IMPROVING PATIENT OUTCOME by Optimizing Antithrombotic Use FINAL 2020-06-04 06 - 56 - 27

SAID.ENO.20.04.
0273 (05/20)
“IMPROVING PATIENT
OUTCOME BY OPTIMIZING
ANTITHROMBOTIC USE IN ACS
PATIENTS” (STEMI & NSTEMI)
[insert name & Institution]
ACS : Acute Coronary Syndrome

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

ATHEROSCLEROSIS –
ATHEROTHROMBOSIS A GENERALIZED
AND PROGRESSIVE DISEASE
Atherothrombosis
Unstable
angina ACS
NSTEMI
Atherosclerosis Thrombosis STEMI
CV death
Stable angina
Adapted from Libby P. Circulation. 2001;104:365-
372
MANAGEMENT STRATEGY IN ACUTE CORONARY SYNDROMES (ACS)
Non-ST elevation ST elevation
Early invasive
Early conservative
strategy in Thrombolysis
strategy in low- Primary PCI
high-risk risk patients
patients
Circulation.2014;130:e344-426
INVASIVE STRATEGY (NSTE-
ACS)
VERY HIGH RISK
 Syok Kardiogenik
 Acute HF
 Aritmia maligna
 Ongoing / recurrent chest pain
 Mechanical complications
 Dynamic ST-T changes ( recurrent )
 Immediate invasive strategy ( <2 hr )

ACS)
HIGH RISK
 Established NSTEMI ( Trop I meningkat )
 Dynamic ST-T changes ( simptomatik / silet )
 Grace Score > 140
 Early invasive strategy (<24 hr)

ACS)
INTERMEDIATE RISK
 DM / CKD
 CHF / EF < 40%
 Early post infark, post PCI, post CABG
 Grace > 109 dan < 140 / recurrent iskemia saat non invasive test
 Invasive strategy (<72 hr)

ANTICOAGULANT IN STEMI : 2013
AHA AND 2017 ESC GUIDELINE
2013 ACCF/AHA GUIDELINE FOR THE
MANAGEMENT OF ST-ELEVATION
MYOCARDIAL INFARCTION (MI)
Anticoagulant Therapy to Support Primary PCI: Recommendations
JACC.2013;61(4):e78-140.
ESC GUIDELINE FOR THE
MANAGEMENT OF ACUTE MI IN
PATIENTS PRESENTING WITH ST-
SEGMENT ELEVATION
Periprocedural and post-procedural antithrombotic therapy in patients undergoing
primary percutaneous coronary intervention
Eur Heart J.2017;DOI:

10.1093/eurheartj/ehx393
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-point - (idem)
did not differ significantly to UFH
- Secondary end points were not
discussed - Secondary end points showed benefit of
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 patients,

Consideration 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 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

ANTICOAGULANT IN NSTEMI :
2013 AHA AND 2017 ESC GUIDELINE
2014 AHA/ACC GUIDELINE FOR THE MANAGEMENT OF
PATIENTS WITH NON–ST-ELEVATION ACUTE CORONARY
SYNDROMES
Summary of Recommendations for Initial Anticoagulant Therapy in Patients
With Definite or Likely NSTE-ACS and PCI
2014 AHA/ACC GUIDELINE FOR THE MANAGEMENT OF PATIENTS
WITH NON–ST-ELEVATION ACUTE CORONARY SYNDROMES
Anticoagulant Therapy in Patients Undergoing PCI: LOE

Recommendations
Class I
An anticoagulant should be administered to patients with NSTE-ACS undergoing PCI to C
reduce the risk of intracoronary and catheter thrombus formation.
Intravenous UFH is useful in patients with NSTEACS undergoing PCI. C
Bivalirudin is useful as an anticoagulant with or without prior treatment with UFH in B
patients with NSTE-ACS undergoing PCI
An additional dose of 0.3 mg/kg IV enoxaparin should be administered at the time of PCI B
to patients with NSTE-ACS who have received fewer than 2 therapeutic subcutaneous
doses (eg, 1 mg/kg SC) or received the last subcutaneous enoxaparin dose 8 to 12 hours
before PCI
If PCI is performed while the patient is on fondaparinux, an additional 85 IU/kg of UFH B
should be given intravenously immediately before PCI because of the risk of catheter
thrombosis

