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Gregg W. Stone MD for the ACUITY Investigators

A Prospective, Randomized Trial of Bivalirudin in Acute Coronary Syndromes Final One-Year Results from the ACUITY Trial. Gregg W. Stone MD for the ACUITY Investigators. Medical management. UFH/Enox + GP IIb/IIIa (n=4,603). PCI. Bivalirudin + GP IIb/IIIa (n=4,604).

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Gregg W. Stone MD for the ACUITY Investigators

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  1. A Prospective, Randomized Trial of Bivalirudin in Acute Coronary SyndromesFinal One-Year Results from the ACUITY Trial Gregg W. Stone MD for the ACUITY Investigators

  2. Medical management UFH/Enox + GP IIb/IIIa (n=4,603) PCI Bivalirudin + GP IIb/IIIa (n=4,604) Angiography within 72h R* Bivalirudin Alone (n=4,612) CABG Study Design – First Randomization Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) 33% Moderate and high risk ACS (n=13,819) 56% Aspirin in all Clopidogrel dosing and timing per local practice 11% *Stratified by pre-angiography thienopyridine use or administration

  3. UFH/Enox + GP IIb/IIIa (N=4,603) GPI upstream (N=2294) GPI CCL for PCI (N=2309) Bivalirudin + GP IIb/IIIa (N=4,604) GPI upstream (N=2311) R* GPI CCL for PCI (N=2293) Bivalirudin Alone (N=4,612) Study Design – Second Randomization Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy Moderate and high risk ACS (n=13,819 Aspirin in all Clopidogrel dosing and timing per local practice *Stratified by pre-angiography thienopyridine use or administration

  4. 3 Primary Endpoints (at 30 Days) 1. Composite net clinical benefit = 2. Ischemic composite or 3. Major bleeding • 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

  5. 1. Composite net clinical benefit = 3 Primary Endpoints (at 30 Days) 2. Ischemic composite or 3. Major bleeding • Non CABG related bleeding • - Intracranial bleeding or intraocular bleeding • -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 product transfusion • Reoperation for bleeding

  6. Baseline Characteristics * creatinine clearance <60 mL/min

  7. Baseline High Risk Features *80.1% were biomarker+ or had baseline STΔ †97% were TIMI intermediate or high risk, or biomarker+, or +STΔ

  8. Primary Endpoint Measures (ITT) – 30 Days UFH/Enoxaparin + GPI vs. Bivalirudin + GPI p value(non inferior)(superior) UFH/Enox + IIb/IIIa Primary endpoint Risk ratio ±95% CI Bival + IIb/IIIa RR (95% CI) <0.001 0.93 Net clinical outcome 11.8% 11.7% 1.01 (0.90-1.12) 0.015 0.39 Ischemic composite 7.7% 7.3% 1.07 (0.92-1.23) Upper boundary non-inferiority <0.001 0.38 Major bleeding 5.3% 5.7% 0.93 (0.78-1.10) Bivalirudin + IIb/IIIa better UFH/Enox + IIb/IIIa better Stone GW et al. NEJM 2006;355:2203-16

  9. Primary Endpoint Measures (ITT) – 30 Days UFH/Enoxaparin + GPI vs. Bivalirudin Alone p value(non inferior)(superior) UFH/Enox + IIb/IIIa Primary endpoint Risk ratio ±95% CI Bival alone RR (95% CI) <0.001 0.015 Net clinical outcome 10.1% 11.7% 0.86 (0.77-0.97) 0.01 0.32 Ischemic composite 7.8% 7.3% 1.08 (0.93-1.24) Upper boundary non-inferiority <0.001 <0.001 Major bleeding 3.0% 5.7% 0.53 (0.43-0.65) Bivalirudin alone better UFH/Enox + IIb/IIIa better Stone GW et al. NEJM 2006;355:2203-16

  10. Medication Compliance: Anti-platelet agents *Greater than 50% of days since last visit

  11. Heparin + IIb/IIIa 4,603 Bivalirudin + IIb/IIIa 4,604 Bivalirudin alone 4,612 Patient Follow-up at 1-Year* All patients N = 13,819 25 Withdrawn 62 Lost to follow-up 25 Withdrawn 66 Lost to follow-up 33 Withdrawn 69 Lost to follow-up Heparin + IIb/IIIa 4,516 (98.1%) 1-year FU Bivalirudin + IIb/IIIa 4,502 (97.8%) 1-year FU Bivalirudin alone 4,521 (98.0%) 1-year FU *Endpoints adjudicated: Composite ischemia (death, MI, unplanned revasc) and stent thrombosis R

