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Gregg W. Stone MD for the ACUITY Investigators

ACUITY PCI A Prospective Trial of Patients with ACS Undergoing PCI after Randomization to Heparin plus GP IIb/IIIa Inhibitors vs. Bivalirudin With or Without GP IIb/IIIa Inhibitors. Gregg W. Stone MD for the ACUITY Investigators. Disclosure. Gregg W. Stone

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Gregg W. Stone MD for the ACUITY Investigators

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  1. ACUITY PCI A Prospective Trial of Patients with ACS Undergoing PCI after Randomization to Heparin plus GP IIb/IIIa Inhibitors vs. Bivalirudin With or Without GP IIb/IIIa Inhibitors Gregg W. Stone MD for the ACUITY Investigators

  2. Disclosure • Gregg W. Stone • Consultant to The Medicines Company and Bristol Myers Squibb Imaging • Lecture fees from The Medicines Company and Nycomed

  3. 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) 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. 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

  5. 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

  6. 3 Primary Endpoints (at 30 Days) 1. Composite net clinical benefit = 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

  7. Composite Ischemia – All pts UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 15 P (log rank) Estimate UFH/Enoxaparin + IIb/IIIa (N=4603) 7.4% 0.37 Bivalirudin + IIb/IIIa (N=4604) 7.9% 10 0.30 Bivalirudin alone (N=4612) 8.0% Cumulative Events (%) 5 0 0 5 10 15 20 25 30 35 Days from Randomization

  8. 15 UFH/Enoxaparin + IIb/IIIa (N=4603) 5.7% 10 5 0 0 5 10 15 20 25 30 35 Major Bleeding (Non CABG) – All pts UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone P (log rank) Estimate 0.41 Bivalirudin + IIb/IIIa (N=4604) 5.3% <0.0001 Bivalirudin alone (N=4612) 3.1% Cumulative Events (%) Days from Randomization

  9. P (log rank) Estimate UFH/Enoxaparin + IIb/IIIa (N=4603) 11.9% 0.89 Bivalirudin + IIb/IIIa (N=4604) 11.9% 0.014 Bivalirudin alone (N=4612) 10.3% Net Clinical Outcomes – All pts UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 15 10 Cumulative Events (%) 5 0 0 5 10 15 20 25 30 35 Days from Randomization

  10. Goals of the ACUITY PCI Sub-study • To examine the outcomes of bivalirudin ± GPIIb/IIIa inhibitors compared to heparin (unfractionated or enoxaparin) + GPIIb/IIIa inhibitors in pts with moderate and high risk ACS undergoing PCI • 3 primary clinical endpoints at 30 days • Angiographic outcomes from a large independent blinded core lab analysis • Specific subgroups and analyses of interest: • Troponin positive pts • Impact of pre-PCI thienopyridine use • “ISAR-REACT-2 like” cohort • Angiographic thrombus

  11. Heparin + IIb/IIIa N = 2,561 Bivalirudin + IIb/IIIa N = 2,609 Bivalirudin alone N = 2,619 Management Strategy (N=13,819) Medical Rx (n=4,491) CABG (n=1,539) 32.2% 11.4% 56.4% PCI (n=7,789)

  12. Baseline Characteristics – PCI pts * creatinine clearance <60 mL/min

  13. Baseline High Risk Features – PCI pts * 84.0% had +biomarkers or baseline ST 97% of all pts had +biomarkers or baseline ST, or were TIMI Int/High risk

  14. Antiplatelet Medications – PCI pts

  15. GP IIb/IIIa Inhibitor Administration – PCI pts * For ischemic complications per protocol in 6.5% of pts

  16. Procedural Characteristics – PCI pts

  17. Device Use – PCI pts

  18. Heparin* + IIb/IIIa (N=2561) 8.4% P (log rank) Estimate 0.15 Bivalirudin + IIb/IIIa (N=2609) 9.4% 0.45 Bivalirudin alone (N=2619) 8.9% Composite Ischemia – PCI pts Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone 15 10 P=0.36 Event Rate (%) 5 0 0 5 10 15 20 25 30 35 Days from Randomization *Heparin=unfractionated or enoxaparin

