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The ESSENCE Study

The ESSENCE Study. The E fficacy and S afety of S ubcutaneous E noxaparin in N on-Q-wave C oronary E vents (Unstable angina and non-Q-wave MI). ESSENCE: Steering Committee. Marc Cohen, MD Committee Chairman. Robert Califf, MD Enrique Gurfinkel, MD

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The ESSENCE Study

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  1. The ESSENCE Study The Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (Unstable angina and non-Q-wave MI)

  2. ESSENCE: Steering Committee Marc Cohen, MD Committee Chairman Robert Califf, MD Enrique Gurfinkel, MD Christine Demers, MD Anatoly Langer, MD Keith A. Fox, MB ChB Alexander G. Turpie, MD

  3. ESSENCE: Clinical Events Committee Marc Cohen, MD Committee Chairman Christine Demers, MD Shaun Goodman, MD Leonard Dreifus, MD John B. Kostis, MD Michael Freedman, MD Jacob Rand, MD Data and Safety Monitoring Committee Robert Makuch, PhDCommittee Chairman John A. Cairns, MD Richard Gorlin, MD Jack Hirsh, MD

  4. Enoxaparin 1mg/kg q 12 H Subcutaneous + ASA Follow-up Visit Day 14 Follow-up Call Day 30 Unstable Angina Non-Q-Wave MI Unfr. Heparin IV dose-adjusted + ASA Follow-up Visit Day 14 Follow-up Call Day 30 Treatment Phase min 48 H, max 8 Days Follow-up Phase ESSENCE: Study Design

  5. Inclusion Criteria • Male or non-pregnant female < 18 years • Recent-onset rest angina • Last episode of angina within 24 hours • Definite evidence of underlying CAD (1 or more): • Ischemic ECG changes on presentation • Previous MI, PTCA, or CABG • Previous angiography with > 50% vessel stenosis

  6. ESSENCE: Exclusion Criteria • Personal physician planning revascularization within 48 hours • Angina related to an evolving Q-wave MI (persistent ST segment elevation) • Angina precipitated by secondary causes (e.g., tachydysrhythmia, etc.) • CABG within 2 months, PTCA within 1 month

  7. ESSENCE: Study Objective Primary Objective: • To demonstrate the superiority of enoxaparin (1 mg/kg subcutaneously q 12H) compared to IV unfractionated heparin (dose-adjusted) on the composite clinical endpoints of death, MI, or recurrent angina • To demonstrate that subcutaneous enoxaparin is at least as safe as unfractionated heparin

  8. All Randomized Analyses • Death, MI, Recurrent Angina: 14 days • Death, MI, Recurrent Angina: 48 hours 30 days • Death, MI: 48 hours 14 days 30 days Primary Analysis Secondary Analyses

  9. Endpoint Definition Recurrent Angina (any of the following): • Angina associated with > 0.1 mV ST shift, or new T-wave inversions in at least 2 contiguous leads • Angina prompting revascularization • Angina prompting re-hospitalization

  10. Endpoint Definition (cont’d) Myocardial Infarction (at least one of the following): • CK-MB > normal (at least 3% of total CK) • Total CK > 2 times upper limit of normal • New significant Q-waves

  11. Endpoint Definition (cont’d) Myocardial Infarction - Post PTCA • CK or CK-MB > 3 times upper limit of normal and at least 50% > prior nadir value Myocardial Infarction - CABG, perioperative(at least one of the following): • CK or CK-MB > 5 times upper limit of normal • New significant Q-waves > 0.04 sec in at least two leads • New regional wall motion abnormality

  12. Endpoint Definition (cont’d) • Death • Death and successfully resuscitated cardiac arrest

  13. Safety Endpoint Definition Major Hemorrhage Must be clinically overt and associated with: • Death • Transfusion of at least 2 units PRBC or whole blood • > 30 gm/L (3 gm/dL) fall in hemoglobin • Retroperitoneal, intracranial, or intraocular hemorrhage

  14. Minor Hemorrhage • Epistaxis lasting more than 5 minutes or requiring intervention • Ecchymosis or hematoma larger than 5 centimeters in its greatest dimension • Macroscopic hematuria not associated with urinary catheter trauma or urinary tract infection • Subconjunctival hemorrhage requiring cessation of medication • Gastrointestinal hemorrhage not related to intubation or nasogastric tube placement

