Enoxaparin Proven Across the ACS Spectrum


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Dr. Irwan, SpJP, FIHA. 3rd Pekanbaru Cardiology Update, August 25th 2013. Pangeran Hotel Pekanbaru. Learn more at PerkiPekanbaru.com

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Enoxaparin Proven Across the ACS Spectrum

  1. 1. Enoxaparin Proven Across the Acute Coronary Syndrome Spectrum Learning from current guidelines Dr. Irwan, SpJP-FIHA Department of Cardiology and Vascular Medicine Faculty of Medicine, Riau University Arifin Achmad Hospital - Pekanbaru
  2. 2. IX VII X II Intrinsic pathway (surface contact) XII XIIa XI Tissue factor IIa Xa XIa IXa VIIa VIII VIIIa Extrinsic pathway (tissue damage) Xa V Va Fibrinogen Fibrin Heparins and LMWH2 Vitamin K antagonists3 Direct thrombin inhibitors4 Factor Xa inhibitors5 (Thrombin)IIa Targets for AnticoagulantsTargets for Anticoagulants 1Adapted with permission from Petitou M, et al. Nature. 1991;350(suppl):30-33. 2Hirsh J, et al. Chest. 2001;119(suppl):64S-94S. 3Hirsh J, Fuster V. Circulation. 1994;89:1449-1468. 4Weitz JI, Hirsh J. Chest. 2001;119(suppl):95S-107S. 5Herbert JM, et al. Cardiovasc Drug Rev. 1997;15:1.
  3. 3. Enoxaparin in ACS Conservative UA/NSTEMI High risk UA/STEMI High risk UA/NSTEMI + early invasive (PCI) Conservative STEMI STEMI + Elective PCI STEMI + Primary PCI
  4. 4. ENOXAPARIN in conservative ACS In the TIMI 11B and ESSENCE trials, meta-analysis showed : • the primary composite outcome was significantly lower in patients treated with enoxaparin compared with UFH after 1 year of follow-up. • no significant differences in the rates of major hemorrhage between enoxaparin and UFH in either trial or in the pooled data. • there was an increased rate of minor hemorrhage with enoxaparin.
  5. 5. INTERACT: • Among patients treated with eptifibatide in the setting of high risk non-ST elevation ACS, administration of enoxaparin is associated with improves outcomes compared to currently recommended therapy (UF Heparin) based on better safety and efficacy A to Z • In patients with high-risk NSTE-ACS treated with AGGRASTAT®† (tirofiban, MSD) and ASA, enoxaparin is an effective noninferior alternative to UFH • Overall rates of bleeding, transfusion, and thrombocytopenia were low in both heparin groups given AGGRASTAT and ASA Slide 8 Adapted from Blazing MA et al JAMA 2004;292(1):55–64. †Registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Enoxaparin in high risk ACS
  6. 6. ENOXAPARIN in high risk + early invasive ACS SYNERGY • Efficacy — not superior but at least as effective as UFH in the overall population (met criteria for non inferiority) • Minor bleeding — more frequent with enoxaparin • An overview of all recent RCTs comparing enoxaparin and UFH shows a consistent effect across the management spectrum
