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Dr Badri Paudel GMC

Atherothrombosis: Thrombus Superimposed on Atherosclerotic Plaque

Adapted with permission from Falk E, et al. Circulation. 1998;92:657-671. Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org.

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Characteristics of Unstable and Stable Plaque

Thin fibrous cap

Inflammatory cells

Few SMCs

Eroded endothelium

Activated macrophages

Thick fibrous cap

Lack of inflammatory cells

Foam cells

Intact endothelium

More SMCs

Adapted with permission from Libby P. Circulation. 1995;91:2844-2850. Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org.

Unstable Stable

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The Stable and Unstable Plaque

Reproduced with permission from Yeghiazarians Y, Braunstein JB, Askari A, et al. Unstable angina pectoris. N Engl J Med. 2000;342:101-114.Copyright © 2000, Massachusetts Medical Society. All rights reserved. 4 badri@gmc

ACS Pathophysiology Plaque Rupture, Thrombosis, and Microembolization

Quiescent plaque

Platelet-thrombin micro-emboli Plaque rupture

Process Plaque formation Inflammation Multiple factors ? Infection Plaque Rupture ? Macrophages Metalloproteinases Thrombosis Platelet Activation Thrombin

Marker Cholesterol LDL C-Reactive Protein Adhesion Molecules Interleukin 6, TNFα, sCD-40 ligand MDA Modified LDL D-dimer, Complement, Fibrinogen, Troponin, CRP, CD40L

Vulnerable plaque

Macrophages Foam Cells

Collagen → platelet activation

TF → Clotting Cascade

Lipid core

Metalloproteinases

Inflammation

Courtesy of David Kandzari.

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Prevalence of CAD (%) in Symptomatic Patients According to Age and Sex

Typical angina Atypical angina Non anginal chest pain

AGE Men Women Men Women Men Women

30-39 69.7 25.8 21.8 4.2 5.2 0.8

40-49 87.3 55.2 46.1 13.3 14.1 2.8

50-59 92.0 79.4 58.9 32.4 21.5 8.4

60-69 94.3 90.6 90.6 54.6 28.1 18.6

3 of 3 criteria 2 of 3 criteria 1 of 3 criteria

1) Retrosternal discomfort.2) Provoked by exercise or stress.3) Relieved by rest or NTG 10

Acute Coronary Syndrome

Ischemic Discomfort Unstable Symptoms

No ST-segment elevation

ST-segment elevation

Unstable NSTEMI STEMI angina

ECG

Acute Reperfusion

History Physical Exam

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Acute Coronary Syndrome

•  The spectrum of clinical conditions ranging from: – unstable angina – NSTEMI – STEMI

•  characterized by the common pathophysiology of a disrupted atheroslerotic plaque

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Thrombus Formation and ACS

UA NQMI STE-MI

Plaque Disruption/Fissure/Erosion

Thrombus Formation

Non-ST-Segment Elevation Acute Coronary Syndrome (ACS)

ST-Segment Elevation Acute Coronary Syndrome (ACS)

Old Terminology:

New Terminology:

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* Based on data from the ARIC study of the National Heart, Lung, and Blood Institute, 1987-1994. Includes Americans hospitalized with definite or probable MI or fatal CHD, not including silent MIs. ACS indicates acute coronary syndrome; MI, myocardial infarction; ARIC, Atherosclerotic Risk in Communities; and CHD, coronary heart disease. From American Heart Association. Heart Disease and Stroke Statistics—2003 Update.

Epidemiology of ACS in the United States •  Single largest cause of death

–  515,204 US deaths in 2000 –  1 in every 5 US deaths

•  Incidence –  1,100,000 Americans will have a new or recurrent coronary

attack each year and about 45% will die* –  550,000 new cases of angina per year

•  Prevalence –  12,900,000 with a history of MI, angina, or both

Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org.

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Prevalence:

Ø  4 times the number of A/c ST elevation MI

Ø 1,300,000 patients with unstable angina or non

ST elevation MI per year in the US.

