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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.

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  1. 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

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

  3. 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

  4. 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

  5. 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 Trial Moderate-high risk NSTE ACS undergoing invasive care (13, 819 patients, 448 centers,17 countries) Exclusion Criteria Inclusion Criteria ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

  6. Medical management Routine upstream GPI in all pts GPI started in CCL for PCI only PCI R1 R2 R2 CABG ACUITY Design –Randomization Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) UFH or Enoxaparin Bivalirudin Moderate- high risk ACS Routine upstream GPI in all pts Angiography within 72h GPI started in CCL for PCI only 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

  7. 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

  8. ACUITY Primary Results by Treatment NI = non-inferiority; Sup = superiority Dr. Gregg Stone, ACC 2006 Presentation

  9. 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

  10. 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

  11. 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

  12. Combined Ischemic EndpointPCI Cohort by Age Groups 12.2 12.3 11.0 9.3 9.0 8.6 8.6 8.2 8.3 7.1 7.0 6.5 N=2240 N=2052 N=2121 N=1376 Patient Age P for all comparisons = NS

  13. P=0.001 P<0.001 16.5 12.3 P=0.010 P=0.033 P=0.007 P=0.001 P=NS 6.7 6.6 P=0.006 6.1 5.5 5.7 4.2 4.3 4.2 3.0 1.7 N=2240 N=2052 N=2121 N=1376 Patient Age Major Bleeding EndpointPCI Cohort Excluding CABG-related bleeding

  14. 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 Patient Age

  15. Minor BleedingPCI Cohort ** ** ** ** 35.5 ** ** 33.2 * 28.9 28.8 28.6 ** 24.7 22.5 20.6 19.5 14.3 14.4 12.5 N=2240 N=2052 N=2121 N=1376 Patient Age *P<0.001; ** P<0.0001 Excluding CABG-related bleeding

  16. Implication for NNT given the ARR in Minor Bleeding with Bivalirudin vs. Heparin/GPI Major Bleeding Rate with Heparin/GPI 14 10 8 7 Patient Age

  17. Limiting Cohort to CrCl >50cc/minaddressing the question of renal dosing 93% 92% 85.5% 62% Patient Age

  18. Combined Ischemic EndpointsPCI Cohort with CrCl >50 cc/min 12.3 P=0.04 10.4 9.6 9.3 8.7 8.5 8.0 8.0 7.8 7.4 6.7 6.6 N=2063 N=1909 N=1813 N=849 Patient Age All other P = NS

  19. Non-CABG Major Bleeding Endpoint PCI Cohort with CrCl >50 cc/min P=0.019 P<0.001 12.7 9.6 P=0.008 =0.049 P=0.002 P=0.021 P=NS 6.3 5.9 5.7 P=0.012 5.0 4.5 4.1 4.3 3.5 2.8 1.9 N=1813 N=849 N=2063 N=1909 Patient Age Patient Age

  20. Implication for NNT Given ARR in Major Bleeding with Bivalirudin vs. Heparin/GPIPCI Cohort with CrCl >50 cc/min 42 45 34 Major Bleeding Rate with Heparin/GPI 20 Patient Age

  21. 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

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