Recommendations
Class I (Cont’d)
In patients with NSTE-ACS, anticoagulant therapy should be discontinued after PCI unless C
there is a compelling reason to continue such therapy.
Class IIa
In patients with NSTE-ACS undergoing PCI who are at high risk of bleeding, it is B
reasonable to use bivalirudin monotherapy in preference to the combination of UFH and a
GP IIb/IIIa receptor antagonist
Class IIb B
Performance of PCI with enoxaparin may be reasonable in patients treated with upstream B
subcutaneous enoxaparin for NSTE-ACS
Class III (Harm)
Fondaparinux should not be used as the sole anticoagulant to support PCI in patients with B
NSTEACS due to an increased risk of catheter thrombosis
ESC GUIDELINES FOR THE MANAGEMENT OF
ACS IN PATIENTS PRESENTING WITHOUT ST-
SEGMENT ELEVATION
Anticoagulant Therapy in Patients Undergoing PCI: Recommendations LOE
Class I
Parenteral anticoagulation is recommended at the time of diagnosis B

according to both ischaemic and bleeding risks.
Fondaparinux (2.5 mg s.c. daily) is recommended as having the most B

favourable efficacy–safety profile regardless of the management strategy.
UFH if concomitant with GPIIb/IIIa inhibitors) is recommended in patients undergoing PCI who did B
not receive any anticoagulant.
Based on
If the initial anticoagulant is fondaparinux, a single bolus of UFH should be added at the time of PCI.
OASIS-5B
Enoxaparin (1 mg/kg twice daily) is recommended when fondaparinux is not available. B
Eur Heart J.2015;doi:10.1093/eurheartj/ehv320

ESC GUIDELINES FOR THE MANAGEMENT OF
ACS IN PATIENTS PRESENTING WITHOUT ST-
SEGMENT ELEVATION

Recommendations
Class IIa
Enoxaparin should be considered as an anticoagulant for PCI in patients B
pretreated with s.c. enoxaparin.
Class III (Harm)
Crossover of heparins (UFH and LMWH) is not recommended. B
Eur Heart J.2015;doi:10.1093/eurheartj/ehv320

PCI CAN BE PERFORMED WITHOUT ADDITIONAL
ANTICOAGULANT AND WITHOUT ROUTINE
ANTICOAGULANT MONITORING
2015 ESC guidelines for

NSTEMI
 LMWH should not be administered in patients with eGFR < 15 mL/min/1.73m2.
 Monitoring of anti-Xa activity is NOT necessary except in patients with eGFR 15–
30 mL/min/1.73m2 or bodyweight >100 kg
If … then …
Last sc enoxaparin < 8h before PCI No additional dose needed
Last sc enoxaparin ≥ 8h before PCI Add 0.3 mg/kg iv bolus
Roffi M, et al.Eur Heart

J.2015;doi:10.1093/eurheartj/ehv320.
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.
 As anticoagulant co-therapy with fibrinolysis, compared to
UFH, the net clinical benefit (i.e absence of death, non-fatal
infarction, and intracranial hemorrhage) favoured enoxaparin. –
2017 ESC guideline
DOSAGE & ADMINISTRATION
GUIDANCE OF ENOXAPARIN IN
ACS
ACS - STEMI
Primary PCI : Non - PCI & Fibrinolytic :

0.5 mg/kg iv, or 30 mg (0.3 mL) iv + 1 mg/kg sc 2x/day*
0.75 mg/kg iv, if stronger anti-coagulation is needed to If age ≥ 75 years old :
manage per-procedural complications 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 dose
1 mg/kg sc 2x/day, or 8 - 12 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;2018

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;2018; Ferguson JJ, et al.JAMA.2004;292:45-54.