Ø 3.1 million hospital days in 1991 badri@gmc

Unstable Anginal Syndromes

•  New onset angina (1 month) •  Crescendo angina

–  Increased frequency,severity or duration

•  Acute coronary syndrome (ACS) –  Ischaemic chest pain > 20 minutes

•  Post infarction angina •  Prinzmetal’s (variant) angina

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ACS Nomenclature

•  UA – Prolonged ischaemic chest pain > 20 min. – ± ST changes – Negative enzyme/biomarkers

•  Non STEMI – Prolonged ischaemic chest pain > 20 min. – ± ST changes – Elevated enzyme/biomarkers

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ACS Nomenclature

•  ST Elevation MI: – Prolonged R/S chest pain > 20 minutes

with – Persisting ST elevation despite NTG

• At least 1 mm in 2 adjacent limb leads • At least 2 mm in 2 adjacent precordial leads • Newonset LBBB (for purpose of thrombolysis)

– Evolution of Q waves (excluding LBBB scenario)

– Enzyme or bio-marker elevation

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Categorize the Severity of Angina

CCS Classification Class 0 asymptomatic

Class I on strenuous activity

Class II on moderate activity > 2 blocks or 2 flights of stairs

Class III on mild activity < 2 blocks or 2 flights of stairs

Class IV

rest or minimal activity

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Categorize the Severity of Angina

CCS Classification Class IV A

Patient admitted to hospital and becomes relatively asymptomatic with aggressive medical therapy

Class IV B

Patient admitted to hospital and continues to experience angina on maximal medical therapy and cannot be safely discharged home, but does not require IV nitroglycerin.

Class IV C Patient admitted to hospital and maximal medical therapy, including IV nitroglycerin, fails to control symptoms or there is hemodynamic instability.

Class IV D

Cardiogenic Shock

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CLASSIFICATION OF UNSTABLE ANGINA

SEVERITY;

CLASS 1 – NEW ONSET, SEVERE OR ACCELARATED ANGINA

ANGINA < 2 MOS DURATION, SEVERE OR OCCURING

3 OR MORE TIMES PER DAY,

OR

ANGINA THAT IS DISTINCTLY MORE FRQUENT AND

PPT BY DISTINCTLY LESS EXERTION

NO REST PAIN IN THE LAST 2 MOS

CLASS II;

ANGINA AT REST – SUBACUTE

PATIENTS WITH ONE OR MORE EPISODES OF ANGINA

AT REST DURING THE PRECEDING MONTH

BUT NOT WITHIN THE LAST 48 HOURS

CLASS III

ANGINA AT REST – ACUTE

PATIENTS WITH ONE OR MORE EPISODES AT REST

WITHIN THE PRECEDING 48 HOURS

CLINICAL CIRCUMSTANCES

CLASS A: SECONDARY UNSTABLE ANGINA Anemia, infection, fever, hypotension thyrotoxicosis, hypoxemia secondary to respiratory failure

CLASS B

PRIMARY UNSTABLE ANGINA Develops in the absence of extracardiac condition

CLASS C POST-INFARCTION ANGINA (within two weeks of DOCUMENTED MI). Occurs in 20% of A/c MIs

INTENSITY OF TREATMENT

May be divided in to 3 groups depending on when it occurs

1.  ABSENCE OR MINIMAL TREATMENT OF CHRONIC

STABLE ANGINA

2. OCCURING IN PRESENCE OF STANDARD RX FOR

CHRONIC STABLE ANGINA (CONVENTIONAL DOSES OF

BETA BLOSKERS, NITRATES, CCB)

3.  OCCURING DESPITE MAXIMALLY TOLERATED DOSES OF

ALL 3 CATEGORIES OF ORAL RX , INCLUDING IV NTG

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Non ST Elevation MI

• Definition: – Prolonged ischaemic chest pain – ST-T changes – Positive serum markers

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Pathogenesis

ACUTE CORONARY SYNDROME

No ST Elevation ST Elevation

Unstable Angina NQMI QwMI Myocardial Infarction

NSTEMI

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What Is the Culprit Lesion?

•  58-year-old male with chronic stable angina

•  Positive stress test with small reversible ischemic defect on nuclear scintigraphy"

Medication prescribed, but six weeks later…3-day history of unstable angina, including���30 minutes of rest pain

•  Medically “cooled off” followed by angiography

Case provided by the McLaren Heart and Vascular Center, Flint, Michigan; used with permission.

