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Safety and Efficacy of Bivalirudin in Patients with Non-ST Elevation Acute Coronary Syndromes Undergoing Medical Management: One Year Results from the Randomized ACUITY Trial.

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  1. Safety and Efficacy of Bivalirudin in Patients with Non-ST Elevation Acute Coronary Syndromes Undergoing Medical Management: One Year Results from the Randomized ACUITY Trial Walter Desmet, Lars Rasmussen, A. Michael Lincoff, Angel Cequier, Hans-Jürgen Rupprecht, Bernard Gersh, Steven Manoukian, Michel Bertrand, Gregg Stone

  2. Presenter Disclosure Information Walter Desmet, MD, PhD Safety and Efficacy of Bivalirudin in Patients With Non-ST Elevation Acute Coronary Syndromes Undergoing Medical Management:One Year Results from the Randomized ACUITY Trial FINANCIAL DISCLOSURE: no disclosure to make UNLABELED/UNAPPROVED USES DISCLOSURE: Bivalirudin is not approved for the indication discussed

  3. Background: Current Management of ACS • Early invasive strategy if moderate-high risk1,2 • Median time to cath 21 hours3 • Revascularization with PCI or CABG1,2 • 55% PCI, 12% CABG, 33% medical mgt3 • Triple anti-platelet therapy1,2 • Aspirin • Clopidogrel (initiated pre or post angiography) • GP IIb/IIIa inhibitors - started upstream in all pts or in the CCL for PCI • Unfractionated or LMW heparin1,2,4 1 Braunwald et al JACC 2002; 2 Bassand et al. EHJ 2007; 3www.crusade.org; 4SYNERGY. JAMA 2004;292:45-54

  4. 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 Not previously tested in contemporary ACS patients Bivalirudin as an Alternative to UFH/LMWH REPLACE 2. Lincoff AM et al. JAMA 2003;289:853-863

  5. 89 (0.6%) Norway Sweden 175 (1.3%) 150 (1.1%) Denmark Finland 51 (0.4%) 132 (1.0%) Netherlands 438 (3.2%) Canada 198 (1.4%) Belgium Poland 14 (0.1%) 162 (1.2%) UK Germany 2561 (18.5%) 155 (1.1%) France 7851 (56.8%) USA Austria 356 (2.6%) Italy 238 (1.7%) 547 (4.0%) Spain 203 (1.5%) New Zealand 499 (3.6%)Australia ACUITY Enrollment 13,819 pts randomized at 448 centers in 17 countries

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

  7. Major Entry Criteria Moderate-high risk unstable angina or NSTEMI Inclusion Criteria Exclusion 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 • 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 were allowed • Allergy to drugs, contrast ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

  8. Primary Endpoints (at 30 days) Net Clinical Outcome (Composite Ischemia, Non-CABG Major Bleeding) Composite Ischemia: • Death from any cause • Myocardial infarction • During medical Rx: Any biomarker elevation >ULN • Post PCI: CKMB >ULN with new Q waves or >3x ULN w/o Q waves • Post CABG: CKMB >5x ULN with new Q waves, >10x ULN w/o Q waves • Unplanned revascularization for ischemia Non CABG related bleeding • Intracranial bleeding or intraocular bleeding • Retroperitoneal bleeding • Access site bleed requiring intervention/surgery • Hematoma ≥5 cm • Hgb  ≥ 3 g/dL with , or  ≥ 4 g/dL without overt source • Blood product transfusion • Reoperation for bleeding

  9. Primary Endpoints (at 1 Year) Composite Ischemia: • Death from any cause • Myocardial infarction • During medical Rx: Any biomarker elevation >ULN • Post PCI: CKMB >ULN with new Q waves or >3x ULN w/o Q waves • Post CABG: CKMB >5x ULN with new Q waves, >10x ULN w/o Q waves • Unplanned revascularization for ischemia

