From Efficacy and Safety of Fondaparinux

in Management of ACS

Acute Coronary Syndrome (ACS)

A Major Cause of Mortality and Morbidity
UA/NSTEMI
In-hospital death and re-infarction: 5-10%1
Six-month mortality in the GRACE registry2 (from admission to 6 months):
- NSTEMI: 13%
- UA: 8%

STEMI
1/3 of STEMI patients will die within 24 h of the onset of ischemia1
In-hospital death and reinfarction: 8-10%3
One-month mortality: 6-7%4

For HCP Use Only

ARI/PRN/06/27/09/13

1.Grech & Ramsdale. Acute coronary syndrome : unstable angina and non-ST segment elevation myocardial infarction. BMJ 2003;326:125961;
2. Fox. et al. An international on acute coronary syndrome care: Insight from the global registry of acute coronary event
Am Heart. Et al J 2004:148:S40-5;
3.Antman et al. ACC/AHA guideline for the management of patiets with ST-Elevation Myocardial infarction. Circulation 2004;110:e82-292;
4.van de Werf et al. Management of acute myocardial infarction in patients presenting with ST-segment Elevation
Eur Heart J 2003;24:28-66

Major Bleeding is Associated with an Increased

Risk of Hospital Death in ACS Patients
GRACE Registry in 24,045 ACS patients

Inhospital death (%)

40

Inhospital major bleeding

OR (95% CI)
1.64 (1.18 to 2.28)*

30

**

**

10

18.6

5.1

Yes

**

**

20

No

16.1

3.0

22.8

15.3
5.3

7.0

0
Overall ACS

UA

NSTEMI

STEMI

*After adjustment for comorbidities, clinical presentation, and hospital therapies.

**p<0.001 for differences in unadjusted death rates

ARI/PRN/06/27/09/13

For HCP Use Only

Moscucci et al. Predictor of majaor bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE)
Eur Heart J 2003;24:1815-23

A comparison of relevant pharmacological properties of the

different anticoagulant in current clinical use
UFH

LMWH

Arixtra

+++

+++

+++

++

+++

+
( for s.c administration )

++

+++

++

++

Inhibition of thrombin generation

++

++

++

Inhibition of thrombin activity

+++

Inhibition of bound thrombin

Rebound of thrombin generation after

discontinuation

+++

++

Platelet Activation

+++

Immune thrombocytopenia

+++

Decreased bone density

+++

Presence of cofactor required

Renal clearance of clinical relevance
Non-specific protein binding
Bioavailability by s.c or oral administration
Predictability of pharmacological effect

ARI/PRN/06/27/09/13

For HCP Use Only

Raffaele D.C, et al. Anticoagulants in Heart Disease : Current Status and Perspectives. Eur Heart J 2007 ; 28 : 880-913

Introductions
Fondaparinux is a Synthetic and Selective Xa Inhibitor
Fondaparinux Sodium, 2.5 mg/0.5 ml solution for injection,
in pre-filled syringe.

Fondaparinux 2,5 mg does not have clinically relevant affect on

routine coagulations test.
Unlike heparins or LMWH, fondaparinux is a synthetic compound and not derived from
animal products.
has rapid onset of action, 100% bioavailability after SC injection.
Elimination Half life is about 17 hours in healthy young subject and
about 21 hours in health elderly subject

ARI/PRN/06/27/09/13

For HCP Use Only

1.

Reff :
ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).
2. Jack Hirsh MD, Fondaparinux 2007. Preface

Fondaparinux
A Synthetic Inhibitor of Factor Xa

Single chemical entity

No risk of pathogen contamination
Highly selective for its target
Once-daily administration
Rapid onset (Cmax/2=25 min)

ARI/PRN/06/27/09/13

For HCP Use Only

No liver metabolism
Does not bind significantly to plasma
proteins other than AT.
No reported cases of HIT
No dose adjustment necessary
in the healty elderly subject.

1.Herbert et al. A Noval Anti-factor Xa antitrombotic Agent . Cardiovasc Drug Rev 1997;15:1-26
2. Van Boeckel et al. The unique antithrombin III binding domain of Heparin: a lead to new Synthetic Antitrombotic. Angew
Chem [Int Ed Engl] 1993;32: 1671-90
3. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).

