1 / 27

Disclosures

williamsryan
Télécharger la présentation

Disclosures

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Early Glycoprotein IIb/IIIa Inhibition in Non-ST-segment Elevation Acute Coronary Syndrome: A Randomized, Double-blind, Placebo-Controlled Trial Evaluating the Clinical Benefits of Early Front-loaded Eptifibatide in the Treatment of Patients with Non-ST-segment Elevation Acute Coronary Syndromes

  2. Disclosures • Funded by Millennium Pharmaceuticals and Schering Plough • All authors disclose research grant funding and/or consulting and speaking honoraria from Schering Plough • Full Relationships with Industry disclosures for all authors are listed in detail in the ACC.09 Presenter Disclosure Digest

  3. Study Structure Study Chairman: E. Braunwald Study Co-Chairmen: R. Califf, F. Van de Werf 35 Investigators 24 Countries represented Cardiology and Emergency Medicine DCRI: K. Newby, L. Berdan, R. Harrington TIMI:R. Giugliano CVC: P. Armstrong, C. Sorochuk Helpline: P. Tricoci, P. Sinnaeve Chairman: D. Weaver Members: J. Alpert, E. Cohen, D. Faxon, L. Fisher, F. Verheugt Schering Plough Physician Lead: J. Strony Ops leaders: A. Kilian, L. Layton Physician Lead: M. Roe Lead Coordinator: D. Montgomery Angio Core: M. Gibson 440 sites 29 countries

  4. Primary Goal • To compare the effect of 2 strategies for eptifibatide administration in high-risk NSTE ACS patients managed with an invasive diagnostic assessment: • A strategy of routine, early administration of eptifibatide to all patients shortly after presentation • A strategy of delayed, provisional eptifibatide administration at the physician’s discretion after coronary angiography and prior to PCI

  5. Study Design High-risk NSTE ACSn = 10,500 2 of 3 high-risk criteria: 1. Age > 60 years 2. + CKMB or TnT/I 3. ST  or transient ST  (Or age 50-59, h/o CVD and + CKMB or TnT/I) Routine, early eptifibatide(180/2/180) Placebo / delayed provisional eptifibatide pre-PCI Randomize within 12 hours of presentation Invasive strategy: 12 to 96 hours after randomization Safety Endpoints at 120 hrs: Bleeding (GUSTO and TIMI scales), Transfusions, Stroke, Non-hemorrhagic SAEs Primary Endpoint: 96-hr Death, MI, Recurrent ischemia requiring urgent revascularization, or Thrombotic bailout Key Secondary Endpoint: 30-d Death or MI

  6. Key Exclusion Criteria • Increased bleeding risk • active bleeding or recent bleed • Recent surgery or trauma • Prior ICH or recent ischemic stroke • Serious concomitant illness or pregnancy • ESRD with dialysis < 30 days • Recent or planned use of direct thrombin inhibitor, fXa inhibitor, abciximab/tirofiban • amendment 1: allowed bivalirudin at PCI • amendment 2: allowed acute fondaparinux or bivalirudin

  7. Blinded Study Drug Administration • Investigational double bolus and infusion regimen • 180 ug/Kg / 2 ug/kg/min / 180 ug/Kg IV eptifibatide (or matching placebo) • Infusion decreased to 1 ug/Kg/min if CrCl <50 mL/min) • Provisional, blinded cross over to open label eptifibatide at time of PCI using blinded bolus kit Bolus kit = Provisional use Open label Eptifibatide PCI Coronary Angio Eptifibatide Eptifibatide Placebo Placebo Open label Eptifibatide Bolus Kit = Bailout use

  8. Statistical Methods • Power at original sample size (10,500 patients) • Primary quadruple composite at 96 hours • 85% Power for RRR 22.5% at alpha = 0.048 • Death or MI at 30 days • 85% Power for RRR 15% at alpha = 0.048 • Sample size reduced to 9500 patients when pooled primary event rate greater than expected late in trial • 98% power for primary endpoint, 81% power for secondary endpoint * Adjusted for single interim efficacy analysis

  9. N = 6595 N = 2897 160 50 136 12 1342 192 625 447 11 374 260 96 103 472 510 2272 128 23 178 155 837 175 51 452 118 57 23 177 47 Enrollment (N = 9492) Follow-up 99.9% complete worldwide

  10. Top 20 Enrolling Sites Enrollment 1/ Austria Franz Leisch (304) 2/ Netherlands A W J van ‘t Hof (301) 3/ USA Kristin Newby (231) 4/ India Keyur Parikh (224) 5/ USA Amir Malik (209) 6/ Israel Basil Lewis (198) 7/ Israel Arie Roth (174) 8/ Germany Peter Schuster(156) 9/ Germany Martin Desaga (151) 10/ Poland Maria Trusz-Gluza (138) 11/ Germany Michael Gross (138) 12/ Germany Uwe Zeymer (133) 13/ USA Yale Cohen (119) 14/ Portugal Luis Providencia(112) 15/ Israel Uri Rosenshein (107) 16/ Poland Piotr Ponikowski(95) 17/ France Khalife Khalife (94) 18/ Israel Eugenia Nikolsky (92) 19/ Switzerland Michael Pieper(90) 20/ Canada Manohara Senaratne (88)