  7. 7. Study N Death or MI at 30 days Major bleeds ESSENCE ’97 3,171 TIMI 11B ’99 3,910 ACUTE II ’02 525 INTERACT ’03 746 A TO Z ’04 3,620 SYNERGY ’04 9,974 ALL 21,946 0 2010 Incidence (%) 10.1 vs. 11.0 0.5 21 OR (95% CI) 0.91 (0.83 – 0.99) 0 105 Incidence (%) 3.9 vs 3.7 0.1 101 OR (95% CI) 1.1 (0.96 – 1.3) 0.5 21 10102 ∞ 102 10 1 NNT (95% CI) 113 (61 – 1,438) Enox + UFH + Enox + UFH + Enox + UFH + Randomized Trial Totality of clinical evidence for Enoxaparin should lead to level A Bassand JP, et al. Eur Heart J. 28:1598-1660. ESC and ACC/AHA NSTE MI ACS GuidelinesESC and ACC/AHA NSTE MI ACS Guidelines UFHUFH EnoxaparinEnoxaparin
  8. 8. ENOXAPARIN in STEMI ASSENT-3 • “In view of the present data and the ease of administration, enoxaparin might be considered an attractive alternative anticoagulant treatment when given in combination with tenecteplase”. EXTRACT-TIMI 25 ● Among STEMI patients undergoing PCI following fibrinolysis, ENOX was superior to UFH for efficacy with similar safety - significantly less death or re MI - both delayed onset and lower incidence of PCI - no difference in bleeding - less stroke
  9. 9. On behalf of, A. Shui, A.J. Jacob, N. Gotcheva, L. Polonetsky, E.M. Antman, E. Braunwald, and the ExTRACT-TIMI 25 Investigators. EHJ in press Enoxaparin vs UFH with Fibrinolysis for STEMI in Pts ≥ 75 years compared with < 75 years
  10. 10. STEMI < 6 h Lytic eligible Lytic choice by MD (TNK, tPA, rPA, SK) ENOX < 75 y: 30 mg IV bolus SC 1.0 mg / kg q 12 h (Hosp DC) ≥ 75 y: No bolus SC 0.75 mg / kg q 12 h (Hosp DC) CrCl < 30: 1.0 mg / kg q 24 h Double-blind, double-dummy ASA Day 30 1°°°° Efficacy Endpoint: Death or Nonfatal MI 1°°°° Safety Endpoint: TIMI Major Hemorrhage Protocol Design UFH 60 U / kg bolus (4000 U) Inf 12 U / kg / h (1000 U / h) Duration: at least 48 h Cont’’’’d at MD discretion
  11. 11. Main Results Primary Endpoint: Death or non-fatal re-MI by 30 days Main Secondary Endpoint: Death, non-fatal re-MI, urgent revascularization by 30 days 12.0 9.9 UFH UFH ENOX ENOX 14.5 11.7 Days Days %% RR = 0.83 p = 0.000003 RR = 0.81 p = 0.000001 N Engl J Med 2006;354:1477-88. 33% RRR in reMI by 48 h (P=0.002) 19% RRR in Death/MI by 72 h (P<0.001) 12% RRR in by 48 h (P=0.02)
  12. 12. Pharmacokinetics Age <75 years (N=60) Age ≥75 years (N=13) P-value AntiXa clearance (L/hr) 0.794 0.654 0.049 Area under curve 0-12hr IU x h/L 9839 4532 <0.001 Area under curve at steady state IU x h/L 10,000 8197 0.005
  13. 13. Day 30 UFH ENOX RRR ARD NNT Effects of enoxaparin vs unfractionated heparin Stratified by age
  14. 14. TIMI major bleeding Stratified by age 1.1 1.9 3.3 2.9 0 1 2 3 4 5 < 75 years n = 17,814 ≥ 75 years n = 2513 %Events Unfractionated heparin Enoxaparin ARD 0.8% RR 1.67 (1.31-2.13) p=<0.0001 ARD 0.4% RR 1.15 (0.74-1.78) p=0.53
  15. 15. ExTRACT TIMI 25 • The Enox strategy as implemented in ExTRACT-TIMI 25 is preferred to the standard UFH strategy in both younger and older patients treated with fibrinolysis.
  16. 16. Slide 19 Enoxaparin in the Cath. Lab. Replacing UFH Is there enough evidence based trial ?
