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

Disclosures Research Funding (Minor): Schering Plough, BMS, Amgen, CV Therapeutics Speakers Bureau: Pfizer

Background Elderly patients presenting with NSTE ACS are at high risk for recurrent ischemic events Use of antithrombotic therapy and an early invasive strategy are beneficial Elderly patients are at high risk for bleeding with antithrombotic therapy and catheter interventions Major bleeding is associated with adverse outcomes Therapy for NSTEACS has become multi-tiered, particularly in pts undergoing PCI The elderly with NSTE ACS experience a high incidence of recurrent ischemic events and death. The use of antithrombotic therapy and an early invasive strategy both reduce the risk of recurrent events. However, elderly are also at particular risk from bleeding complications related to antithrombotic therapy and catheter interventions. As new therapeutic agents continue to be added to the list of beneficial therapies, the ideal combination of these agents remains debated. There is continued need for optimizing the therapeutic regimen to minimize treatment associated risks.

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

ACUITY Trial Moderate-high risk NSTE ACS undergoing invasive care (13, 819 patients, 448 centers,17 countries) Inclusion Criteria Exclusion Criteria 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 No angiography within 72h Acute STEMI or shock Bleeding diathesis or major bleed within 2 weeks Platelet count ≤100,000/mm3 INR >1.5 control CrCl ≤30 ml/min Abcx or ≥2 prior LMWH doses Prior UFH, LMWH (1 dose), eptifibatide and tirofiban OK ACUITY enrolled moderate risk ACS pts undergoing invasive care to evaluate a number of antithrombotic strategies in this population. ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

ACUITY Design –Randomization Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) UFH or Enoxaparin Routine upstream GPI in all pts GPI started in CCL for PCI only Medical management PCI CABG R2 Moderate- high risk ACS Bivalirudin Routine upstream GPI in all pts Angiography within 72h R1 GPI started in CCL for PCI only ACUITY had two randomization points. The first randomization was to one of three treatment arms, and the second randomization was within the combined hep or bival with GPI treatment arms to either upstream or cardiac cath lab initiation of the GPI. In this trial, approximately 7% of patients with Bivalirudin monotherapy also received “Bail Out” GPI inhibitors. The use of oral antiplatelet agents was high among all three treatment arms; use of ASA occurred in over 98%; use of clopidogrel either prior to enrollment, or prior to intervention occurred in approximately 85%. Aspirin in all Clopidogrel dosing and timing per local practice* Bivalirudin Alone *Stratified by pre-angiography thienopyridine use or administration ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

ACUITY Primary Endpoint at 30 days Net Clinical Endpoint Composite ischemic and non-CABG major bleeding endpoints Ischemic Endpoint Death, MI, or unplanned revascularization Non-CABG Major Bleeding Endpoint Intracranial, intraocular, or 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 transfusion

ACUITY Primary Results by Treatment Heparin + GP IIb/IIIa (4603) Bivalirudin + GP IIb/IIIa (4604) Bivalirudin alone (4612) Endpoint Rate P Value Net clinical outcome 11.7% 11.8% <0.001 NI 10.1% 0.015 Sup Ischemic events 7.3% 7.7% 0.007 NI 7.8% 0.011 NI Major bleeding 5.7% 5.3% 3.0% <0.001 Sup NI = non-inferiority; Sup = superiority Dr. Gregg Stone, ACC 2006 Presentation

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

Baseline Characteristics by Age Subgroups PCI Cohort n=7,789; 56% <55 55-64 65-74 ≥75 N (%) 2,052 (26.3) 2,240 (28.8) 2,121 (27.2) 1,376 (17.7) Age (yrs) 48.0 ±4.9 59.6 ±2.8 69.3 ±2.9 79.3 ±3.5 Weight (kg) 92.1 ±19.9 88.4 ±17.7 83.4 ±16.0 76.4 ±14.1 Female (%) 18.4 23.3 29.8 40.6 HTN 50.7 63.4 73.4 77.0 DM 22.0 28.1 30.7 29.4 CVA 2.5 5.0 6.9 9.4 Renal Insuff 2.1 4.5 7.3 11.0 EF <30% 2.5 3.6 3.4 4.3 Continuous Variables as Means ± SD

Cardiac Markers and Creatinine Clearance PCI Cohort n=7,789; 56% <55 55-64 65-74 ≥75 N (%) 2,052 (26.2) 2,240 (28.8) 2,121 (27.2) 1,376 (17.7) Hgb (mg/dl) 14.6 ±1.5 14.3±1.5 13.9 ±1.6 13.4 ±1.6 Troponin I (>ULN) 65.2 63.9 63.8 62.8 CrCl (ml/min) 127 ±62 107 ±318 79 ±36 59 ±36 CrCl ≥ 90 (%) 84.8 60.9 25.8 4.7 CrCl 60-90 (%) 13.4 33.0 53.0 36.3 CrCl 30-60 (%) 1.0 5.4 20.6 55.2 CrCl <30 (%) 0.8 0.7 0.6 3.7 Continuous Variables as Means ± SD

