Enoxaparin has been shown to be effective across the spectrum of acute coronary syndromes based on multiple randomized controlled trials. For conservative management of unstable angina/NSTEMI, enoxaparin was found to be superior to unfractionated heparin in reducing the primary composite outcome of death and myocardial infarction at 1 year follow-up, with similar rates of major hemorrhage. For high risk ACS patients undergoing an early invasive strategy, enoxaparin was at least as effective as unfractionated heparin with a higher rate of minor bleeding. In STEMI patients, enoxaparin was superior to unfractionated heparin for efficacy when used with fibrinolysis or

1. Enoxaparin
Proven Across
the Acute Coronary Syndrome
Spectrum
Learning from current guidelines
Dr. Irwan, SpJP-FIHA
Department of Cardiology and Vascular Medicine
Faculty of Medicine, Riau University
Arifin Achmad Hospital - Pekanbaru

2. IX VII
X
II
Intrinsic pathway
(surface contact)
XII XIIa
XI
Tissue factor
IIa
Xa
XIa
IXa VIIa
VIII VIIIa
Extrinsic pathway
(tissue damage)
Xa
V Va
Fibrinogen Fibrin
Heparins and
LMWH2
Vitamin K antagonists3
Direct thrombin inhibitors4
Factor Xa inhibitors5
(Thrombin)IIa
Targets for AnticoagulantsTargets for Anticoagulants
1Adapted with permission from
Petitou M, et al. Nature. 1991;350(suppl):30-33.
2Hirsh J, et al. Chest. 2001;119(suppl):64S-94S.
3Hirsh J, Fuster V. Circulation. 1994;89:1449-1468.
4Weitz JI, Hirsh J. Chest. 2001;119(suppl):95S-107S.
5Herbert JM, et al. Cardiovasc Drug Rev. 1997;15:1.

5. Enoxaparin in ACS
Conservative UA/NSTEMI
High risk UA/STEMI
High risk UA/NSTEMI + early invasive
(PCI)
Conservative STEMI
STEMI + Elective PCI
STEMI + Primary PCI

7. ENOXAPARIN in
conservative ACS
In the TIMI 11B and ESSENCE trials,
meta-analysis showed :
• the primary composite outcome was
significantly lower in patients treated
with enoxaparin compared with UFH
after 1 year of follow-up.
• no significant differences in the rates
of major hemorrhage between
enoxaparin and UFH in either trial or
in the pooled data.
• there was an increased rate of minor
hemorrhage with enoxaparin.

8. INTERACT:
• Among patients treated with eptifibatide in the setting of
high risk non-ST elevation ACS, administration of
enoxaparin is associated with improves outcomes
compared to currently recommended therapy (UF Heparin)
based on better safety and efficacy
A to Z
• In patients with high-risk NSTE-ACS treated with
AGGRASTAT®† (tirofiban, MSD) and ASA, enoxaparin is an
effective noninferior alternative
to UFH
• Overall rates of bleeding, transfusion, and
thrombocytopenia were low in both heparin groups given
AGGRASTAT and ASA
Slide 8
Adapted from Blazing MA et al JAMA 2004;292(1):55–64.
†Registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
Enoxaparin in high risk ACS

9. ENOXAPARIN in
high risk + early invasive ACS
SYNERGY
• Efficacy — not superior but at least as
effective as UFH in the overall population (met
criteria for non inferiority)
• Minor bleeding — more frequent with
enoxaparin
• An overview of all recent RCTs comparing
enoxaparin and UFH shows a consistent effect
across the management spectrum