  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% Ischemic Composite Endpoint(Death, MI, unplanned revascularization for ischemia) UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 25 20 15 Composite ischemia (%) 10 Bivalirudin+GPI vs. Hep+GPI HR [95% CI] = 1.05 (0.94-1.16) 5 Bivalirudin alone vs. Hep+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

  13. Ischemic Composite Endpoint – GPIIb/IIIa Inhibitor Timing Randomization Routine Upstream GPI vs. Deferred Selective GPI 25 P (log rank) P (log rank) 30 day 1 year Estimate Estimate 20 Routine upstream IIb/IIIa 7.1% 15.7% 0.10 0.15 Deferred selective IIb/IIIa 8.1% 17.2% 15 Composite ischemia (%) 10 5 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization

  14. P (log rank) P (log rank) 30 day 1 year Estimate Estimate p=0.30 Routine upstream IIb/IIIa 0.18 0.20 7.1% 15.7% Deferred selective IIb/IIIa 0.59 0.88 8.1% 17.2% Bivalirudin alone 7.9% — 16.4% — Ischemic Composite Endpoint – GPIIb/IIIa Inhibitor Timing Randomization GPI Strategies vs. Bivalirudin Alone 25 20 15 Composite ischemia (%) 10 5 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization

  15. 17.7% 16.4% 1.14 (0.99-1.30) 14.6% 16.1% 0.95 (0.80-1.14) 16.2% 17.2% 0.97 (0.86-1.11) 16.4% 14.3% 1.20 (1.01-1.44) 19.8% 19.2% 1.09 (0.96-1.23) 21.1% 20.7% 1.04 (0.79-1.36) 9.0% 9.6% 0.97 (0.76-1.24) Composite Ischemia at 1-year UFH/Enoxaparin + GPIIb/IIIa vs. Bivalirudin alone 1 yr KM estimate UFH/Enox + IIb/IIIa Hazard ratio ±95% CI Bival alone HR (95% CI) Pint Biomarkers (CK/Trop) Elevated (n=5072) Normal (n=3402) 0.11 Pre Thienopyridine Yes (n=5751) No (n=3305) 0.07 Actual Treatment PCI (n=5179) CABG (n=1040) Medical (n=2994) 0.67 Bivalirudin alone better UFH/Enox + IIb/IIIa better

  16. Stent Thrombosis (Protocol): Definite/Probable P1 = Bivalirudin+GPI vs. UFH/Enox+GPI; P2 = Bivalirudin alone vs. UFH/Enox+GPI

  17. 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% Mortality: 524 total deaths at 1-year UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 5 Bivalirudin+GPI vs. Hep+GPI HR [95% CI] = 0.99 (0.80-1.22) 4 Bivalirudin alone vs. Hep+GPI HR [95% CI] = 0.95 (0.77-1.18) 3 Mortality (%) 2 30 day 1 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization

  18. 30 day P (log rank) Estimate p=0.45 UFH/Enoxaparin + IIb/IIIa 1.4% — Bivalirudin + IIb/IIIa 0.53 1.6% Bivalirudin alone 0.39 1.6% 30d - 1 year P (log rank) Estimate 3.1% — 0.54 2.7% 0.21 2.3% Early and Late MortalityLandmark analysis 4 3 Mortality (%) 2 1 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization

  19. 30 day P (log rank) 1 year P (log rank) Estimate Estimate p=0.78 UFH/Enoxaparin + IIb/IIIa (N=2560) 0.9% — 3.1% — 0.45 0.91 Bivalirudin + IIb/IIIa (N=2606) 1.2% 2.4% 0.63 0.75 Bivalirudin alone (N=2619) 1.1% 2.2% Early and Late Mortality – PCI SubgroupLandmark analysis 4 3 Mortality (%) 2 1 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization

  20. Routine upstream IIb/IIIa Deferred selective IIb/IIIa Mortality – GPIIb/IIIa Inhibitor Timing Randomization Routine Upstream GPI vs. Deferred Selective GPI 5 4 3 Mortality (%) 2 P (log rank) P (log rank) 30 day 1 year Estimate Estimate 1 1.4% 4.3% 0.34 0.66 1.6% 4.3% 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization

  21. p=0.82 Routine upstream IIb/IIIa 0.30 0.87 Deferred selective IIb/IIIa 0.93 0.54 Bivalirudin alone 1.6% — Mortality – GPIIb/IIIa Inhibitor Timing Randomization GPI Strategies vs. Bivalirudin Alone 5 4 3 Mortality (%) 2 P (log rank) P (log rank) 30 day 1 year Estimate Estimate 1 1.4% 4.3% 1.6% 4.3% 3.8% — 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization

  22. 4.8% 5.0% 1.04 (0.80-1.34) 2.4% 3.6% 0.84 (0.55-1.28) 3.5% 4.2% 0.90 (0.68-1.18) 4.0% 4.4% 1.05 (0.74-1.48) 3.2% 4.0% 0.95 (0.70-1.29) 6.8% 6.7% 1.03 (0.64-1.66) 4.0% 4.3% 0.95 (0.66-1.37) Death at 1-year UFH/Enoxaparin + GPIIb/IIIa vs. Bivalirudin alone 1 yr KM estimate UFH/Enox + IIb/IIIa Hazard ratio ±95% CI Bival alone HR (95% CI) Pint Biomarkers (CK/Trop) Elevated (n=5072) Normal (n=3402) 0.40 Pre Thienopyridine Yes (n=5751) No (n=3305) 0.52 Actual Treatment PCI (n=5179) CABG (n=1040) Medical (n=2994) 0.96 Bivalirudin alone better UFH/Enox + IIb/IIIa better

  23. UFH/Enoxaparin + IIb/IIIa Bivalirudin alone REPLACE-2 + ACUITY-PCI: Mortality UFH/Enoxaparin + GPI vs. Bivalirudin Alone 4 1 year P (log rank) Estimate 3.9% — 3 0.27 3.1% Mortality (%) 2 1 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization

  24. 30 day 30d - 1 year P (log rank) P (log rank) Estimate Estimate UFH/Enoxaparin + IIb/IIIa (n=5568) 0.7% 3.0% — — 0.24 0.79 Bivalirudin alone (n=5613) 0.6% 2.0% REPLACE-2 + ACUITY-PCI: Mortality UFH/Enoxaparin + GPI vs. Bivalirudin Alone 4 3 Mortality (%) 2 1 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization

  25. Patients with Major Bleed (N=645) 14.9% Patients with MI (N=705) 11.4% Patients w/o Major Bleed (N=13,168) 3.6% Patients w/o MI (N=13,108) 3.8% Impact of Major Adverse Events Within 30 Days on Subsequent Mortality Pts with vs. without MI and Major Bleeding within 30d 25 1 year Estimate 20 15 Mortality (%) 10 5 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization

  26. Major Bleed only (without MI) (N=551) 12.5% MI only (without Major Bleed) (N=611) 8.6% No MI or Major Bleed (N=12,557) Both MI and Major Bleed (N=94) 28.9% 3.4% p=0.04 Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year 1 yearEstimate 30 25 20 Mortality (%) 15 10 5 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization

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

  28. Influence of Non-CABG Major Bleeding and MI in the First 30 Days on the Risk of Death Over 1 Year HR ± 95% CI Deaths (n/%) P-value HR (CI) 0.5 1 2 4 8 16

  29. Conclusions • In patients with moderate and high risk ACS undergoing an early invasive strategy with the use of GP IIb/IIIa inhibitors • Bivalirudin is an acceptable substitute for either unfractionated heparin or enoxaparin • Compared to either UFH/enoxaparin with GP IIb/IIIa inhibition or bivalirudin with GP IIb/IIIa inhibition • A bivalirudin alone strategy results in marked reduction of bleeding at 30 days, and similar rates of mortality and composite ischemia at 1-year • The results of this study further establish the important relationship between iatrogenic bleeding complications and the long-term prognosis in patients with ACS

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