Current treatment of NSTE-

Acute Coronary Syndrome:

The Role of Anticoagulant

Dr. Hariadi Hariawan, SpPD, SpJP (K)

 Chest pain

ST elevation ST depression
ECG ST segment

Bio-chemistry Troponin rise / Troponin

fall normal

NSTEACS
Diagnosis

STEACS-STEMI NSTEMI UA
Adapted from Hamm CW et al. Eur Heart J 2011;32:2999 – 3054

2
 GRACE REGISTRY
STEMI
Higher mortality 6
months after discharge
NSTEMI
in NSTEMI vs STEMI –
aggressive long term
management
UA

I
Higher in hospital
I
mortality of
STEMI vs NSTEMI
- need urgent
treatment
Fox KAA et al. BMJ 2006;333:1091-1094
STEMI Management
STEMI Diagnosis

Primary-PCI capable EMS or non primary-PCI

center capable center

Preferably < PCI possible < 120 min?

60 min
Immediate transfer to PCI
center
Primary-PCI Yes No
Preferably ≤ 90 min
(≤ 60 min in early presenters) Preferably ≤
Rescue-PCI
30 min
Immediately Immediate transfer to PCI
center
No Succesful Immediate
fibrinolysis ? fibrinolysis ?
Yes
Heparin Preferably 3-24 h
Coronary angiography Steg G et al. Eur Heart J. 2012;33:2569-619

4
NSTEACS Treatment Strategy

Adapted from : Roffi M et al. Eur Heart J 2016;37(3):267-315

 Risk Stratification
HIGH RISK
• Relevant rise or fall in troponin
• Dynamic ST- or T-wave changes
(symptomatic or silent)
• GRACE Score > 140
INTERMEDIETE RISK
• Diabetes mellitus
• Renal insufficiency
(eGFR <60 mL/min/1.73 m²)
• LVEF < 40% or congestive HF
• Early post infarction angina
• Prior PCI
• Prior CABG
• GRACE risk score 109 - 140
VERY HIGH RISK
• Haemodynamic instability or cardiogenic
shock
• Recurrent or ongoing chest pain
refractory to medical treatment
• Life-threatening arrhythmias or cardiac
arrest
• Mechanical complications of MI
• Acute heart failure
• Recurrent dynamic ST-T wave changes,
particularly with intermittent ST-
elevation
LOW RISK
• Any characteristics not mentioned
above
Roffi M et al. Eur Heart J 2016;37(3):267-315
 Risk GRACE In-hospital
category Risk Score death
(tertile) (%)
Low ≤ 108 <1
Intermediate 109 - 140 1-3
Khalill R et al. Exp Clin Cardiol.2009; 14(2): e25 – e30 High > 140 >3
 Initial Treatment
Checklist of treatments when an ACS diagnosis
appears likely
Initial therapeutic measures Aspirin
Oxygen
Initial dose of 150–300 mg non-enteric formulation
Insufflation (4–8 L/min) if oxygen followed by 75–100 mg/day
saturation is <90%
P2Y12 inhibitor
Nitrates
Loading dose of ticagrelor or clopidogrel
Sublingual or intravenous (caution
if systolic blood Anticoagulation
pressure is <90 mmHg) Choice between different options depends on
Morphine strategy:
• Fondaparinux 2.5 mg/daily sc
3–5 mg intravenous or
• Enoxaparin 1 mg/kg twice daily sc
subcutaneously, if severe pain
• UFH i.v. bolus 60–70 IU/kg (maximum 5000 IU)
followed by infusion of 12–15 IU/kg/h
(maximum 1000 IU/h) titrated to aPTT 1.5–2.5 × control

Oral ß-Blocker
If tachycardic or hypertensive without signs of heart failure
Roffi M et al. Eur Heart J 2016;37(3):267-315; Hamm CW et al. Eur Heart J 2011;32:2999 – 3054
 NSTEACS Guideline