10. Study N Death or MI at 30 days Major bleeds
ESSENCE ’97 3,171
TIMI 11B ’99 3,910
ACUTE II ’02 525
INTERACT ’03 746
A TO Z ’04 3,620
SYNERGY ’04 9,974
ALL 21,946
0 2010
Incidence (%)
10.1 vs. 11.0
0.5 21
OR (95% CI)
0.91 (0.83 – 0.99)
0 105
Incidence (%)
3.9 vs 3.7
0.1 101
OR (95% CI)
1.1 (0.96 – 1.3)
0.5 21 10102 ∞ 102 10 1
NNT (95% CI)
113 (61 – 1,438)
Enox
+
UFH
+
Enox
+
UFH
+
Enox
+
UFH
+
Randomized Trial
Totality of clinical evidence for
Enoxaparin should lead to level A
Bassand JP, et al. Eur Heart J. 28:1598-1660.
ESC and ACC/AHA NSTE MI ACS GuidelinesESC and ACC/AHA NSTE MI ACS Guidelines
UFHUFH
EnoxaparinEnoxaparin

11. ENOXAPARIN in STEMI
ASSENT-3
• “In view of the present data and the ease of
administration, enoxaparin might be considered an
attractive alternative anticoagulant treatment when
given in combination with tenecteplase”.
EXTRACT-TIMI 25
● Among STEMI patients undergoing PCI following fibrinolysis,
ENOX was superior to UFH for efficacy with similar safety
- significantly less death or re MI
- both delayed onset and lower incidence of PCI
- no difference in bleeding
- less stroke

12. On behalf of, A. Shui, A.J. Jacob, N. Gotcheva, L.
Polonetsky, E.M. Antman, E. Braunwald, and the
ExTRACT-TIMI 25 Investigators. EHJ in press
Enoxaparin vs UFH with Fibrinolysis
for STEMI in Pts ≥ 75 years
compared with < 75 years

13. STEMI < 6 h
Lytic eligible
Lytic choice by MD
(TNK, tPA, rPA, SK)
ENOX
< 75 y: 30 mg IV bolus
SC 1.0 mg / kg q 12 h (Hosp DC)
≥ 75 y: No bolus
SC 0.75 mg / kg q 12 h (Hosp DC)
CrCl < 30: 1.0 mg / kg q 24 h
Double-blind, double-dummy
ASA
Day 30
1°°°° Efficacy Endpoint: Death or Nonfatal MI
1°°°° Safety Endpoint: TIMI Major Hemorrhage
Protocol Design
UFH
60 U / kg bolus (4000 U)
Inf 12 U / kg / h (1000 U / h)
Duration: at least 48 h
Cont’’’’d at MD discretion

14. Main Results
Primary Endpoint:
Death or non-fatal re-MI by 30 days
Main Secondary Endpoint:
Death, non-fatal re-MI, urgent
revascularization by 30 days
12.0
9.9
UFH UFH
ENOX ENOX
14.5
11.7
Days Days
%% RR = 0.83
p = 0.000003
RR = 0.81
p = 0.000001
N Engl J Med 2006;354:1477-88.
33% RRR in reMI by 48 h (P=0.002)
19% RRR in Death/MI by 72 h (P<0.001)
12% RRR in by 48 h (P=0.02)

15. Pharmacokinetics
Age <75 years
(N=60)
Age ≥75 years
(N=13)
P-value
AntiXa clearance (L/hr) 0.794 0.654 0.049
Area under curve 0-12hr IU x h/L 9839 4532 <0.001
Area under curve at steady state IU x h/L 10,000 8197 0.005

16. Day 30 UFH ENOX RRR ARD NNT
Effects of enoxaparin vs
unfractionated heparin
Stratified by age

17. TIMI major bleeding
Stratified by age
1.1
1.9
3.3
2.9
0
1
2
3
4
5
< 75 years
n = 17,814
≥ 75 years
n = 2513
%Events
Unfractionated heparin Enoxaparin
ARD 0.8%
RR 1.67 (1.31-2.13)
p=<0.0001
ARD 0.4%
RR 1.15 (0.74-1.78)
p=0.53

18. ExTRACT TIMI 25
• The Enox strategy as implemented in
ExTRACT-TIMI 25 is preferred to the
standard UFH strategy in both younger and
older patients treated with fibrinolysis.

