acute coronary syndromes pharmacist: (acs) elevation myocardial infarction (stemi) – review...

3/3/2016

1

Acute Coronary Syndromes

(ACS)

Liane Horiuchi, Pharm.D.

PGY-1 Pharmacy Resident

Memorial Hospital Miramar

March 13, 2016

www.fshp.org

Disclosures

• Nothing to disclose concerning possible financial or

personal relationships with commercial entities that

may have a direct or indirect interest in the subject of

this presentation

2

Objectives

• Pharmacist:

– Distinguish between unstable angina (UA), non-ST

elevation myocardial infarction (NSTEMI) and ST-

segment elevation myocardial infarction (STEMI)

– Review treatment modalities in ACS

– Describe different reperfusion therapies and their roles

• Technician:

– Define ACS and its associated risk factors

– Review what drugs are used to treat ACS

– Explain the significance of timely treatment of ACS

3

Acute Coronary Syndrome (ACS)

• Definition: Clinical syndromes compatible with acute

myocardial ischemia and/or infarction due to an abrupt

reduction in coronary blood flow.

4

UAUA

NSTEMINSTEMISTEMISTEMI

3/3/2016

2

Risk Factors

Non-Modifiable

• Age

• Gender

• Ethnicity

• Family history

Modifiable

• Hypertension

• Hyperlipidemia

• Diabetes mellitus

• Smoking

• Overweight/Obesity

• Physical inactivity

5

Coronary Artery Disease

• 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.

Heart Disease and Stroke Statistics – 2015 Update. Circulation 2015.6

Diagnosis

Combination of Combination of Diagnostic Criteria

4 Differential Diagnosis

Non-CardiacChronic Stable

AnginaPossible ACS Definite ACS

NSTE

(NSTEMI/UA)STEMI

7NSTE: Non-ST-Segment Elevation

ACS Pathophysiology and Characteristics

Finks SW. Acute Coronary Syndromes. ACCP Updates in Therapeutics 2015.8

3/3/2016

3

Goals of Therapy

• UA/NSTEMI goals

– Prevent total occlusion

• Antiplatelets (ASA, P2Y12, +/- GPIs) + antithrombotic

– Control chest pain and associated symptoms

• STEMI goals

– Restore patency

• Door-to-needle < 30 min (Fibrinolytics)

• Door-to-balloon < 90 min (PCI)

• If >120 min to PCI, fibrinolysis unless CI

– Prevent complications

– Control chest pain and associated symptoms

9

Initial Management of NSTE-ACS

(UA/NSTEMI)

Immediate Management

• 12 Lead ECG (done by EMS & ED)

• History & Physical Examination

1. Nature of the anginal symptoms

2. Prior history of CAD

3. Sex (Male)

4. Older age (Most important in CHD)

5. Increasing number of traditional risk factors

• Cardiac Biomarkers (Troponin)

• TIMI and GRACE risk scores

11

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:

ST ↑↑↑↑= STEMI ST ↓↓↓↓= NSTEMI ↔↔↔↔ = UA (?)

• Inverted T waves may also indicate 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

12

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4

Timing of Release of Biomarkers After

Acute Myocardial Infarction

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

13

-Serial cardiac troponins at presentation

and 3-6 hours after symptom onset

Risk Assessment Tools

• 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

14

TIMI Risk Assessment for NSTE-ACS

Antman EM. JAMA 2000. 15

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

GRACE Risk Assessment

Amsterdam EA, et al. AHA/ACC guideline for the management NSTEMI ACS. Circulation 2014.16

3/3/2016

5

TIMI Risk Assessment for STEMI

Morrow DA. Circulation 2000. 17

Deciding between Early Invasive vs.

Conservative Strategies

Definitive/Likely ACS

Initiate ASA, BB, Nitrates,

Anticoagulants, Telemetry

Early Invasive Strategy

• TIMI Risk Score >3

•GRACE>140

• New ST segment depression

• Positive biomarkers

•High risk features

Ischemia Driven Strategy

•TIMI Risk Score 0-1 (Esp. Women)

•GRACE<109

•No ST segment deviation

•Negative Biomarkers

Coronary angiography

(24-48 hours)