  17. 17. ATOLL An international randomized study comparing IV enoxaparin to IV UFH in primary PCI G. Montalescot, M. Cohen, P. Goldstein, K. Huber, C. Pollack, U. Zeymer, E. Vicaut for the ATOLL investigators G. MONTALESCOT, DISCLOSURE: Research Grants (to the Institution) from Abbott Vascular, Bristol Myers Squibb, Boston Scientific, Centocor, Cordis, Eli-Lilly, Fédération Française de Cardiologie, Fondation de France, Guerbet Medical, INSERM, Medtronic, Pfizer, Sanofi-Aventis Group, Société Française de Cardiologie; Consulting or Lecture Fees from Accumetrics, Astra-Zeneca, Bayer, Biotronik, Boehringer-Ingelheim, Bristol- Myers Squibb, Daichi-Sankyo, Eisai, Eli-Lilly, Menarini, MSD, Novartis, Portola, Sanofi-Aventis Group, Schering- Plough , Servier and The Medicines Company. ATOLL: Acute STEMI Treated with primary PCI and intravenous enoxaparin Or UFH to Lower ischemic and bleeding events at short- and Long-term follow-up (Investigator-driven study) ESC,Stockholm-August30,2010–Hotlinesession
  18. 18. Intravenous 0.5mg/kg Enoxaparin Time (hours) Anti-XaIU/mL 0 2 4 6 8 10 12 14 16 18 20 0 0.4 0.8 1.2 0.5 mg/kg IV 1 mg/kg SC •Choussat et al (elective PCI) •Miller et al (ACS-PCI) •Carnendran et al (elective PCI) •STEEPLE (elective PCI) •PROTECT –TIMI30 (ACS-PCI) •Silvain et al (elective PCI) •FINESSE (primary PCI) •Brieger et al. (Primary PCI) PD experience Clinical experience Choussat et al. JACC. 2002;40:1943-50. Miller L. J Invasive Cardiol. 2002;14:247-50 Carnendran et al. J Invasive Cardiol. 2003;15:235-8. Montalescot et al. N Engl J Med. 2006;355:1006-17. Gibson et al. JACC. 2006;47:2364-2373 Silvain et al. JACC. 2010;55:617-25 Montalescot et al. JACC Cardiovasc Interv. 2010;3:203-12 Brieger et al. Catheter Cardiovasc Interv. 2010 [in press]Sanchez-Pena P. Br J Clin Pharmacol. 2005;60:364-73.
  19. 19. Intravenous enoxaparin vs. UFH in PCI 57% Major Bleeding (p=0.004) 23% Death or re-MI (p<0.001) Montalescot G et al. N Engl J Med 2006;355:1006 –17 Gibson MC et al. J Am Coll Cardiol 2007;49:2238–46 ?
  20. 20. ATOLL Trial design STEMI Primary PCI 1°°°° EP: Death, Complication of MI, Procedure Failure, Major Bleeding Main 2°°°° EP: Death, recurrent MI / ACS, Urgent Revascularization 30 days Randomization as early as possible (MICU +++) Real life population (shock, cardiac arrest included) No anticoagulation and no lytic before Rx Similar antiplatelet therapy in both groups ENOXAPARIN IV 0.5 mg/kg with or without GPIIbIIIa UFH IV 50-70 IU with GP IIbIIIa 70-100IU without GP IIbIIIa (Dose ACT-adjusted) IVRS Primary PCI ENOXAPARIN SC UFH IV or SC
  21. 21. Primary Endpoint Death, Complication of MI, Procedure Failure or Major Bleeding
  22. 22. All Safety Endpoints
  23. 23. Death, Complication of MI or Major bleeding Net clinical benefit
  24. 24. Conclusions • This multinational randomized study, includes 910 patients recruited over 2 years, that shows a 17% RRR close to significance (P= 0.07) on an innovative efficacy/safety composite primary endpoint and was significant on all the major secondary standard endpoints used in ACS such as the triple endpoint (Death, MI, Revascularization) • Lovenox® confirming it as a better alternative to UFH in all ACS settings.