19. Slide 19
Enoxaparin in the Cath. Lab. Replacing UFH
Is there enough evidence based trial ?

20. ATOLL
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
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: 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)
ESC,Stockholm-August30,2010–Hotlinesession

21. Intravenous 0.5mg/kg Enoxaparin
Time (hours)
Anti-XaIU/mL
0 2 4 6 8 10 12 14 16 18 20
0
0.4
0.8
1.2
0.5 mg/kg IV
1 mg/kg SC
•Choussat et al (elective PCI)
•Miller et al (ACS-PCI)
•Carnendran et al (elective PCI)
•STEEPLE (elective PCI)
•PROTECT –TIMI30 (ACS-PCI)
•Silvain et al (elective PCI)
•FINESSE (primary PCI)
•Brieger et al. (Primary PCI)
PD experience Clinical experience
Choussat et al. JACC. 2002;40:1943-50.
Miller L. J Invasive Cardiol. 2002;14:247-50
Carnendran et al. J Invasive Cardiol. 2003;15:235-8.
Montalescot et al. N Engl J Med. 2006;355:1006-17.
Gibson et al. JACC. 2006;47:2364-2373
Silvain et al. JACC. 2010;55:617-25
Montalescot et al. JACC Cardiovasc Interv. 2010;3:203-12
Brieger et al. Catheter Cardiovasc Interv. 2010 [in press]Sanchez-Pena P. Br J Clin Pharmacol. 2005;60:364-73.

22. Intravenous enoxaparin vs. UFH in PCI
57%
Major Bleeding
(p=0.004)
23%
Death or re-MI
(p<0.001)
Montalescot G et al. N Engl J Med 2006;355:1006 –17
Gibson MC et al. J Am Coll Cardiol 2007;49:2238–46
?

23. ATOLL Trial design
STEMI Primary PCI
1°°°° EP: Death, Complication of MI, Procedure Failure, Major Bleeding
Main 2°°°° EP: Death, recurrent MI / ACS, Urgent Revascularization
30 days
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
ENOXAPARIN IV
0.5 mg/kg
with or without GPIIbIIIa
UFH IV
50-70 IU with GP IIbIIIa
70-100IU without GP IIbIIIa
(Dose ACT-adjusted)
IVRS
Primary PCI
ENOXAPARIN SC UFH IV or SC

24. Primary Endpoint
Death, Complication of MI, Procedure Failure or Major Bleeding

25. All Safety Endpoints

26. Death, Complication of MI or Major bleeding
Net clinical benefit

27. Conclusions
• This multinational randomized study,
includes 910 patients recruited over 2 years,
that shows a 17% RRR close to significance
(P= 0.07) on an innovative efficacy/safety
composite primary endpoint and was
significant on all the major secondary
standard endpoints used in ACS such as
the triple endpoint (Death, MI,
Revascularization)
• Lovenox® confirming it as a better
alternative to UFH in all ACS settings.

28. Enoxaparin benefit vs UFH
IV enoxaparin 0.5 mg/kg for PCI
• 1 shot ± GP IIb/IIIa inhibitors
• no ACT monitoring
• stable anticoagulation for 2 hours
(duration of PCI)

29. 29
What are the Guidelines telling us
for UA, NSTEMI & STEMI ?
ESC
&
ACCF / AHA