Recurrent Signs/Symptoms

Heart failure

Arrhythmias

Remains Stable

↓

Assess EF and/or Stress Testing

↓

EF<40% OR Positive stress

Go to Angiography

Adapted from Moezzi SA, Acute Coronary Syndrome. 18

AHA/ACC Guideline Classification of

Recommendations and Level of Evidence

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

19

Management of ACS

Anti-ischemic

Therapy

Oxygen

Nitroglycerin

β-blocker

Morphine

Antiplatelet

Therapy

Aspirin

P2Y12

inhibitor

GP IIb/IIIainhibitor

Anticoagulant

Therapy

UFH

Enoxaparin

Fondaparinux

Bivalirudin

Disease

modifying

therapy

Statin

ACE inhibitor

20

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6

Initial Management of ACS:

MONA + β-blockerDose Comments

Morphine 1-5mg IV q5min if sx not

relieved by NTG or recur

Oxygen If SaO2<90% or high-risk

features or hypoxia

Nitroglycerin (NTG)

CI: Sildenafil/ vardenafil

(w/in 24h), tadalafil (w/in

48h)

0.4mg spray or SL q5min x ≤3

doses

Call 911 if unresponsive to 1st dose

5-10mcg/min IV; titrate to CP

relief or 200mcg/min

-Used in first 48h for tx of persistent CP, HF

-Avoid if SBP<90mmHg or ≥30mmHg

below baseline

Aspirin (ASA) Chew and swallow non-enteric

coated 162-325mg x 1

-Reduces mortality

-Clopidogrel: If ASA allergy or GI

intolerance

Beta-blocker PO/IV initiated within 24 hours if

eligible

-Oral preferred

-Reduces mortality

-Avoid if signs of HF, ↑ risk of cardiogenic

shock, or CI

21

Lüscher TF, et al. European Heart Journal. August 2011. 22

Management of NSTE-ACS: Dual

Antiplatelet Therapy (DAPT)

Loading Dose Maintenance Dose COR LOE

Aspirin 162-325mg non-enteric coated 81-162mg daily I A

P2y12

inhibitors

Loading Dose

(PO)

Maintenance

Dose (PO)

Comments COR LOE

Clopidogrel

(Plavix)

300mg

(ischemia guided)

600mg

(PCI)

75mg daily Best if patient cannot drink full

class of water

I B

Ticagrelor*

(Brilinta)

180mg 90mg BID CI: ICH, severe hepatic disease I B

Prasugrel

(Effient)

60mg 10mg daily Option for PCI w/stenting; avoid

in Hx of TIA or stroke, >75y, or

<60kg

IIa B

AHA/ACC Guideline for the management NSTEMI ACS. Circulation 2014.23

*Reasonable to use in preference to clopidogrel in NSTE-ACS. (IIa, B)

*Recommended maintenance dose of aspirin is 81 mg daily.

DAPT for at least 12 months

PGY12 Antagonists

Adapted from Finks SW. Acute Coronary Syndromes. ACCP Updates in Therapeutics 2015. 24

Parameter Clopidogrel Prasugrel Ticagrelor

FDA Indication ACS managed medically or PCI ACS PCI ACS managed medically or PCI

Peak Platelet

Inhibition

LD: 300mg, ~6h,

600mg, ~2h

LD: 60mg, ~1-1.5h LD: 180mg, <1h

Adverse Effects Bleeding, GI hemorrhage Bleeding, HTN, HLD, A.fib,

bradyarrhythmia

Bleeding, ↑Scr, dyspnea

Metabolism Prodrug; 2-step process

involving 2C19 and 3A4

Prodrug; converted to active

metabolite via P450 pathways

Not prodrug; reversible

noncompetitive binding. 3A4

(primary), 3A5, Pgp

T1/28h metabolite 3.7h metabolite (2-15h range) 7h (parent), 9h(active metabolite)

Non-responders CYP2C19, CYP3A4 and Pgp

polymorphisms or interactions

No known issues No known issues

Drug/Disease

Interactions

PPIs inhibit 2C19 Less prone Careful with asthma, bradycardia;

limit ASA <100mg

Clinical trials CREDO, CURE, PCI-CURE,

CLARITY, COMMIT

TRITON-TIMI 38 PLATO*

3/3/2016

7

Management of NSTE-ACS:

Anticoagulant

Loading Dose Maintenance Dose Comments COR LOE

Heparin 60 IU/kg IVB

over >1 min

(Max 4000 IU)

12 IU/kg/hr (max1000IU/hr)

x 48h or until PCI performed

aPTT goal: 50-75s I B

Enoxaparin

(Lovenox)

30mg IVB 1mg/kg SQ Q12h x 24-48h

CrCl<30: Q24h

Highest bleeding

risk of 4 agents

I A

Fondaparinux

(Arixtra) -

2.5mg SQ daily

CrCl<30: Avoid

Best for those

with high risk of

bleeds

I B

Bivalirudin

(Angiomax)

