Acute Coronary Syndromes -Recognition, Risk Stratification, and

ManagementClaudia P. Hochberg, MD, FACC

August 12, 2013

Topics to Cover

• Identification of the patient with ACS• Initiation of anti-thrombotic therapy and

anti-ischemic therapy• Risk stratification as it relates to the

decision of early invasive vs. conservative strategy

• Secondary prevention/risk factor modification

124 Class I recommendations

23 Class III recommendations

Acute Coronary Syndrome

• An ischemic myocardial event that is a direct consequence of atherosclerotic plaque activation and/or local thrombus formation

• May be divided into that association with ST segment elevation and that associated with ST segment depression

• Spectrum: UANSTEMISTEMI

Acute Myocardial Infarction: Definition

1. Typical rise and fall of biochemical markers of myocardial necrosis (troponin or CK-MB) with at least one of the following:

a) ischemic symptoms

b) development of pathologic Q waves on EKG

c) ischemic EKG changes (ST depression or elevation)

d) coronary intervention

2. Pathologic findings of an acute MI

Unstable Angina: Guideline Definition

Three principal presentations:• Rest angina >20 minutes in last week• New onset angina in last 2 months• Increasing angina - increased frequency,

duration, or severity

Hospital Admissions for ACS: Unstable Angina/NSTEMI vs STEMI

Acute Coronary Acute Coronary SyndromeSyndrome

2.3 Million Hospital Admissions2.3 Million Hospital AdmissionsACSACS

UA/NSTEMIUA/NSTEMI

1.43 million Admissions per Year

829,000Admissions per Year

STEMI STEMI

Sodnick EJ, et al. National Center for Health Statistics. 2001.

Mr JS65 yo male with h/o HTN, hyperlipidemiaHad 1st episode of chest pain (a “pressure” with

radiation to his left shoulder) 2 weeks prior to admit, while shoveling snow. Over the 3 days prior to admit he had 4 episodes of chest pain, initially with mild exertion, and finally at rest. The pain resolved spontaneously in 3-4 minutes.

Meds: atenolol, amlodipine, HCTZ, atorvastatin, aspirin

BP: 136/95 HR: 92No vascular bruits, no murmur, +S4, no congestion

How can we tell if this man is having an ACS?

BaselineAcute presentation

Labs normal except troponin 0.15, CK: 370

Swap, C. J. et al. JAMA 2005;294:2623-2629.

Chest Pain History and Diagnosis of Acute Myocardial Infarction (AMI)

Likelihood that Signs and Symptoms Represent ACS

Secondary to CADHIGH

• Left arm or chest pain typical of prior angina

• Hx of CAD or MI• CHF• Transient MR murmur• Hypotension• New ECG changes (ST

deviation > 1mm; Twave inversion in many leads)

• Elevated biomarkers (troponin/CK-MB)

Intermediate• Left arm or chest pain

• Age > 70 years• Male• Diabetes• PVD,CVA• Q waves on ECG• ST deviation 0.5-1.0

mm, Twave inversion > 1 mm

• Normal biomarkers

Circulation. 2007;116:e148–e304.

Likelihood that Signs and Symptoms Represent ACS

Secondary to CADLow

• Probable ischemic symptom in absence of intermediate risk markers

• Recent cocaine use• Pain reproduced by palpation• T wave inversion < 1 mm• Normal ECG• Normal biomarkers

Circulation. 2007;116:e148–e304.

Initial Anti-Ischemic Therapies(Class I)

• Bed Rest (~ 24 hours)• Oxygen• Nitrates• Morphine Sulfate• Beta-blocker (within the 1st 24 hours in patients

without contraindications)• Non-dihydropyridine CCB (verapamil/dilt) in

patients with contraindications to BB• ACE inhibitor for HTN, low LVEF or CHF or DM• Discontinue NSAIDs Circulation. 2007;116:e148–

e304.

What Anti-Thrombotic Therapy Should be Used in the Initial Hours

of Management of ACS?

The Vulnerable PlaqueImages from Falk E, et al. Circulation. 1998;92:657-671.