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Atherosclerosis is a Diffuse Process

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Pathogenesis

•  Plaque rupture or erosion •  Thrombosis with/without occlusion •  Necrosis contingent on

–  Severity of plaque rupture –  Duration of ischaemia –  Lability of occlusive thrombus –  Adequacy of collaterals –  Vasoconstriction –  Downstream platelet/fibrin emboli

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Unstable Angina: Platelet Plugging of the Capillaries

From: Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death Davies MJ, Circulation 1986

“The results support the view that platelet aggregates in the myocardium represent an embolic phenomenon and are a potential cause of unstable angina. The association of myocardial necrosis with such emboli could precipitate sudden death from ventricular fibrillation.”

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Unstable Angina-Triggers Systemic factors

•  Hyper-coagulable state •  Increased vascular resistance •  Coronary spasm •  Increased cortisol & catecholamines •  Vasoconstriction •  Increased arterial pressure •  Circadian variation

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Unstable Angina Triggering Situations •  Awakening •  Excessive physical exertion •  Mental stress •  Anger •  Cigarette smoking •  Coffee & alcohol consumption •  Sexual activity

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Non ST Elevation MI

90% of acute MIs are caused by thrombus formation from rupture of unstable plaques

Ruptured Plaque

33 badri@gmc Extensive subendocardial myocardial infarction (yellow arrows)

Sub-endocardial MI

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Occlusive Thrombus

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Transmural Infarction

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AntmanAntman et al. et al. JAMAJAMA. 2000;284:835. Available at: . 2000;284:835. Available at: www.www.timitimi.org..org.

TIMI Risk Score for UA/NSTEMITIMI Risk Score for UA/NSTEMI7 Independent Predictors7 Independent Predictors

nn Age Age ≥≥65 years65 yearsnn ≥≥3 CAD risk factors3 CAD risk factors

((↑↑ cholchol, , FHxFHx, HTN, DM, smoking), HTN, DM, smoking)nn Prior CAD (cath stenosis >50%) Prior CAD (cath stenosis >50%) nn ASA in last 7 daysASA in last 7 daysnn ≥≥2 Anginal events 2 Anginal events ≤≤24 hours24 hoursnn ST deviation ST deviation nn Elevated cardiac markers (CKElevated cardiac markers (CK--MB orMB or troponintroponin))

www.timi.org

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TIMI Risk Score for UA/NSTEMI

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Low Risk Intermediate Risk

High Risk Very High Risk

Non ST ↑ ACS 30 Day Death/MI Risk

< 3 % 3-8 % 8-15 % >15%

No higher risk features • Single short duration (<10 min.) rest pain • Crescendo angina/New onset angina (Mod severity) 6 Hour Observation • ECG X 2 normal, unchanged or non-specific ST Δ’s • Negative biomarkers X 2

Rest pain < 20 min. New onset/ Crescendo angina (Low threshold severity) • ECG non-specific abnormalities or normal • Biomarkers normal or borderline ↑ Increased baseline risk • DM • Previous CABG/MI • Recent PCI

Rest pain > 20 min. Prolonged recurrent pains

• ECG ST depression < 2mm • Deep T inversion (e.g. > 5 mm) • T inversion > 2 mm

– Especially in > 5 leads

• Isolated biomarker clearly +ve

• ST depression < 2mm With ↑ CK-MB or Tn • ST depression > 2mm

– Multiple leads – With pain

• Transient ST ↑ > 1 mm

• Hemodynamic instability

– ↓ BP/CHF

Refractory ischaemia with ST shift

D Fitchett, SG Goodman M Gupta, A Langer. Can J Card 2002; 18 (11):1179-1190. 41 badri@gmc

www.timi.org

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Testing for ACS - Serum Markers

•  Creatine Kinase, an intracellular enzyme involved in transferring phosphate grps from ATP to creatine in Cardiac & skeletal muscle and brain

•  CK-BB = brain •  CK-MM = skeletal •  CK-MB = cardiac

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Testing for ACS - Serum Markers

•  CK –  elevates 4-8 hours after coronary Art. Occlusion –  Peaks = 12 to 24 hours –  Nml = 3 to 4 days