  11. Baseline Characteristics Routine Delayed Early Provisional Eptifibatide Eptifibatide (n=4722) (n=4684) Age (yrs) 67 (60, 75) 68 (60, 75) Female (%) 32 31 Diabetes mellitus (%) 30 31 Hypertension (%) 71 72 Dyslipidemia (%) 58 58 Prior MI (%) 27 28 Creatinine Clearance <50 mL/min (%) 18 18 Troponin positive (%) 84 84 ST-segment shifts (%) 62 62 Symptoms to presentation (hrs) 3.3 (1.4, 8.0) 3.2 (1.5, 7.8) Presentation to randomization (hrs) 5.4 (3.3, 8.8) 5.7 (3.4, 8.8)

  12. In-hospital Management Routine Early Eptifibatide(n=4722) Delayed Provisional Eptifibatide(n=4684) Cardiac Catheterization (%) 98 98 Randomization to cath (hrs) 21.4 (16.9, 34.2) 21.4 (16.7, 31.0) In-hospital Management (%) CABG 13 13 Medically Treated only 30 31 PCI 59 60 Provisional (before wire) 25 27 Bailout (after wire) 11 12 Use of Established Rx (%) Beta-blocker 88 88 Statin 86 87 ACEI / ARB 78 79 Clopidogrel (intended early) 75 75

  13. 96-Hour Primary Efficacy Results Routine EarlyEptifibatide(n=4722) DelayedProvisional Eptifibatide(n=4684) OR(95% CI) P Death, MI, RIUR, TBO 9.3% 10.0% 0.92 0.23 (0.80-1.06) Death 0.8% 0.9% 0.96 0.87 (0.62-1.50) Death or MI 7.5% 8.3% 0.89 0.13 (0.77-1.04) Death, MI, RIUR 8.4% 9.4% 0.89 0.11 (0.77-1.03 ) MI, myocardial infarction; RIUR, recurrent ischemia requiring urgent revascularization; TBO, thrombotic bailout

  14. Kaplan-Meier Curves for Primary Endpoint 15 10.0% 10 Delayed provisional eptifibatide 9.3% Death, MI, RIUR or TBO (%) P = 0.23 (stratified for intended early clopidogrel use) 5 Routine early eptifibatide 0 0 8 16 24 32 40 48 56 64 72 80 88 96 Time Since Randomization (Hours)

  15. 30-Day Secondary Efficacy Results Routine EarlyEptifibatide(n=4722) DelayedProvisional Eptifibatide(n=4684) P OR(95% CI) Death or MI 11.2% 12.3% 0.89 0.079 (0.79-1.01) Death 2.8% 2.6% 1.10 0.46 (0.86-1.41) Death, MI, RIUR 12.5% 13.8% 0.89 0.065 (0.79-1.01) MI, myocardial infarction; RIUR, recurrent ischemia requiring urgent revascularization

  16. Kaplan-Meier Curves for 30-day Death or MI 15 12.4% Delayed provisional eptifibatide 10 11.2% Death or MI (%) Routine early eptifibatide P = 0.079 (stratified for intended early clopidogrel use) 5 0 6 8 10 12 14 16 18 20 22 24 26 28 30 0 2 4 Time Since Randomization (Days)

  17. Delayed Odds Ratio for Upstream Routine Early Provisional Baseline Characteristic Eptifibatide (95% CI) Eptifibatide, % Eptifibatide, % Overall 9.3 10.0 Men 9.1 9.8 Women 9.7 10.4 8.6 9.5 Age < 75 yr Age > 11.4 11.4 75 yr 9.5 10.6 Troponin positive 7.7 6.8 Troponin negative Diabetes 8.9 10.6 No Diabetes 9.5 9.8 8.8 9.5 Early clopidogrel intended 10.8 11.5 No early clopidogrel intended 0.5 0.6 0.7 0.8 0.9 1 2 Early Eptifibatide Better Delayed Provisional Eptifibatide Better 96-hour Primary Efficacy ResultsPrespecified Subgroups

  18. Delayed Odds Ratio for Upstream Routine Early Provisional Baseline Characteristic Eptifibatide (95% CI) Eptifibatide, % Eptifibatide, % Overall 11.2 12.3 Men 11.4 12.0 Women 10.7 13.0 Age < 75 yr 10.2 11.6 Age > 14.0 14.6 75 yr Troponin positive 11.6 13.0 Troponin negative 8.1 8.4 11.7 13.8 Diabetes 10.9 11.7 No Diabetes 10.3 12.0 Early clopidogrel intended 13.7 13.4 No early clopidogrel intended 0.5 0.6 0.7 0.8 0.9 1 2 Early Eptifibatide Better Delayed Provisional Eptifibatide Better 30-day Death or MI Prespecified Subgroups