Plaque rupture

Platelet adhesion

Platelet activation

Platelet aggregation

Thrombotic occlusion

Characteristics of Unstable and Stable Plaque

Thin fibrous cap

Inflammatory cells

FewSMCs

Erodedendothelium

Activatedmacrophages

Thickfibrous cap

Lack ofinflammatory cells

Foam cells

Intactendothelium

MoreSMCs

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

Plaque Rupture, Thrombosis, and Plaque Rupture, Thrombosis, and MicroembolizationMicroembolization

Quiescent plaqueQuiescent plaque

Platelet-thrombin micro-emboliPlatelet-thrombin micro-emboliPlaquePlaque rupturerupture

ProcessPlaque formation

InflammationMultiple factors? Infection

Plaque Rupture? MacrophagesMetalloproteinases

ThrombosisPlatelet ActivationThrombin

ProcessPlaque formation

InflammationMultiple factors? Infection

Plaque Rupture? MacrophagesMetalloproteinases

ThrombosisPlatelet ActivationThrombin

MarkerCholesterolLDL

C-Reactive ProteinAdhesion MoleculesInterleukin 6, TNFαsCD-40 ligand

MDA Modified LDL

D-dimer, Complement,Fibrinogen, Troponin, CRP, CD40L

MarkerCholesterolLDL

C-Reactive ProteinAdhesion MoleculesInterleukin 6, TNFαsCD-40 ligand

MDA Modified LDL

D-dimer, Complement,Fibrinogen, Troponin, CRP, CD40L

Vulnerable plaqueVulnerable plaque

MacrophagesFoam Cells

Collagen → platelet activation

TF TF → Clotting Clotting CascadeCascade

Lipid coreLipid core

Metalloproteinases

InflammationInflammation

Courtesy of David Kandzari.

Thrombus Formation and ACS

UA NQMI QWMI

Plaque Disruption/Fissure/Erosion

Thrombus Formation

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

ST-Segment Elevation

Acute Coronary Syndrome

(ACS)

Old Terminology:

NewTerminology:

Pathogenesis of Acute Coronary

Syndromes:The integral role

of platelets

PlaqueFissure or Rupture

PlateletAggregation

PlateletActivation

PlateletAdhesion

ThromboticOcclusion

20

Antiplatelet Therapy in ACS• Act by inhibiting different platelet functions

(aggregation, release of granule contents, platelet-mediated vascular constriction)

■ Aspirin: blocks cyclooxygenase which mediates the first step in the biosynthesis of prostaglandins and thromboxanes from arachidonic acid    

■ P2Y12 receptor blockers:clopidogrel, ticlopidine, prasugrel, ticagrelor all block the binding of ADP to P2Y12R-->inhibits activation of the GP IIb/IIIa complex and platelet aggregation

■ GP IIb/IIIa inhibitors:inhibit the final common pathway of platelet aggregation (cross-bridging of platelets by fibrinogen)

20

Fibrin

TX

A2

Thro

mbi

n

AD

P

Epi

vWFCollagen

GpIb

AA PGH2 TXA2

ADPFibrinogen

GPIIb/IIIa

GPIIb/IIIa

Aspirin

TXA2 receptor antagonist

TSI

thienopyridineGpIIB/IIIA inhibitors

? Anti-vWF ? Anti-GpIb

Region of vascular injury

UF heparin LMWH Thrombin inhibitors

Awtry EH, Loscalzo J 2003

22

Aspirin• The Antithrombotic Trialists' Collaboration

• Aspirin (75-1500 mg daily) in 200,000 patients

• Antiplatelet therapy produced a significant 46% reduction in the combined end point of subsequent nonfatal myocardial infarction (MI), nonfatal stroke, or vascular death (8.0 vs 13.3%) in patients with unstable angina

• 30 percent reduction in patients with acute myocardial infarction (10.4 vs 14.2 %)

• No significant difference in efficacy between lower and higher daily doses (75 to 325 versus 500 to 1500 mg)

• The addition of a second antiplatelet agent (eg, dipyridamole, ticlopidine, or intravenous glycoprotein IIb/IIIa inhibitor) significantly lowered the combined end point

22

Text

• Antithrombotic Trialists' Collaboration. BMJ 2002; 324:71.

placebo aspirin0

2

4

6

8

10

12

% D

evel

opin

g M

ITreatment of Unstable Angina

Results of a study from the Montreal Heart Institute

Theroux P, et al. N Engl J Med. 1988;319:1105-1111.