0.1mg/kg IVB 0.25mg/kg/hr IV

if planned invasive surgery

Only in early

invasive strategy

or hx of HIT

I B


Management of NSTE-ACS:

GP IIb/IIIa inhibitor

GP IIb/IIIa

inhibitor

Loading Dose Maintenance Dose Comments COR LOE

Eptifibatide

(Integrilin)

180mcg/kg IVB

over 1-2 min

(Max 22.6 mg)

2mcg/kg/min IV

infusion x 12-72h

(Max 15 mg/hr)

CrCl<50: 1 mcg/kg/min

(Max 7.5 mg/hr)

•Continue until

discharge, CABG

initiation, or 72h

•CrCl<10mL/min

• CI: dialysis pts

IIb B

Tirofiban

(Aggrastat)

25mcg/kg IVB 0.15mcg/kg/min for up

to 18h

CrCl<60: 0.075

mcg/kg/min

IIb B


• Intermediate/High risk: GP IIb/IIIa inhibitor may be considered as part of initial tx in

early invasive strategy.

Other Early Hospital Therapies

• Nitrates: Topical or Oral

• ACE-Inhibitors:– CHF, EF<40%, HTN, DM, stable CKD (ARB if intolerant)

• Aldosterone antagonist:– On ACE-I and β-blocker with EF<40%, Sx HF or DM and if

CrCl>30 ml/min and K<5.0 mEq/L

• Calcium Channel Blocker: – For ischemic symptoms when β-blocker not successful, CI, or

intolerant

• Statins: High-intensity

• Nonsteroidal anti-inflammatory drugs (NSAIDs):– (Except aspirin) Should not be initiated and should be discontinued

during hospitalization

27

Immediate Invasive Strategy

• <90 minutes from presentation

• Refractory angina

• S/sx of HF or new/worsening mitral regurgitation

• Hemodynamic/electrical instability

• Recurrent angina or ischemia despite intensive medication

treatment

• Severe VT or VF

• Severe comorbidities

28

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8

Initial Management of STEMI

STEMI Treatment:

Reperfusion Therapy

Percutaneous Coronary

Intervention (PCI) Pharmacologic:

Fibrinolytic

https://www.nghs.com/fullpanel/uploads/files/cardiac-cath-lab.jpg30

Percutaneous Coronary

Intervention (PCI)

• Balloon angioplasty alone

• Balloon angioplasty with stents

– Bare metal stents (BMS)

– Drug-eluting stent (DES)

• Anti-proliferative agents: Sacrolimus, Paclitaxel, Everolimus, Zotarolimus

http://www.ica.artguys.com/IMAGES/Percutaneous-Coronary-Intervention.jpg31

Management of STEMI:

Reperfusion Therapy

ACCF/AHA Guideline for the Management of STEMI. 2013.

32

Bold lines are preferred strategies.

DIDO= door-in-door-out

*Patients with cardiogenic shock or severe HF initially seen at non-PCI-capable hospital should be

transferred for cardiac catheterization and revascularization as soon as possible, irrespective of time

delay from MI onset (I, B)

3/3/2016

9

STEMI Management

• Reperfusion therapy for all eligible patients with STEMI with

symptom onset ≤ 12 hrs

– Reperfusion therapy options: Percutaneous Coronary Intervention

(PCI) or fibrinolytic therapy

– First line� Primary PCI

• PCI- capable hospital (90 min) vs. non-PCI capable hospital (120

min)

– Second line� Fibrinolytic therapy

• If time is > 120 min to get to PCI hospital

33

STEMI Management

• Reperfusion therapy reasonable for patients with STEMI

with symptom onset in prior 12-24 hours if:

– Clinical and/or ECG evidence of ongoing ischemia

– First line: Primary PCI

• PCI also first line if..

– STEMI + cardiogenic shock, acute severe HF, or CI to fibrinolytics

34


DAPT with Primary PCI


Aspirin 162 – 325mg

prior to procedure

81 -325mg daily

Indefinitely (I,A)

I B (LD)

P2Y12

inhibitors


Clopidogrel 600mg 75mg daily I B

Prasugrel 60mg 10mg daily I B

Ticagrelor 180mg 90mg BID* I B

ACCF/AHA Guideline for the Management of STEMI. 2013. 35

*The recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg daily.