  15. USA 30% Canada 40% 936 1259 266 710 South America 8% Europe 22% Enrollment by Region Number of Patients by Region

  16. Characteristic Heparin Enoxaparin(n = 1564) (n = 1607) Gender Male 1033 (66.0%) 1079 (67.1%) Female 531 (34.0%) 528 (32.9%) ECG Changes 894 (57.2%) 897 (55.8%) Final Adm. Dx Unstable Angina 1102 (70.7%) 1089 (68.1%) Non-Q MI 327 (21.0%) 335 (20.9%) Q-wave MI 41 (2.6%) 68 (4.3%) Age (median) 65 64 Weight (median) 77 kg 78 kg Baseline Characteristics

  17. Risk Factor Heparin Enoxaparin(n = 1564) (n = 1607) Diabetes mellitus 21.7% 22.4% Smoking 23.6% 24.8% Hypertension 54.5% 53.3% Hypercholesterolemia 44.2% 44.8% Family Hx of CAD 41.6% 42.1% Baseline Characteristics

  18. Medical History Heparin Enoxaparin(n = 1564) (n = 1607) Prior history of: ASA use 62.5% 61.5% MI 47.6% 45.0% PTCA 21.2% 21.5% CABG 19.4% 19.7% Baseline Characteristics (cont’d)

  19. Anti-anginal Therapy During First 48 H Heparin Enoxaparin (n = 1564) (n = 1607) Beta-Blocker 1084 (69.3%) 1106 (68.8%) Calcium Channel Blocker 776 (49.6%) 796 (49.5%) IV Nitrates 797 (51.0%) 844 (52.5%) Oral/Topical Nitrates 984 (62.9%) 985 (61.3%) All Three Classes 418 (26.7%) 429 (26.7%) All Randomized Population

  20. Anti-anginal Therapy From 48 H to Hospital Discharge Heparin Enoxaparin (n = 1564) (n = 1607) Beta-Blocker 1011 (64.6%) 1023 (63.7%) Calcium Channel Blocker 778 (49.7%) 795 (49.5%) IV Nitrates 370 (23.7%) 336 (20.9%) Oral/Topical Nitrates 1033 (66.0%) 1029 (64.0%) All Three Classes 424 (27.1%) 410 (25.5%) All Randomized Population

  21. Aspirin Use During Hospitalization Dose Heparin Enoxaparin (n = 1564) (n = 1607) < 100 mg 1.7% 2.1% 100-325 mg 97.5% 97.6% > 325 mg 0.8% 0.3% ASA stopped during hospitalization 8.0% 8.1% All Randomized Population

  22. Time Period Heparin Enoxaparin(n = 1564) (n = 1607) Time from qualifying angina to Rx: Š 12 hours 1139 (74.8%) 1119 (70.7%) 12 - Š 24 hours 338 (22.2%) 389 (24.6%) > 24 hours 47 (3.1%) 75 (4.7%) Duration of treatment Median 2.6 days 2.6 days Time to Treatment

  23. Blinding Procedures aPTT ESSENCE Blood Sample Site Site Lab aPTT Result IV Infusion Adjustment • Unblinded Med. Professional • Rx Codes • Nomogram • Mock Value • aPTT CRF Pages • File

  24. Time Interval Heparin Enoxaparin (hours) (n = 1529) (n = 1578) 6 to <12 934 (61%) 946 (60%) 12 to <24 1297 (85%) 1249 (79%) 24 to <48 1372 (90%) 1403 (99%) 48 to <72 896 (59%) 934 (59%) 72 to <96 455 (30%) 458 (29%) Blinding Procedures Number of aPTTs Ordered by Investigators per Group

  25. Time Interval (n) aPTT <55 s aPTT 55-85 s aPTT >85 s 12 to <24 h - Endpoint 92 19.6% 43.5% 37.0% - No Endpoint 1205 15.1% 46.2% 38.7% 24 to <48 h - Endpoint 81 22.2% 46.9% 30.9% - No Endpoint 1291 14.3% 51.7% 34.0% Heparin Patients With or Without Endpoint aPTT Values (Triple Endpoint at 48 Hours)

  26. Time interval aPTT aPTT aPTT (hours) <55 s 55-85 s >85 s TIMI 9B 24 to <48 48.5%33.0% 18.4% 48 to <72 52.1%32.8% 15.1% ESSENCE 24 to <48 15.1%51.1% 33.8% 48 to <72 18.0%59.4% 22.6% aPTT Distribution Comparison to TIMI 9B % Patients in each aPTT range - heparin group

  27. Heparin Enoxaparin Relative Risk (n = 1564) (n = 1607) Reduction Odds Ratio P Value 48 Hours 7.4% 6.2% 16.2% 0.83 0.178 14 Days 19.8% 16.6% 16.2% 0.80 0.019 30 Days 23.3% 19.8% 15.0% 0.81 0.016 Triple Endpoint Rates All Randomized Population Death, MI, Recurrent Angina (Protocol Definition)

