TCT Presentation October 2006 Outcomes in Elderly Patients Undergoing PCI Treated with Bivalirudin Monotherapy versus Glycoprotein IIb/IIIa Inhibitors with Heparin or LMWH: Results from the Randomized ACUITY Trial Karen P. Alexander, E. Magnus Ohman, Michel E. Bertrand, Frederic Feit, Charles V. Pollack Jr, James Hoekstra, Bernard J. Gersh, Harvey D. White, Gregg W. Stone for the ACUITY Investigators

TCT Presentation October 2006 Disclosures n Research Funding (Minor): Schering Plough, BMS, Amgen, CV Therapeutics n Speakers Bureau: Pfizer

TCT Presentation October 2006 Background n Elderly patients presenting with NSTE ACS are at high risk for recurrent ischemic events l Use of antithrombotic therapy and an early invasive strategy are beneficial n Elderly patients are at high risk for bleeding with antithrombotic therapy and catheter interventions l Major bleeding is associated with adverse outcomes n Therapy for NSTEACS has become multi-tiered, particularly in pts undergoing PCI

TCT Presentation October 2006 Bivalirudin n Bivalirudin is a direct thrombin inhibitor with certain advantages l Circulating and clot bound thrombin, no requirement for AT III, may reduce thrombin mediated platelet activity l Clearance by proteolysis, with minor renal contribution l Short half life, no required monitoring n Studied in trials which enrolled PCI pts with various comparison groups * l Similar protection from ischemic events l Superior bleeding profile compared to standard combination therapy * Replace-2, Protect TIMI 30, ACUITY, BAT

TCT Presentation October 2006 n n Chest pain ≥10’ within 24h n n At least one of: l l New ST depression or transient ST elevation ≥1 mm l l Troponin I, T, or CKMB  l l Documented CAD l l All other 4 TIMI risk criteria Age ≥65 years Aspirin within 7 days ≥2 angina episodes w/i 24h ≥3 cardiac risk factors ACUITY Design. Stone GW et al. AHJ 2004;148:764–75 n n No angiography within 72h n n Acute STEMI or shock n n Bleeding diathesis or major bleed within 2 weeks n n Platelet count ≤100,000/mm3 n n INR >1.5 control n n CrCl ≤30 ml/min n n Abcx or ≥2 prior LMWH doses l l Prior UFH, LMWH (1 dose), eptifibatide and tirofiban OK Inclusion Criteria Exclusion Criteria ACUITY Trial Moderate-high risk NSTE ACS undergoing invasive care (13, 819 patients, 448 centers,17 countries)

TCT Presentation October 2006 Moderate- high risk ACS ACUITY Design –Randomization Angiography within 72h Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) ACUITY Design. Stone GW et al. AHJ 2004;148:764–75 Aspirin in all Clopidogrel dosing and timing per local practice* Aspirin in all Clopidogrel dosing and timing per local practice* Medical management PCI CABG Bivalirudin Alone UFH or Enoxaparin Routine upstream GPI in all pts GPI started in CCL for PCI only Bivalirudin R2R2 R2R2 Routine upstream GPI in all pts GPI started in CCL for PCI only R1R1 *Stratified by pre-angiography thienopyridine use or administration

TCT Presentation October 2006 ACUITY Primary Endpoint at 30 days n Net Clinical Endpoint l Composite ischemic and non-CABG major bleeding endpoints n Ischemic Endpoint l Death, MI, or unplanned revascularization n Non-CABG Major Bleeding Endpoint l Intracranial, intraocular, or retroperitoneal bleeding l Access site bleed requiring intervention/surgery l Hematoma ≥5 cm l Hgb  ≥3g/dL with an overt source or  ≥4g/dL w/o overt source l Blood transfusion

