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

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

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:

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

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

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

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

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

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 [ ]19.3 [ ]19.6 [ ] Randomization to first PCI 4.92 [2.0 – 21.2]4.92[ 2.0 – 20.6]5.08 [ ] Antithrombin study drug to PCI 4.05 [ ]3.85 [ ]3.98 [ ] Duration of PCI (min)25 [16-41]25 [15-40]25 [15-42]

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.

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 (%) Weight (median [IQR], kg) 83 [73, 94]82 [72, 94]0.82 Diabetes(%) Hypertension (%) Hyperlipidemia (%) Current smoker (%) Prior MI (%) Prior PCI (%) Prior CABG (%) Thienopyridine exposure Renal insufficiency* (%) High Risk* (%) * creatinine clearance <60 mL/min *Elevated cardiac markers and/or ST changes

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 (%) Attempted vessels per patient (%) >= Target Vessel LAD (%) RCA (%)

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 (%) Weight (median [IQR], kg)84 [74, 96]82 [72, 93]<0.001 Diabetes(%) Hypertension (%) Hyperlipidemia (%) Current smoker (%) Prior MI (%) Prior PCI (%) <0.001 Prior CABG (%) Renal insufficiency* (%) Thienopyridine exposure <0.001 High Risk* (%) <0.001 * creatinine clearance <60 mL/min *Elevated cardiac markers and/or ST changes

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( )0.57( )0.90( )1.05( )0.37( ) 0.77( )

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 ( )0.57 ( )1.05( )0.37 ( )

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

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 ( )0.59 ( )1.10 ( )0.45 ( )

Duration 0.90 ( ) 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 ( ) 0.59 ( ) Time to PCI ≤24h 0.66 ( ) 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 ( ) 0.34 ( ) Time to PCI >24h PCI  Results adjusted for baseline characteristics

Duration 0.95 ( ) 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 ( ) 0.61 ( ) Time to PCI ≤24h 0.73 ( ) 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 ( ) 0.41 ( ) Time to PCI >24h High-Risk PCI  Results adjusted for baseline characteristics

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.

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