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Objectives
Acute Coronary Syndromes Pharmacist:
(ACS) Distinguish between unstable angina (UA), non-ST
elevation myocardial infarction (NSTEMI) and ST-
segment elevation myocardial infarction (STEMI)
Review treatment modalities in ACS
Liane Horiuchi, Pharm.D.
PGY-1 Pharmacy Resident Describe different reperfusion therapies and their roles
Memorial Hospital Miramar Technician:
March 13, 2016
Define ACS and its associated risk factors
Review what drugs are used to treat ACS
Explain the significance of timely treatment of ACS
www.fshp.org 3

Disclosures Acute Coronary Syndrome (ACS)


Definition: Clinical syndromes compatible with acute
Nothing to disclose concerning possible financial or myocardial ischemia and/or infarction due to an abrupt
personal relationships with commercial entities that reduction in coronary blood flow.
may have a direct or indirect interest in the subject of
this presentation UA

STEMI NSTEMI

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Risk Factors Diagnosis


Combination of
Diagnostic
Non-Modifiable Modifiable Criteria
Age Hypertension 4 Differential
Gender Hyperlipidemia Diagnosis

Ethnicity Diabetes mellitus


Family history Smoking Chronic Stable
Non-Cardiac Possible ACS Definite ACS
Angina
Overweight/Obesity
Physical inactivity
NSTE
STEMI
(NSTEMI/UA)

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NSTE: Non-ST-Segment Elevation 7

Coronary Artery Disease ACS Pathophysiology and Characteristics

Average age at first MI is 65 years for men and 71.8 years for
women.

Each year, 635,000 Americans suffer a new coronary event,


and ~300,000 will suffer a recurrent attack.

Approximately every 43 seconds, an American will have an


MI.

Causes 1 out of every 7 deaths in the U.S.

6 8
Heart Disease and Stroke Statistics 2015 Update. Circulation 2015. Finks SW. Acute Coronary Syndromes. ACCP Updates in Therapeutics 2015.

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Goals of Therapy Immediate Management


UA/NSTEMI goals 12 Lead ECG (done by EMS & ED)
Prevent total occlusion History & Physical Examination
Antiplatelets (ASA, P2Y12, +/- GPIs) + antithrombotic 1. Nature of the anginal symptoms
Control chest pain and associated symptoms 2. Prior history of CAD
STEMI goals 3. Sex (Male)
Restore patency 4. Older age (Most important in CHD)
Door-to-needle < 30 min (Fibrinolytics) 5. Increasing number of traditional risk factors
Door-to-balloon < 90 min (PCI)
Cardiac Biomarkers (Troponin)
If >120 min to PCI, fibrinolysis unless CI
Prevent complications TIMI and GRACE risk scores
Control chest pain and associated symptoms

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Echocardiogram (ECG)
EMS & w/in 10 min at ED, then q15-30min if not initially diagnostic
ST-changes developing at rest strongly suggest acute ischemia:
Initial Management of NSTE-ACS ST = STEMI ST = NSTEMI = UA (?)
Inverted T waves may also indicate UA/NSTEMI
(UA/NSTEMI) Q waves suggesting prior MI indicate a high likelihood of CAD
ST elevation in posterior leads V7-V9 qualifies the patient for
reperfusion therapy as a STEMI
Normal ECG no NSTEMI or UA

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Timing of Release of Biomarkers After


TIMI Risk Assessment for NSTE-ACS
Acute Myocardial Infarction

-Serial cardiac troponins at presentation


and 3-6 hours after symptom onset

*CAD risk factors: HTN, hyperlipidemia, DM, smoker, family hx of early MI

13 Antman EM. JAMA 2000. 15


Anderson JL, et al. J Am Coll Cardiol 2007.

Risk Assessment Tools GRACE Risk Assessment


TIMI: Thrombolysis in Myocardial Infarction
Percent risk of all-cause mortality at 14 days in NSTE-ACS and at 30
days in STEMI-ACS
Risk score determined by sum of presence of 7 variables at admission
(1 point each)

GRACE: Global Registry of Acute Coronary Events


Predicts in-hospital and 6 month mortality across ACS patients

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Amsterdam EA, et al. AHA/ACC guideline for the management NSTEMI ACS. Circulation 2014.