TCT Presentation October 2006 ACUITY Primary Results by Treatment Heparin + GP IIb/IIIa (4603) Bivalirudin + GP IIb/IIIa (4604) Bivalirudin alone (4612) EndpointRateRate P Value Rate Net clinical outcome 11.7%11.8% <0.001 NI 10.1% Sup Ischemic events 7.3%7.7% NI 7.8% NI Major bleeding 5.7%5.3% <0.001 NI 3.0% <0.001 Sup NI = non-inferiority; Sup = superiority Dr. Gregg Stone, ACC 2006 Presentation

TCT Presentation October 2006 Purpose n To compare age subgroup results with Bivalirudin monotherapy, heparin/GPI and Bival/GPI in PCI patients in ACUITY l Ischemic Endpoints l Major and Minor Bleeding n Describe differences across age l In terms of absolute risk reduction l Among those with preserved renal function

TCT Presentation October 2006 Baseline Characteristics by Age Subgroups PCI Cohort n=7,789; 56% < ≥75 N (%)2,052 (26.3)2,240 (28.8)2,121 (27.2)1,376 (17.7) Age (yrs)48.0 ± ± ± ±3.5 Weight (kg)92.1 ± ± ± ±14.1 Female (%) HTN DM CVA Renal Insuff EF <30% Continuous Variables as Means ± SD

TCT Presentation October 2006 Cardiac Markers and Creatinine Clearance PCI Cohort n=7,789; 56% < ≥75 N (%)2,052 (26.2)2,240 (28.8)2,121 (27.2)1,376 (17.7) Hgb (mg/dl)14.6 ± ± ± ±1.6 Troponin I (>ULN) CrCl (ml/min)127 ±62107 ±31879 ±3659 ±36 CrCl ≥ 90 (%) CrCl (%) CrCl (%) CrCl <30 (%) Continuous Variables as Means ± SD

TCT Presentation October 2006 Combined Ischemic Endpoint PCI Cohort by Age Groups Patient Age N=2052 N=2240 N=2121 N=1376 P for all comparisons = NS

TCT Presentation October 2006 Major Bleeding Endpoint PCI Cohort Patient Age N=1376 N=2121 N=2240 N=2052 P=0.006 P=0.001 P=NS P<0.001 P=0.007 P=0.010 P=0.033 P=0.001 Excluding CABG-related bleeding

TCT Presentation October 2006 Patient Age Implication for Number Needed to Treat (NNT) Given the Absolute Risk Reduction (ARR) in Major Bleeding with Bivalirudin vs. Heparin/GPI

TCT Presentation October 2006 Minor Bleeding PCI Cohort Patient Age N=1376 N=2121 N=2240 N=2052 ** * *P<0.001; ** P< Excluding CABG-related bleeding

TCT Presentation October 2006 Patient Age Implication for NNT given the ARR in Minor Bleeding with Bivalirudin vs. Heparin/GPI Major Bleeding Rate with Heparin/GPI

TCT Presentation October 2006 Limiting Cohort to CrCl >50cc/min addressing the question of renal dosing 93% Patient Age 92% 85.5% 62%

TCT Presentation October 2006 Combined Ischemic Endpoints Combined Ischemic Endpoints PCI Cohort with CrCl >50 cc/min Patient Age N=1909 N=2063 N=1813 N=849 All other P = NS P=0.04

TCT Presentation October 2006 Non-CABG Major Bleeding Endpoint PCI Cohort with CrCl >50 cc/min Patient Age N=849 N=1813 N=2063 N= Patient Age P=0.012 P=0.002 P=NS P<0.001 P=0.021 P=0.008 =0.049 P=0.019

TCT Presentation October 2006 Patient Age Major Bleeding Rate with Heparin/GPI Implication for NNT Given ARR in Major Bleeding with Bivalirudin vs. Heparin/GPI PCI Cohort with CrCl >50 cc/min

TCT Presentation October 2006 Conclusions n Ischemic and hemorrhagic events increase with age n Across all age groups, bivalirudin is associated with significantly less major and minor bleeding and similar ischemic outcomes l Even among those with preserved renal function l ARR for major bleeding was greatest in the elderly (age >75) NNT of 16 to prevent one major bleed NNT of 8 to prevent one minor bleed n Dose all agents carefully, fewer agents may be better