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The Optimal Anticoagulant in

Acute Coronary Syndrome


Acute Coronary Syndrome

Acute thrombosis induced by a ruptured or eroded atherosclerotic


coronary plaque, with or without concomitant vasoconstriction,
causing a sudden and critical reduction in blood flow

Hamm CW et al. EurHeart J 2011;32:2999 –3054; Bentzon JF et al. Circ Res. 2014;114:1852-1866 2
Acute Coronary Syndrome

• Associated with fatal complications, including death


Requires rapid evaluation and prompt management
– TIME is MUSCLE, MUSCLE is SURVIVAL

• To assess the general clinical condition of patient: stable or not


stable
• To determine the working dx
• To start initial and definitive management plan immediately
• To control risk factor (secondary prevention)

Should be performed rapidly yet accurately

3
Chest pain

ST elevation ST depression
ECG ST segment

Bio-chemistry Troponin rise / Troponin


fall normal

Diagnosis

STEMI NSTEMI UA
Adapted from Hamm CW et al. Eur Heart J 2011;32:2999 – 3054 4
Semakin lama penanganan, Semakin lama,
Semakin besar resiko mortalitas Necrosis semakin besar
Diagnosis validation, risk assessment and
rhythm monitoring

STEMI  Reperfusion Strategies


NSTEMI/UAP  Risk Assesment
1. Ischaemic risk score assessment (GRACE score).
2. Echocardiogram
3. Optional: chest X-ray, CT, MRI or nuclear imaging for
differential diagnoses (e.g. aortic dissection, pulmonary
embolism, etc.).
4. Bleeding risk assessment (CRUSADE score)

Roffi M et al. Eur Heart J 2016;37(3):267-315 6


PEDOMAN TATALAKSANA
SINDROM KORONER AKUT
PERHIMPUNAN DOKTER SPESIALIS
KARDIOVASKULAR INDONESIA
2015
Invasive Strategy NSTEMI
Immediate invasive
Very High Risk
(< 2hr)

Early invasive
High Risk
(<24hr)

Invasive
Intermediate risk
(<72hr)

Selective invasive
Low risk
strategy
Roffi M et al. European Heart Journal 2015. doi:10.1093/eurheartj/ehv320
HIGH RISK VERY HIGH RISK

• Relevant rise or fall in troponin • Haemodynamic instability or cardiogenic


• Dynamic ST- or T-wave changes shock
(symptomatic or silent) • Recurrent or ongoing chest pain
• GRACE Score > 140 refractory to medical treatment
• Life-threatening arrhythmias or cardiac
INTERMEDIATE RISK arrest
• Mechanical complications of MI
• Diabetes mellitus • Acute heart failure
• Renal insufficiency • Recurrent dynamic ST-T wave changes,
(eGFR <60 mL/min/1.73 m²) particularly with intermittent ST-
• LVEF < 40% or congestive HF elevation
• Early post infarction angina
• Prior PCI LOW RISK
• Prior CABG • Any characteristics not mentioned above
• GRACE risk score 109 - 140

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


Cath lab or later ?
Benefit of early intervention in high risk patients

Kaplan–Meier Cumulative Risk of the Primary Outcome (death, myocardial infarction, or stroke), Stratified According
to GRACE Risk Score at Baseline.

Mehta, SR et al. N Engl J Med 2009;360:2165-75.


12
SAID.ENO.17.11.0435

Anticoagulant in STEMI :
2013 AHA and 2017 ESC Guideline
Thrombosis
Anticoagulant Therapy to Support Primary PCI: Recommendations

JACC.2013;61(4):e78-140.
Periprocedural and post-procedural antithrombotic therapy in patients undergoing
primary percutaneous coronary intervention

Eur Heart J.2017;DOI:


10.1093/eurheartj/ehx393
Adjunctive Anticoagulant Therapy to Support PCI
After Fibrinolytic Therapy

Class of Level of
Recommendation Evidence

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


Anticoagulant in Non- STEMI :
2014 AHA and 2015 ESC Guideline
2014 AHA/ACC Guideline for the Management of Patients With
Non–ST-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
Non–ST-Elevation Acute Coronary Syndromes

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

Circulation.2014;130:e344-426
Discharge

Hamm CW et al. Eur Heart J 2011;32:2999 – 3054 27


ACS PERKI GUIDELINE

Buku Pedoman Tatalaksana Sindrom Koroner Akut, Perki 2015


THANK YOU

29
Patients with NSTE ACS, chest discomfort <24 hours,
2: Age >60 y,  ST segment,  cardiac biomarkers
ASA, clopidogrel, GP IIb/IIIa,
planned cath/PCI per local practice

Randomize
Fondaparinux N = 20,078 Enoxaparin
2.5 mg sc qd 1 mg/kg sc bid
Outcomes
Primary: Efficacy Death, MI, refractory ischemia at 9 d
Safety Major bleeding at 9 d
Benefit/risk Death, MI, refractory ischemia, major bleeding at 9 d
Secondary: Primary outcomes plus each component at 30 d and 6 mo

MICHELANGELO OASIS 5 Steering Committee.


Am Heart J. 2005;150:1107-14.
Subject Flow & Concomitant Drugs OASIS 5
Study-Drug Administration in PCI patients – OASIS 5 :

+/- Additional fondaparinux


Fondaparinux
Fondaparinux
Crossover of heparins (UFH and
No additional anticoagulan LMWH) is not recommended.
Enoxaparin – 2015 ESC Guideline; class IIIb
UFH

*GP IIb/IIIa inhibitor may or may not be given

Yusuf S, et al.N Eng J Med.2006;354.