  28. Odds Ratios for Triple Endpoint Components 48 hours 14 days 30 days Death 1.11 0.97 0.80 MI 0.76 0.70 0.73 Recurrent angina 0.81 0.80 0.85 Odds Ratios By Timepoint Odds ratio = enoxaparin:heparin

  29. Time-to-Worst Event 30% 25% 20% 15% 10% Heparin Enoxaparin 5% 0% 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 Time (Days) Death, MI, Recurrent Angina All Randomized Population Death, MI, or Recurrent Angina

  30. 30% 25% 20% 15% 10% Heparin Enoxaparin 5% 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 Time (Days) Time-to-First Event Death, MI, Recurrent Angina All Randomized Population % with Death, MI, Recurrent Angina

  31. 10% 8% 6% 4% Heparin Enoxaparin 2% 0 0 6 12 18 24 30 36 42 48 Time-to-First Triple Endpoint (48 H) Percent of Patients with Death, MI, or Recurrent Angina Time (Hours)

  32. ESSENCE: Study Design Enoxaparin 1mg/kg q 12 H Subcutaneous + ASA Follow-up visit Day 14 Follow-up call Day 30 Unstable Angina Non-Q Wave MI Unfr. Heparin IV dose-adjusted + ASA Follow-up visit Day 14 Follow-up call Day 30 Treatment Phase min 48H, max 8 Days Follow-up Phase

  33. ESSENCE: Primary Results: Death, MI, Recurrent Angina 30% Heparin Enoxaparin 23.3% 25% 19.8% 20% 19.8% % Death, MI or Recurrent Angina 16.6% RRR 15 % P=0.016 15% RRR 16.2 % P=0.019 10% 5% 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 Time (Days)

  34. ESSENCE: Subgroup Analyses Favors Unfr. Heparin Favors Enoxaparin Overall Result Male Female Age-1st Tertile Age-2nd Tertile Age-3rd Tertile ECG Changes No ECG Changes * ST Depression No ST Depression T Wave Inversion No T Wave Inversion Diabetes Mellitus No Diabetes Mellitus Prior Aspirin Use No Prior Aspirin Use e ** -2 e ** -1 e ** 0 e ** 1 e ** 2 Log(Odds Ratio)

  35. Composite Heparin Enoxaparin Relative Risk P ValueEndpoint (Day 14) (n = 1564) (n = 1607) Reduction Death, MI, RA: 309 (19.8%) 266 (16.6%) 16.2% 0.019ECG Changes, Rehosp. or Rev. Death, MI, RA: 261 (16.7%) 218 (13.6%) 18.6% 0.014Rehosp. or Revasc. Death, MI, RA: 226 (14.5%) 178 (11.1%) 23.4% 0.004Revasc. Death = Death + Resuscitated cardiac arrest Efficacy Results Additional Analyses Triple Endpoint All Randomized Population

  36. Relative Heparin Enoxaparin Risk Time interval no. (%) no. (%) Reduction P Value All Randomized 48 Hours 21 (1.3) 18 (1.1) 16.6% 0.119 14 Days 96 (6.1) 79 (4.9) 19.9% 0.132 30 Days 121 (7.7) 99 (6.2) 20.4% 0.081 All Treated 48 Hours 20 (1.3) 16 (1.0) 22.5% 0.126 14 Days 93 (6.1) 76 (4.8) 20.8% 0.115 30 Days 118 (7.7) 96 (6.1) 21.2% 0.069 Double Endpoint Rates Death, MI (Protocol Definition)

  37. 10% 8% 6% Percent of Patients with Death or MI 4% Heparin Enoxaparin 2% 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 Time (Days) Time-to-First Double Endpoint All Randomized Patients

  38. Heparin Enoxaparin Relative Risk Time Point (n = 1529) (n = 1578) Reduction P Value 48 Hours 20 (1.3%) 17 (1.1%) 17.6% 0.118 14 Days 94 (6.0%) 74 (4.6%) 23.4% 0.075 30 Days 117 (7.5%) 93 (5.8%) 22.6% 0.054 Double Endpoint Rates All Randomized Population True Death, MI

  39. Revascularizations and Procedures All Randomized Population Heparin Enoxaparin Relative Risk (n = 1564) (n = 1607) Reduction P Value Revascular 504 (32.2%) 434 (27.1%) 16.0% 0.001 CABG 214 (13.7%) 198 (12.3%) 10.0% 0.254 PTCA 293 (18.7%) 236 (14.7%) 21.6% 0.002 Diagnostic Catheterization 812 (51.9%) 770 (47.9%) 7.7% 0.024