Anticoagulant with Primary PCIAnticoagulant Loading Dose Follow-Up Dose COR LOE

UFH

With GP IIb/IIIa antagonist

planned

50- to 70-U/kg IVB to

achieve therapeutic ACT‡

Supplemental doses to

target ACT

I C

With no GP IIb/IIIa

antagonist planned:

70- to 100-U/kg IVB to

achieve therapeutic ACT§

Supplemental doses to

target ACT

I C

Lovenox

(Enoxaparin)

If last dose <8h, none

If last dose >8h, 0.3mg/kg

IVB if last dose 8-12h

prior

I B

Bivalirudin

(Angiomax)

0.75mg/kg IVB 1.75mg/kg/h IV*,

discontinue at end of PCI

or continue up to 4h as

needed

I B

Fondaparinux

(Arixtra)

Not recommended as sole anticoagulant for primary

PCI

III B

‡ Recommended ACT with planned GP IIb/IIIa antagonist tx is 200-250s.

§ 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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3/3/2016

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Management of STEMI undergoing

PCI: GP IIb/IIIa inhibitor



Abciximab

(ReoPro)

0.25mg/kg IVB 0.125mcg/kg/min (max

10mcg/min) x 12h

IIa A

Tirofiban

(Aggrastat)

high bolus dose

25mcg/kg IVB

over 3 min 0.15mcg/kg/min* x 18-24h

IIa B

Eptifibatide

(Integrilin)

double bolus

180mcg/kg IVB x 2

(10 min apart)

2mcg/kg/min** 18-24h IIa B

*In patients with CrCl <30 mL/min, reduce infusion by 50%

**In patients with CrCl <50 mL/min, reduce infusion by 50%, avoid in HD

• Of uncertain benefit if pretreated with P2Y12.

Management of STEMI: Anticoagulant

with Fibrinolytic Therapy

Anticoagulant Loading Dose Maintenance Dose COR LOE

UFH 60U/kg IVB

(Max 4000 U)

12 U/kg/h

(Max 1000U/h)

-Obtain aPTT at 1.5-2x control

x 48h or until revascularization

I C

Enoxaparin ≤75y: 30mg IVB

>75y: omit bolus

≤75y: 1mg/kg SQ q12h

>75y: 0.75mg/kg SQ q12h

CrCl <30:1mg/kg SQ q24h

index hospitalization, up to 8d

or until revascularization

I A

Fondaparinux 2.5mg IVB 2.5mg SQ daily for index hosp

up to 8d or until

revascularization

CrCl <30: CI

I B


Reperfusion choice: Fibrinolytic

Fibrinolytic Agent Dose Patency rate Side effects

Alteplase

(rt-PA, Activase)

15mg IVP, then 0.75 mg/kg over

30 min (max 50mg), then 0.5mg/kg

(max 35 mg) over next 60 min

(total dose ≤ 100 mg)

73-84% Stroke, ICH

Reteplase

(r-PA, Retavase)

10 units IV; repeat dose in 30 min 84% Reperfusion

arrhythmias,

anemia

Tenecteplase

(TNK-tPA, TNKase)

Single IV dose:

Weight < 60 kg: 30mg

Weight 60-69 kg: 35mg



Weight >90 kg: 50mg

85% Minor bleeding,

reperfusion

arrhythmias


Reperfusion choice: Fibrinolytics

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

3/3/2016

11

STEMI: Reperfusion therapy routes

2. Fibrinolytic

therapy

1. PCI

(Recommended)

3. Fibrinolytic,

then PCI

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


2. Fibrinolytic

therapy

1. PCI

(Recommended)

3. Fibrinolytic,

then PCI


1. Reperfusion choice: PCI

Timeline of Antithrombotic therapy

During PCI

STEMI

diagnosed

After PCI

Aspirin

indefinitely and

P2Y12 inhibitor x

1 year

Before PCI:

� ASA 162-325 mg LD

� P2Y12 Inhibitor LD (any of following)

1. Clopidogrel 600 mg

2. Prasugrel 60 mg

3. Ticagrelor 180 mg

LD of Antiplatelets:

Aspirin and P2Y12

Inhibitor

+/-

GP IIb/IIIa antagonist

Anticoagulants:

UFH +/- GP

IIb/IIIa antagonist

or

Bivalirudin

Before PCI

After PCI:

� ASA 81-325 mg daily

� P2Y12 Inhibitor (any of the

following)

1. Clopidogrel 75mg daily

2. Prasugrel 10 mg daily

3. Ticagrelor 90mg BID

During PCI:

� Refer to dosing table



2. Fibrinolytic

therapy

1. PCI

3. Fibrinolytic,

then PCI


3/3/2016

12

2. Reperfusion choice: Fibrinolytic


With Fibrinolytic

STEMI

diagnosed

LD of Antiplatelets:

Aspirin and P2Y12

Inhibitor

Anticoagulants:

UFH or

Enoxaparin (IV

& SQ)

Fondaparinux

Before Fibrinolytic

Aspirin indefinitely

and

P2Y12 inhibitor x

14 days-1 year

Before fibrinolytic:

-ASA 162-325 mg LD

-Clopidogrel as only P2Y12 inhibitor

• Age ≤ 75 y: 300 mg LD

• Age > 75: No LD, give 75 mg

2. Enoxaparin:

-Age < 75y: 30 mg IV bolus, then 1 mg/kg SQ q12h

-Age > 75y: no bolus; 0.75 mg/kg SQ q12h

3. Fondaparinux:

2.5 mg IV, then 2.5 mg SQ daily in 24h

Duration for both: Up to 8 days, or until

revascularization

After Fibrinolytic

With Fibrinolytic:

1. UFH: 60 U/kg IV bolus, then 12 U/kg/hr

infusion adjusted for aPTT 1.5-2x control

(~50-70s for 48h or until revascularization)

After Fibrinolytic: See dosing tableAdapted from Calil M, Perrin D. Acute Coronary Syndromes.

45


2. Fibrinolytic

therapy

1. PCI

3. Fibrinolytic,

then PCI


PCI after fibrinolytic therapy

COR LOE

Immediate transfer for cardiogenic shock or severe acute HF

irrespective of delay from MI onset

I B

Urgent transfer for failed reperfusion or reocclusion IIa B

As part of invasive strategy in stable* patients with PCI between

3-24h after successful fibrinolysis

IIa B

*absence of low output, hypotension, persistent tachycardia, apparent shock, high-grade ventricular or sx supraventricular

tachyarrhythmias, and spontaneous recurrent ischemia


With PCI

3. Reperfusion Choice: PCI after

fibrinolytic therapy


STEMI

diagnosed

LD of aspirin and

P2Y12 Inhibitor if did

not receive one before

Anticoagulants:

Continue UFH

or

Continue

Enoxaparin (IV)

Before PCI After PCI

Aspirin indefinitely and

P2Y12 inhibitor x 1 year

(DES) or for 30 days – 1

year (BMS)

Before PCI:

-If PCI ≤ 24h after fibrinolytic

therapy: Clopidogrel 300 mg LD

-If PCI > 24h after fibrinolytic

therapy: Clopidogrel 600 mg LD or

Prasugrel 60 mg

With PCI:

Enoxaparin

-If last dose ≤ 8h, no additional

drug

-If last dose > 8h, give 0.3 mg/kg

IV bolus

After PCI:

- Clopidogrel as maintenance

P2Y12 inhibitor


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Coronary Artery Bypass Graft (CABG)

• Limited role

• Indications:

– STEMI w/coronary anatomy not amenable to PCI + ongoing

ischemia, cardiogenic shock, severe HF

– STEMI at time of operative repair of mechanical defects

49

Coronary Artery Bypass Graft (CABG)

• Anti-thrombotic therapy:

� Give aspirin before CABG surgery

� Discontinue clopidogrel or ticagrelor ≥ 24h before “on-

pump” CABG

� Discontinue short acting IV GP IIb/IIIa antagonists ≥ 2-4h

before urgent CABG

� Discontinue abciximab ≥ 12h before urgent CABG

50

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

– P2Y12 inhibitor + ASA x ≥ 12 months

• Clopidogrel

• Ticagrelor

• Prasugrel (option for BMS or DES)

51

References

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:e1–e157.

3. Braunwald et al. J Am Coll Cardiol. 2000;36:970-1062.

4. Bruhl, SR. Acute Coronary Syndrome. Internal Medicine Didactics. July 2010.

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

Myocardial Infarction (STEMI).

6. Finks SW. Acute Coronary Syndromes. Cardiology I. ACCP Updates in Therapeutics 2015.

7. Lüscher TF et al. ESC Guidelines for the management of acute coronary syndromes in patients

presenting without persistent ST-segment elevation. European Heart Journal. August 2011.

8. O’Gara PT et al. ACCF/AHA Guideline for the Management of STEMI: A Report of the American

College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J

Am Coll Cardio. 2013; 61(4):e78-e140.

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, 2007:773–80.

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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acute coronary syndromes pharmacist: (acs) elevation myocardial infarction (stemi) – review...

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