Fondaparinux Mechanism of Action

Intrinsic
pathway

Extrinsic
pathway

Antithrombin

AT

AT

Fondaparinux

Xa

Xa

Pro-thrombin

Thrombin

Reutilized
Fibrinogen
ARI/PRN/06/27/09/13

For HCP Use Only

Fibrin clot

1. Olson et al. Role of the antithrombin-binding Pentasaccharide in heparin acceleration of antithrombin-proteinase reaction
J Biol Chem 1992;267:12528-38
2. Turpie et al. A synthetic Pentasaccharide for the Prevention of deep-vein trombosis after total hip replacement.

ArixtraTM indications

Treatment of ACS

Prevention of VTE After

MOS & Abdominal Surgery

Treatment of UA/NSTEMI.

Hip Fracture.

Adjuctive Treatment STEMI.

Knee Replacement Surgery.

Prevention of VTE in
Medical Patients

Congestive Heart Failure.

Acute Respiratory Illness.
Acute Infection Inflammatory
diseases

Hip Replacement Surgery.

Abdominal Surgery.

Reff :
1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).
2. Salim Yusuf, et al. Comparison of Fondaparinux and Enoxaprine in Acute Coronary Syndrome.
The fifth organization to assess strategies in Acute Ischemic Syndrome investigator. N Egl J Med 2006:354:1446-76
3. Salim Yusuf. Et al. The OASIS 6 trial. Effect of Fondaparinux on Mortality and Reinfarction in Patients with Acute ST-segment elevation MI.
Jama 2006; 259:1519-30.
4. Turpei Agg, et al. Fondaparinux vs Enoxaparine for the prevention of VTE in MOS.
A meta-analysis of randomized double blind studies. Arch Intern Med 2002;162:1883-40.
5. Cohen AT, et al : Efficacy and Safety Fondaparinux for The Prevention of VTE in older medical patients,
For HCP Use Only
BMJ 2006: 332: 325-9
6. AgnelliG et al. Randomized Clinical Trial of post operative fondaparinux versus perioperative daltaparine of venous
ARI/PRN/06/27/09/13
thromboembolism in high risk abdominal surgery. Br J Surg 2005;92:1212-20.

ArixtraTM Study
Treatment of ACS
OASIS 5 Study : 20,000
patients with UA/NSTEMI.
OASIS 6 Study : 12,000
patients with STEMI.

Prevention of VTE After

MOS & Abdominal Surgery
MOS Meta Analysis Study
: 7,344 patients.
a)
b)
c)
d)

EPHESUS : Elective Hip

Surgery : 2309 patients
PENTHATHLON : Total hip
Surgery: 2275 patients
PENTAMAKS : Major Knee
Surgery : 1,049 Patiets.
PENTHIFRA : Hip Fracture
Surgery : 1,711 Patiets.

Prevention of VTE in
Medical Patients
Artemis Study : 890
Acutely ill medical
patients.

PEGASUS Study : 2,048

patient untder going Major
Abdominal Surgery
Reff :
1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).
2. Salim Yusuf, et al. Comparison of Fondaparinux and Enoxaprine in Acute Coronary Syndrome.
The fifth organization to assess strategies in Acute Ischemic Syndrome investigator. N Egl J Med 2006:354:1446-76
3. Salim Yusuf. et al. The OASIS 6 trial. Effect of Fondaparinux on Mortality and Reinfarction in Patients with Acute ST-segment elevation MI.
Jama 2006; 259:1519-30.
4. Turpei Agg, et al. Fondaparinux vs Enoxaparine for the prevention of VTE in MOS.
A meta-analysis of randomized double blind studies. Arch Intern Med 2002;162:1883-40.
5. Cohen AT, et al : Efficacy and Safety Fondaparinux for The Prevention of VTE in older medical patients,
BMJ 2006: 332: 325-9

For HCP Use Only

ARI/PRN/05/27/09/13

20,078 Pasien

Study Hypothesis OASIS 5

Fondaparinux 2.5 mg s.c. once daily

will show similar efficacy
to enoxaparin,
while improving bleeding

ARI/PRN/06/27/09/13

For HCP Use Only

1. Michelangelo OASIS 5 Steering Committee. Am Heart J 2005;150:1107.e1-.e10

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

OASIS 5: An International, Multicenter, Randomized, Double-Blind,

Double-Dummy Trial in 41 Countries

20,078 patients with UA/NSTEMI

Aspirin, Clopidogrel, anti-GPIIb/IIIa,
planned Cath/PCI as per local practice

Randomization

Fondaparinux

Enoxaparin

2.5 mg s.c. od up to 8 days

1 mg/kg s.c. bid for 2-8 days

1 mg/kg s.c. od if ClCr<30mL/min

Vital status ascertained in 20,066 (99.9%)

