Periprocedural and post-procedural antithrombotic therapy in patients undergoing

primary percutaneous coronary intervention

Eur Heart J.2017;DOI:

10.1093/eurheartj/ehx393
STEMI with AF
 The difference between 2013 ACCF/AHA guideline
and 2017 ESC (enoxaparin on PCI)

ACCF/AHA ESC
Main ATOLL Study ATOLL Study
Consideration - The primary composite end- - (idem)
point did not differ
significantly to UFH
- Secondary end points were - Secondary end points showed benefit of
not discussed enoxaparin
- No indication of increased bleeding
from use of enoxaparin over UFH.
- In the per protocol analysis, i.v
enoxaparin was superior vs UFH in
reducing the primary end points.
Additional N/A A meta-analysis of 23 PCI trials (30,966
Consideration patients, 33% primary PCI), enoxaparin was
associated with a significant reduction in
death compared to UFH.

Primary end-points: 30-day death, complication of myocardial infarction, procedural failure and major bleeding
Secondary end-points: death, recurrent myocardial infarction or ACS or urgent revascularization

ACCF/AHA : American College of Cardiology/American Heart Association; ESC : European Society of Cardiology; UFH : unfractionated
heparin, PCI : percutaneous coronary intervention
 Adjunctive Anticoagulant Therapy with
Fibrinolytic Therapy

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

 Adjunctive Anticoagulant Therapy with
Fibrinolytic Therapy

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

 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
– Enox vs UFH 41% RRR in the rate of the main secondary endpoint
mg/kg, if needed)
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 (Thrombolysi mg/kg SC q12h p<0.001)
s) – Enox vs 33% RRR in non-fatal re-infarction
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 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.
 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.

Result of the pre-specified per-protocol analysis

• Pre-randomization anticoagulation was not permitted in ATOLL. Later crossover,
however, did occur in a small group of patients that was removed from the study
population of this per-protocol analysis.
• Primary end point : all-cause mortality, complication of myocardial
infarction, procedural failure, or major bleeding.
• Secondary end point : all-cause mortality, recurrent acute coronary
syndrome, or urgent revascularization
 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.

Result of the prespecified per-protocol analysis

• Enoxaparin reduced significantly the rates of the primary end point by 23%
(p=0.012) and secondary end point by 63% (p<0.0001)
• Enoxaparin resulted in less major bleeding (RR 0.46; p=0.050)

All cause mortality was also

reduced by enoxaparin by 64%
(p=0.003)
 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 :
• In the per protocol analysis of the ATOLL trial, 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.
 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

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

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

ARD: Absolute Risk Difference

RR: Relative Risk
Morrow DA, et al.Eur Heart J.2010;31:2097-102.
Systematic Review and Meta-analysis
• Low-molecular-weight heparins vs. unfractionated heparin in the
setting of percutaneous coronary intervention for ST-elevation
myocardial infarction: a meta-analysis” - J Thromb
Haemost.2011;9:1902-15
• “Efficacy and safety of enoxaparin versus unfractionated heparin
during percutaneous coronary intervention: systematic review and
meta-analysis” – BMJ 2012;344:e553
• “Comparison of bleeding complications and 3-year survival with low-
molecular-weight heparin versus unfractionated heparin for acute
myocardial infarction: The FAST-MI registry” – Archives of
Cardiovascular Disease.2012;105:347-54
 Low-molecular-weight heparins vs. unfractionated heparin in the
setting of percutaneous coronary intervention for
ST-elevation myocardial infarction: a meta-analysis
Navarese EP, De Luca G, Castriota F, et al. J Thromb Haemost.2011;9:1902-15

10 studies (n=16,286)

Individual and summary relative risk for mortality in patients treated with LMWHs vs UFH
 Low-molecular-weight heparins vs. unfractionated heparin in the
setting of percutaneous coronary intervention for
ST-elevation myocardial infarction: a meta-analysis
Navarese EP, De Luca G, Castriota F, et al. J Thromb Haemost.2011;9:1902-15

10 studies (n=16,286)

Individual and summary adjusted relative risk for mortality in patients treated with LMWHs vs UFH

“LMWH were associated with greater efficacy and safety than UFH in STEMI patients
treated with PCI.”
 Low-molecular-weight heparins vs. unfractionated heparin in the
setting of percutaneous coronary intervention for
ST-elevation myocardial infarction: a meta-analysis
Navarese EP, De Luca G, Castriota F, et al. J Thromb Haemost.2011;9:1902-15

10 studies (n=16,286)

LMWH treatment was

associated with a significant
reduction in the rate of major
bleeding complications in the
PCI group

Individual and summary relative risk for major bleeding in patients treated with LMWHs vs UFH
 Low-molecular-weight heparins vs. unfractionated heparin in the
setting of percutaneous coronary intervention for
ST-elevation myocardial infarction: a meta-analysis
Navarese EP, De Luca G, Castriota F, et al. J Thromb Haemost.2011;9:1902-15

Theoretically explanation for LMWH greater efficacy :

• LMWHs have a four-fold greater activity against activated factor X
• LMWHs : much more predictable anticoagulant response than UFH as they
do not bind to plasma proteins
• Pleiotropic effects such as blunting the increase in von-Willebrand factor
and a relative lack of associated platelet activation might influence its
antithrombotic properties in addition to superior anticoagulant effects
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

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
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
 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 and 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.

• 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 STEMI and has
benefit over UFH.
THANK YOU