•  CK-MB –  Detectable 4-8 hrs –  Peak = before 24 hrs –  Nml = in 48hrs

•  CK-MB normally can be 5% of total CK (Rapid Index)

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Cardiac Markers

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BIOCHEMICAL CARDIAC MARKERS IN PTS WITH SUSPECTED ACS WITHOUT STE

CK-MB

1. Rapid, cost-efficient,

accurate assays 2. Ability to detect early

reinfarction

Myoglobin

1. High sensitivity 2. Useful in early

detection of MI 3. Detection of

reperfusion 4. Most useful in ruling

out MI

Troponins

1. Powerful for stratification 2. Greater sensitivity and

specificity than CK-MB 3. Detection of recent MI up to

2 weeks after onset 4. Useful for selection of

therapy 5. Detection of reperfusion

Advantages

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BIOCHEMICAL CARDIAC MARKERS IN PTS WITH SUSPECTED ACS WITHOUT STE

CK-MB 1. Lack of specificity

with skeletal muscle disease/injury

2. Low sensitivity during early MI (<6 h) or late (>36 h) after symptom onset and for minor myocardial damage

Myoglobin

1. Very low specificity with skeletal muscle injury or disease

2. Rapid return to normal

Troponins

1. Low sensitivity in early phase of MI (<6 h after symptom onset)

2. Limited ability to detect late minor reinfarction

Disadvantages

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When to do what?

Treat first…ask questions later!!!!

Therapy of ACS

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General Measures

•  Rest, oxygen and EKG monitoring •  Exclude secondary causes (10-15% ) -  Anemia -  Arrythmias -  Heart Failure -  Hypoxemia -  Infection -  Uncontrolled HTN -  Stress -  Thyrotoxicosis

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Unstable Angina/ACS Therapeutic Goals-1 •  Prevent re-thrombosis & prevent

downstream embolization –  Anti-platelet therapy

• ASA (65-75% ↓ early events;50%↓ death/MI 2-24 months)

• Clopidogrel 300-600 mg → 75 mg OD • Glycoprotein IIB/IIIA inhibitors

–  Anti-coagulant therapy (↓ death MI additional 40%) • UFH or LMWH

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Unstable Angina/ACS Therapeutic Goals-1

•  Control ischaemia – β-blockers – Nitrates – CCB’s

•  Relieve Obstruction – Cardiac cath – PCI – CABG

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0.5 1 1.5

8.6 7.1 0.82 (0.69-0.97) 18 .02

6.5 5.2 0.79 (0.65-0.96) 21 .02

5.3 4.1 0.77 (0.62-0.95) 23 .02

1.8 1.4 0.80 (0.55-1.16) 20 .24

Day

2

8

14

43

UFH (%)

Enox (%)

OR (95 CI)

Favors Enox

Favors UFH

%↓ P

OR Heterogeneity: All P=NS. Antman et al. Circulation. 1999;100:1602-1608.

Death or MI

TIMI 11B/ESSENCE Meta-analysis: Enoxaparin vs Unfractionated Heparin

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Severity of Angina Determines the Therapy

CCS Angina Class

Definition: Angina with

Number of medications

Choice of Rx

I

Strenuous activity 1 ASA1 + NTG prn

II Moderate activity • > 2 blocks or 2 flights of stairs

2 ASA1 + β-blocker or Rate limiting CCB2,3

III Mild activity • < 2 blocks or 2 flights of stairs

3 ASA1 + β-blocker or Rate limiting CCB2,3 + Long acting nitrate

IV A Rest or minimal activity • Patient admitted to hospital

and becomes relatively asymptomatic with aggressive medical therapy

4 ASA1 + β-blocker + CCB3 (do not combine verapamil and β-blocker) + Long acting nitrate

IV B Rest or minimal activity. • Patient admitted to hospital

and continues to experience angina on maximal medical therapy and cannot be safely discharged home, but does not require IV nitroglycerin.

IV C Rest or minimal activity.

• Patient admitted to hospital

and maximal medical therapy, including IV nitroglycerin, fails to control symptoms or there is hemodynamic instability.