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AHA/ACC Guideline Classification of


TIMI Risk Assessment for STEMI Recommendations and Level of Evidence

Morrow DA. Circulation 2000. 17 19


AHA/ACC Guideline for the management NSTEMI ACS. Circulation 2014.

Deciding between Early Invasive vs.


Conservative Strategies Management of ACS
Definitive/Likely ACS
Initiate ASA, BB, Nitrates,
Anticoagulants, Telemetry Disease
Anti-ischemic Antiplatelet Anticoagulant
modifying
Therapy Therapy Therapy
therapy
Early Invasive Strategy Ischemia Driven Strategy
TIMI Risk Score >3 TIMI Risk Score 0-1 (Esp. Women) Oxygen UFH
GRACE<109
Aspirin
GRACE>140 Statin
New ST segment depression No ST segment deviation
Positive biomarkers Negative Biomarkers Nitroglycerin Enoxaparin
P2Y12
High risk features inhibitor
-blocker Fondaparinux
Remains Stable GP IIb/IIIa ACE inhibitor
Recurrent Signs/Symptoms Morphine inhibitor Bivalirudin

Coronary angiography Heart failure
Assess EF and/or Stress Testing
(24-48 hours) Arrhythmias
EF<40% OR Positive stress
Go to Angiography
Adapted from Moezzi SA, Acute Coronary Syndrome. 18 20

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Initial Management of ACS: Management of NSTE-ACS: Dual


MONA + -blocker Antiplatelet Therapy (DAPT)
Dose Comments
Loading Dose Maintenance Dose COR LOE
Morphine 1-5mg IV q5min if sx not
relieved by NTG or recur Aspirin 162-325mg non-enteric coated 81-162mg daily I A
Oxygen If SaO2<90% or high-risk
features or hypoxia P2y12 Loading Dose Maintenance Comments COR LOE
inhibitors (PO) Dose (PO)
Nitroglycerin (NTG) 0.4mg spray or SL q5min x 3 Call 911 if unresponsive to 1st dose
doses Clopidogrel 300mg 75mg daily Best if patient cannot drink full I B
CI: Sildenafil/ vardenafil (Plavix) (ischemia guided) class of water
5-10mcg/min IV; titrate to CP -Used in first 48h for tx of persistent CP, HF
(w/in 24h), tadalafil (w/in 600mg
relief or 200mcg/min -Avoid if SBP<90mmHg or 30mmHg
48h) (PCI)
below baseline
Ticagrelor* 180mg 90mg BID CI: ICH, severe hepatic disease I B
Aspirin (ASA) Chew and swallow non-enteric -Reduces mortality (Brilinta)
coated 162-325mg x 1 -Clopidogrel: If ASA allergy or GI Prasugrel 60mg 10mg daily Option for PCI w/stenting; avoid IIa B
intolerance (Effient) in Hx of TIA or stroke, >75y, or
Beta-blocker PO/IV initiated within 24 hours if -Reduces mortality <60kg DAPT for at
eligible -Avoid if signs of HF, risk of cardiogenic *Reasonable to use in preference to clopidogrel in NSTE-ACS. (IIa, B) least 12
-Oral preferred shock, or CI *Recommended maintenance dose of aspirin is 81 mg daily. months
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AHA/ACC Guideline for the management NSTEMI ACS. Circulation 2014.

PGY12 Antagonists
Parameter Clopidogrel Prasugrel Ticagrelor
FDA Indication ACS managed medically or PCI ACS PCI ACS managed medically or PCI

Peak Platelet LD: 300mg, ~6h, LD: 60mg, ~1-1.5h LD: 180mg, <1h
Inhibition 600mg, ~2h

Adverse Effects Bleeding, GI hemorrhage Bleeding, HTN, HLD, A.fib, Bleeding, Scr, dyspnea
bradyarrhythmia

Metabolism Prodrug; 2-step process Prodrug; converted to active Not prodrug; reversible
involving 2C19 and 3A4 metabolite via P450 pathways noncompetitive binding. 3A4
(primary), 3A5, Pgp
T1/2 8h metabolite 3.7h metabolite (2-15h range) 7h (parent), 9h(active metabolite)

Non-responders CYP2C19, CYP3A4 and Pgp No known issues No known issues


polymorphisms or interactions
Drug/Disease PPIs inhibit 2C19 Less prone Careful with asthma, bradycardia;
Interactions limit ASA <100mg

Clinical trials CREDO, CURE, PCI-CURE, TRITON-TIMI 38 PLATO*


CLARITY, COMMIT

22 Adapted from Finks SW. Acute Coronary Syndromes. ACCP Updates in Therapeutics 2015. 24
Lscher TF, et al. European Heart Journal. August 2011.

