ANTICOAGULANT THERAPY IN ACS: FOCUS

TO ENOXAPARIN

WIZA ERLANDA, MD

MAT-ID-2200152-v1.0 (02/22)
 TOPICS
• Optimum Anticoagulation in ACS patients : Summary
from Guidelines
• Evidence of Enoxaparin Across ACS Spectrum :
Summary from Key Studies
• Optimizing Risk-Benefit Ratio : Highlights of Important
Findings
• Drug Administration Guidance
Periprocedural and post-procedural antithrombotic therapy in patients undergoing
primary percutaneous coronary intervention

Eur Heart J.2017;DOI:

10.1093/eurheartj/ehx393
ESC 2020 NSTEMI GUIDELINE

Assessing bleeding vs
thrombotic risk is important
before prescribing
antithrombotic therapy

Notably, both ischaemic and

bleeding complications
significantly influence the
outcome of NSTE-ACS patients
and their overall mortality risk.

Collet JP et al European Heart Journal (2020) 00, 1-79

Algorithm for antithrombotic therapy in NSTE-ACS patients without AF
undergoing PCI

Collet JP et al European Heart Journal (2020) 00, 1-79

Enoxaparin in ACS Spectrum
Acute
Coronary
Syndrome

ESSENCE
STEMI NSTEMI / UA
SYNERGY – TIMI11b

PCI Thrombolysis

ATOLL ExTRACT-
TIMI 25
 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
– Enox vs UFH mg/kg, if needed) 41% RRR in the rate of the main secondary endpoint
Reduced death, complication of myocardial infarction, or
major bleeding
Per protocol analysis : Enoxaparin resulted in significant Per protocol analysis : Enoxaparin resulted in
improvement of the NET CLINICAL BENEFIT (RR 0.46; less major bleeding (RR 0.46; p=0.050)
p=0.0002)

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 (Thrombolysis mg/kg SC q12h p<0.001)
) – Enox vs 33% RRR in non-fatal re-infarction
UFH ≥ 75 yo : 0.75 mg/kg Similar rate of intracranial hemorrhage
q12h Reduced in the composite of death, nonfatal
reinfarction, or nonfatal intracranial hemorrhage (10.1 vs
12.2%,p<0.001)

SYNERGY 3 NSTEMI 10,027 1 mg/kg q12h SC Similar primary endpoint Higher rate of TIMI major bleeding (9.1 vs
(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 MI increased GUSTO severe bleeding with enox vs
with enox 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, MI Similar rate of major bleeding
ESSENCE 4 Enox vs UFH 3,171 or recurrent Higher minor bleeding
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.
ESC, Stockholm - August 30, 2010 – Hotline session
ATOLL
An international randomized study
comparing IV enoxaparin to IV UFH in primary PCI
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)

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 Trial design
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
MICU: Mobile Intensive Care Unit
IVRS: Interactive Voice Response System STEMI  Primary PCI

ENOXAPARIN IV UFH IV (n=460)

IVRS 50-70 IU with GP IIbIIIa
0.5 mg/kg (n=450) 70-100IU without GP IIbIIIa
with or without GPIIbIIIa
(Dose ACT-adjusted)
Primary PCI
ENOXAPARIN SC UFH IV or SC

1° EP: Death, Complication of MI, Procedure Failure, Major Bleeding

Main 2° EP: Death, recurrent MI / ACS, Urgent Revascularization
Primary Endpoint
Death, Complication of MI, Procedure Failure or Major Bleeding
40

35
RRR = 17%

% of patients
30 33.7 P = 0.07
25 28

20 UFH
15 ENOX

10

5
RRR: Relative Risk Reduction
0
 A Direct Comparison of Intravenous Enoxaparin With Unfractionated
Heparin in Primary Percutaneous Coronary Intervention
(from the ATOLL Trial) - Collet JP, Huber K, Cohen M, et al.Am J Cardiol.2013;112:1367-
72.

CONCLUSION :
• Pertinent to >87% of the study population,
enoxaparin was superior to UFH in reducing ischemic
end points and mortality.
• The present per protocol analysis of the ATOLL trial
confirms further these data when the drug is properly
used without switching with UFH.
 The SYNERGY trial

Superior Yield of the New strategy of

Enoxaparin,
Revascularization &
GlYcoprotein IIb/IIIa Inhibitors
 High-Risk At least 2 of 3 required:
ACS Patients • Age  60
• ST  (transient) or 
SYNERGY Study Design • (+) CK-MB or Troponin
Randomize
(n = 10,027)
Enoxapari IV
n Heparin
60 U/kg  12 U/kg/hr
1 mg/kg SC Q12H
(aPTT 50-70 sec)

Early invasive strategy

Other therapy per AHA/ACC Guidelines
(ASA, -blocker, ACE, clopidogrel, GP IIb/IIIa)

Primary endpoint: Death or MI at 30 days

1
 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

1
 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

1
Impact of Antithrombin Crossover – SYNERGY Trial
 Impact of Antithrombin Crossover – SYNERGY Trial
2 main highlights :
The clinical benefit seen in SYGERGY patients with no prerandomized
antithrombin or postrandomization therapy same as prerandomization therapy
showed :
o 12% relative risk reduction in mortality (0.89; 95%CI 0,70-1.11), and
o 18% significant relative risk reduction in death or nonfatal MI (0.82; 95%CI
0.73 – 0.95)
Overall, it appears that changing antithrombin therapy during the treatment course is NOT
associated with any treatment benefit and is associated with an INCREASED risk of
bleeding. SYNERGY
Trial

2015 ESC Guideline - NSTEMI Level Ref

Anticoagulant Therapy in Patients Undergoing PCI:
Recommendations
Class III (Harm)
Crossover of heparins (UFH and LMWH) is not recommended. B 216
 Efficacy and safety of enoxaparin versus unfractionated heparin during
percutaneous coronary intervention: systematic review and meta-analysis
Silvain J, Beygui F, Pollack C, et al.BMJ.2012;344:e553

23 studies (n=30,966)
 Efficacy and safety of enoxaparin versus unfractionated heparin
during percutaneous coronary intervention: systematic review and
meta-analysis
Silvain J, Beygui F, Pollack C, et al.BMJ.2012;344:e553
23 studies (n=30,966)
 Efficacy and safety of enoxaparin versus unfractionated heparin during
percutaneous coronary intervention: systematic review and meta-analysis
Silvain J, Beygui F, Pollack C, et al.BMJ.2012;344:e553

CONCLUSION :
• During percutaneous coronary intervention, enoxaparin seems
to be superior to UFH in reducing all cause mortality and
ischaemic and bleeding end points.
• This superiority was particularly evident in patients with STEMI
undergoing primary PCI
 Dosage & Administration
Guidance of ACS
Enoxaparin
- STEMI
in ACS
Primary PCI : Non - PCI & Fibrinolytic :
0.5 mg/kg iv, or 30 mg (0.3 mL) iv + 1 mg/kg sc
0.75 mg/kg iv, if stronger anti-coagulation is 2x/day*
needed to manage per-procedural complications If age ≥ 75 years old :
0.75 mg/kg 2x/day
for 8 days
*12-hour intervals
If PCI > 2 hours :
Add 0.25 mg/kg iv

If subsequent PCI :
After PCI, when needed : < 8 hours of last enox : no additional
1 mg/kg sc 2x/day, or dose
40 mg sc od (prophylactic 8 - 12 hours of last enox : 0.3 mg/kg
dose) iv
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;2018
 SAID.ENO.18.03.0104

Dosage & Administration Guidance of

Enoxaparin in ACS
ACS – Non STEMI
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.