  19. Safety Results (through 120 hours) Routine EarlyEptifibatide(n=4686) DelayedProvisional Eptifibatide(n=4643) OR(95% CI) P Bleeding (all patients, %) TIMI major 2.6 1.8 1.42 (1.07-1.89) 0.015 TIMI major or minor 5.8 3.4 1.75 (1.43-2.14) <0.001 GUSTO severe 0.8 0.9 0.99 (0.64-1.55) 0.97 GUSTO moderate or severe 7.6 5.1 1.52 (1.28-1.80) <0.001 PRBC transfusion 8.6 6.7 1.31 (1.12-1.53) 0.001 Bleeding (CABG) Re-operation for bleeding (%) 6.0 8.4 0.70 (0.39-1.27) 0.24 Chest tube output (mL/24 H) 720 770 -- 0.41 Thrombocytopenia (<100K, %) 3.3 2.8 1.19 (0.93-1.51) 0.17 Stroke (total, %) 0.6 0.8 0.79 (0.48-1.30) 0.36

  20. PURSUIT PRISM PRISM PLUS Theroux PARAGON B PARAGON A 0.88 (0.79-0.97) COMBINED 1998 (n = 23,967) ACUITY Timing EARLY ACS EARLY ACS + ACUITY COMBINED 2009 (n = 42,666) 0.89 (0.84-0.95) Small Molecule GP IIb/IIIa Inhibition in NSTE ACS 0.92 (0.82-1.01) 0.25 0.50 1.0 2.0 4.0 Odds Ratio for 30-day Death or MI Relative to Control

  21. Conclusions • Among high-risk NSTE ACS patients, a strategy of routine, early eptifibatide compared with delayed, provisional eptifibatide at PCI • did not significantly reduce the primary composite of death, MI, RIUR, or TBO at 96h • resulted in a trend toward reduction in death or MI at 30 days, but no difference in 30-day mortality • resulted in higher rates of non-life-threatening bleeding and transfusions

  22. Implications • The results of EARLY ACS do not support a strategy of routine early eptifibatide use in high-risk NSTE ACS patients managed with an invasive strategy • If subgroups of patients with high likelihood of benefit and low bleeding risk could be identified, it might be reasonable to consider early eptifibatide use in selected high-risk NSTE ACS patients who are intended to undergo angiography

  23. Available Today at www.nejm.org

  24. EARLY ACS Steering Committee Australia P. Aylward Austria K. Huber Canada M. Labinaz, A. Langer, J-F. Tanguay Czech Rep P. Widimsky Denmark P. Grande France G. Steg Germany C. Bode, U. Zeymer Hungary M. Keltai India D. Prabhakaran Israel B. Lewis Italy D. Ardissino Netherlands A. van ‘t Hof New Zealand H. White Norway D. Atar Poland W. Ruzyllo Portugal M. Carrageta Russia V. Sulimov Spain A. Betriu South Africa A. Dalby Switzerland F. Mach United Kingdom K. Fox, K Karsch United States B. Gibler, N. Kleiman, H. Herrmann, J. Hochman, J. Hoekstra, M. Ohman, W. O’Neill, C. Pollack, M. Schweiger

  25. Back-up slides

  26. Randomization N=9406 Medical Only N=3490 PCI N=5389 CABG N=519 Strategy During First 96 Hours Delayed Provisional Eptifibatide (N=4680) Total Events = 469 Early Eptifibatide (N=4718) Total Events = 439 CABG (N=251) Pre-CABG Events = 22 Post CABG Events = 46 CABG (N=268) Pre-CABG Events = 33 Post-CABG Events = 52 Medical Only (N=1706) Total Events = 71 Medical Only (N=1784) Total Events = 71 PCI (N=2666) Pre-PCI Events = 82 Post-PCI Events = 201 PCI (N=2723) Pre-PCI Events = 87 Post-PCI Events = 243 Total Events on Medical Treatment = 71 + 82 +33 Total Events on Medical Treatment = 71 + 87 + 22 Group Events Risk Rate Group Events Risk Rate Medical 186 4718 4.1% Medical 180 4680 4.0% Post PCI 201 2584 8.0% Post PCI 243 2636 10.5% Post CABG 52 235 23.4% Post CABG 46 229 20.6%

  27. Primary and Key Secondary Efficacy ResultsBy Clopidogrel Strata at Randomization Routine EarlyEptifibatide Delayed ProvisionalEptifibatide OR(95% CI) 96-hr Death, MI, RIUR, TBO Clopidogrel intended 8.8 9.5 0.92 (0.78-1.08) No Clopidogrel intended 10.8 11.5 0.93 (0.72-1.20) 30-day Death / MI Clopidogrel intended 10.3 12.0 0.85 (0.73-0.91) No Clopidogrel intended 13.7 13.4 1.03 (0.81-1.31)

More Related