Combined Ischemic Endpoint PCI Cohort by Age Groups 12.3 12.2 11.0 9.3 9.0 8.6 8.6 8.3 8.2 7.0 7.1 6.5 There were no significant differences in the occurrence of the combined ischemic endpoint, or its components, in any of the 4 age groups. This is consistent with the results of the overall ACUITY trial which demonstrated noninferiority for bivalirudin. N=2052 N=2240 N=2121 N=1376 Patient Age P for all comparisons = NS

Major Bleeding Endpoint PCI Cohort 4.3 4.2 1.7 5.7 6.6 3.0 6.7 5.5 12.3 16.5 6.1 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 The rate of major bleeding increases significantly with age. However, across all age groups, there was a significantly lower rate of major bleeding with bivalirudin monotherapy. Among those age >75, the rate of major bleeding was 11% overall, 16.5% with bivalirudin with GPI, but just 6.1% with bival alone. Excluding CABG-related bleeding

Implication for Number Needed to Treat (NNT) Given the Absolute Risk Reduction (ARR) in Major Bleeding with Bivalirudin vs. Heparin/GPI 40 38 37 16 While the relative risk reduction in bleeding was similar across age with bivalirudin, there was a greater absolute risk reduction seen in the older patient subgroups. The impact of absolute risk reduction is also shown by the calculation of the NNT to prevent one event. Specifically, while an ARR of 2.5% corresponds to a NNT of 40, an ARR of over 6% in the elderly (age >75) corresponds to a NNT of 16 with bivalirudin to prevent one major bleeding event. Patient Age

Minor Bleeding PCI Cohort ** ** ** ** 35.5 ** ** 33.2 * 28.9 28.6 28.8 ** 24.7 22.5 19.5 20.6 14.3 14.4 12.5 The rate of minor bleeding also increases significantly with age. Across all age groups, there was a significantly lower, and nearly half, the rate of minor bleeding with bivalirudin monotherapy compared to the other treatment arms. N=2052 N=2240 N=2121 N=1376 Patient Age *P<0.001; ** P<0.0001 Excluding CABG-related bleeding

Implication for NNT given the ARR in Minor Bleeding with Bivalirudin vs. Heparin/GPI Major Bleeding Rate with Heparin/GPI 14 10 8 7 When the ARR in minor bleeding, which is between 10 and 15% for bival vs. heparin/GPI, is applied across age groups, the NNT with bival is in the single digits above age 65 years. Patient Age

Limiting Cohort to CrCl >50cc/min addressing the question of renal dosing 93% 92% 85.5% 62% By limiting the population to those with CrCl above 50, we can eliminate the question of dose adjustment for the GP IIb/IIIa inhibitors as a contributor to the bleeding rates observed in those two arms. The ACUITY population had an exclusion for pts with crcl <30, and the average renal function was >60 mg/dL in each age group, so this additional cut made little difference in the size of the groups <75. However, 40% of pts over age 75 were excluded from this comparison. Patient Age

Combined Ischemic Endpoints PCI Cohort with CrCl >50 cc/min 12.3 P=0.04 10.4 9.6 9.3 8.7 8.5 7.8 8.0 8.0 7.4 6.7 6.6 Again, no significant differences across age subgroups were noted in ischemic endpoints in the three treatment arms. N=1909 N=2063 N=1813 N=849 Patient Age All other P = NS

Non-CABG Major Bleeding Endpoint PCI Cohort with CrCl >50 cc/min 12.7 9.6 P=0.008 =0.049 P=0.002 P=0.021 6.3 P=NS 5.9 P=0.012 5.7 5.0 4.5 4.1 4.3 3.5 And similar significantly lower bleeding was noted in the bival monotherapy arms. 2.8 1.9 N=1909 N=2063 N=1813 N=849 Patient Age Patient Age

Implication for NNT Given ARR in Major Bleeding with Bivalirudin vs Implication for NNT Given ARR in Major Bleeding with Bivalirudin vs. Heparin/GPI PCI Cohort with CrCl >50 cc/min 42 45 34 Major Bleeding Rate with Heparin/GPI 20 The rate of major bleeding in the hep/GPI arm is lower among the subset with crcl >50 as shown in the bars, with a 9.6% occurrence in the elderly age >75. However, the relationship between absolute risk and the NNT is similar with a NNT of 19 with Bivalirudin alone versus Hep and GPI to prevent one major bleed. This is compared with a NNT of 12 in all patients over age 75. Patient Age

Conclusions Ischemic and hemorrhagic events increase with age Across all age groups, bivalirudin is associated with significantly less major and minor bleeding and similar ischemic outcomes Even among those with preserved renal function 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 Dose all agents carefully, fewer agents may be better The antithrombotic analogy to “start low, go slow” when initiating drugs in the elderly, may well be “Dose carefully, fewer agents may be better.”