Advanced the anticoagulant

Co-therapy in STE-ACS patients:

Role of Enoxaparine
I Made Junior Rina Artha, MD, FIHA, FAsCC

Sanglah Hospital/
Faculty of Medicine Universitas Udayana
TOPICS

• Optimum Anticoagulation in ACS patients : Summary

from Guidelines
• Role of Enoxaparin in ACS Spectrum : Summary from
Studies
• Optimizing Risk-Benefit Ratio : Highlights of Important
Findings
Current Situation on Reperfusion
Treatment for STEMI
Number of Number of
Population in The Population with Risk
Number of MI
Territory for Developing
Patients Based on
(province/distric STEMI
Medical Record
covered by the (extrapolated from
hospital) national prevalence)

n = 63rb n = 459
n = 4,225jt
(1,5 %) (67 %)

Source : Riskesdas 2018

ACS Patient Distribution in
RSUP Sanglah Bali (2018)

ACS
N=754

STEMI
NSTEMI/UAP
N= 373
N= 381 (50,5%)
(49,5%)

Reperfusion No Reperfusion
N= 289
(77,5%) N= 84 (22,5%)

Fibrinolysis PPCI
N= 171 Autolysis
N= 118 N= 0 (0%)
(40,8%) (59,2%)
In Hospital Mortality Rate STEMI Patient Based on
Reperfusion

Reperfusion (n=289) No Reperfusion (n=84)

In Hospital Mortality Rate STEMI Patient Based on
Reperfusion

N= 10 (8,5%)
N= 10 (5,8%)

PPCI (n=171) Fibrinolisis (n=118)

Heparin use in ACS

UAP/NSTEMI (N=381) STEMI (N=373)

Anticoagulant in STEMI : 2013 AHA and 2017 ESC
Guideline
Adjunctive Anticoagulant Therapy to Support PCI
After Fibrinolytic Therapy
2013 AHA guideline
Class of Level of
Recommendation Evidence

O’Gara PT, Kushner FG, Ascheim DD, et al. JACC.2013;61(4):e78 - 140

 Adjunctive Anticoagulant Therapy with Fibrinolytic
Therapy
2017 ESC guideline

Ibanez B, et al.Eur Heart J.2017:1-66

Adjunctive Anticoagulant Therapy with Fibrinolytic
Therapy
2017 ESC guideline

Ibanez B, et al.Eur Heart J.2017:1-66

ACS Spectrum
Acute
Coronary
Syndrome

STEMI NSTEMI / UA

PCI Thrombolysis
Summary of Evidence
Study Subjects N Dose of Enox Efficacy Safety (enox vs UFH)

ATOLL 1 STEMI 910 0.5 mg/kg IV Similar primary endpoint Similar rate of major and minor bleeding
(primary PCI) (additional 0.25
41% RRR in the rate of the main secondary endpoint
– Enox vs mg/kg, if needed)
UFH Reduced death, complication of myocardial
infarction, or major bleeding
Per protocol analysis : Enoxaparin resulted in
Per protocol analysis : Enoxaparin resulted
significant improvement of the NET CLINICAL BENEFIT
(RR 0.46; p=0.0002) in less major bleeding (RR 0.46; p=0.050)

ExTRACT- STEMI 20,506 30 mg IV –> 1.0 17% RRR in the primary endpoint Higher rate of major bleeding (2.1 vs 1.4%;
TIMI 25 2 (Thrombolysi mg/kg SC q12h p<0.001)
33% RRR in non-fatal re-infarction
s) – Enox vs
UFH ≥ 75 yo : 0.75 mg/kg Similar rate of intracranial hemorrhage
Reduced in the composite of death, nonfatal
q12h
reinfarction, or nonfatal intracranial hemorrhage
(10.1 vs 12.2%,p<0.001)
SYNERGY NSTEMI 10,027 1 mg/kg q12h SC Similar primary endpoint Higher rate of TIMI major bleeding (9.1 vs
3
(PCI) – Enox 7.6%; p=0.008)
vs UFH Non-significant GUSTO severe bleeding
Subpopulation receiving consistent therapy : 18% Subpopulation receiving consistent therapy
significant relative risk reduction in death or nonfatal : increased GUSTO severe bleeding with
MI with enox enox vs UFH (2.9% vs. 2.1%, p 0.0465).
TIMI 11b NSTEMI – 3,910 1 mg/kg q12h SC ≈ 20% RRR in the composite triple end point (death, Similar rate of major bleeding
– ESSENCE Enox vs UFH + MI or recurrent
4 Higher minor bleeding
3,171 Angina)
At 1 yr FU, 13% RRR in the composite triple end point

1. Montalescot G, et al.Lancet.2011;378:693-703; 2. Antman EM, et al.N Eng J Med.2006;354:1477-88. 3. SYNERGY Trial

Investigators.JAMA.2004;292:45-54. 4. Antmant EM, et al.Circulation.1999;1602-8.
Protocol Design
STEMI < 6 h
Lytic eligible
Lytic choice by MD
ASA (TNK, tPA, rPA, SK)

