bleeding Ischemia Net Clinical Outcome 1.14 (0.92-1.41) 0.59 (0.45-0.76) Time to PCI ≤24h 0.66 (0.49-0.89) RR (95% CI) Odds ratio ±95% CI Odds ratio ±95% CI Bivalirudin alone better Heparin + IIb/IIIa better Bleeding Ischemia Net Clinical Outcome 0.98 (0.67-1.43) 0.34 (0.21-0.55) Time to PCI >24h PCI  Results adjusted for baseline characteristics

19. Duration 0.95 (0.79-1.14) RR (95% CI) Odds ratio ±95% CI Odds ratio ±95% CI Bivalirudin alone better Heparin + IIb/IIIa better Bleeding Ischemia Net Clinical Outcome 1.13 (0.89-1.43) 0.61 (0.46-0.82) Time to PCI ≤24h 0.73 (0.53-1.01) RR (95% CI) Odds ratio ±95% CI Odds ratio ±95% CI Bivalirudin alone better Heparin + IIb/IIIa better Bleeding Ischemia Net Clinical Outcome 0.99 (0.66-1.48) 0.41 (0.26-0.67) Time to PCI >24h High-Risk PCI  Results adjusted for baseline characteristics

20. Duration Conclusions  Delay greater than 24 hours in time to PCI in ACS patients may be associated with increased ischemia and bleeding compared to rapid intervention.  Bleeding complications are not increased when using bivalirudin alone.  Compared with Heparin/Enoxaparin with IIb/IIIa inhibitor, bivalirudin monotherapy significantly reduces major bleeding while providing similar ischemic protection regardless of time to PCI.  Delay greater than 24 hours in time to PCI in ACS patients may be associated with increased ischemia and bleeding compared to rapid intervention.  Bleeding complications are not increased when using bivalirudin alone.  Compared with Heparin/Enoxaparin with IIb/IIIa inhibitor, bivalirudin monotherapy significantly reduces major bleeding while providing similar ischemic protection regardless of time to PCI.

21. Duration Limitations  Unblinded non-randomized subgroup analysis  Time to intervention may have been influenced by factors not collected in the study  Unblinded non-randomized subgroup analysis  Time to intervention may have been influenced by factors not collected in the study