• For prolonged rest pain > 20 minutes Rx heparin LMWH > UFH Enoxaparin (Lovenox®) (ESSENCE / TIMI 11B / TIMI 11B-ESSENCE Metanalysis)

• Add clopidogrel 300 mg stat 75 mg OD (CURE) where non-interventional approach is standard of care or early angiography not readily available.

• For recurrent pain > 24 hours consider angiography

• With planned angiography/PCI within 24-48 hours consider adding glycoprotein IIb/IIIa inhibitor/re-evaluate clopidogrel

• tirofiban (Aggrastat®) o TACTICS-TIMI 18 o PRISM-PLUS

• eptifibitide (Integrilin®) -PURSUIT • With ST elevation consider for thrombolytic

protocol

IV D Cardiogenic Shock Inotropic Agents IABP Angiography Revascularization

1Consider clopidogrel 75mg OD with recent MI, CVA, PVD in ASA intolerant or allergic patients (CAPRIE).

2Rate limiting CCB(calcium channel blocker): diltiazem or verapamil (do not combine verapamil and β-blocker) 3For patients with chronotropic incompetence use long acting DHP- CCB (amlodipine, felodipine or nifedipine)

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Unstable Angina -Therapy

1.  ASA-always!!! 2.  Heparin-if rest

component or UA!! LMWH > UFH

3.  Add Clopidogrel for Troponin +/dynamic ST changes

4.  Lytics-NO!!!(TIMI IIIB) 5.  Add IIB/IIIA inhibitors

if planned cath/PCI within 24-48 hours or transient ST elevation

6.  Beta-Blockers-yes!!!exertional component

7.  Calcium blockers-rest pain!!rate limiting CaB

8.  Nitrates-yes!!!multiple routes(IV >rapidity)

9.  IABP-Tertiary centre 10.  Cardiac

catheterization-if pain >48 hours

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Management Strategy for ACS/NSTEMI

ACS/NSTEMI

Aggressive Therapy (early cath/intervention)

Conservative Therapy (medical Rx/non-invasive evaluation)

Non-cardiac exacerbation of known CAD •  Anemia •  Infection •  Hyperthyroidism •  Other medical causes

Patient preference Stability Normal LV Function Good exercise tolerance Relative C/I to CABG/PCI Brief duration of ischaemia No ST changes Negative biomarkers

Dynamic ST changes Positive Enzymes or Biomarkers

Recurrent ischaemia on medical Rx Prolonged ischaemic pain

PTCA < 6 months Known severe CAD

LV dysfunction •  Pre-existing

•  new MR •  new CHF

Intolerance to medical Rx Recurrent ventricular

arrythmia’s/SCD Early positive non-invasive test

Poor exercise tolerance 55 badri@gmc badri@gmc 56

badri@gmc Reproduced with Permission of CHRC 57 58 badri@gmc

Platelets and Anti-Platelet Therapies

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Pathogenesis of Acute Coronary Syndromes: The integral role of platelets

Plaque Fissure or Rupture

Platelet Aggregation

Platelet Activation

Platelet Adhesion

Thrombotic Occlusion

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Adhesion

The Role of Platelets in Atherothrombosis

Aggregation 3

Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org.

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Activation 2 61 badri@gmc

ADP

• Ticlopidine • Clopidogrel

• Heparin • LMW Heparin • Direct Thrombin Inhibitors

• Aspirin

Epinephrine Collagen Arachidonic

Acid

Thrombin

IIb/IIIa receptors

fibrin

The Platelet

• GP IIb/IIIa inhibitors

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Platelet Inhibition With GP IIb/IIIa Inhibitors

Reproduced with permission from Yeghiazarians Y, Braunstein JB, Askari A, et al. Unstable angina pectoris. N Engl J Med. 2000;342:101-114. Copyright © 2000, Massachusetts Medical Society. All rights reserved.

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placebo aspirin heparin ASA+hep 0 2 4 6 8

10 12

% D

evel

opin

g M

I

Treatment

Treatment of Unstable Angina Results of a study from the Montreal Heart Institute

Data from Theroux P, Quimet H, McCans J, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med. 1988;319:1105-1111. 66 badri@gmc

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Reproduced with permission from Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494-502. Copyright © 2001, Massachusetts Medical Society. All rights reserved.