  25. 25. Enoxaparin benefit vs UFH IV enoxaparin 0.5 mg/kg for PCI • 1 shot ± GP IIb/IIIa inhibitors • no ACT monitoring • stable anticoagulation for 2 hours (duration of PCI)
  26. 26. 29 What are the Guidelines telling us for UA, NSTEMI & STEMI ? ESC & ACCF / AHA
  27. 27. ACCF / AHA guidelines 2011 (UA / NSTEMI)
  28. 28. 2011 ACC/AHA Recommendation on the Use of Antithrombotics in UA/NSTEMI
  29. 29. ESC guidelines 2012 (AMI - STEMI) 33 Recommendations Class Level An injectable anticoagulant must be used in primary PCI. I C Enoxaparin (with or without routine GP IIb/IIIa blocker) may be preferred over UFH. IIb B Fondaparinux is not recommended for primary PCI. III B The use of fibrinolysis before planned primary PCI is not recommended. III A Recommendations Class Level The anticoagulant can be : * Enoxaparin i.v. followed by s.c. (using the regimen described below) (preferred over UFH). I A * UFH given as a weight-adjusted i.v. bolus & infusion. I C In patients treated with streptokinase, fondaparinux i.v. bolus followed by s.c. dose 24 h later. IIa B Antithrombin co-therapy with fibrinolysis Tabel 12 : Periprocedural antithrombotic medication in primary PCI Anticoagulants UFH with or without routine GP IIb/IIIa blocker must be used in patients not receiving bivalirudin or enoxaparin. I C Tabel 13 : Fibrinolytic therapy Bivalirudin (with use of GP IIb/IIIa blocker restricted to bailout) is recommended over UHF & GP IIb/IIIa blocker. I A Anticoagulation is recommended in STEMI patients treated with lytics until revascularization (if performed) or for the duration of hospital stay up to 8 days. I C
  30. 30. ESC guidelines 2012 (AMI - STEMI) 34 Enoxaparin 0.5 mg/kg i.v. bolus. In patients <75 years of age : In patients >75 years of age : In patients with creatinine clearance of <30 mL/min, regardles of age : the s.c. doses are given once every 24 h. Enoxaparin Same dose as with fibrinolytic therapy. With primary PCI Tabel 16 : Doses of antiplatelet & antithrombin co-therapies Doses of antithrombin co-therapies Enoxaparin No adjusment of bolus dose. Following thrombolysis, in patients with creatinin clearance <30 mL/min, the s.c. doses are given once every 24 h. Enoxaparin With fibrinolytic therapy Tabel 18 : Recommendation 30 mg i.v. bolus followed 15 min later by 1 mg/kg s.c. every 12 h until hospital discharge for a maximum of 8 days. The first two doses should not exceed 100 mg. no i.v. bolus; start with s.c. dose of 0.75 mg/kg with a maximum of 75 mg for the first two s.c. doses. Initial dosing of antithrombotic agents in patients with chronic kidney disease (estimated creatinine clearance <60 mL/min) Without reperfusion therapy
  31. 31. ACCF / AHA guidelines 2013 (STEMI)
  32. 32. ACCF/AHA/SCAI Guideline on PCI and CABG 2011 update
  33. 33. Key points - Loading dose for all P2Y12 inhibitors is recommended (Class I-A) - 600 mg loading recommended for clopidogrel - Limitations imposed on prasugrel - Issue of compliance posed against ticagrelor
  34. 34. Key points Enoxaparin -An additional dose of 0.3 mg/kg IV enoxaparin should be administered at the time of PCI to patients who have received fewer than 2 therapeutic subcutaneous doses (eg, 1 mg/kg) or received the last subcutaneous enoxaparin dose 8 to 12 hours before PCI. (Class I-B) -Performance of PCI with enoxaparin may be reasonable in patients either treated with ““““upstream”””” subcutaneous enoxaparin for UA/NSTEMI or who have not received prior antithrombin therapy and are administered IV enoxaparin at the time of PCI. (Class IIb-B) -UFH should not be given to patients already receiving therapeutic subcutaneous enoxaparin. (Class III-B: HARM) Fondaparinux -Fondaparinux should not be used as the sole anticoagulant to support PCI. An additional anticoagulant with anti-IIa activity should be administered because of the risk of catheter thrombosis. (Class III-C: HARM)
  35. 35. Enoxaparin Proven Across the ACS Spectrum Conservative UA/NSTEMI * TESMA 1997 High risk UA/STEMI * A TO Z 2004 High risk UA/NSTEMI + early invasive (PCI) * SYNERGY 2004 Conservative STEMI * EXTRACT TIMI25 2005 STEMI + Elective PCI * STEEPLE 2006 STEMI + Primary PCI * ATOLL 2010