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Presenters’ Disclosure Information: Relationships Related to this Presentation

Presenters’ Disclosure Information: Relationships Related to this Presentation. Research Grants and/or Consultant fees: Mahaffey: Aventis, AstraZeneca, Berlex, Lilly, Daiichi, Millennium, Merck, Schering-Plough, The Medicines Company Ferguson:

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Presenters’ Disclosure Information: Relationships Related to this Presentation

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  1. Presenters’ Disclosure Information:Relationships Related to this Presentation Research Grants and/or Consultant fees: Mahaffey: • Aventis, AstraZeneca, Berlex, Lilly, Daiichi, Millennium, Merck, Schering-Plough, The Medicines Company Ferguson: • Aventis, AstraZeneca, Bristol Myers Squibb, Guidant, Merck, Sanofi, Schering-Plough, The Medicines Company

  2. The SYNERGY Trial Kenneth W. Mahaffey, M.D. James J. Ferguson, M.D. On behalf of the SYNERGY Investigators

  3. The SYNERGY Trial Superior Yield of the New strategy of Enoxaparin, Revascularization & GlYcoprotein IIb/IIIa Inhibitors

  4. Key Prior Trials • ESSENCE / TIMI 11b: • Superiority of enoxaparin vs UFH in conservative management strategy • NICE Registries: • Comparable safety and efficacy to historical controls in PCI • ACUTE 2 / INTERACT / AtoZ • Contemporary trials in higher risk patients

  5. Key Questions • What is the role of enoxaparin in high-risk NSTEMI ACS patients managed with an early invasive treatment strategy ? • Can we safely bring patients on enoxaparin rapidly forward to the catheterization laboratory ?

  6. High-RiskACS Patients • At least 2 of 3 required: • Age  60 • ST  (transient) or  • (+) CK-MB or Troponin Study Design Randomize(n = 10,000) Enoxaparin IV Heparin 60 U/kg  12 U/kg/hr (aPTT 50-70 sec) 1 mg/kg SC Q12H Early invasive strategy Other therapy per AHA/ACC Guidelines (ASA, -blocker, ACE, clopidogrel, GP IIb/IIIa) Primary endpoint: Death or MI at 30 days

  7. Control group 15% death/MI • 17% reduction primary endpoint • Type I error of 5% (2-sided) • 90% power • Sample size ~10,000 patients zone of noninferiority 1.1 Sample size: 8000  10,000 pts For crossover and interim event rate Statistical Assumptions

  8. Belgium 355 Germany 456 Italy 72 Poland 381 Spain 412 Turkey 139 Europe: 5163 Canada: 1616 USA: 5702 Brazil: 289 Argentina: 192 Australia: 253 New Zealand: 160 12 Countries. 467 Sites. 10,027 Patients.

  9. Age 16% (+) ECG 44% 20% 20% (+) Biomarkers Inclusion Criteria

  10. Baseline Characteristics Enoxaparin UFH (n = 4993) (n = 4985) Median age (years) 68 68 Female sex (%) 34 34 Hypertension (%) 68 68 Diabetes (%) 29 30 Hypercholesterolemia (%) 58 59 Family history of CAD (%) 46 45 Myocardial infarction (%) 29 28 CHF (%) 9 9 Stroke (%) 5 5 PVD (%) 10 10 CABG (%) 16 17 PCI (%) 21 19

  11. Concomitant Medications Enoxaparin UFH (n = 4993) (n = 4985) Aspirin (%) 95 95 Beta blocker (%) 86 86 Ace inhibitor (%) 64 62 Statin (%) 69 70 Clopidogrel (%) 62 63 GP IIb-IIIa inhibitor (%) 56 58

  12. Pre-randomization Therapy Enoxaparin UFH All Patients(n = 4993) (n = 4985) (n = 9978) Received pre-randomization (%): No antithrombin 24 25 24 UFH only 29 30 29 Enoxaparin only 42 42 43 UFH and enoxaparin 3 3 3

  13. In-hospital Procedures Enoxaparin UFH (n = 4993) (n = 4985) Cath during baseline hosp (%) 9292 Time to cath* 2221 (hours) (6, 44) (6, 43) Percutaneous intervention 46 47 Time to PCI* 23 22 (hours) (6, 49) (6, 48) CABG (%) 19 18 Time to CABG* 91 89 (hours) (44, 167) (45, 166) Days hospitalized* 5 4 (3, 8) (3, 8) *Median (25th ,75th)

  14. The SYNERGY Trial Kenneth W. Mahaffey, M.D. James J. Ferguson, M.D. On behalf of the SYNERGY Investigators

  15. Primary Results (30 Days) Enoxaparin UFH Unadjusted(n = 4993) (n = 4985) P-value Death and MI (%) 14.0 14.5 0.396 Death (%) 3.2 3.1 0.705 MI (%) 11.7 12.7 0.135