Lost to follow-up at day 9: fondaparinux: n=7 and enoxaparin: n=5

ARI/PRN/06/27/09/13

For HCP Use Only

Reff :
1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).
2. Salim Yusuf, et al. Comparison of Fondaparinux and Enoxaprine in Acute Coronary Syndrome.
The fifth organization to assess strategies in Acute Ischemic Syndrome investigator. N Egl J Med 2006:354:1446-76.

Study Objectives and Outcomes

Objectives
Primary efficacy objective: To demonstrate non-inferiority of fondaparinux
compared with enoxaparin
Primary safety objective:
To determine whether fondaparinux was
superior to enoxaparin in preventing major
bleeding

Outcomes (centrally adjudicated)

Primary efficacy: 1st occurrence of the composite of death, MI, or refractory
ischemia (RI) up to day 9

Primary safety:

Major bleeding up to day 9

Risk benefit:

Death, MI, refractory ischemia, major bleeds up to day 9

Secondary:

Above & each component separately at days 30 and 180

ARI/PRN/06/27/09/13

For HCP Use Only

Reff :
1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).
2. Salim Yusuf, et al. Comparison of Fondaparinux and Enoxaprine in Acute Coronary Syndrome.
The fifth organization to assess strategies in Acute Ischemic Syndrome investigator. N Egl J Med 2006:354:1446-76.

Arixtra has the same efficacy vs Enoxaparin

at Day 9 (Primary Efficacy: death/MI/RI)
Time to event death/MI/RI up to day 9
0.06

Cumulative Hazard

0.05
0.04

Enoxaparin

0.03

Fondaparinux

0.02

HR: 1.01
95% CI: 0.90-1.13
p=0.007 for non-inferiority

0.01
0.0

Days
Fondaparinux: 5.8% (579 events) Enoxaparin: 5.7% (573 events)

ARI/PRN/06/27/09/13

For HCP Use Only

Reff :
1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).
2. Salim Yusuf, et al. Comparison of Fondaparinux and Enoxaprine in Acute Coronary Syndrome.
The fifth organization to assess strategies in Acute Ischemic Syndrome investigator. N Egl J Med 2006:354:1446-76.

Arixtra Significanly reduced Major Bleeding vs Enoxaparine at day 9

Cumulative Hazard

0.04

Enoxaparin
HR: 0.52
95% CI: 0.44-0.61 p<0.001

0.03

48 %

0.02

Fondaparinux

0.01

0.0
0

Days
ARI/PRN/06/27/09/13

For HCP Use Only

Reff :
1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).
2. Salim Yusuf, et al. Comparison of Fondaparinux and Enoxaprine in Acute Coronary Syndrome.
The fifth organization to assess strategies in Acute Ischemic Syndrome investigator. N Egl J Med 2006:354:1446-76.

Arixtra Significantly Reduced Mortality vs. Enoxaparin up to Day 30

0.04

Cumulative Hazard

Enoxaparin

17 %

0.03

Fondaparinux

0.02

0.01

HR: 0.83
95% CI: 0.71-0.97
p=0.02

0.0
0
ARI/PRN/06/27/09/13

3
For HCP Use Only

12

15
Days

18

21

24

27

30

Reff :
1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).
2. Salim Yusuf, et al. Comparison of Fondaparinux and Enoxaprine in Acute Coronary Syndrome.
The fifth organization to assess strategies in Acute Ischemic Syndrome investigator. N Egl J Med 2006:354:1446-76.

Arixtra Reduced the Rate of the Composite of Death, MI or

Stroke up to 6 Months
0.14
0.12

Cumulative Hazard

11 %

Enoxaparin

0.10

Fondaparinux

0.08
0.06
0.04
HR: 0.89
95% CI: 0.82-0.97
p=0.007

0.02
0.0
0

20

40

60

80

100

120

140

160

180

Days
ARI/PRN/06/27/09/13

For HCP Use Only

Reff :
1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).
2. Salim Yusuf, et al. Comparison of Fondaparinux and Enoxaprine in Acute Coronary Syndrome.
The fifth organization to assess strategies in Acute Ischemic Syndrome investigator. N Egl J Med 2006:354:1446-76.

