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The Role of Enoxaparin

Across ACS Spectrum


Dr. I Ketut Susila, SpJP, FIHA
TOPICS

Role of Enoxaparin in Conservative ACS-NSTE


(UA/NSTEMI)
Role of Enoxaparin in High risk ACS-NSTE
(UA/NSTEMI)+ early invasive PCI
Role of Enoxaparin in Conservative ACS-STEMI
Role of Enoxaparin in ACS-STEMI + Elective PCI
2015 ESC Guidelines management ACS-NSTE
2015 ESC Guidelines management ACS-NSTE
2015 ESC Guidelines for the management ACS-NSTE
Risk criteria mandating invasive strategy in NSTE-ACS

2015 ESC Guidelines management ACS-NSTE


Anticoagulant in NSTE -ACS: 2014
AHA and 2015 ESC Guideline
2014 AHA/ACC Guideline for the Management of
Patients With NonST-Elevation Acute Coronary
Syndromes
Summary of Recommendations for Initial Anticoagulant Therapy in
Patients With Definite or Likely NSTE-ACS and PCI

Circulation.2014;130:e344-426
2014 AHA/ACC Guideline for the Management of
Patients With NonST-Elevation Acute Coronary
Syndromes

Circulation.2014;130:e344-426
2014 AHA/ACC Guideline for the Management of
Patients With NonST-Elevation Acute Coronary
Syndromes

Circulation.2014;130:e344-426
ESC guidelines 2015
(ACS NSTE)
ESC guidelines 2015
(ACS NSTE)
2011 ACC/AHA Recommendation

on the Use of Antithrombotics in UA/NSTEMI


ANGINA PEKTORIS TIDAK STABIL DAN
INFARK MIOKARD NON ST ELEVASI

Pemberian antikoagulan disarankan untuk semua pasien yang


mendapatkan terapi antiplatelet
(Kelas I-A).

Fondaparinuks memiliki profil keamanan yang


baik. Dosis yang diberikan adalah 2,5 mg setiap
hari secara subkutan (Kelas I-A).

2015
Enoksaparin (1 mg/kg dua kali sehari) baik untuk pasien
dengan risiko perdarahan rendah
(Kelas I-B).
ENOXAPARIN in
high risk NSTE-ACS + early invasive

SYNERGY
Efficacy not superior but at least as effective as UFH
(Unfractionated Heparin) 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.

Bassand JP, et al. Eur Heart J. 28:1598-1660.


ESC and ACC/AHA NSTE MI ACS Guidelines 2014
Pooled Analysis of Randomized Trial
comparing enoxaparin & UFH in NSTEMI ACS

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
Enox UFH Enox UFH Enox UFH
+ + + + + +
0 10 20 0.5 1 2 1 10 102 102 10 1 0 5 10 0.1 0.5 1 2 10
Incidence (%) OR (95% CI) NNT (95% CI) Incidence (%) OR (95% CI)
UFH 10.1 vs. 11.0 0.91 (0.83 0.99) 113 (61 1,438) 3.9 vs 3.7 1.1 (0.96 1.3)
Enoxaparin
Bassand JP, et al. Eur Heart J. 28:1598-1660.
2014 AHA/ACC Guideline for the Management of
Patients With NonST-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
Circulation.2014;130:e344-426
ESC Guidelines for the management of ACS STEMI 2015
Anticoagulant Therapy in Patients Undergoing PCI: LOE
Recommendations
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 efficacysafety profile regardless of the management strategy.

UFH if concomitant with GPIIb/IIIa inhibitors) is recommended in patients undergoing PCI B


who did not receive any anticoagulant.

If the initial anticoagulant is fondaparinux, a single bolus of UFH should be added at the Based
B on
time of PCI. OASIS-5

Enoxaparin (1 mg/kg twice daily) is recommended when fondaparinux is not available. B


Eur Heart J.2015;doi:10.1093/eurheartj/ehv320
Anticoagulant Therapy in Patients Undergoing PCI: LOE
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


ENOXAPARIN in ACS -STEMI
ASSENT-3 1
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 2
Among STEMI patients undergoing PCI following fibrinolysis,
ENOXAPARIN was superior to UFH for efficacy with similar safety profile.
- significantly less death or re MI
- both delayed onset and lower incidence of PCI
- no difference in bleeding
- less stroke

Reff.
1. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin:
the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
2. N Engl J Med 2006;354:1477-88.
Main Results
ExTRACT TIMI 25
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)