SAID.ENO.20.04.0273 (05/20)
REFERENCES 1:
1. Title
2. Topics
3. Libby P. Circulation. 2001;104:365-372
4 Circulation.2014;130:e344-426
5. Title
6. JACC.2013;61(4):e78-140.
7. Eur Heart J.2017;DOI: 10.1093/eurheartj/eh
8. ACCF/AHA : American College of Cardiology/American Heart Association; ESC : European Society of Cardiology;
UFH : unfractionated heparin, PCI : percutaneous coronary intervention
9. O’Gara PT, Kushner FG, Ascheim DD, et al. JACC.2013;61(4):e78 – 140
10-11 Ibanez B, et al.Eur Heart J.2017:1-66
12. Title
13-19. Circulation.2014;130:e344-426
20-23.. Yusuf S, et al.N Eng J Med.2006;354
24. Scheme
25. A.Montalescot G, et al.Lancet.2011;378:693-703; 25B.Antman EM, et al.N Eng J Med.2006;354:1477-88. 25C..
SYNERGY Trial Investigators.JAMA.2004;292:45-54. 4. 25D.Antmant EM, et al.Circulation.1999;1602-8.
26-30. G. Montalescot, M. Cohen, P. Goldstein. Lancet 2011 Aug 20;378(9792):693-703
31-33. Collet JP, Huber K, Cohen M, et al.Am J Cardiol.2013;112:1367-72.
34-39. Silvain J, Beygui F, Pollack C, et al.BMJ.2012;344:e553
40-47. Antman EM, Morrow DA, McCabe CH, et al.N Eng J Med.2006;354:1477-88.
48-56. Cohen M, Mahaffey K, Pieper K, et al.J Am Coll Cardiol.2006;48:1346-54
57. Conclusion
58-62. Cohen M, et al. N Engl J. Med 1997 ; 337: (447-452)
63. White HD, et al.Am Heart J.2009;157:125-31
64-65. Mahaffey KW, et al.International Journal of Cardiology.2010;139(2):123-33
REFERENCES 2:
66A. J Thromb Haemost.2011;9:1902-15

66B. BMJ 2012;344:e553
66C. Archives of Cardiovascular Disease.2012;105:347-54
67-68. Navarese EP, De Luca G, Castriota F, et al. J Thromb Haemost.2011;9:1902-15
69-76. Silvain J, Beygui F, Pollack C, et al.BMJ.2012;344:e553
77-78. Petersen JL, Mahaffey KW, Hasselblad V, et al.JAMA.2004;292:89-96
79-80. Puymirat E, Aissaoui N, Silvain J, et al.Archives of Cardiovascular Disease.2012;105:347 - 54
81. Collet JPh, Montalescot G, Lison L, et al.Circulation.2001;103:658-63
82. Martin ML, Fry ETA, Sanderink GCM, et al.Catheter Cardiovasc Interv.2004;61:163-70
83. Roffi M, et al.Eur Heart J.2015;doi:10.1093/eurheartj/ehv320.
84. Conclusion
85. Montalescot G, et al.Lancet.2011;378:693-703; Lovenox [pa
86A. Lovenox [package insert]. Jakarta: Aventis Pharma;2018
86B. Ferguson JJ, et al.JAMA.2004;292:45-54.
87-88. List References
OASIS-5: STUDY
DESIGN
Patients with NSTE ACS, chest discomfort <24 hours,
2: Age >60 y,  ST segment,  cardiac biomarkers
ASA, clopidogrel, GP IIb/IIIa,

planned cath/PCI per local practice
Randomize
Fondaparinux N = 20,078 Enoxaparin
2.5 mg sc qd 1 mg/kg sc bid
Outcomes
Primary: Efficacy Death, MI, refractory ischemia at 9 d
Safety Major bleeding at 9 d
Benefit/risk Death, MI, refractory ischemia, major bleeding at 9 d
Secondary: Primary outcomes plus each component at 30 d and 6 mo
Yusuf S, et al.N Eng J Med.2006;354.