  16. 1.0 0.95 Freedom from Death / MI 0.9 0.85 Enoxaparin UFH 0.8 0 5 10 15 20 25 30 Days from Randomization Death and MI at 30 Days 1.1 HR 0.96 (0.87-1.06)

  17. In-hospital Cardiac Events Enoxaparin UFH(n = 4993) (n = 4985) CHF (%) 8.0 7.9 Cardiogenic shock (%) 2.0 2.3 Cardiac arrest (%) 2.0 2.2 Ventricular tachycardia/fib (%) 4.8 4.9 Atrial fib / flutter (%) 8.6 7.7 2nd or 3rd degree heart block (%) 1.0 1.1 Acute mitral regurgitation (%) 0.3 0.3 Pulmonary edema (%) 0.2 0.2 Deep vein thrombosis (%) 0.2 0.2 Ventricular septal defect (%) 0.1 < 0.1

  18. Bleeding Events Enoxaparin UFH(n = 4993) (n = 4985) P-value GUSTO severe 2.9 2.4 0.106 TIMI major - clinical: 9.1 7.6 0.008 CABG-related 6.8 5.9 0.081 Non-CABG-related 2.4 1.8 0.025 H/H drop - algorithm 15.2 12.5 0.001 Any RBC transfusion 17.0 16.0 0.155 ICH < 0.1 < 0.1 NS

  19. PCI Patients: Thrombotic Complications Enoxaparin UFH (n = 2321) (n = 2364) Any unsuccessful PCI 3.6 3.4 Any threatened abrupt closure 1.1 1.0 Any abrupt closure 1.3 1.7 Emergency CABG 0.3 0.3

  20. No prior UFH Enox Both Pre-randomization

  21. Pre-randomization Randomization No prior UFH Enox Both

  22. 2.9 2.4 Total(n = 9978) 14.0 14.5 9.1 7.6 3.1 1.8 No Prior Rx (n = 2440) 12.6 14.8 9.7 6.9 ConsistentTherapy (n = 6138) 3.1 2.2 13.3 15.9 9.3 7.9 Prior Antithrombin Therapy: Efficacy and Safety BLEEDING GUSTO Severe TIMI Major 30-DAY DEATH / MI Enox UFH (%) (%) Enox UFH (%) (%)

  23. Pre-randomization Randomization No prior UFH Enox Both

  24. Pre-randomization Randomization Crossover No prior UFH Enox Both

  25. Enoxaparin UFH GUSTO Severe TIMI Major (n = 9180) (n =798) (n = 9978) (n = 9180) (n =798) (n = 9978) Crossovers: Relation to Bleeding

  26. Total Population Death / MI Consistent Rx Death / MI (n = 9180) (n =798) (n = 6130) (n = 5637) (n =493) (n = 9978) Crossovers: Relation to Outcome Enoxaparin UFH

  27. Systematic Overview:30-Day Death/MI and In-hospital Transfusions 30-DAY DEATH / MI IN-HOSPITALTRANSFUSIONS Enox UFH Enox UFH 0.8% 0.9% 6.2% 7.7% ESSENCE 2.6% 3.3% 5.0% 9.0% INTERACT 0.7% 0.6% TIMI 11B 7.4% 8.3% 2.5% 4.3% ACUTE 2 7.9% 8.1% 1.0% 0.8% AtoZ 7.4% 7.9% 17.0% 16.0% SYNERGY 14.0% 14.5%

  28. Systematic Overview:Death/MI and Bleeding Enox UFH 10.1% 11.0% (n = 21,946) 8.2% 7.8% (n = 22,104) 4.8% 4.1% (n = 22,104) AtoZ did not include CABG data.

  29. Systematic Overview—No Pre-rando Therapy: Death/MI and Bleeding Enox UFH 8.1% 9.5% (n = 9835) 5.6% 5.5% (n = 8627) 3.5% 2.7% (n = 8627) AtoZ did not include CABG data.

  30. Summary The study • High-risk population treated with an early invasive management strategy

  31. Summary • High-risk population treated with an early invasive management strategy The results • Efficacy — not superior but at least as effective as UFH in the overall population • met criteria for non-inferiority

  32. TIMI Major GUSTO Severe Transfusion UFH 7.6 % 2.4 % 16.0 % Enoxaparin 9.1 % 2.9 % 17.0 % Summary • High-risk population treated with an early invasive management strategy The results • Efficacy — not superior but at least as effective as UFH in the overall population p = 0.007 p = 0.106 p = 0.155 • Bleeding — more frequent with enoxaparin

  33. Summary Issues to consider • Prior antithrombotic therapy • Post-randomization management • Bleeding definitions • Age, renal function

  34. Summary • Prior antithrombotic therapy • Post-randomization management • Bleeding definitions • Age, renal function The study in context • An overview of all recent RCTs comparing enoxaparin and UFH shows a consistent effect across the management spectrum

  35. Summary The message • Current role — enoxaparin is an effective and safe alternative to UFH for the early invasive management of high risk ACS patients.

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