  10. Invasive Management *in patients receiving study antithrombin pre angiography †median (IQR)

  11. Overall 30-day Results by Treatment Arm †non-inferiority; ‡superiority Stone GW et al. NEJM 2006;355:2203-16

  12. 30 day P (log rank) 1 year P (log rank) Estimate Estimate p=0.55 UFH/Enoxaparin + IIb/IIIa 7.4% — 16.3% — 0.36 0.38 Bivalirudin + IIb/IIIa 7.8% 16.5% 0.34 0.31 Bivalirudin alone 7.9% 16.4% 1 Year Composite Ischemia by Treatment Arm Overall Population UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 25 20 15 Ischemic Composite (%) 10 Bivalirudin+GPI vs. H+GPI HR [95% CI] = 1.05 (0.94-1.16) 5 Bivalirudin alone vs. H+GPI HR [95% CI] = 1.05 (0.95-1.17) 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization Stone GW. ACC 2007 presentation

  13. p=0.90 UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone P (log rank) 1 year P (log rank) Estimate Estimate 1.4% — 4.4% — 0.53 0.93 1.6% 4.2% 0.39 0.66 1.6% 3.8% 1 Year Mortality by Treatment Arm Overall Population UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 5 Bivalirudin+GPI vs. H+GPI HR [95% CI] = 0.99 (0.80-1.22) 4 Bivalirudin alone vs H+GPI HR [95% CI] = 0.95 (0.77-1.18) 3 Mortality (%) 2 1 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization Stone GW. ACC 2007 presentation

  14. Heparin + IIb/IIIa N = 1,493 Bivalirudin + IIb/IIIa N = 1,496 Bivalirudin alone N = 1,502 Management Strategy (N=13,819) CABG (n=1,539) PCI (n=7,789) 56.4% 11.1% 32.5% MM (n=4,491)

  15. MM 32.5 % PCI 56.4 % Angiography within 72h R* CABG 11.1% Purpose of this post-hoc analysis Compare clinical outcome of patients managed medically 1) to clinical outcome in revascularized patients 2) between the 3 randomization groups *Stratified by pre-angiography thienopyridine use or administration ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

  16. Patient Characteristics

  17. Medical Management (MM) Non-Medical Management (non-MM) 16 12 8 4 0 Net Clinical Outcome Composite Ischemia Major Bleeding 30-day Results by Management Strategy P<0.001 14.0% P<0.001 9.9% 30 day events (%) P<0.001 5.5% 5.5% 3.1% 2.9%

  18. Heparin + GP IIb/IIIa (N = 1,493) Bivalirudin + GPI (N = 1,496) 10 P=0.06 P=0.09 Bivalirudin (N = 1,502) 8 P=0.67 P=0.36 P<0.001 P=0.004 6 4 2 0 Net Clinical Outcome Composite Ischemia Major Bleeding 30 Day Results by Treatment Arm Medical Management Population 6.5% 30 day events (%) 5.1% 4.9% 4.4% 3.4% 3.1% 2.8% 2.5% 1.9%

  19. Medical Management (MM) (N = 4,491) Non-Medical Management (non-MM) (N = 9,328) 20 16 12 8 4 0 Composite Ischemia Mortality 1 Year Results by Management Strategy P<0.0001 19.0% Percentage (%) 8.9% P=0.65 3.9% 3.7%

  20. P=0.99 P=0.81 Heparin + GP IIb/IIIa (N = 1,493) Bivalirudin + GPI (N = 1,496) Bivalirudin (N = 1,502) 1 Year Results by Treatment Arm Medical Management Population 10 9.0% 9.0% 8.7% P=0.84 P=0.75 8 Percentage (%) 6 4.0% 3.9% 3.8% 4 2 0 Ischemic Composite Mortality

  21. Influence of Major Bleeding and MI in the First 30 Days on Risk of Death Over 1 Year Medical Management Population HR (95% CI) P-value HR ± 95% CI Cox model adjusted for baseline predictors, with non-CABG major bleeding and MI as time-updated covariates

  22. Comprise a unique patient cohort with different demographic risk factors fewer high-risk features (trop  / ECG ∆) less major bleeding fewer ischemic events than patients requiring PCI or CABG Conclusions Patients triaged to medical management with moderate and high risk NSTE-ACS

  23. Conclusions In moderate and high risk NSTE-ACS patients triaged to medical management • Bivalirudin with or without a GPI results in marked reduction of bleeding at 30 days, while preserving the ischemic and mortality benefit at 1-year • Early iatrogenic bleeding complications are significantly associated with long-term prognosis

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