  19. p=0.16 p=0.45 p=0.16 p=0.19 p=0.37 p=0.53 p=0.31 P=0.87 Components of Ischemia – PCI pts Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone *Heparin=unfractionated or enoxaparin

  20. Adjudicated Stent Thrombosis PCI Patients With ≥1 Stent Implanted (N=7,211) RR 1.00 [0.61-1.64] p=0.99 RR 0.82 [0.51-1.30] p=0.39 RR 1.23 [0.77-1.96] p=0.39

  21. Heparin* + IIb/IIIa (N=2561) 6.8% P (log rank) Estimate 0.31 Bivalirudin + IIb/IIIa (N=2609) 7.6% <0.001 Bivalirudin alone (N=2619) 3.5% Major Bleeding (Non-CABG) – PCI pts Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone 15 10 Event Rate (%) P<0.0001 5 0 0 5 10 15 20 25 30 35 Days from Randomization *Heparin=unfractionated or enoxaparin

  22. Major Bleeding (non-CABG) – PCI pts *P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor

  23. Bleeding Endpoints – PCI pts *P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor

  24. Heparin* + IIb/IIIa (N=2561) 13.5% P (log rank) Estimate 0.10 Bivalirudin + IIb/IIIa (N=2609) 15.1% 0.049 Bivalirudin alone (N=2619) 11.7% Net Clinical Outcomes – PCI pts Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone 15 P=0.001 10 Event Rate (%) 5 0 0 5 10 15 20 25 30 35 Days from Randomization *Heparin=unfractionated or enoxaparin

  25. Impact of Baseline Troponins – PCI pts UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone RR [95%CI] 0.93 [0.77-1.12] RR [95%CI] 1.12 [0.88-1.42] RR [95%CI] 0.59 [0.44-0.80] RR [95%CI] 0.75 [0.57-0.99] RR [95%CI] 1.02 [0.74—1.42] RR [95%CI] 0.36 [0.22-0.61] Troponin + Troponin - Interaction P values = 0.46, 0.86 and 0.28 respectively

  26. Influence of Thienopyridine Exposure – PCI pts 30 Day Primary Endpoint Adverse Events RR [95%CI] 0.81 (0.68-0.96) RR [95%CI] 0.96 (0.77-1.20) RR [95%CI] 0.50 (0.37-0.67) RR [95%CI] 1.07 (0.83-1.39) RR [95%CI] 1.37 (1.00-1.88) RR [95%CI] 0.61 (0.39-0.97) Thienopyridine Exposed* Not Thienopyridine Exposed *Thienopyridine at any time, any dose, up to time of PCI Interaction P values = 0.17, 0.19 and 0.65 respectively

  27. “ISAR-REACT-2 Like” Patients (N=1,358) Troponin+ PCI pts, Thienopyridine use prior to PCI, GPI started after angiography but before PCI RR [95%CI] 0.84 [0.62-0.1.13] RR [95%CI] 1.00 [0.67-1.49] RR [95%CI] 0.53 [0.34-0.83]

  28. Heparin + IIb/IIIa 1,190 pts, 1,616 lsns Bivalirudin + IIb/IIIa 1,254 pts, 1,680 lsns Bivalirudin alone 1,220 pts, 1,617 lsns Core Lab Analysis: Patient Flow All patients N = 13,819 US patients, total and PCI N = 7,851 and 4,254 Goals: 7,000 acquired 6,300 interpretable US core lab analysis, total and PCI N = 6,921 (88.2%) and 3,664 (86.1%) PCI core lab analysis

