The Efficacy and Safety of Subcutaneous Enoxaparin in NonQwave Coronary Events Unstable angina and n - PowerPoint PPT Presentation

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The Efficacy and Safety of Subcutaneous Enoxaparin in NonQwave Coronary Events Unstable angina and n

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Robert Califf, MD Enrique Gurfinkel, MD. Christine Demers, MD Anatoly Langer, MD ... Michael Freedman, MD Jacob Rand, MD. Marc Cohen, MD. Committee Chairman ... – PowerPoint PPT presentation

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Title: The Efficacy and Safety of Subcutaneous Enoxaparin in NonQwave Coronary Events Unstable angina and n


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, PhD Committee Chairman John A.
Cairns, MD Richard Gorlin, MD Jack Hirsh, MD

4
ESSENCE Study Design
5
Inclusion Criteria
  • Male or non-pregnant female lt 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 gt 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
Analyses
All Randomized
Primary Analysis
  • Death, MI, Recurrent Angina 14 days
  • Death, MI, Recurrent Angina 48 hours 30 days
  • Death, MI 48 hours 14 days 30 days

Secondary Analyses
9
Endpoint Definition
  • Recurrent Angina (any of the following)
  • Angina associated with gt 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 (contd)
  • Myocardial Infarction (at least one of the
    following)
  • CK-MB gt normal (at least 3 of total CK)
  • Total CK gt 2 times upper limit of normal
  • New significant Q-waves

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

12
Endpoint Definition (contd)
  • 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
  • gt 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
Enrollment by Region
Number of Patients by Region
16
Baseline Characteristics
17
Baseline Characteristics
18
Baseline Characteristics (contd)
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)
lt 100 mg 1.7 2.1 100-325 mg 97.5 97.6 gt
325 mg 0.8 0.3 ASA stopped during
hospitalization 8.0 8.1
All Randomized Population
22
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
Blinding Procedures
Number of aPTTs Ordered by Investigators per Group
25
Heparin Patients With or Without Endpoint
aPTT Values
(Triple Endpoint at 48 Hours)
26
aPTT Distribution
Comparison to TIMI 9B
Patients in each aPTT range - heparin group
27
Triple Endpoint Rates
All Randomized Population
Death, MI, Recurrent Angina (Protocol Definition)
28
Odds Ratios for Triple Endpoint Components
Odds Ratios By Timepoint
  • 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 ratio enoxaparinheparin
29
Time-to-Worst Event
Death, MI, Recurrent Angina
All Randomized Population
Death, MI, or Recurrent Angina
30
Time-to-First Event
Death, MI, Recurrent Angina
All Randomized Population
with Death, MI, Recurrent Angina
31
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 P0.016
15
RRR 16.2 P0.019
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
Efficacy Results
Additional Analyses Triple Endpoint
All Randomized Population
36
Double Endpoint Rates
Death, MI (Protocol Definition)
37
Time-to-First Double Endpoint
All Randomized Patients
38
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 Diagn
ostic Catheterization 812 (51.9) 770
(47.9) 7.7 0.024
40
Odds Ratio
Effect of Baseline Characteristic on Triple
Endpoint
Favors Unfr. Heparin
Log (Odds Ratio)
41
Randomized Not Treated
Endpoints at Day 14
42
Major Hemorrhagic Events
All Treated Population
43
Major Hemorrhagic Events to 30 Days
All Treated Population
44
Major Hemorrhagic Events On-treatment
All Treated Population
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) Ca
usality Spontaneous 1 (0.1) 7 (0.4) Surgery/inst
rumentation 17 (1.1) 10 (0.6) CABG 0 0 Seconda
ry to other trauma 0 0
On-treatment 12 hours post discontinuation of
study therapy
45
Hemorrhagic Events to 30 Days
All Treated Population
46
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 (P0.004)
  • 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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