In multiple studies aspirin significantly reduces risk of:

- subsequent MI

- cardiac death

- overall mortality

(>50% reduction)

Aspirin

Class I

1. 160-325mg should be given on day one and continued indefinitely (may be decreased to 81mg daily after the acute event if no PCI, or after PCI).

Class IIb

1. Other antiplatelet agents such as clopidogrel (300-600 mg po loading dose, then 75 mg QD) or prasugrel may be substituted if true aspirin allergy is present.

Circulation. 2007;116:e148–e304.

25

P2Y12 Receptor Blockers• CURE trial: randomly assigned 12,562 patients who presented

within 24 hours after the onset of a NSTEMI to aspirin alone (75 to 325 mg/day) or with clopidogrel (300 mg loading dose followed by 75 mg/day) for 9 to 12 months

• High risk patients :

– electrocardiogram (ECG) changes

– elevated cardiac enzymes

– 60 % did not receive revascularization

– Primary endpoint: cardiovascular death, myocardial infarction, or stroke

– At an average follow-up of nine months, combination therapy led to a significant reduction in the combined primary endpoint (9.3 vs 11.4%), largely due to fewer MIs (5.2 vs 6.7%)

– Clopidogrel increased the rate of major bleeding (3.7 vs 2.7 %) but not in life-threatening bleeding or hemorrhagic stroke

25Yusuf S, et al. N Engl J Med. 2001;345:494-502.

Yusuf S, et al. N Engl J Med. 2001;345:494-502.

2

4

6

8

10

12

14

% W

ith E

ven

t

Clopidogrel + Aspirin

3 6 9

Placebo + Aspirin

Follow-up (months)

P=.00009

0 12

20%RRR

CURE: Primary Composite End Point(CV Death/MI/Stroke)

CURE Bleeding Complications

Data 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.

ACC/AHA Recommendations - Antiplatelet Therapy for NSTE-ACS

• Class I– Clopidogrel if ASA-allergic or intolerant– Clopidogrel in addition to ASA if early invasive

approach not planned (for 1–12 months)– Clopidogrel in addition to ASA, if invasive

approach is planned– Clopidogrel should be withheld for 5-7 days if

CABG planned

Circulation. 2007;116:e148–e304.

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

Oler A, et al. JAMA. 1996;276:811-815.

Anticoagulants Unfractionated Heparin (UFH)

Most widely usedMost widely used antithrombotic antithrombotic agent agent

Disadvantages include:Disadvantages include:PoorPoor bioavailability bioavailability

No inhibition of clot-bound thrombinNo inhibition of clot-bound thrombin

Dependent onDependent on antithrombin antithrombin III (ATIII) cofactor III (ATIII) cofactor

Variable effectsVariable effects

Frequent monitoring (Frequent monitoring (aPTTaPTT) to ensure therapeutic levels) to ensure therapeutic levels

ReboundRebound ischemia ischemia after discontinuation after discontinuation

Risk of heparin-inducedRisk of heparin-induced thrombocytopenia thrombocytopenia (HIT) (HIT)

Anticoagulants Low-Molecular-Weight Heparin (LMWH)

Fraction of standard (UFH) heparinFraction of standard (UFH) heparinAdvantages over UFH:Advantages over UFH:

GreaterGreater bioavailability bioavailabilityNo need to closely monitorNo need to closely monitorResistant to inhibition by activated plateletsResistant to inhibition by activated plateletsLower incidence of HITLower incidence of HITEnhanced anti-factorEnhanced anti-factor Xa Xa activity activity

Effective subcutaneous administrationEffective subcutaneous administrationEnoxaparinEnoxaparin,, dalteparin dalteparin,, reviparin reviparin,, nadroparin nadroparin,,fraxiparinfraxiparin, others, othersDiffer in anti-Differ in anti-XaXa/anti-/anti-IIaIIa ratios ratios

UFH vs LMWH

ESSENCE

30%

25%

20%

15%

10%

09 13

Days After Randomization

17 215

5%

25 29

Unfractionated Heparin

Enoxaparin (Lovenox)

Dea

th,

MI

or

Rec

urre

nt A

ngin

a

P = 0.02Risk Reduction 16.2%

Cohen M, et al. N Engl J Med. 1997;337:447-452.