RoffiM, PatronoC EurHeart J.2015 Aug 29. pii: ehv320.41

 Recommendations for anticoagulants

RoffiM, PatronoC EurHeart J.2015 Aug 29. pii: ehv320.41

 Recommendations for anticoagulants

RoffiM, PatronoC EurHeart J.2015 Aug 29. pii: ehv320.41

 Recommendations for anticoagulants

RoffiM, PatronoC EurHeart J.2015 Aug 29. pii: ehv320.41

 Recommendations for anticoagulants

RoffiM, PatronoC EurHeart J.2015 Aug 29. pii: ehv320.41

 Recommendations for anticoagulants

RoffiM, PatronoC EurHeart J.2015 Aug 29. pii: ehv320.41

 Sites of Antithrombotic Drug
Action
Tissue factor Collagen
Aspirin
Plasma clotting ADP
cascade
Fondaparinux Clopidogrel
Thromboxane A2 Prasugrel
AT
Prothrombin Cangrelor
Heparin AT Factor Platelet activation
LMWHs Xa Eptifibatide
AT
Abciximab
Thrombin Platelet aggregation Tirofiban
Bivalirudin (GPI)
Hirudin
Argatroban Fibrinogen Fibrin

Fibrinolytics Thrombus
Selective Factor Xa Inhibitor in Management
of ACS
 A comparison of relevant pharmacological properties of the
different anticoagulant in current clinical use
UFH LMWH Arixtra
Presence of cofactor required +++ +++ +++

Renal clearance of clinical relevance ± ++ +

Non-specific protein binding +++ + +

Bioavailability by s.c or oral administration + ++ +++

( for s.c administration )

Predictability of pharmacological effect - ++ ++

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 +++ + -

Raffaele D.C, et al. Anticoagulants in Heart Disease : Current

Status and Perspectives. Eur Heart J 2007 ; 28 : 880-913
 Fondaparinux
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

eliminated mainly by the kidneys, and is contraindicated if CrCl is <20 mL/min

1. 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 liver metabolism

 No risk of pathogen contamination  Does not bind significantly to plasma
 Highly selective for its target proteins other than AT.
 Once-daily administration  No reported cases of HIT
 Rapid onset (Cmax/2=25 min)  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 Extrinsic
pathway pathway
Antithrombin

AT AT Xa Xa

Fondaparinux Pro-thrombin Thrombin

Reutilized
Fibrinogen 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. N Engl J Med 2001;344:619-25
 Fondaparinux Indications

Treatment of ACS Prevention of VTE After Prevention of VTE in

MOS & Abdominal Surgery Medical Patients

 Treatment of UA/NSTEMI.  Hip Fracture.  Congestive Heart Failure.

 Acute Respiratory Illness.
 Adjuctive Treatment STEMI.  Knee Replacement Surgery.  Acute Infection Inflammatory
diseases
 Hip Replacement Surgery.

Abdominal Surgery.

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
6. AgnelliG et al. Randomized Clinical Trial of post operative fondaparinux versus perioperative daltaparine of venous thromboembolism in high risk abdominal surgery. Br J Surg 2005;92:1212-20.
 Fondaparinux Study
Treatment of ACS Prevention of VTE After Prevention of VTE in
MOS & Abdominal Surgery Medical Patients

 OASIS 5 Study : 20,000  MOS Meta Analysis Study :  Artemis Study : 890
patients with UA/NSTEMI. 7,344 patients. Acutely ill medical
a)EPHESUS : Elective Hip patients.
 OASIS 6 Study : 12,000 Surgery : 2309 patients
patients with STEMI. b) PENTHATHLON : Total hip
Surgery: 2275 patients
c) PENTAMAKS : Major Knee
Surgery : 1,049 Patiets.
d) PENTHIFRA : Hip Fracture
Surgery : 1,711 Patiets.
 PEGASUS Study : 2,048 patient
untder going Major Abdominal
Surgery

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
Study Hypothesis OASIS 5

Fondaparinux 2.5 mg s.c. once daily

will show similar efficacy
to enoxaparin,
while improving bleeding

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

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

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.
 Fondaparinux 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

0.05
Cumulative Hazard

0.04
Enoxaparin
0.03
Fondaparinux
0.02
HR: 1.01
0.01
95% CI: 0.90-1.13
0.0 p=0.007 for non-inferiority

0 1 2 3 4 5 6 7 8 9
Days
Fondaparinux: 5.8% (579 events) Enoxaparin: 5.7% (573 events)

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.
Fondaparinux Significanly reduced Major Bleeding vs
Enoxaparin at day 9

0.04 Enoxaparin
HR: 0.52
95% CI: 0.44-0.61 48 %
0.03
Cumulative Hazard

p<0.001

0.02

Fondaparinux
0.01

0.0

0 1 2 3 4 5 6 7 8 9
Days

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.
 Fondaparinux Significantly Reduced Mortality vs.
Enoxaparin up to Day 30
0.04

