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Gregg W. Stone MD for the ACUITY Investigators

The ACUITY PCI trial compares outcomes of ACS patients undergoing PCI with different anticoagulants. Key endpoints include clinical benefits at 30 days and angiographic results. Various subgroups and analyses are examined.

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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 (anytime before PCI) Not Thienopyridine Exposed 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.  $297/pt  $827/pt Mean Initial Hospitalization Costs $15,258 $14,953 $14,448 $14,423 $14,126 p<0.001 for overall comparison Cohen DJ. TCT2006

  39. Independent Predictors of Hospital Cost * Also adjusted for age, gender, and diabetes Cohen DJ. TCT2006

  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 reduced hemorrhagic complications, thereby improving overall event-free survival

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