2

4

6

8

10

12

14

% W

ith E

vent

Clopidogrel + Aspirin

3 6 9

Placebo + Aspirin

Follow-up (months)

P=.00009

0 12

20% RRR

The Primary Composite End Point in the CURE Trial

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GP IIb/IIIa Dosing and Administration for Up-Front Therapy in Patients with NSTE-ACS

•  Dosing: –  Integrilin: 180 mcg/kg bolus (over 1-2 min), then 2 mcg/kg/

min continuous infusion –  Aggrastat: Initial 0.4 mcg/kg/min for 30 min, then continuous

infusion at 0.1 mcg/kg/min

•  Always also treat with ASA and some form of heparin (UFH or LMWH)

•  Patients most commonly treated 2-4 days •  Follow platelet count qD and D/C for significant fall •  Adjust doses for renal insufficiency:

–  Integrilin: For creatinine 2-4 mg/dL, decrease infusion to 1 mcg/kg/min; avoid if creatinine >4 mg/dL

–  Aggrastat: For CrCl < 30 mL/min, cut all doses in 1/2 68 badri@gmc

ACC/AHA Recommendations for Antiplatelet Therapy in Patients with NSTE-ACS •  Class I

–  ASA –  Clopidogrel if ASA-allergic or intolerant –  Clopidogrel in addition to ASA if early invasive approach not planned –  Clopidogrel should be withheld for 5-7 days if CABG planned –  GP IIb/IIIa inhibitor if cardiac cath and PCI planned

•  Class IIa –  GP IIb/IIIa inhibitor in patients with high-risk features if invasive

strategy not planned –  GP IIb/IIIa inhibitor in patients receiving clopidogrel if cardiac cath

and PCI planned

•  Class IIb –  GP IIb/IIIa inhibitor in patients without high-risk features and PCI not

planned

•  Class III –  Abciximab in patients in whom PCI is not planned

Available at: www.acc.org/clinical/guidelines/unstable/unstable.pdf.

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Contraindications to GP IIb/IIIa Rx

•  Active or recent bleeding (4-6 weeks) •  Severe hypertension (SBP >180-200 mm Hg; DBP >110 mm Hg) •  Any hemorrhagic CVA (+/- intracranial neoplasm, AVM, or aneurysm) •  Any CVA within 30 days–2 years •  Major surgery or trauma within 4-6 weeks •  Thrombocytopenia ( <100,000/mm3 ) •  Bleeding diathesis/warfarin with elevated INR •  (Doses must be avoided with renal insufficiency or failure)

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Antithrombin Therapy Studies and Recommendations

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RR: Death/MI

ASA Alone 68/655=10.4%

Heparin + ASA 55/698=7.9%

0.1 1 10

Summary Relative Risk 0.67 (0.44-0.1.02)

Theroux

RISC

Cohen 1990

ATACS

Holdright

Gurfinkel

Comparison of Heparin + ASA vs ASA Alone

ASA indicates acetylsalicylic acid; RISC, Research on InStability in Coronary artery disease; ATACS, Antithrombotic Therapy in Acute Company Syndromes; RR, relative risk; and MI, myocardial infarction. Data from Oler A, Whooley MA, Oler J, et al. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina: a meta-analysis. JAMA. 1996;276:811-815. Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org.

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Dea

th, M

I or

Urg

ent R

evas

cula

rizat

ion

Unfractionated Heparin Enoxaparin (Lovenox)

Days

20

16

12

8

4

2 4 6 8 10 12 14 0

1 6 . 7 %

1 4 . 2 %

p = 0.03 Relative Risk Reduction = 15%

TIMI 11B: Enoxaparin vs. Heparin in NSTE-ACS

Adapted from Antman EM, et al. Circulation. 1999;100:1593-1601. 73 badri@gmc

Guidelines for the Use of Enoxaparin in Patients with NSTE-ACS

•  1 mg/kg SQ q12 hours (actual body weight) –  An initial 30 mg IV dose can be considered