SUBJECT FLOW & CONCOMITANT DRUGS – OASIS 5
Study-Drug Administration in PCI patients – OASIS 5 :
≤ 6 ho
urs +/- Additional fondaparinux
Fondaparinux
>6h
ours Fondaparinux
≤ 6 ho
urs No additional anticoagulan
Crossover of heparins (UFH and
Enoxaparin
>6h
ours UFH LMWH) is not recommended.
– 2015 ESC Guideline; class IIIb
*GP IIb/IIIa inhibitor may or may not be given
Treatments among Patients Undergoing PCI within the First 8 Days after Randomization
Yusuf S, et al.N Eng J Med.2006;354.

OASIS-5: TREATMENT EFFECT ON
PRIMARY EFFICACY OUTCOME AT 9
DAYS
Death, MI, refractory ischemia
0.06 HR 1.01
(0.90-1.13)
0.05
0.04 Fondaparinux
Cumulative
event rate 0.03
0.02
Enoxaparin
0.01
0
0 1 2 3 4 5 6 7 8 9
Time (days)
OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

CLINICAL EVENTS AFTER PCI: DAY 30
14 P=0.004
11.7
12
Event Rate (%)
9.5
10 P=0.60 P<0.0001
8
5.4 5.7 5.4
6 P=0.68
4 2.8
2.1 2
2
0
Death MI Major Bleeds Death,
MI,Stroke or
Major Bleed
Enox (n=3089) Fonda (n=3118)

ENOXAPARIN IN ACS SPECTRUM
Acute
Coronary
Syndrome
STEMI NSTEMI / UA ESSENCE

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 41% RRR in the rate of the main secondary endpoint
mg/kg, if needed)
UFH 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 less major bleeding (RR 0.46; p=0.050)
0.46; 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)
SYNERG NSTEMI 10,027 1 mg/kg q12h SC Similar primary endpoint Higher rate of TIMI major bleeding (9.1 vs
Y3 (PCI) – 7.6%; p=0.008)
Enox vs Non-significant GUSTO severe bleeding
UFH Subpopulation receiving consistent therapy : 18% Subpopulation receiving consistent therapy :
significant relative risk reduction in death or nonfatal MI increased GUSTO severe bleeding with enox
with 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, MI Similar rate of major bleeding
– Enox vs 3,171 or recurrent
ESSENCE UFH Angina) Higher minor bleeding
4
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.
ATOLL
ESC, Stockholm - August 30, 2010 – Hotline session
AN INTERNATIONAL RANDOMIZED STUDY

COMPARING IV ENOXAPARIN TO IV UFH IN PRIMARY PCI
 G. Montalescot, M. Cohen, P. Goldstein, K. Huber, C. Pollack, U. Zeymer, E. Vicaut for the ATOLL investigators
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
30 days
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
L L 40
TO 35
RRR = 17%
A
% of patients
30 33.7 P = 0.07
25 28
20 UFH
15 ENOX
10
RRR: Relative Risk Reduction

DEATH, COMPLICATION OF MI OR MAJOR BLEEDING
Net clinical benefit
L L 16
TO 14 15
RRR = 32%
A
% of patients
12 P = 0.03
10
10,2
8 UFH
6 ENOX
0
L L ALL SAFETY ENDPOINTS
TO P = NS for all
A
14
12
10
%of patients
2 2.7
2.4 2.9 2.3
0
Protocole definitions NS: Non Significant

(STEEPLE)
A DIRECT COMPARISON OF INTRAVENOUS ENOXAPARIN WITH
UNFRACTIONATED
HEPARIN IN PRIMARY PERCUTANEOUS CORONARY
INTERVENTION
T O (FROM THE ATOLL TRIAL)