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Management of NSTE-ACS:
Anticoagulant Other Early Hospital Therapies
Loading Dose Maintenance Dose Comments COR LOE
Nitrates: Topical or Oral
Heparin 60 IU/kg IVB 12 IU/kg/hr (max1000IU/hr) aPTT goal: 50-75s I B ACE-Inhibitors:
over >1 min x 48h or until PCI performed CHF, EF<40%, HTN, DM, stable CKD (ARB if intolerant)
(Max 4000 IU)
Aldosterone antagonist:
Enoxaparin 30mg IVB 1mg/kg SQ Q12h x 24-48h Highest bleeding I A On ACE-I and -blocker with EF<40%, Sx HF or DM and if
(Lovenox) CrCl<30: Q24h risk of 4 agents CrCl>30 ml/min and K<5.0 mEq/L
Calcium Channel Blocker:
Fondaparinux 2.5mg SQ daily Best for those I B For ischemic symptoms when -blocker not successful, CI, or
(Arixtra) - CrCl<30: Avoid with high risk of intolerant
bleeds Statins: High-intensity
Bivalirudin 0.1mg/kg IVB 0.25mg/kg/hr IV Only in early I B Nonsteroidal anti-inflammatory drugs (NSAIDs):
(Angiomax) if planned invasive surgery invasive strategy (Except aspirin) Should not be initiated and should be discontinued
or hx of HIT during hospitalization

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AHA/ACC Guideline for the management NSTEMI ACS. Circulation 2014.

Management of NSTE-ACS:
GP IIb/IIIa inhibitor Immediate Invasive Strategy
Intermediate/High risk: GP IIb/IIIa inhibitor may be considered as part of initial tx in
early invasive strategy. <90 minutes from presentation
GP IIb/IIIa Loading Dose Maintenance Dose Comments COR LOE Refractory angina
inhibitor
S/sx of HF or new/worsening mitral regurgitation
Eptifibatide 180mcg/kg IVB 2mcg/kg/min IV Continue until IIb B
(Integrilin) over 1-2 min infusion x 12-72h discharge, CABG Hemodynamic/electrical instability
(Max 22.6 mg) (Max 15 mg/hr) initiation, or 72h Recurrent angina or ischemia despite intensive medication
CrCl<50: 1 mcg/kg/min CrCl<10mL/min
(Max 7.5 mg/hr) CI: dialysis pts treatment
Severe VT or VF
Tirofiban 25mcg/kg IVB 0.15mcg/kg/min for up IIb B
(Aggrastat) to 18h
Severe comorbidities
CrCl<60: 0.075
mcg/kg/min

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AHA/ACC Guideline for the management NSTEMI ACS. Circulation 2014.

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Percutaneous Coronary
Intervention (PCI)
Balloon angioplasty alone
Initial Management of STEMI
Balloon angioplasty with stents
Bare metal stents (BMS)
Drug-eluting stent (DES)
Anti-proliferative agents: Sacrolimus, Paclitaxel, Everolimus,
Zotarolimus

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http://www.ica.artguys.com/IMAGES/Percutaneous-Coronary-Intervention.jpg

STEMI Treatment: Management of STEMI:


Reperfusion Therapy Reperfusion Therapy

Percutaneous Coronary
Intervention (PCI) Pharmacologic:
Fibrinolytic
Bold lines are preferred strategies.
DIDO= door-in-door-out
30 *Patients with cardiogenic shock or severe HF initially seen at non-PCI-capable hospital should be
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https://www.nghs.com/fullpanel/uploads/files/cardiac-cath-lab.jpg transferred for cardiac catheterization and revascularization as soon as possible, irrespective of time
delay from MI onset (I, B) ACCF/AHA Guideline for the Management of STEMI. 2013.

