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Gregg W. Stone MD for the ACUITY Investigators

Prospective, Randomized Comparison of Heparin Plus IIb/IIIa Inhibition and Bivalirudin With or Without IIb/IIIa Inhibition in Patients with Acute Coronary Syndromes. Gregg W. Stone MD for the ACUITY Investigators. Background: Current Management of ACS.

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Gregg W. Stone MD for the ACUITY Investigators

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  1. Prospective, Randomized Comparison of Heparin Plus IIb/IIIa Inhibition and Bivalirudin With or Without IIb/IIIa Inhibition in Patients with Acute Coronary Syndromes Gregg W. Stone MD for the ACUITY Investigators

  2. 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 Bertrand et al. EHJ 2002; 3www.crusade.org; 4SYNERGY. JAMA 2004;292:45-54

  3. Bivalirudin as an Alternative to UFH/LMWH • 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 REPLACE 2. Lincoff AM et al. JAMA 2003;289:853-863

  4. Bivalirudin in ACS: Hypotheses • In moderate-high risk patients with ACS undergoing an invasive strategy, compared to UFH or LMWH + GP IIb/IIIa inhibitors: • Bivalirudin + GP IIb/IIIa inhibitors will result in less adverse ischemic events and less bleeding • Bivalirudin alone will result in similar rates of ischemic events and markedly reduced bleeding

  5. Medical management UFH or Enoxaparin + GP IIb/IIIa PCI Bivalirudin + GP IIb/IIIa Angiography within 72h R* Bivalirudin Alone CABG Study Design – First Randomization Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800) 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

  6. UFH or Enoxaparin Medical management Routine upstream GPI in all pts GPI started in CCL for PCI only PCI Bivalirudin Routine upstream GPI in all pts R R GPI started in CCL for PCI only Bivalirudin Alone CABG Study Design – Second Randomization Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800) Moderate- high risk ACS Angiography within 72h Aspirin in all Clopidogrel dosing and timing per local practice 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. Study Medications • Anti-thrombin agents (started pre angiography) 1 Target aPTT 50-75 seconds 2 If last enoxaparin dose ≥8h - <16h before PCI; 3 If maintenance dose discontinued or ≥16h from last dose 4 Discontinued at end of PCI with option to continue at 0.25mg/kg for 4-12h if GPIIb/IIIa inhibitor not used 5 Bivalirudin option for off-pump same as PCI dose. For on-pump bivalirudin discontinued 2 hours before 6 Option to continue with pre-PCI anti-thrombotic regimen at physician discretion

  9. 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

  10. 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

  11. Statistical Plan • Anticipated event rates on UFH/Enox + GP IIb/IIIa • Ischemic composite: 6.5% • Major bleeding: 9.0% • Net clinical outcome: 12.4% • Significance testing • Sequential non-inferiority and superiority tests • Non-inferiority tests: One-sided a=0.025; =25% • Superiority tests: Two sided a=0.05 • Hochberg procedure1 used to control type I error •  Sample size estimate = 13,800 patients 1Benjamini & Hochberg. J R Stat Soc 1995

  12. Event Rates and Power Calculations NI = non-inferiority; Sup = superiority

  13. Event Rates and Power Calculations NI = non-inferiority; Sup = superiority

  14. Event Rates and Power Calculations NI = non-inferiority; Sup = superiority

  15. Study Organization • Principal Investigator Gregg W. Stone • Columbia University, NYC, NY • Executive Committee Michel Bertrand • Hosp. Cardiologique, Lambersart, France • A. Michael Lincoff • Cleveland Clinic, Cleveland, Ohio • Jeffrey W. Moses • Columbia University, NYC, NY • Magnus Ohman • Duke University, Durham, NC • Harvey D. White • Green Lane Hosp., Auckland, NZ

  16. Steering Committee Frederick Feit (Chair)New York University NYC, NY Antonio Columbo (EU Chair) Ospedael San Raphael Milano, Italy Ramin EbrahimiVA Medical Ctr West Los Angeles Los Angelas, CA Lars Hvilsted RasmussenAlborg Sygehus, Afdeling Syd Alborg, Denmark Hans-Jürgen RupprechtGpr Klinikum Rüsselsheim Rüsselsheim, Germany Phil AylwardFlinders Medical Centre Bedford Park, Australia Angel CequierCiutat Sanitària Belvitge Barcelona, Spain Walter DesmetUniversity Hospital, Gasthuisberg Leuven, Belgium Harold DariusKrankenhaus Neukölln Berlin, Germany Martial HamonUniversity Hospital Caen Cedex, France James HoekstraWake Forest University Lewisville, NC Charles V. PollackPennsylvania Hospital Philadelphia, PA Study Organization

  17. Study Organization Statistical Committee Stuart Pocock London School of Hygiene and Tropical Medicine, London, UK Jim Ware Harvard University, Boston, Mass. Data Monitoring The Medicines Company/Nycomed Data Management eTrials/The Medicines Company Clinical Events Committee Roxana Mehran, Director Cardiovascular Research Foundation, NY Angio. Core Laboratory Alexandra Lansky, Director Cardiovascular Research Foundation, NY Health Economics and David J. Cohen (Chair) Cost-Effectiveness Beth Israel Deaconess,Boston, Mass.