Death, MI, refractory ischemia

0.06 HR 1.01
(0.90-1.13)
0.05
0.04 Fondaparinux
Cumulative
event rate 0.03
0.02
Enoxaparin
0.01
0
0 1 2 3 4 5 6 7 8 9
Time (days)

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


P=0.004

14
11.7
12
Event Rate (%)

9.5
10 P=0.60 P<0.0001
8
5.4 5.7 5.4
6
P=0.68 2.8
4 2.1 2
2
0
Death MI Major Bleeds Death,
MI,Stroke or
Major Bleed

Enox (n=3089) Fonda (n=3118)


Enoxaparin
HR 0.93
0.14 (0.86-1.00)
P = 0.06
0.12
Fondaparinux
0.10
Cumulative 0.08
event rate
0.06

0.04

0.02

0
0 20 40 60 80 100 120 140 160 180
Time (days)

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


Death, MI, refractory ischemia, major bleeding
HR 0.86 Enoxaparin
0.20
(0.81-0.93)
P < 0.001
0.15
Fondaparinux

Cumulative 0.10
event rate

0.05

0
0 20 40 60 80 100 120 140 160 180
Time (days)

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


ACS Spectrum

Acute
Coronary
Syndrome

STEMI NSTEMI / UA

PCI Thrombolysis
Summary of Evidence
Study Subjects N Dose of Enox Efficacy Safety (enox vs UFH)

ATOLL 1 STEMI 910 0.5 mg/kg IV Similar primary endpoint Similar rate of major and
(primary PCI) (additional 0.25 41% RRR in the rate of the main minor bleeding
mg/kg, if needed) secondary endpoint
Reduced death, complication of
myocardial infarction, or major
bleeding
ExTRACT-TIMI STEMI 20,506 30 mg IV –> 1.0 17% RRR in the primary endpoint Higher rate of major
25 2 (Thrombolysis) mg/kg SC q12h 33% RRR in non-fatal re-infarction bleeding (2.1 vs 1.4%;
≥ 75 yo : 0.75 p<0.001)
Reduced in the composite of death,
mg/kg q12h nonfatal reinfarction, or nonfatal Similar rate of intracranial
intracranial hemorrhage (10.1 vs hemorrhage
12.2%,p<0.001)
SYNERGY 3 NSTEMI 10,027 1 mg/kg q12h SC Similar primary endpoint Higher rate of TIMI major
(PCI) bleeding (9.1 vs 7.6%;
p=0.008)
Non-significant GUSTO
severe bleeding
TIMI 11b – NSTEMI 3,910 + 1 mg/kg q12h SC ≈ 20% RRR in the composite triple Similar rate of major
ESSENCE 4 3,171 end point (death, MI or recurrent bleeding
Angina) Higher minor bleeding
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.
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
ESC, Stockholm - August 30, 2010 – Hotline session

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)
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 Trial design
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
MICU: Mobile Intensive Care Unit
IVRS: Interactive Voice Response System
STEMI  Primary PCI

ENOXAPARIN IV UFH IV (n=460)


IVRS 50-70 IU with GP IIbIIIa
0.5 mg/kg (n=450) 70-100IU without GP IIbIIIa
with or without GPIIbIIIa
(Dose ACT-adjusted)
Primary PCI
ENOXAPARIN SC UFH IV or SC

30 days
1° EP: Death, Complication of MI, Procedure Failure, Major Bleeding
Main 2° EP: Death, recurrent MI / ACS, Urgent Revascularization
Death, Complication of MI, Procedure Failure or Major Bleeding

RRR: Relative Risk Reduction


Net clinical benefit
NS: Non Significant
A Direct Comparison of Intravenous Enoxaparin With Unfractionated
Heparin in Primary Percutaneous Coronary Intervention
(from the ATOLL Trial) - Collet JP, Huber K, Cohen M, et al.Am J Cardiol.2013;112:1367-72.

• Primary end point

• Secondary end point

Baseline and
Of 910 randomized patients,
Procedural characteristics
795 patients (87.4%) are
were well balanced
included in this per protocol
between the 2 treatment
analysis
groups
A Direct Comparison of Intravenous Enoxaparin With Unfractionated
Heparin in Primary Percutaneous Coronary Intervention
(from the ATOLL Trial) - Collet JP, Huber K, Cohen M, et al.Am J Cardiol.2013;112:1367-72.

Enoxaparin resulted in
significant improvement of the
NET CLINICAL BENEFIT (RR 0.46;
p=0.0002)

All cause mortality was also


reduced by enoxaparin by 64%
(p=0.003)
A Direct Comparison of Intravenous Enoxaparin With Unfractionated
Heparin in Primary Percutaneous Coronary Intervention
(from the ATOLL Trial) - Collet JP, Huber K, Cohen M, et al.Am J Cardiol.2013;112:1367-72.

CONCLUSION
STEMI < 6 h
Lytic eligible
Lytic choice by MD
ASA (TNK, tPA, rPA, SK)

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


Unfractionated heparin Enoxaparin
ARD 0.8% ARD 0.4%
RR 1.67 (1.31-2.13) RR 1.15 (0.74-1.78)
5 p=<0.0001 p=0.53

4
% Events

3.3
2.9
3
1.9
2
1.1
1
0
< 75 years ≥ 75 years
n = 17,814 n = 2513
ARD: Absolute Risk Difference
RR: Relative Risk