Death

, M

I or

Urg

en

t R

evasc

ula

riza

tion

Unfractionated Heparin

Enoxaparin (Lovenox)

Days

20

16

12

8

4

2 4 6 8 10 12 140

16.7%

14.2 %

p = 0.03

Relative Risk Reduction = 15%

Antman EM, et al. Circulation. 1999;100:1593-1601.

TIMI 11B

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 during PCI

Low Molecular Weight Heparin in ACS

Effects on Triple EndpointsDay

FRIC (dalteparin; n=1482) 6

FRAXIS (nadroparin; n=2357) 14

ESSENCE (enoxaparin; n=3171) (p=0.032) 14

TIMI 11 B (enoxaparin; n=3910) (p=0.029) 14

_________________________________________________________________

0.75 1 1.5

LMWH better UFH better

Triple endpoints: Death, MI, recurrent ischemia

TIMI Risk Score For UA/NSTEMI

4.78.3

13.2

19.926.2

40.9

3.58.6

14.920

28.8

14.1

0

10

20

30

40

50

0/1 2 3 4 5 6/7

D/M

I/D

/MI/ U

rg R

evasc

U

rg R

evasc

(%)

(%)

Number of Risk FactorsNumber of Risk Factors

UFHUFH

ENOXENOX

Antman Antman et al et al JAMA 284 JAMA 284 : 835, 2000: 835, 2000

•• Age Age >> 65 y 65 y•• >> 3 CAD Risk Factors 3 CAD Risk Factors•• Prior Prior Stenosis Stenosis > 50 %> 50 %•• ST deviationST deviation•• >> 2 2 Anginal Anginal events events << 24 h 24 h•• ASA in last 7 daysASA in last 7 days•• Elev Elev Cardiac MarkersCardiac Markers

ACC/AHA Recommendations for Antithrombin Therapy in Patients

with NSTE-ACS• Class I:

Anticoagulation should be added to antiplatelet therapy as soon as possible after recognition of ACS– If early invasive strategy: may use UFH (60-70 U/kg to

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), enoxaparin (1 mg/kg subcutaneously q12 hr)

– If conservative strategy: may use UFH, enoxaparin, or fondaparinux

• Class IIa– Enoxaparin or fondaparinux is preferable to UFH as

an anticoagulant unless CABG is planned within 24 hours

Circulation. 2007;116:e148–e304.

ACC/AHA Recommendations for Antithrombin Therapy in Patients

with NSTE-ACS• Class I:

Anticoagulation should be added to antiplatelet therapy as soon as possible after recognition of ACS– If early invasive strategy: may use UFH (60-70 U/kg to

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), enoxaparin (1 mg/kg subcutaneously q12 hr), or direct thrombin inhibitors (bivalirudin or fondiparinux)

– If conservative strategy: may use UFH, enoxaparin, or fondaparinux

• Class IIa– Enoxaparin or fondaparinux is preferable to UFH as

an anticoagulant unless CABG is planned within 24 hours

** Unfractionated heparin preferred in patients with creatinine > 2.0 (Cr clearance <30) or weight >120 kg

Circulation. 2007;116:e148–e304.

PURSUIT

PRISM

PRISM PLUS

PARAGON B

PARAGON A

Theroux

0.25 0.50 1.0 2.0 4.0

Odds Ratio for 30-day Death or MI Relative to Control

COMBINED 1998 (n = 23,967)

0.88 (0.79-0.97)

IIb/IIIa Inhibitors in ACS

ACC/AHA Recommendations - Antiplatelet Therapy for NSTE-ACS

• Class I– Clopidogrel OR GP IIb/IIIa inhibitor, in addition to ASA, if

invasive approach is 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

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

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

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

PURSUIT

PRISM

PRISM PLUS

PARAGON B

PARAGON A

Theroux

0.25 0.50 1.0 2.0 4.0

Odds Ratio for 30-day Death or MI Relative to Control

COMBINED 2009 (n = 42,666)

0.89 (0.84-0.95)

COMBINED 1998 (n = 23,967)

0.88 (0.79-0.97)

EARLY ACS

ACUITY Timing

EARLY ACS + ACUITY0.92 (0.82-1.01)

IIb/IIIa Inhibitors in ACS

• Among high-risk NSTE ACS patients, a strategy of routine, early eptifibatide compared with delayed, provisional eptifibatide at PCI did not significantly reduce the primary composite of death, MI; resulted in a trend toward reduction in death or MI at 30 days, but no difference in 30-day mortality; resulted in higher rates of non-life-threatening bleeding and transfusions

• The results of EARLY ACS do not support a strategy of routine early eptifibatide use in high-risk NSTE ACS patients managed with an invasive strategy

Early ACS - Conclusions

NEJM on line March 30, 2009

How Best to Risk Stratify Patients with ACS?