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Management of STEMI:
STEMI Management
DAPT with Primary PCI
Reperfusion therapy for all eligible patients with STEMI with
Loading Dose Maintenance Dose COR LOE
symptom onset 12 hrs
Reperfusion therapy options: Percutaneous Coronary Intervention Aspirin 162 325mg 81 -325mg daily I B (LD)
(PCI) or fibrinolytic therapy prior to procedure Indefinitely (I,A)
First line Primary PCI
PCI- capable hospital (90 min) vs. non-PCI capable hospital (120
min) P2Y12 Loading Dose Maintenance Dose COR LOE
inhibitors
Second line Fibrinolytic therapy
Clopidogrel 600mg 75mg daily I B
If time is > 120 min to get to PCI hospital
Prasugrel 60mg 10mg daily I B

Ticagrelor 180mg 90mg BID* I B


*The recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg daily.
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ACCF/AHA Guideline for the Management of STEMI. 2013.

Management of STEMI:
STEMI Management Anticoagulant with Primary PCI
Anticoagulant Loading Dose Follow-Up Dose COR LOE
Reperfusion therapy reasonable for patients with STEMI UFH
with symptom onset in prior 12-24 hours if: With GP IIb/IIIa antagonist 50- to 70-U/kg IVB to Supplemental doses to I C
planned achieve therapeutic ACT target ACT
Clinical and/or ECG evidence of ongoing ischemia
First line: Primary PCI With no GP IIb/IIIa 70- to 100-U/kg IVB to Supplemental doses to I C
antagonist planned: achieve therapeutic ACT target ACT

Lovenox If last dose <8h, none I B


PCI also first line if.. (Enoxaparin) If last dose >8h, 0.3mg/kg
STEMI + cardiogenic shock, acute severe HF, or CI to fibrinolytics IVB if last dose 8-12h
prior
Bivalirudin 0.75mg/kg IVB 1.75mg/kg/h IV*, I B
(Angiomax) discontinue at end of PCI
or continue up to 4h as
needed
Fondaparinux Not recommended as sole anticoagulant for primary III B
(Arixtra) PCI
34 Recommended ACT with planned GP IIb/IIIa antagonist tx is 200-250s. 36
Recommended ACT with no planned GP IIb/IIIa antagonist tx is 250-300s (HemoTec device) or 300-350s (Hemochron device).
* Reduce infusion to 1mg/kg/h w/estimated CrCl <30.

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Management of STEMI undergoing


PCI: GP IIb/IIIa inhibitor Reperfusion choice: Fibrinolytic

Loading Dose Maintenance Dose COR LOE


Fibrinolytic Agent Dose Patency rate Side effects
Abciximab 0.25mg/kg IVB 0.125mcg/kg/min (max IIa A Alteplase 15mg IVP, then 0.75 mg/kg over 73-84% Stroke, ICH
(ReoPro) 10mcg/min) x 12h (rt-PA, Activase) 30 min (max 50mg), then 0.5mg/kg
(max 35 mg) over next 60 min
(total dose 100 mg)
Tirofiban 25mcg/kg IVB IIa B
(Aggrastat) over 3 min 0.15mcg/kg/min* x 18-24h Reteplase 10 units IV; repeat dose in 30 min 84% Reperfusion
high bolus dose (r-PA, Retavase) arrhythmias,
anemia
Tenecteplase Single IV dose: 85% Minor bleeding,
Eptifibatide 180mcg/kg IVB x 2 2mcg/kg/min** 18-24h IIa B (TNK-tPA, TNKase) Weight < 60 kg: 30mg reperfusion
(Integrilin) (10 min apart) Weight 60-69 kg: 35mg arrhythmias
double bolus Weight 70-79 kg: 40mg
Weight 80-89 kg: 45mg
*In patients with CrCl <30 mL/min, reduce infusion by 50% Weight >90 kg: 50mg
**In patients with CrCl <50 mL/min, reduce infusion by 50%, avoid in HD
Of uncertain benefit if pretreated with P2Y12. 37 39
ACCF/AHA Guideline for the Management of STEMI. 2013. ACCF/AHA Guideline for the Management of STEMI. 2013.