AResultLof the pre-specified
- .
COLLET JP, HUBER K, COHEN M, ET AL.AM J CARDIOL.2013;112:1367-72
per-protocol analysis

L
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
Baseline and
Of 910 randomized patients, 795
Procedural characteristics
patients (87.4%) are included in
were well balanced between
this per protocol analysis
the 2 treatment groups
A DIRECT COMPARISON OF INTRAVENOUS ENOXAPARIN WITH
UNFRACTIONATED
HEPARIN IN PRIMARY PERCUTANEOUS CORONARY
INTERVENTION
TO (FROM THE ATOLL TRIAL)

A L - Result of the prespecified per-protocol analysis .
COLLET JP, HUBER K, COHEN M, ET AL.AM J CARDIOL.2013;112:1367-72
LEnoxaparin 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)
Enoxaparin resulted in significant

improvement of the NET
CLINICAL BENEFIT (RR 0.46;
p=0.0002)
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
TO (FROM THE ATOLL TRIAL)
A L - COLLET JP, HUBER K, COHEN M, ET AL.AM J CARDIOL.2013;112:1367-72.
L
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.
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)
23 studies (n=30,966)
23 studies (n=30,966)
STEMI
23 studies (n=30,966)
NON- STEMI
UNFRACTIONATED HEPARIN DURING PERCUTANEOUS
CORONARY INTERVENTION: SYSTEMATIC REVIEW AND
META-ANALYSIS
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
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
Antman EM, Morrow DA, McCabe CH, et al.N Eng J Med.2006;354:1477-88.

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)

BLEEDING ENDPOINTS
(TIMI)
30 DAYS
10 UFH
ENOX
8
ARD 0.7% ARD 0.4% ARD 0.1%
6
% Events
RR 1.53 RR 1.39 RR 1.27

P<0.0001 P = 0.014 P = 0.14
4
2.1
1.4
2 0.9 1.3 0.7 0.8
0 Major Bleed Nonfatal ICH
(fatal + nonfatal) Major Bleed
No difference in fatal major bleeds
FOR EVERY 1000 PTS
TREATED WITH
ENOXAPARIN
< 75 yo
≥ 75 yo

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

3 FACTORS CONTRIBUTED TO THE
TREATMENT DIFFERENCES
• Superior anti-thrombotic effect

• Longer duration of treatment with enoxaparin
• UFH : at least 48 hrs (median 2.0 days)
• Enoxaparin : until hospital discharge or max 8 days (median 7.0 days)

• Rebound increase in thrombotic events after
discontinuation of UFH

NET CLINICAL BENEFIT
AT 30 DAYS
Prespecified Definitions UFH (%) ENOX (%) RRR (%)
Death or Nonfatal MI or
12.3 10.1 18
Nonfatal Disabl. Stroke
P <0.0001
Death or Nonfatal MI or
12.8 11.0 14
Nonfatal Major Bleed P <0.0001
Death or Nonfatal MI or 12.2 10.1 17

Nonfatal ICH P <0.0001
0.8 0.9 1 1.25
ENOX Better RR UFH Better

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.

