EnoxaparinProven Across

the Acute Coronary Syndrome Spectrum

Learning from current guidelines

Dr. Irwan, SpJP-FIHA

Department of Cardiology and Vascular MedicineFaculty of Medicine, Riau UniversityArifin Achmad Hospital - Pekanbaru

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 andLMWH2

Vitamin K antagonists 3

Direct thrombin inhibitors 4

Factor Xa inhibitors 5

(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.

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

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.

INTERACT:• Among patients treated with eptifibatide in the set ting of

high risk non-ST elevation ACS, administration of enoxaparin is associated with improves outcomes compared to currently recommended therapy (UF Hepar in) 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 gi ven AGGRASTAT and ASA

Slide 8Adapted 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

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

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 20 10

Incidence (%)

10.1 vs. 11.0

0.5 21

OR (95% CI)

0.91 (0.83 – 0.99)

0 10 5

Incidence (%)

3.9 vs 3.7

0.1 101

OR (95% CI)

1.1 (0.96 – 1.3)

0.5 21 10102 ∞ 10210 1

NNT (95% CI)

113 (61 – 1,438)

Enox +

UFH +

Enox +

UFH +

Enox +

UFH +

Randomized TrialTotality 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

UFHUFHEnoxaparinEnoxaparin

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 fibri nolysis,

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

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

STEMI < 6 hLytic 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 301°°°° Efficacy Endpoint: Death or Nonfatal MI

1°°°° Safety Endpoint: TIMI Major Hemorrhage

Protocol Design

UFH60 U / kg bolus (4000 U)

Inf 12 U / kg / h (1000 U / h)Duration: at least 48 h

Cont ’’’’d at MD discretion

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 = 0.83p = 0.000003

RR = 0.81p = 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)

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 81 97 0.005

Day 30 UFH ENOX RRR ARD NNT

Effects of enoxaparin vsunfractionated heparin

Stratified by age

TIMI major bleedingStratified by age

1.1

1.9

3.32.9

0

12

34

5

< 75 yearsn = 17,814

≥ 75 yearsn = 2513

% E

vent

s

Unfractionated heparin EnoxaparinARD 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

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.

Slide 19

Enoxaparin in the Cath. Lab. Replacing UFH

Is there enough evidence based trial ?

ATOLLAn 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 MyersSquibb, 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)

ES

C, S

tock

holm

-A

ugus

t 30,

201

0 –

Hot

line

sess

ion

Intravenous 0.5mg/kg Enoxaparin

Time (hours)

Ant

i-Xa

IU/m

L

0 2 4 6 8 10 12 14 16 18 20

0

0.4

0.8

1.20.5 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;14:247-50Carnendran 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;47:2364-2373Silvain et al. JACC. 2010;55:617-25Montalescot et al. JACC Cardiovasc Interv. 2010;3:203-12Brieger et al. Catheter Cardiovasc Interv. 2010 [in press]Sanchez-Pena P. Br J Clin Pharmacol. 2005;60:364-73.

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 –17Gibson MC et al. J Am Coll Cardiol 2007;49:2238–46

?

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 RxSimilar antiplatelet therapy in both groups

ENOXAPARIN IV0.5 mg/kg

with or without GPIIbIIIa

UFH IV50-70 IU with GP IIbIIIa

70-100IU without GP IIbIIIa(Dose ACT-adjusted)

IVRS

Primary PCI ENOXAPARIN SC UFH IV or SC

Primary EndpointDeath, Complication of MI, Procedure Failure or Maj or Bleeding

All Safety Endpoints

Death, Complication of MI or Major bleeding

Net clinical benefit

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.

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

What are the Guidelines telling us for UA, NSTEMI & STEMI ?

ESC &

ACCF / AHA

ACCF / AHA guidelines 2011 (UA / NSTEMI)

2011 ACC/AHA Recommendation

on the Use of Antithrombotics in UA/NSTEMI

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

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

ACCF / AHA guidelines 2013 (STEMI)

ACCF/AHA/SCAI Guideline on PCI and CABG

2011 update

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

Key points

Enoxaparin-An additional dose of 0.3 mg/kg IV enoxaparin shoul d be administered at the time of PCI to patients who hav e received fewer than 2 therapeutic subcutaneous doses (eg, 1 mg/kg) or received the last subcutaneous enoxaparin dose 8 to 12 hours bef ore PCI. (Class I-B)

-Performance of PCI with enoxaparin may be reasonabl e in patients either treated with ““““upstream ”””” subcutaneous enoxaparin for UA/NSTEMI or who have not received prior antithromb in therapy and are administered IV enoxaparin at the time of PCI. (Class IIb- B)

-UFH should not be given to patients already receivi ng therapeutic subcutaneous enoxaparin. (Class III-B: HARM)

Fondaparinux-Fondaparinux should not be used as the sole anticoa gulant to support PCI. An additional anticoagulant with anti- IIa activity should be administered because of the risk of catheter thr ombosis. (Class III-C: HARM)

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

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