Management of STEMI: Anticoagulant


with Fibrinolytic Therapy Reperfusion choice: Fibrinolytics
Anticoagulant Loading Dose Maintenance Dose COR LOE
UFH 60U/kg IVB 12 U/kg/h I C
(Max 4000 U) (Max 1000U/h)
-Obtain aPTT at 1.5-2x control
x 48h or until revascularization
Enoxaparin 75y: 30mg IVB 75y: 1mg/kg SQ q12h I A
>75y: omit bolus >75y: 0.75mg/kg SQ q12h
CrCl <30:1mg/kg SQ q24h
index hospitalization, up to 8d
or until revascularization
Fondaparinux 2.5mg IVB 2.5mg SQ daily for index hosp I B
up to 8d or until
revascularization
CrCl <30: CI

ACCF/AHA Guideline for the Management of STEMI. 2013. 38 Adapted from ACCF/AHA Guideline for the Management of STEMI. 2013. 40

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STEMI: Reperfusion therapy routes 1. Reperfusion choice: PCI


Timeline of Antithrombotic therapy
1. PCI
Anticoagulants:
(Recommended) LD of Antiplatelets: UFH +/- GP
IIb/IIIa antagonist Aspirin
Aspirin and P2Y12
or indefinitely and
STEMI
Inhibitor
Bivalirudin P2Y12 inhibitor x
diagnosed +/-
1 year
2. Fibrinolytic GP IIb/IIIa antagonist

therapy
Before PCI During PCI After PCI

Before PCI: During PCI: After PCI:


 ASA 162-325 mg LD  Refer to dosing table  ASA 81-325 mg daily
 P2Y12 Inhibitor LD (any of following)  P2Y12 Inhibitor (any of the
3. Fibrinolytic, 1. Clopidogrel 600 mg following)
1. Clopidogrel 75mg daily
then PCI 2. Prasugrel 60 mg
2. Prasugrel 10 mg daily
3. Ticagrelor 180 mg
3. Ticagrelor 90mg BID

41 Adapted from Calil M, Perrin D. Acute Coronary Syndromes. 43


Adapted from Calil M, Perrin D. Acute Coronary Syndromes.

STEMI: Reperfusion therapy routes STEMI: Reperfusion therapy routes


1. PCI 1. PCI
(Recommended)

2. Fibrinolytic 2. Fibrinolytic
therapy therapy

3. Fibrinolytic, 3. Fibrinolytic,
then PCI then PCI

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Adapted from Calil M, Perrin D. Acute Coronary Syndromes. Adapted from Calil M, Perrin D. Acute Coronary Syndromes.

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2. Reperfusion choice: Fibrinolytic PCI after fibrinolytic therapy


Timeline of Antithrombotic therapy
Anticoagulants:
LD of Antiplatelets:
UFH or COR LOE
Aspirin and P2Y12 Aspirin indefinitely
Enoxaparin (IV
Inhibitor and
& SQ) Immediate transfer for cardiogenic shock or severe acute HF I B
STEMI Fondaparinux P2Y12 inhibitor x
14 days-1 year irrespective of delay from MI onset
diagnosed

Urgent transfer for failed reperfusion or reocclusion IIa B


Before Fibrinolytic With Fibrinolytic After Fibrinolytic

Before fibrinolytic: 2. Enoxaparin: As part of invasive strategy in stable* patients with PCI between IIa B
-ASA 162-325 mg LD -Age < 75y: 30 mg IV bolus, then 1 mg/kg SQ q12h
-Clopidogrel as only P2Y12 inhibitor 3-24h after successful fibrinolysis
-Age > 75y: no bolus; 0.75 mg/kg SQ q12h
Age 75 y: 300 mg LD
Age > 75: No LD, give 75 mg 3. Fondaparinux: *absence of low output, hypotension, persistent tachycardia, apparent shock, high-grade ventricular or sx supraventricular
With Fibrinolytic: 2.5 mg IV, then 2.5 mg SQ daily in 24h tachyarrhythmias, and spontaneous recurrent ischemia
1. UFH: 60 U/kg IV bolus, then 12 U/kg/hr
infusion adjusted for aPTT 1.5-2x control Duration for both: Up to 8 days, or until
(~50-70s for 48h or until revascularization) revascularization
45 ACCF/AHA Guideline for the Management of STEMI. 2013. 47
After Fibrinolytic: See dosing table
Adapted from Calil M, Perrin D. Acute Coronary Syndromes.