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
STUDY DESIGN • ST  (transient) or 
• (+) 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 15.212.50.001
Any RBC transfusion 17.016.00.155
ICH< 0.1 < 0.1 NS
1
IMPACT OF ANTITHROMBIN
CROSSOVER
IMPACT OF ANTITHROMBIN
CROSSOVER
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
A SUBGROUP ANALYSIS OF THE IMPACT OF
PRERANDOMIZATION ANTITHROMBIN
THERAPY ON OUTCOMES IN THE
SYNERGY TRIAL
COHEN M, MAHAFFEY K, PIEPER K, ET AL.J AM COLL CARDIOL.2006;48:1346-54
 Purpose : to compare the effect of receiving pretreatment with antithrombin
before randomization (efficacy & safety) in the SYNERGY trial
 IMPORTANT CONCERN : a substantial proportion of the SYNERGY
patients had been initiated on enoxaparin or UFH by a treating physician before
enrollment.
 Flowchart of patient subgroups by pretreatment :
PRE RANDOMIZATION ANTITHROMBIN
THERAPY ON OUTCOMES IN THE SYNERGY
TRIAL
Analysis of subjects receiving CONSISTENT therapy* : (n = 6,138 from 9,978)
*patient had received a pretreatment in the emergency department of the same drug as the randomized therapy or had received
no pretreatment at all.
Result : Secondary End Points Through 30 Days for Consistent Therapy Subgroup
 Those who received consistent therapy with enoxaparin experienced fewer deaths or MIs than those
who received consistent therapy with UFH (seen at 48h and persisted through 14 and 30 days)
 There was increased GUSTO severe bleeding with consistent therapy with enoxaparin versus UFH
(2.9% vs. 2.1%, p 0.0465).
PRE
RANDOMIZATION ANTITHROMBIN
THERAPY ON OUTCOMES IN THE
SYNERGY TRIAL
Analysis of subjects receiving CONSISTENT therapy* : (n = 6,138 from 9,978)
*patient had received a pretreatment in the emergency department of the same drug as the randomized therapy or had received
no pretreatment at all.
Result : Secondary End Points Through 30 Days for Consistent Therapy Subgroup
CONCLUSION : Treatment with antithrombin therapy before randomization had potential

impact on comparison of study drug effects. After adjustment, consistent therapy with
enoxaparin might be superior to UFH in reducing death or nonfatal MI, with a modest
excess in bleeding.
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.
 As anticoagulant co-therapy with fibrinolysis, compared to UFH,
the net clinical benefit (i.e absence of death, non-fatal infarction,
and intracranial hemorrhage) favoured enoxaparin. – 2017 ESC
guideline
ESSENCE
Death, MI, or recurrent angina at 1-year follow-up
40
P = 0.022
Cumulative Event Rate (%)
30
20
UFH
10
Enoxaparin
0
0 2 4 6 8 10 12 14
Months
Source: Goodman SG, et al. J Am Coll Cardiol.

2000;36:693.
ESSENCE
Efficacy results at 1-year follow-up
Absolute Relative
UFH Enoxaparin
difference difference* P
Triple endpoint %
30 days 23.3 19.8 3.5 0.81 0.016
1 year 35.7 32.0 3.7 0.87 0.022
Double endpoint
30 days 7.7 6.2 1.6 0.78 0.081
1 year 13.5 11.5 2.0 0.84 0.082
* Hazard ratio or odds ratio.

Source: Goodman SG, et al. J Am Coll Cardiol.
2000;36:693.
ESSENCE Study : The ability of UFH to maintain the aPTT is shown
below
The ability of UFH to maintain aPTT

target (55-85 sec) was :
- 46.0% during 24 hours;
- 59.6% during day 4.
* aPTT was measured at baseline and 4-6 hours after
initiation of treatment
ENOXAPARIN IN PATIENTS WITH RENAL
IMPAIRMENT
Sub analysis from STEEPLE trial

 Major bleeding occurred more often in patients with renal impairment
compared with those without (2.7% vs 1.5%, P = .04).
 Enoxaparin was associated with less major bleeding than UFH with
normal renal function (0.9% for enoxaparin 0.5 mg/kg or 1.0% for enoxaparin 0.75 mg/kg
vs 2.6%, respectively; both P = .01 vs UFH),
 a trend toward less major bleeding with impaired renal function (2.6% or 1.8%
vs 3.8%, P = .18 for enoxaparin 0.5 mg/kg and P = .47 for 0.75 mg/kg vs UFH)
 The incidence of death, nonfatal myocardial infarction, or urgent target-
vessel revascularization was similar between patients with and without
renal impairment
White HD, et al.Am Heart J.2009;157:125-31.