Enoxaparin
17 %
0.03
Cumulative Hazard

Fondaparinux
0.02

0.01
HR: 0.83
95% CI: 0.71-0.97
p=0.02
0.0

0 3 6 9 12 15 18 21 24 27 30
Days
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.
 Fondaparinux Reduced the Rate of the Composite
of Death, MI or Stroke up to 6 Months
0.14
11 %
0.12 Enoxaparin

0.10 Fondaparinux
Cumulative Hazard

0.08

0.06

0.04
HR: 0.89
0.02 95% CI: 0.82-0.97
p=0.007
0.0
0 20 40 60 80 100 120 140 160 180
Days
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.
 Major Bleeding Lower with Fondaparinux
Irrespective of Renal Function
0.10

Enoxaparin
(dose adjusted for renal function)
0.08

Fondaparinux
Major Bleed
0.06
0.04
0.02

40 60 80 100 120 140

GFR mL/min/1.73 m2
Fox KAA. Ann Int Med 2007;147:304-310
 Recommendations for Anticoagulants in Patients
with Normal and Impaired Renal Function

RoffiM, PatronoC EurHeart J.2015 Aug 29. pii: ehv320.41

 Swedeheart Registry Study

Retrospective: data was taken from hospital

Metode Study
 Insights from ‘real-world’ data:
Introduction to the SWEDEHEART registry
 The SWEDEHEART registry is an ongoing nation wide registry with 72
participating Swedish hospitals providing data from patients admitted to coronary
care units since 1st September 2006. Data have been analysed from patients with
symptoms suggestive of an acute coronary syndrome and recruited until 31st
December 20104

 Data from the SWEDEHEART registry have identified predictors of risk after MI,
trends in patient characteristics and treatment benefits of various agents5,6

 ‘Real-world’ data from a prospective multicentre cohort study of

over 40,000 NSTEMI patients in the SWEDEHEART registry were
analysed to compare effects of Arixtra® (fondaparinux) and LMWH on
clinical outcomes4

ACTION = Acute Coronary Treatment and Intervention Outcomes Network;
LMWH = low-molecular-weight heparin;
MINAP = Myocardial Ischaemia National Audit Project;
NSTEMI = non-ST elevation myocardial infarction;
SWEDEHEART = Swedish Web-System for Enhancement and Development of Evidence-Based Care
in Heart Disease Evaluated According to Recommended Therapies.
1. Herrett E, et al. Heart 2010; 96:1264–1267;
2. Peterson ED, et al. Circ Cardiovasc Qual Outcomes 2009; 2:491–499;
3. Chung SC, et al. Lancet 2014; 383:1305–1312;
4. Szummer K, et al. JAMA 2015; 313:707–716;
5. Kajermo U, et al. Stroke 2014; 45:1324–1330;
6. Jernberg T, et al. JAMA 2011; 305:1677–1684.
40,616 patients with NSTE-ACS from 2006 to 2010 (SwedeHeart Registry)
LMWH 63.6% or Fondaparinux 36.4%

ESC Meeting Barcelona 2014

40,616 patients with NSTE-ACS from 2006 to 2010 (SwedeHeart Registry)
LMWH 63.6% or Fondaparinux 36.4%

ESC Meeting Barcelona 2014

Fondaparinux Contraindications

Hypersensitivity Active Clinically

to Arixtra Bleeding

Acute Bacterial CC < 20

Endocarditis ml/min

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

 Treatment of Bleeding

Discontinuation
and search for Surgical
the primary Haemostasis.
cause

Blood Fresh plasma

replacements transfusion.

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

 Summary
In NSTEACS risk stratification is need to identify the right
time for invasive strategy and referred to PCI hospital
Fondaparinux 2.5 mg SC once daily is recommended by ESC
guideline for UA/NSTEMI patients as having favorable efficacy-
safety (Class I)
Based on OASIS 5, Fondaparinux (Arixtra®) is a selective factor
Xa inhibitor which offers good efficacy with less bleeding risk
compared to enoxaparin for management UA/NSTEMI
Fondaparinux can be used for low to moderate renal
impairment and it’s contraindicated for severe renal
impairment with CrCl < 20 ml/min
THANK YOU