12,092 Pasien

Study Hypothesis OASIS 6

Fondaparinux 2.5 mg s.c. once daily

will show superior efficacy
compared with usual care

An International, Multicenter, Randomized, Double-Blind, DoubleDummy Trial in 41 Countries

12,092 patients with STEMI

<12 h of symptom onset

Randomization

Fondaparinux

ARI/PRN/06/27/09/13

For HCP Use Only

2.

Standard Care

Reff :
1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).
Salim yusuf, et al. The OASIS 6 trial. Effect of Fondaparinux on Mortality and Reinfarction in Patients with Acute ST-segment elevation MI.
Jama 2006; 259:1519-30.

12,092 patients with STEMI

Thrombolytics (SK, TPA, TNK, RPA),
Primary PCI or no reperfusion

Stratum 2

Stratum 1
UFH not indicated

Fondaparinux s.c.
2.5 mg od/8 days*

Placebo
8 days*

Randomization

UFH Indicated

Fondaparinux s.c.
2.5 mg od/8 days*

UFH i.v.
24-48 h

Vital status known at hospital discharge in 12,085 (99.9%)

Follow-up: Day 30=12,072 (99.8%) Study end=12,052 (99.7%)
ARI/PRN/06/27/09/13

Reff :
1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).
Salim Yusuf , et alThe OASIS 6 trial. Effect of Fondaparinux on Mortality and Reinfarction in Patients with Acute ST-segment elevation MI.
Jama 2006; 259:1519-30.

For HCP Use Only

2.

Study Objectives
Primary efficacy objective
To evaluate whether fondaparinux was superior to usual care (UFH or
placebo) in preventing death or recurrent MI in patients with STEMI
Primary safety objective
To evaluate the safety of fondaparinux compared with usual care, in
terms of severe bleeding, in patients with STEMI

Reff :
1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).
Salim yusuf. Et al. The OASIS 6 trial. Effect of Fondaparinux on Mortality and Reinfarction in Patients with Acute ST-segment elevation MI.
Jama 2006; 259:1519-30.

ARI/PRN/06/27/09/13
2.

For HCP Use Only

Arixtra Significantly Reduced the Rate

of Death/Reinfarction up to Day 30
0.16

Cumulative Hazard

0.14
UFH or placebo
0.12
0.10

Fondaparinux

0.08
0.06
0.04

HR: 0.86
95% CI: 0.77-0.96
p=0.008

0.02
0
0

12

15

18

21

24

27

30

Days
ARI/PRN/06/27/09/13

For HCP Use Only

2.

Reff :
1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).
Salim Yusuf. Et al.The OASIS 6 trial. Effect of Fondaparinux on Mortality and Reinfarction in Patients with Acute ST-segment elevation MI.
Jama 2006; 259:1519-30.

The Benefit of Arixtra Appeared at Day 9

9-day outcomes

Fondaparinux Placebo/UFH
n=6056
n=6036

HR

95%CI

p value

Death/Reinfarction

7.4%

8.9%

0.83

0.73-0.94

0.003

Death

6.1%

7.0%

0.87

0.75-1.00

0.043

Reinfarction

1.6%

2.3%

0.67

0.52-0.88

0.004

Hazard Ratio (log scale)

ARI/PRN/06/27/09/13

Reff :
1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).
Salim yusuf, et al . The OASIS 6 trial. Effect of Fondaparinux on Mortality and Reinfarction in Patients with Acute ST-segment elevation MI.
Jama 2006; 259:1519-30.

For HCP Use Only

2.

0.1
1.0
10
Fondaparinux better Placebo/UFH better

There Was No Increased Risk of 30-Day Severe Bleeding in the

Arixtra Group
UFH or placebo

0.016

Cumulative Hazard

0.014

0.012
Fondaparinux

0.010
0.008
0.006
0.004

HR: 0.79
(95% CI: 0.58-1.09)
p=0.15

0.002
0

Fondaparinux: 1.0% (61 events)

UFH or placebo: 1.3% (79 events)

ARI/PRN/06/27/09/13

12

15

18

21

24

27

30

Days

Reff :
1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).
2. Salim yusuf., et al The OASIS 6 trial. Effect of Fondaparinux on Mortality and Reinfarction in Patients with Acute ST-segment elevation MI.
Jama 2006; 259:1519-30.
For HCP Use Only

Conclusion

The OASIS 5 showed that Arixtra 2.5 mg was associated with a

significant reduction 48% of major bleeding in the day 9 vs

Enoxaparine.