30. ACCF / AHA guidelines 2011
(UA / NSTEMI)

31. 2011 ACC/AHA Recommendation
on the Use of Antithrombotics in UA/NSTEMI

33. ESC guidelines 2012
(AMI - STEMI)
33
Recommendations Class Level
An injectable anticoagulant must be used in primary PCI. I C
Enoxaparin (with or without routine GP IIb/IIIa blocker) may be preferred over UFH. IIb B
Fondaparinux is not recommended for primary PCI. III B
The use of fibrinolysis before planned primary PCI is not recommended. III A
Recommendations Class Level
The anticoagulant can be :
* Enoxaparin i.v. followed by s.c. (using the regimen described below) (preferred over UFH). I A
* UFH given as a weight-adjusted i.v. bolus & infusion. I C
In patients treated with streptokinase, fondaparinux i.v. bolus followed by s.c. dose 24 h later. IIa B
Antithrombin co-therapy with fibrinolysis
Tabel 12 :
Periprocedural antithrombotic medication in primary PCI
Anticoagulants
UFH with or without routine GP IIb/IIIa blocker must be used in patients not receiving bivalirudin or
enoxaparin.
I C
Tabel 13 :
Fibrinolytic therapy
Bivalirudin (with use of GP IIb/IIIa blocker restricted to bailout) is recommended over UHF & GP IIb/IIIa
blocker.
I A
Anticoagulation is recommended in STEMI patients treated with lytics until revascularization (if
performed) or for the duration of hospital stay up to 8 days. I C

34. ESC guidelines 2012
(AMI - STEMI)
34
Enoxaparin 0.5 mg/kg i.v. bolus.
In patients <75 years of age :
In patients >75 years of age :
In patients with creatinine clearance of <30 mL/min, regardles of age :
the s.c. doses are given once every 24 h.
Enoxaparin Same dose as with fibrinolytic therapy.
With primary PCI
Tabel 16 :
Doses of antiplatelet & antithrombin co-therapies
Doses of antithrombin co-therapies
Enoxaparin
No adjusment of bolus dose. Following thrombolysis, in patients with creatinin
clearance <30 mL/min, the s.c. doses are given once every 24 h.
Enoxaparin
With fibrinolytic therapy
Tabel 18 :
Recommendation
30 mg i.v. bolus followed 15 min later by 1 mg/kg s.c. every 12 h until hospital discharge
for a maximum of 8 days. The first two doses should not exceed 100 mg.
no i.v. bolus; start with s.c. dose of 0.75 mg/kg with a maximum of 75 mg for the first
two s.c. doses.
Initial dosing of antithrombotic agents in patients with chronic kidney disease
(estimated creatinine clearance <60 mL/min)
Without reperfusion therapy

35. ACCF / AHA guidelines 2013
(STEMI)

38. ACCF/AHA/SCAI Guideline
on PCI and CABG
2011 update

39. Key points
- Loading dose for all P2Y12 inhibitors is recommended (Class I-A)
- 600 mg loading recommended for clopidogrel
- Limitations imposed on prasugrel
- Issue of compliance posed against ticagrelor

40. Key points
Enoxaparin
-An additional dose of 0.3 mg/kg IV enoxaparin should be
administered at the time of PCI to patients who have received fewer
than 2 therapeutic subcutaneous doses (eg, 1 mg/kg) or received the
last subcutaneous enoxaparin dose 8 to 12 hours before PCI. (Class
I-B)
-Performance of PCI with enoxaparin may be reasonable in patients
either treated with ““““upstream”””” subcutaneous enoxaparin for
UA/NSTEMI or who have not received prior antithrombin therapy and
are administered IV enoxaparin at the time of PCI. (Class IIb-B)
-UFH should not be given to patients already receiving therapeutic
subcutaneous enoxaparin. (Class III-B: HARM)
Fondaparinux
-Fondaparinux should not be used as the sole anticoagulant to
support PCI. An additional anticoagulant with anti-IIa activity should
be administered because of the risk of catheter thrombosis. (Class
III-C: HARM)

41. Enoxaparin Proven Across
the ACS Spectrum
Conservative UA/NSTEMI
* TESMA 1997
High risk UA/STEMI
* A TO Z 2004
High risk UA/NSTEMI + early invasive (PCI)
* SYNERGY 2004
Conservative STEMI
* EXTRACT TIMI25 2005
STEMI + Elective PCI
* STEEPLE 2006
STEMI + Primary PCI
* ATOLL 2010

42. THANK YOUTHANK YOUTHANK YOUTHANK YOU