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


Anticoagulant in STEMI : 2013
AHA and 2012 ESC Guideline
ESC guidelines 2012 (ACS - STEMI)
Tabel 12 :
Periprocedural antithrombotic medication in primary PCI
Recommendations Class Level
Anticoagulants
An injectable anticoagulant must be used in primary PCI. I C
Bivalirudin (with use of GP IIb/IIIa blocker restricted to bailout) is recommended over UHF & GP IIb/IIIa
I A
blocker.
Enoxaparin (with or without routine GP IIb/IIIa blocker) may be preferred over UFH. IIb B
UFH with or without routine GP IIb/IIIa blocker must be used in patients not receiving bivalirudin or
I C
enoxaparin.
Fondaparinux is not recommended for primary PCI. III B
The use of fibrinolysis before planned primary PCI is not recommended. III A

Tabel 13 :
Fibrinolytic therapy
Recommendations Class Level
Antithrombin co-therapy with fibrinolysis
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
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

25
ESC guidelines 2012 (ACS - STEMI)
Tabel 16 :
Doses of antiplatelet & antithrombin co-therapies
Doses of antithrombin co-therapies
With primary PCI
Enoxaparin 0.5 mg/kg i.v. bolus.
With fibrinolytic therapy
In patients <75 years of age :
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.
In patients >75 years of age :
Enoxaparin
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.
In patients with creatinine clearance of <30 mL/min, regardles of age :
the s.c. doses are given once every 24 h.
Without reperfusion therapy
Enoxaparin Same dose as with fibrinolytic therapy.

Tabel 18 :
Initial dosing of antithrombotic agents in patients with chronic kidney disease
(estimated creatinine clearance <60 mL/min)
Recommendation
No adjusment of bolus dose. Following thrombolysis, in patients with creatinin
Enoxaparin
clearance <30 mL/min, the s.c. doses are given once every 24 h.

26
Anticoagulant Therapy to Support Primary PCI:
Recommendations
Anticoagulant in PCI

Eur Heart J.2012;DOI: 10.1093/eurheartj/ehs215


Adjunctive Anticoagulant Therapy to
Support PCI After Fibrinolytic Class
Therapy
of Level of
Recommendatio Evidence
n

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


INFARK MIOKARD DENGAN ELEVASI
SEGMEN ST

Antikoagulan direkomendasikan pada pasien-pasien STEMI


yang diobati dengan fibrinolitik hingga revaskularisasi (bila
dilakukan) atau selama dirawat di rumah sakit hingga 5
hari (Kelas I-A).

Enoksaparin secara subkutan (lebih disarankan


dibandingkan heparin tidak terfraksi) (Kelas I-A). 2015
Heparin tidak terfraksi diberikan secara bolus
intravena sesuai berat badan dan infus selama 2
hari (Kelas I-C).
Fondaparinuks intravena secara bolus dilanjutkan
dengan dosis subkutan 24 jam kemudian (Kelas
IIa-B).
Summary of Evidence
Subjects N Dose of Enox Efficacy Safety (enox vs UFH)

STEMI Study 0.5 mg/kg IV Similar primary endpoint Similar rate of major and
(primary PCI) ATOLL 1 (additional 0.25 minor bleeding
41% RRR in the rate of the main
mg/kg, if needed) secondary endpoint
Reduced death, complication of
myocardial infarction, or major
bleeding

STEMI ExTRAC 30 mg IV > 1.0 17% RRR in the primary endpoint Higher rate of major
(Thrombolysis) T-TIMI mg/kg SC q12h bleeding (2.1 vs 1.4%;
33% RRR in non-fatal re-infarction
25 2 p<0.001)
75 yo : 0.75 Reduced in the composite of death,
mg/kg q12h Similar rate of intracranial
nonfatal reinfarction, or nonfatal
hemorrhage
intracranial hemorrhage (10.1 vs
12.2%,0<0.001)
NSTEMI SYNERG 1 mg/kg q12h SC Similar primary endpoint Higher rate of TIMI major
(PCI) Y3 bleeding (9.1 vs 7.6%;
p=0.008)
Non-significant GUSTO
severe bleeding
NSTEMI TIMI 11b 1 mg/kg q12h SC 20% RRR in the composite triple Similar rate of major
end point (death, MI or recurrent bleeding
ESSENC Angina) Higher minor bleeding
E4 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.
Enoxaparin in ACS STEMI and PCI
Intravenous enoxaparin vs. UFH in PCI

17% RRR in Primery


andpointthe
(P<0,07)
23% RRR rate
57% secondary endpoint (
Major Bleeding p<0,03)
(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;49:223846
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.


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

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