  18. Study Organization Biomarker Substudy George Dangas (Chair) Columbia University, NYC, NY W. Craig Hooper CDC, Atlanta, GA Steven R. Steinhubl University of Kentucky, Lexington, KY Data Safety and Bernard J. Gersh (Chair) Monitoring Committee Mayo Clinic, Rochester, Minn David Faxon Brigham & Women’s Hosp., Boston, Mass. Spencer King Fuqua Heart Center, Atlanta, GA Stuart Pocock London, UK Hartzell Schaff Mayo Clinic, Rochester, Minn David O. Williams Rhode Island Hosp., Providence, RI

  19. (4) Norway Sweden (6) (5) Denmark Finland (3) (4) Netherlands Canada (26) (5) Belgium Poland (1) (12) UK Germany (66) (8) France USA (246) Austria (4) Italy (15) (25) Spain (4) New Zealand (17) Australia ACUITY Enrollment 13,819 pts randomized at 448 centers in 17 countries

  20. 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

  21. Top 20 Enrollers B. McLaurin, MD Anderson Area Medical Center, Anderson, SC D. Cox, MD Mid Carolina Cardiology, Charlotte, NC M. Zubair Jafar, MD Hudson Valley Heart Center, Poughkeepsie, NY H. Chandna, MD Victoria Heart and Vascular Center, Victoria, TX F. Harmann, MD Universittsklilnik Schleswig- Holstein Campus Lbeck, Lbeck, Germany F. Leisch, MD Allgemeines ffentl. Krankenhaus der Landershauptstadt Linz, Linz, Austria M. Desaga, MD Klinikum Dachu der Landeshaupstadt Linz, Linz, Germany R.H. Strasser, MD Technische Universitt Dresden, Dresden, Germany T. Stuckey, MD Lebauer CV Research Foundation, Greensboro, NC I. H. Lieber, MD North Houston Heart Center, Kingwood, TX R. Zelman, MD Cape Cod Research Institute, Hyannis, MA J. Neuzner, MD Klinikum Kassel GmbH, Kassel, GA K. Huber, MD Welhelminespital der Stadt Wien, Vienna, Austria H. White, MD Auckland City Hospital, Auckland, New Zealand M. Buerke, MD Klinikum der Martin-Luther- Universitt Halle-Wittenber, Halle, Germany S. Konstantinides, MD George-August-Universitt Gttingen Goettingen, Germany K. E. Hauptmann, MD Krankenhaus der Barmherzigen Bruder Medizinische Klinkill, Trier, Germany E. Mostel, MD Palm Beach Gardens Medical Center/Palm Beach Cardiology, Palm Beach Gardens, FL A. Cequier, MD Ciutat Santaria Bellvitge, Barcelona, Spain M. Mockel, MD Charite Universitatsmedizin Berlin, Germany

  22. 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 – Patient Flow Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy Moderate- high risk ACS Aspirin in all Clopidogrel dosing and timing per local practice *Stratified by pre-angiography thienopyridine use or administration

  23. Baseline Characteristics

  24. Baseline High Risk Features

  25. Invasive Management *In patients receiving study antithrombin pre angiography †median (IQR)

  26. Primary Endpoint Measures (ITT) UFH/Enoxaparin + GPI vs. Bivalirudin + GPI PNI <0.0001 PSup = 0.93 PNI = 0.007 PSup = 0.39 PNI =0.0001 PSup = 0.38

  27. Primary Endpoint Measures (ITT) 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 Upper boundary non-inferiority 7.7% 7.3% 1.07 (0.92-1.23) <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

  28. Primary Endpoint Measures (ITT) UFH/Enoxaparin + GPI vs. Bivalirudin Alone PNI <0.0001 PSup = 0.015 PNI = 0.011 PSup = 0.32 PNI <0.0001 PSup <0.0001

  29. Primary Endpoint Measures (ITT) 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) 0.02 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

  30. PSup = 0.32 PSup = 0.34 PSup = 0.35 PSup = 0.78 Components of the Ischemic Composite UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone

  31. Major Bleeding Endpoints UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone PSup=0.31 PSup<.001 PSup=0.38 PSup<0.0001