ENOXAPARIN IN OBESE PATIENTS
Sub analysis from SYNERGY trial

 Thirty-two percent of patients were obese (BMI ≥ 30)
 Obese patients were more likely to be underdosed than non-obese
patients.
 After adjustment, increased BMI was not an independent predictor of
bleeding outcomes or 30-day death/myocardial infarction, but increased
BMI was predictive of lower 1-year mortality in the subgroup of patients
with BMI at baseline below approximately 30 kg/m2
 Standard dosing of enoxaparin should be used in patients without extreme
obesity due to limited outcome data in these patients.
Mahaffey KW, et al.International Journal of Cardiology.2010;139(2):123-33.

ENOXAPARIN IN ELDERLY PATIENTS
Sub analysis from SYNERGY trial

 25.5% (2540) of study population were 75 years of age.
 After adjustment, advanced age (per 10 years) was associated with 30-day
death or MI [risk odds ratios [ROR] : 1.14, P = 0.002], 30-day death (ROR: 1.54, P <
0.0001), and 1-year death (ROR: 1.47, P < 0.0001), as well with TIMI major
bleeding (ROR: 1.21, P = 0.001), GUSTO severe bleeding (ROR: 1.20, P = 0.047),
and transfusion (ROR: 1.04, P = 0.324).
 Although higher rates of adverse events are seen in the oldest subgroup
(age 75 years) treated with enoxaparin, statistical comparisons confirm similar
efficacy and safety of enoxaparin and UFH across age subgroups as was
demonstrated overall in SYNERGY.
Mahaffey KW, et al.International Journal of Cardiology.2010;139(2):123-33.

SYSTEMATIC REVIEW & 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 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
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
23 studies (n=30,966)
Efficacy and safety of enoxaparin versus
unfractionated heparin during percutaneous
coronary intervention: systematic review and meta-
analysis
23 studies (n=30,966)
Efficacy and safety of enoxaparin versus
unfractionated heparin during percutaneous
coronary intervention: systematic review and meta-
analysis
23 studies (n=30,966)
UNFRACTIONATED HEPARIN DURING PERCUTANEOUS
CORONARY INTERVENTION: SYSTEMATIC REVIEW AND
META-ANALYSIS
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 BLEEDING COMPLICATIONS AMONG PATIENTS
RANDOMIZED TO ENOXAPARIN OR UNFRACTIONATED HEPARIN
FOR ANTITHROMBIN THERAPY IN NSTEMI - A SYSTEMATIC
OVERVIEW
Petersen JL, Mahaffey KW, Hasselblad V, et al.JAMA.2004;292:89-96.
 In a systematic overview of approximately 22,000 patients across the
spectrum of ACS, enoxaparin is more effective than UFH in
preventing the combined end point of death or MI
Intention-To-Treat population: Efficacy end points at 30 days

EFFICACY AND BLEEDING COMPLICATIONS AMONG PATIENTS
RANDOMIZED TO ENOXAPARIN OR UNFRACTIONATED HEPARIN
FOR ANTITHROMBIN THERAPY IN NSTEMI - A SYSTEMATIC
OVERVIEW
No Prerandomization Therapy Population: Efficacy End Points at 30 Days
The substantial and consistent treatment benefit in patients who had

not received prior antithrombin therapy indicates that enoxaparin may be
superior to UFH as a first-line agent in ACS.
EFFICACY AND BLEEDING COMPLICATIONS AMONG
PATIENTS RANDOMIZED TO ENOXAPARIN OR
UNFRACTIONATED HEPARIN FOR ANTITHROMBIN THERAPY
IN NSTEMI - A SYSTEMATIC OVERVIEW
Overall Safety Analysis: Major Bleeding Up to 7 Days After Randomization

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 –
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.
 A prospective study (n=451; 28% underwent PCI) in NSTEMI/UA patients found

that PCI within 8 hours of the last enoxaparin sc (and sheaths are pulled
out ≥ 10 hours after enoxaparin sc) seems to be safe and effective
“No instances of abrupt closure or
Target anti-Xa
urgent revascularization after PCI
were reported.”
Collet JPh, Montalescot G, Lison L, et al.Circulation.2001;103:658-