  40. Favors Enoxaparin Overall Result Male Female Age-1st Tertile Age-2nd Tertile Age-3rd Tertile ECG Changes No ECG Changes ST Depression No ST Depression T Wave Inversion No T Wave Inversion Diabetes Mellitus No Diabetes Mellitus Prior Aspirin Use No Prior Aspirin Use e ** -2 e ** -1 e ** 0 e ** 1 e ** 2 Effect of Baseline Characteristic on Triple Endpoint Odds Ratio Favors Unfr. Heparin Log (Odds Ratio)

  41. Heparin Enoxaparin (n = 35) (n = 29) • Triple Endpoint 6 (17.1%) 5 (17.2%) • Death 2 (5.7%) 2 (6.9%) • MI 1 (2.9%) 1 (3.4%) • RA 3 (8.6%) 2 (6.9%) Randomized Not Treated Endpoints at Day 14

  42. Heparin Enoxaparin Study Period (n = 1529) (n = 1578) P Value no. (%) no. (%) 30 Days 107 (7.0) 102 (6.5) 0.566 On-treatment 18 (1.2) 17 (1.1) 0.892 On-treatment = 12 hours post discontinuation of study therapy Major Hemorrhagic Events All Treated Population

  43. Major Hemorrhage Heparin Enoxaparin (n = 1529) (n = 1578) no. (%) no. (%) Associated with Death 1 (0.1) 0 Retroperitoneal location 1 (0.1) 1 (0.1) Intracranial location 1 (0.1) 0 Drop in hemoglobin 82 (5.4) 77 (4.9) Transfusion > 2 units blood 84 (5.5) 83 (5.3) Causality Spontaneous 6 (0.4) 15 (1.0) Surgery/instrumentation 98 (6.4) 87 (5.5) CABG 84 (5.5) 75 (4.8) Secondary to other trauma 2 (0.1) 1 (0.1) Major Hemorrhagic Events to 30 Days All Treated Population

  44. All Treated Population Major Hemorrhagic Events On-treatment Major Hemorrhage Heparin Enoxaparin (n = 1529) (n = 1578) no. (%) no. (%) Associated with Death 0 0 Retroperitoneal location 0 1 (0.1) Intracranial location 0 0 Drop in hemoglobin 12 (0.8) 9 (0.6) Transfusion  2 units blood 15 (1.0) 13 (0.8) Causality Spontaneous 1 (0.1) 7 (0.4) Surgery/instrumentation 17 (1.1) 10 (0.6) CABG 0 0 Secondary to other trauma 0 0 On-treatment = 12 hours post discontinuation of study therapy

  45. Event Heparin Enoxaparin P Value (n = 1529) (n = 1578) All Hemorrhage 217 (14.2) 290 (18.4) 0.001 Major Hemorrhage 107 (7.0) 102 (6.5) 0.566 Minor Hemorrhage (only) 110 (7.2) 188 (11.9) <0.001 Drug Discontinued 25 (1.6) 28 (1.8) Required Transfusion 7 (0.5) 5 (0.3) Serious as per Investigator 8 (0.5) 5 (0.3) Hemorrhagic Events to 30 Days All Treated Population

  46. 250 Ecchymosis injection site 200 Hematoma sheath site Ecchymosis not at inj. site 150 Other Number of Events 100 Macroscopic Hematuria Epistaxis or Gingival 50 Gastrointestinal 0 Heparin Enoxaparin Minor Hemorrhagic Events to 30 Days All Treated Population

  47. Conclusions • At 14 days, the risk of death, myocardial infarction or recurrent angina was significantly lower in patients assigned to enoxaparin compared to heparin (P= 0.019) • When a more focused definition of recurrent angina is used (angina prompting revascularization), there remains a significant benefit (P=0.004) • This significant reduction is sustained through 30 days

  48. Conclusions • The secondary composite endpoint of death or MI demonstrated a strong trend toward fewer events in the enoxaparin group at 30 days

  49. Conclusions • The rate of major hemorrhagic events associated with enoxaparin treatment vs heparin treatment is comparable • There is an increase in the rate of minor hemorrhagic events associated with enoxaparin treatment vs heparin treatment, due mainly to angiography sheath-site and medication injection-site ecchymosis or hematoma

  50. Conclusions • Resource utilization consistently favored enoxaparin as demonstrated by a reduction in the number of diagnostic catheterizations and the number of revascularizations during the 30-day period

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