•  Adjust dosing if CrCl <30 cc/min –  1 mg/kg SQ q24 hours

•  Do not follow PTT; do not adjust based on PTT •  Stop if platelets ↓ by 50% or below 100,000/mm3 •  If patient to undergo PCI:

–  0-8 hours since last SQ dose: no additional antithrombin therapy –  8-12 hours since last SQ dose: 0.3 mg/kg IV immediately prior to

PCI

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ACC/AHA Recommendations for Antithrombin Therapy in Patients with NSTE-ACS

•  Class I –  Anticoagulation with subcutaneous LMWH or intravenous

UFH should be added to antiplatelet therapy –  Dose of UFH 60-70 U/kg (max 5000) IV followed by infusion

of 12-15 U/kg/hr (initial max 1000 U/hr) titrated to aPTT 1.5-2.5 times control

–  Dose of enoxaparin 1 mg/kg subcutaneously q12 hr; the first dose may be preceded by a 30-mg IV bolus

•  Class IIa –  Enoxaparin is preferable to UFH as an anticoagulant unless

CABG is planned within 24 hours

Available at: www.acc.org/clinical/guidelines/unstable/unstable.pdf.

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Early Invasive Strategy Studies and Recommendations in Patients with NSTE-ACS

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Months

4%

20%

16%

12%

8%

TACTICS

1 2 3 4 5 6

15.9%

19.4% Initial Medical Rx

Early Cath + PTCA

Adapted with permission from Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med. 2001;344:1879-1887. Copyright © 2001, Massachusetts Medical Society. All rights reserved.

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The Primary Composite Ischemic End Point in RITA-3

Reproduced with permission from Fox KA, Poole-Wilson PA, Henderson RA, et al. Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Randomised Intervention Trial of Unstable Angina. Lancet. 2002;360:743-751.

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ACC/AHA Class I Recommendations for Invasive and Medical Strategies in Patients with NSTE-ACS

•  Class I –  An early invasive strategy in patients with any high-risk

indicators: •  Recurrent angina/ischemia at rest or with low-level activities •  Elevated troponin •  New or presumed new ST-segment depression •  Recurrent angina/ischemia with CHF Sx and S3 gallop,

pulmonary edema, worsening rales, or new or worsening MR •  High-risk findings on noninvasive stress testing •  Depressed LVEF (<40%) •  Hemodynamic instability •  Sustained ventricular tachycardia •  PCI with 6 months or prior CABG

–  In the absence of any of the above high-risk indicators, either an early conservative or an early invasive strategy

Available at www.acc.org/clinical/guidelines/unstable/unstable.pdf.

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Peri- and Post-Discharge Therapies and Risk Modification

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MIRACL: Acute Statin Rx

Cum

ulat

ive

Even

ts

5%

10%

15%

Time Since Randomization (weeks) 4 8 12 16

RR=0.84 P=0.048

17.4% 14.8%

Placebo High-dose statin

Adapted with permission from Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285:1711-1718. Copyright © 2001, American Medical Association. All rights reserved.

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ACC/AHA Class I Recommendations for Long-Term Medical Therapy in Patients with NSTE-ACS

•  Class I –  Aspirin 75-325 mg qD –  Clopidogrel 75 mg qD when ASA is not tolerated because of

hypersensitivity or GI intolerance –  Combined ASA + clopidogrel for 9 months after NSTE-ACS –  Beta blockers unless contraindicated –  Lipid-lower agents and diet if LDL > 100-130 mg/dL –  ACEI for patients with CHF, LV dysfunction (EF <40%),

hypertension, or diabetes

Available at: www.acc.org/clinical/guidelines/unstable/unstable.pdf.

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ACC/AHA Class I Recommendations for Long-Term Risk Factor Modification in Patients with NSTE-ACS •  Class I

–  Specific instruction on smoking cessation –  Specific instruction on optimal weight, diet, and daily

exercise –  Lipid-lowering therapy (statin) for LDL >100-130 mg/dL –  A fibrate or niacin if HDL <40 mg/dL occurring as an isolated

finding or in combination with other lipid abnormalities –  Hypertension control to a BP of <130/85 mm Hg –  Tight control of hyperglycemia in diabetics

Available at: www.acc.org/clinical/guidelines/unstable/unstable.pdf.

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