The Oasis 5 showed that Arixtra 2.5 mg significantly reduced risk of

death at 30 day by 17% compare to Enoxaparine.

The OASIS 6 Fondaparinux significantly reduced mortality without

increasing major bleeding compared with Placebo or UFH.

Fondaparinux result were consistent vs. placebo and vs. UFH especially

during long-term follow-up.

For HCP Use Only

ARI/PRN/06/27/09/13

3.

Reff :
1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).
2. Salim Yusuf, et al. Comparison of Fondaparinux and Enoxaprine in Acute Coronary Syndrome.
The fifth organization to assess strategies in Acute Ischemic Syndrome investigator. N Egl J Med 2006:354:1446-76
Salim Yusuf et al. The OASIS 6 trial. Effect of Fondaparinux on Mortality and Reinfarction in Patients with Acute ST-segment elevation MI.

Arixtra in special populations

Children

Elderly from 75 year

Renal Impairment :
1. For Prevention CC <30
ml/min
2. Treatment of
UA/NSTEMI and STEMI
CC < 20 ml/min

ARI/PRN/06/27/09/13

For HCP Use Only

Patients with body

weight less than 50 kg

Hepatic Impairment

1.

Reff :
ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).

Arixtra Contraindications

ARI/PRN/06/27/09/13

Hypersensitivity to
Arixtra

Active Clinically
Bleeding

Acute Bacterial
Endocarditis

CC < 20 ml/min

For HCP Use Only

1.

Reff :
ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).

Arixtra Warning and Precaution

Route of
Administration

PCI and Risk of

guiding catheter
thrombus

Spinal/epidural
anaesthesia/spin
al puncture.

ARI/PRN/06/27/09/13

For HCP Use Only

Haemorrhage

Elderly patients,
Low body weight,
Severe hepatic
impairment and
HIT.

1.

Reff :
ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).

Arixtra Interactions
Fondaparinux does not markedly inhibit CYP450s in vitro.

Thus Arixtra is not expected to interact with other

medicinal products in vivo by inhibition of CYP-mediated
metabolism.

ARI/PRN/06/27/09/13

For HCP Use Only

1.

Reff :
ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).

Pregnancy and lactation

Pregnancy

Arixtra should not be prescribed to pregnant women

unless the benefit outweighs the risk.
Lactation
Breast-feeding is not recommended during treatment with
Arixtra

ARI/PRN/06/27/09/13

For HCP Use Only

1.

Reff :
ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).

Treatment of Overdose

ARI/PRN/06/27/09/13

Discontinuation and
search for the primary
cause

Surgical Haemostasis.

Blood replacements

Fresh plasma
transfusion.

For HCP Use Only

1.

Reff :
ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).

ESC Guideline

1.

Christian W. Hamm.et al. ESC guideline for the management of acute coronary syndrome in patients
presenting without persistent ST-Segment elevation. Eur Heart J. 2011. 1-56.

ARI/PRN/06/27/09/13

For HCP Use Only

Recommendations for Anticoagulation

ESC Guideline 2011
Anticoagulation is recommended for all patients in addition
to antiplatelet therapi
( I-A )
Anticoagulation should be selected according to the risk of both
ischaemic and bleeding risk, and according to efficacy-safety
profile
Of the chose agent ( I-C )
Fondaparinux (2,5 mg Subcutaneously daily) is recommended as
having the most favourable efficacy-safety profile with respect to
anticoagulation

(1-A).
Enoxaparine (1 mg/kg twice daily) is recommended when
fondaparinux is not Available.
(1-C)
ARI/PRN/06/27/09/13

For HCP Use Only

Christian W. Hamm, et al. ESC Guideline for the management of acute

Coronary syndromes in patients presenting without ST- segment elevation.
Eur Heart Journal, 2011. 1-56

PRN/06/27/09/13

Full Prescribing Information is Available on request.