Double-blind, double-dummy
ENOX UFH
< 75 y: 30 mg IV bolus 60 U / kg bolus (4000 U)
SC 1.0 mg / kg q 12 h (Hosp DC) Inf 12 U / kg / h (1000 U / h)
≥ 75 y: No bolus Duration: at least 48 h
SC 0.75 mg / kg q 12 h (Hosp DC) Cont’d at MD discretion
CrCl < 30: 1.0 mg / kg q 24 h
Day 30
1° Efficacy Endpoint: Death or Nonfatal MI
1° Safety Endpoint: TIMI Major Hemorrhage
Main Results
Primary Endpoint: Main Secondary Endpoint:
Death or non-fatal re-MI by 30 days Death, non-fatal re-MI, urgent
revascularization by 30 days

UFH UFH
12.0 14.5
9.9 11.7
ENOX ENOX

% %
RR = 0.83 RR = 0.81
p = 0.000003 p = 0.000001

Days Days

33% RRR in reMI by 48 h (P=0.002) 12% RRR in by 48 h (P=0.02)

19% RRR in Death/MI by 72 h (P<0.001)

N Engl J Med 2006;354:1477-88.

TIMI major bleeding Stratified by age

Unfractionated heparin Enoxaparin

ARD 0.8% ARD 0.4%
RR 1.67 (1.31-2.13) RR 1.15 (0.74-1.78)
5 p=<0.0001 p=0.53

4 3.3
2.9
% Events

3
1.9
2
1.1
1
0
< 75 years ≥ 75 years
n = 17,814 n = 2513
ARD: Absolute Risk Difference
RR: Relative Risk
Bleeding Endpoints (TIMI) 30 days
1-year outcome of ExTRACT-TIMI 25

Conclusion : Compared with UFH for 48 h, a strategy using enoxaparin as an adjunct to

fibrinolysis resulted in a sustained reduction in death or MI at 1 year with no additional
benefit after 30 days. Mortality was not reduced at 1 year with the enoxaparin strategy.

Morrow DA, et al.Eur Heart J.2010;31:2097-102.

 Comparison of bleeding complications and 3-year survival with low-molecular-
weight heparin versus unfractionated heparin for acute myocardial infarction: The
FAST-MI registry – Puymirat E, Aissaoui N, Silvain J, et al.Archives of Cardiovascular
Disease.2012;105:347 - 54
Nation-wide registry study (real-world experience) included consecutive AMI patients
admitted to an intensive care unit less than 48 hours from symptom onset in 223
participating centres in France (n=2,854)
 Comparison of bleeding complications and 3-year survival with low-
molecular-weight heparin versus unfractionated heparin for acute
myocardial infarction: The FAST-MI registry – Puymirat E, Aissaoui N, Silvain J, et
al.Archives of Cardiovascular Disease.2012;105:347 - 54

Nation-wide registry study (real-world experience) included consecutive AMI patients

admitted to an intensive care unit less than 48 hours from symptom onset in 223
participating centres in France (n=2,854)

CONCLUSION : LMWH in real-world clinical practice is associated with less

bleeding and a better 3-year survival rate in patients with AMI.
 SAID.ENO.18.03.0104

Dosage & Administration Guidance of Enoxaparin in ACS

Primary PCI : Non - PCI & Fibrinolytic :

0.5 – 0.75 mg/kg iv 30 mg (0.3 mL) iv + 1 mg/kg sc 2x/day
If age ≥ 75 years old :
0.75 mg/kg 2x/day
If PCI > 2 hours : for 8 days
Add 0.25 mg/kg iv

If subsequent PCI :
After PCI, when needed :
< 8 hours of last enox : no additional dose
1 mg/kg sc 2x/day, or
> 8 hours of last enox : 0.3 mg/kg iv
40 mg sc od (prophylactic dose)

No routine anticoagulant monitoring is needed

Note : the use of Lovenox in primary PCI is not yet approved by Badan POM and its safety and efficacy have only
been established for the approved conditions.

Montalescot G, et al.Lancet.2011;378:693-703; Lovenox [package insert]. Jakarta: Aventis Pharma;2017.

 SAID.ENO.18.03.0104

Dosage & Administration Guidance of Enoxaparin in ACS

Initial Tx:
1 mg/kg sc 2x/day
for 2-8 days

If subsequent PCI is performed :

< 8 hours of last enox : no additional dose
> 8 hours of last enox : 0.3 mg/kg iv

No routine anticoagulant monitoring is needed

Lovenox [package insert]. Jakarta: Aventis Pharma;2017; Ferguson JJ, et al.JAMA.2004;292:45-54.

CONCLUSION
• High-risk ACS patients needs revascularization
treatment with PCI as one of the main choice
• Optimum anticoagulation is one of key treatment
success
• How we choose anticoagulant agents is based on the
risk of thrombosis and bleeding
• Enoxaparin has been studied extensively across ACS
spectrum and has benefit over UFH.
MATUR SUKSMA