  29. Procedural Events – PCI pts Any adverse angiographic event (core lab)

  30. Procedural Events – PCI pts Final adverse angiographic events (core lab)

  31. TIMI Flows – PCI ptsCore lab vesselanalysis P1 = H+GPI vs. Biv+GPI; P2 = H+GPI vs. Biv alone

  32. Myocardial Blush – PCI pts Core lab vesselanalysis P1 = H+GPI vs. Biv+GPI; P2 = H+GPI vs. Biv alone

  33. Primary Endpoint Measures Patients with ≥1 PCI Thrombotic Lesion at Baseline (n=712) p=0.37 p=0.58 p=0.67 p=0.03 p=0.22 p=0.61 *Heparin=unfractionated or enoxaparin

  34. Angiographic Outcomes (core lab analysis)Pts with ≥1 PCI Thrombotic Lesions at Baseline (n=712) * New or ↑ thrombus, abrupt closure, no reflow, or distal embolization

  35. P value (vs Biv) KM Estimate 15 Bivalirudin + IIb/IIIa Upstream (N=1341) 8.5% 0.71 UFH/Enox + IIb/IIIa CCl for PCI (N=1289) 9.1% 0.97 UFH/Enox + IIb/IIIa Upstream (N=1272) 7.7% 0.20 Bivalirudin + IIb/IIIa CCL for PCI (N=1268) 10.4% 0.14 Bivalirudin alone (N=2619) 9.0% 10 Cumulative Events (%) 5 0 0 5 10 15 20 25 30 35 Days from Randomization Composite Ischemia – PCI pts All sub randomized groups P=0.20 *Heparin=unfractionated or enoxaparin

  36. 15 10 Cumulative Events (%) 5 0 0 5 10 15 20 25 30 35 Days from Randomization Major Bleeding (Non-CABG) – PCI pts All sub randomized groups P value (vs Biv) KM Estimate Bivalirudin + IIb/IIIa Upstream (N=1341) 8.5% <0.001 UFH/Enox + IIb/IIIa CCl for PCI (N=1289) 6.6% <0.001 UFH/Enox + IIb/IIIa Upstream (N=1272) 7.0% <0.001 Bivalirudin + IIb/IIIa CCL for PCI (N=1268) 6.5% <0.001 Bivalirudin alone (N=2619) 3.5% P<0.0001 *Heparin=unfractionated or enoxaparin

  37. P value (vs Biv) KM Estimate Bivalirudin + IIb/IIIa Upstream (N=1341) 0.003 14.9% UFH/Enox + IIb/IIIa CCl for PCI (N=1289) 0.03 14.2% UFH/Enox + IIb/IIIa Upstream (N=1272) 0.31 12.7% Bivalirudin + IIb/IIIa CCL for PCI (N=1268) 0.002 15.3% Bivalirudin alone (N=2619) 11.7% Net Clinical Outcomes – PCI pts All sub randomized groups 15 P=0.006 10 Cumulative Events (%) 5 0 0 5 10 15 20 25 30 35 Days from Randomization *Heparin=unfractionated or enoxaparin

  38. REPLACE-2 vs. ACUITY PCI ACUITY PCI REPLACE-2 (PCI) p = 0.40 p<0.001 p = 0.30 p = 0.45 p<0.001 p = 0.49 * R2 major bleeding definition applied to both

  39. Study Limitations • Even though the baseline characteristics of the 3 groups were well matched, the ACUITY PCI sub-study is not technically a randomized trial • The ACUITY PCI sub-study was under-powered for non-inferiority testing and subgroups • All analyses should be considered hypothesis generating • Given the complexity of the trial, the study design was open label, and as such bias cannot be excluded • The rate of provisional IIb/IIIa inhibitor use for ischemic complications was almost identical to that in the blinded REPLACE-2 trial • Use of blinded CECs and core labs reduces but does not eliminate the potential for bias

  40. Conclusions and Clinical Implications • In patients with moderate and high risk ACS undergoing PCI • Replacing upstream heparin with bivalirudin in pts treated with GP IIb/IIIa inhibitors provides similar clinical and angiographic outcomes • Replacing heparin and GP IIb/IIIa inhibitors with bivalirudin alone (with provisional IIb/IIIa inhibitor use in <10% of pts) results in similar rates of ischemia with markedly reduced hemorrhagic complications, thereby improving overall event-free survival

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