63
 A pharmacokinetic response study (n=55) found that sc enoxaparin (1mg/kg

bid) provides sufficient anti-Xa level for PCI 2-8 hours after last dose.
 An additional 0.3 mg/kg enoxaparin IV 8-12 hours after last sc dose reliably
maintains anti-Xa level within target for at least additional 2 hours.
Time interval Anti-Xa within target

2-8 hr after last sc dose 98%
Following iv bolus 96%
Further 2 hr 91%
Martin ML, Fry ETA, Sanderink GCM, et al.Catheter Cardiovasc Interv.2004;61:163-

70.

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SAID.ENO.20.04.

ACS : Acute Coronary Syndrome

 Evidence of Enoxaparin Across ACS Spectrum : Summary from Key

 Drug Administration Guidance

Non-ST elevation ST elevation

 Immediate invasive strategy ( <2 hr )

 Early invasive strategy (<24 hr)

 Invasive strategy (<72 hr)

Eur Heart J.2017;DOI:

Additional N/A A meta-analysis of 23 PCI trials (30,966 patients,

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

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

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

Anticoagulant Therapy in Patients Undergoing PCI: LOE

Anticoagulant Therapy in Patients Undergoing PCI: LOE

Parenteral anticoagulation is recommended at the time of diagnosis B

Fondaparinux (2.5 mg s.c. daily) is recommended as having the most B

Eur Heart J.2015;doi:10.1093/eurheartj/ehv320

Anticoagulant Therapy in Patients Undergoing PCI: LOE

Eur Heart J.2015;doi:10.1093/eurheartj/ehv320

2015 ESC guidelines for

Roffi M, et al.Eur Heart

Primary PCI : Non - PCI & Fibrinolytic :

No routine anticoagulant monitoring is needed

Montalescot G, et al.Lancet.2011;378:693-703; Lovenox [package insert]. Jakarta: Aventis Pharma;2018

If subsequent PCI is performed :

No routine anticoagulant monitoring is needed

Lovenox [package insert]. Jakarta: Aventis Pharma;2018; Ferguson JJ, et al.JAMA.2004;292:45-54.

66A. J Thromb Haemost.2011;9:1902-15

ASA, clopidogrel, GP IIb/IIIa,

Yusuf S, et al.N Eng J Med.2006;354.

Study-Drug Administration in PCI patients – OASIS 5 :

Yusuf S, et al.N Eng J Med.2006;354.

OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

Enox (n=3089) Fonda (n=3118)

STEMI NSTEMI / UA ESSENCE

AN INTERNATIONAL RANDOMIZED STUDY

MICU: Mobile Intensive Care Unit

ENOXAPARIN IV UFH IV (n=460)

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

RRR: Relative Risk Reduction

Net clinical benefit

Protocole definitions NS: Non Significant

T O (FROM THE ATOLL TRIAL)

TO (FROM THE ATOLL TRIAL)

Enoxaparin resulted in significant

All cause mortality was also

Antman EM, Morrow DA, McCabe CH, et al.N Eng J Med.2006;354:1477-88.

Antman EM, Morrow DA, McCabe CH, et al.N Eng J Med.2006;354:1477-88.

RR 1.53 RR 1.39 RR 1.27

Antman EM, Morrow DA, McCabe CH, et al.N Eng J Med.2006;354:1477-88.

Unfractionated heparin Enoxaparin

Antman EM, Morrow DA, McCabe CH, et al.N Eng J Med.2006;354:1477-88.

• Superior anti-thrombotic effect

• Enoxaparin : until hospital discharge or max 8 days (median 7.0 days)

Antman EM, Morrow DA, McCabe CH, et al.N Eng J Med.2006;354:1477-88.

Prespecified Definitions UFH (%) ENOX (%) RRR (%)

Death or Nonfatal MI or 12.2 10.1 17

0.8 0.9 1 1.25

ENOX Better RR UFH Better

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

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

Early invasive strategy