STEMI: Reperfusion therapy routes 3. Reperfusion Choice: PCI after


fibrinolytic therapy
1. PCI Timeline of Antithrombotic therapy
Anticoagulants: Aspirin indefinitely and
Continue UFH P2Y12 inhibitor x 1 year
LD of aspirin and
or (DES) or for 30 days 1
STEMI P2Y12 Inhibitor if did
Continue year (BMS)
diagnosed not receive one before
Enoxaparin (IV)
2. Fibrinolytic
therapy
Before PCI With PCI After PCI

Before PCI: With PCI: After PCI:


-If PCI 24h after fibrinolytic Enoxaparin - Clopidogrel as maintenance
therapy: Clopidogrel 300 mg LD -If last dose 8h, no additional P2Y12 inhibitor
3. Fibrinolytic, -If PCI > 24h after fibrinolytic drug
therapy: Clopidogrel 600 mg LD or -If last dose > 8h, give 0.3 mg/kg
then PCI Prasugrel 60 mg IV bolus

46 Adapted from Calil M, Perrin D. Acute Coronary Syndromes. 48


Adapted from Calil M, Perrin D. Acute Coronary Syndromes.

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Coronary Artery Bypass Graft (CABG) Late Hospital/Post-hospital Care


Anti-ischemia Management
Nitroglycerin
Statins: High intensity if no CI
Beta Blockers
ACE inhibitors
Aldosterone antagonists
Oral Antiplatelet Therapy
Aspirin
Limited role P2Y12 inhibitor + ASA x 12 months
Clopidogrel
Indications: Ticagrelor
STEMI w/coronary anatomy not amenable to PCI + ongoing Prasugrel (option for BMS or DES)

ischemia, cardiogenic shock, severe HF


STEMI at time of operative repair of mechanical defects
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References
Coronary Artery Bypass Graft (CABG)
1. Amsterdam EA, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-
elevation acute coronary syndromes. Circulation. 2014.
2. Anderson JL, et al. J Am Coll Cardiol 2007;50:e1e157.
Anti-thrombotic therapy: 3. Braunwald et al. J Am Coll Cardiol. 2000;36:970-1062.
4. Bruhl, SR. Acute Coronary Syndrome. Internal Medicine Didactics. July 2010.
 Give aspirin before CABG surgery 5. Calil M, Perrin D. Acute Coronary Syndromes. Overview of ACCF/AHA Guidelines for Acute
Management of UA/Non-ST-Elevation Myocardial Infarction (NSTEMI) and ST-Elevation
 Discontinue clopidogrel or ticagrelor 24h before on- Myocardial Infarction (STEMI).
pump CABG 6. Finks SW. Acute Coronary Syndromes. Cardiology I. ACCP Updates in Therapeutics 2015.
7. Lscher TF et al. ESC Guidelines for the management of acute coronary syndromes in patients
 Discontinue short acting IV GP IIb/IIIa antagonists 2-4h presenting without persistent ST-segment elevation. European Heart Journal. August 2011.
8. OGara PT et al. ACCF/AHA Guideline for the Management of STEMI: A Report of the American
before urgent CABG College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J
Am Coll Cardio. 2013; 61(4):e78-e140.
 Discontinue abciximab 12h before urgent CABG 9. Shapiro BP, Jaffe AS. Cardiac biomarkers. In: Murphy JG, Lloyd MA, editors. Mayo Clinic
Cardiology: Concise Textbook. 3rd ed. Rochester, MN: Mayo Clinic Scientific Press and New York:
Informa Healthcare USA, 2007:77380.
10. TIMI Calculator: Morrow DA. Circulation 2000. Antman EM. JAMA 2000.
11. https://www.thrombosisadviser.com/static/media/images/upload/anticoagulants-and-antiplatelets-
target.jpg

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