  32. Major Bleeding (Primary Endpoint) Values in yellow = P<0.05

  33. Minor Bleeding (Non CABG) Values in yellow = P<0.05

  34. Bleeding Endpoints (Non-CABG) P1 = Bivalirudin+GPI vs. UFH/Enox+GPI; P2 = Bivalirudin alone vs. UFH/Enox+GPI

  35. 10.6% 0.86 (0.71-1.03) 0.05 0.86 (0.74-0.99) 0.02 0.03 0.16 7.8% 13.7% 10.4% 0.90 (0.77-1.05) 8.9% 10.8% 0.09 9.5% 0.79 (0.64-0.97) 9.2% 10.9% 11.8% 0.87 (0.75-1.00) 0.09 12.9% 0.03 0.71 0.90 (0.78-1.04) 0.12 16.8% 9.5% 0.16 16.1% 9.8% 14.7% 11.5% 11.6% 13.5% 10.9% 0.96 (0.77-1.19) 0.82 (0.68-0.98) 0.86 (0.70-1.04) 0.88 (0.75-1.02) Net Clinical Outcome Composite UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone UFH/Enox + IIb/IIIa Risk ratio ±95% CI Bival Alone RR (95% CI) P Pint Age <65 (n=5051) Age ≥65 (n=4164) 0.89 Men (n=6444) Women (n=2771) 0.91 Diabetes (n=2585) No diabetes (n=6630) 0.28 CrCl ≥60 (n=6993)CrCl <60 (n=1644) 0.43 US (n=5224)OUS (n=3991) 0.47 Bivalirudin alone better UFH/Enox + IIb/IIIa better

  36. 12.2% 13.7% <0.001 13.0% 0.61 9.2% 0.96 (0.80-1.14) 0.23 12.2% 0.92 (0.80-1.06) 0.76 (0.65-0.89) 13.3% 0.01 10.6% 7.1% 11.3% 11.1% 1.02 (0.86-1.21) 0.81 (0.69-0.95) 8.6% 9.4% 0.75 (0.61-0.93) 0.01 0.83 6.4% 10.2% 0.63 (0.43-0.91) 0.01 0.34 9.4% 10.2% 0.92 (0.77-1.10) 13.9% 15.2% 0.92 (0.76-1.11) 0.36 Net Clinical Outcome Composite UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone UFH/Enox + IIb/IIIa Risk ratio ±95% CI Bival Alone RR (95% CI) P Pint Biomarkers (CK/Trop) Elevated (n=5368) Normal (n=3841) 0.35 ST Deviation Yes (n=3197) No (n=6008) 0.42 TIMI Risk Score Low (0-2) (n=1291) Intermed (3-4) (n=4407) High (5-7) (n=2449) 0.18 Pre Thienopyridine Yes (n=5192) No (n=4023) 0.02 Bivalirudin alone better UFH/Enox + IIb/IIIa better

  37. 8.3% 11.6% 9.8% 13.3% 0.85 (0.67-1.06) 0.87 (0.75-1.00) 0.15 0.09 0.84 0.86 9.2% 10.6% 9.4% 18.2% 0.97 (0.75-1.26) 0.98 (0.78-1.23) 12.5% 5.1% 14.4% 6.5% 0.78 (0.58-1.04) 0.87 (0.73-1.05) 0.09 0.14 Net Clinical Outcome Composite UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone UFH/Enox + IIb/IIIa Risk ratio ±95% CI Bival Alone RR (95% CI) P Pint Actual treatment PCI (n=5170) CABG (n=1048) Medical (n=2989) 0.59 Rand. to angio/interv. Early (<3.0 h) Intermediate (3.0-19.7 h) Late (≥19.7 h) tertiles 0.62 A-thrombin crossover No prior AT (n=3290) Consistent Rx (n=5519) Crossover (n=3211) 9.1% 10.0% 0.91 (0.73-1.12) 0.36 0.46 0.56 6.7% 7.1% 0.94 (0.80-1.10) 10.6% 12.6% 0.84 (0.65-1.10) 0.21 Bivalirudin alone better UFH/Enox + IIb/IIIa better

  38. P (log rank) Estimate UFH/Enoxaparin + IIb/IIIa (N=4603) 11.7% 0.89 Bivalirudin + IIb/IIIa (N=4604) 11.8% 0.014 Bivalirudin alone (N=4612) 10.1% Net Clinical Outcome Composite Endpoint 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

  39. Ischemic Composite Endpoint UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 15 P (log rank) Estimate UFH/Enoxaparin + IIb/IIIa (N=4603) 7.3% 0.37 Bivalirudin + IIb/IIIa (N=4604) 7.7% 10 0.30 Bivalirudin alone (N=4612) 7.8% Cumulative Events (%) 5 0 0 5 10 15 20 25 30 35 Days from Randomization

  40. 15 UFH/Enoxaparin + IIb/IIIa (N=4603) 5.7% 10 5 0 0 5 10 15 20 25 30 35 Major Bleeding Endpoint 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) 3.0% Cumulative Events (%) Days from Randomization

  41. Event Rates and Power Calculations NI = non-inferiority; Sup = superiority

  42. Summary Conclusions: Primary Results NI = non-inferiority; Sup = superiority

  43. Summary Conclusions: Primary Results NI = non-inferiority; Sup = superiority

  44. Summary Conclusions: Primary Results NI = non-inferiority; Sup = superiority

  45. Conclusions: Primary Results NI = non-inferiority; Sup = superiority

  46. Clinical Implications • In patients with moderate-high risk ACS undergoing an early invasive strategy with use of GP IIb/IIIa inhibitors • Bivalirudin is an acceptable substitute for either unfractionated heparin or enoxaparin • However, compared to either UFH/enoxaparin with GP IIb/IIIa inhibition or bivalirudin with GP IIb/IIIa inhibition • A bivalirudin alone strategy results in significantly greater net clinical benefit and enhanced survival free from adverse events at 30 days

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