45

Risk Stratification• Based on validated risk prediction models

that include the most important predictors of outcomes

• Certain patients that are such high risk that they need not be risk stratified:– cardiogenic shock– overt CHF or LV dysfunction– Rest angina despite max medical therapy– Hemodynamic instability, mechanical

complications– Unstable ventricular arrythmias 43

TIMI Risk Score for UA/NSTEMI

• Age >65 years• 3 or more CAD risk factors

– HTN, DM, Hyperlipidemia, smoking, + family hx

• Prior CAD (cath stenosis>50%)• ASA in last 7 days• 2 or more anginal events in last 24 hours• ST deviation on admission ECG• Elevated cardiac markers (troponin/CK-MB)

Antman EM, et al. JAMA.. 2000;284:835-842.

The TIMI Risk Score and Incidence of Adverse Ischemic Events in

Patients with NSTE-ACS

Antman EM, et al. JAMA.. 2000;284:835-842. Download at: http://www.timi.org/

4.78.3

13.219.9

26.2

40.9

0

10

20

30

40

50

0/1 2 3 4 5 6/7# of Risk Factors1

4 d

ay D

eath

, M

I, o

r U

rgent

Revasc

ula

riza

tion

(%

)

TIMI Risk Score for UA/NSTEMI• Higher TIMI risk scores correlated with more severe angiographic disease

• PRISM-PLUS:

– Increasing TIMI risk scores from 0-2 (low risk) to 5-7 (high risk) were associated with increases in the frequency of high-risk angiographic findings:

• >70 % culprit stenosis (from 58 to 81%)

• multivessel disease (43 to 80%)

• visible thrombus (30 to 41%)

• left main disease

The TIMI risk score can also identify patients most likely to benefit from particular therapies:

■ In TACTICS-TIMI 18, only patients with score ≥3 benefited from early invasive strategy

■ The degree of troponin elevation and magnitude of ST segment deviation were independent predictors of an adverse outcome and of benefit from an early invasive strategy

■ In TIMI 11B and ESSENCE, enoxaparin was associated with better 14-day and six-week post-discharge outcomes compared to UFH; these benefits were primarily seen in high-risk patients with risk scores ≥4 and ≥5, respectively

49

GRACE Risk Calculator

• Estimates the risk of in-hospital and six-month mortality among all patients with an ACS

• This end point is different from the composite end point in the TIMI risk score of all-cause mortality, new or recurrent MI, or severe recurrent ischemia requiring revascularization

• While the GRACE prediction model is well validated and its use is recommended by multiple guideline organizations, its complexity makes it somewhat difficult to use in some clinical settings

47

GRACE Risk Calculator – 6 month mortality after ACS

Eagle et al. JAMA 2004;291:2727–33.

GRACE Risk Calculator – 6 month mortality after ACS

55

15

14

1411 3

112

4%

32%

Eagle et al. JAMA 2004;291:2727–33.Download at: http://www.outcomes-umassmed.org/grace

Prognostic Value of Troponin T or I in ACS: A Meta-Analysis

1.9

6.76.4

20.8

0

5

10

15

20

25

Death Death/MI

%

RR 3.9(2.9-5.3)

RR 3.8(2.6-5.5)

Neg

Pos (Trop I + T)

Heidenreich PA, et al. JACC. 2001;38:478-485.

Troponin I Levels and Mortality in Patients with NSTE-ACS

0

2

4

6

8

0- <0.4

0.4-<1.0

1.0-<2.0

2.0-<5.0

5.0-<9.0

>9.0

% M

orta

lity

at 4

2 D

ays

Adapted with permission from Antman EA, Tanasijevic MJ, Thompson B, et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med. 1996;335:1342-1349. Copyright © 1996, Massachusetts Medical Society. All rights reserved.

Troponin I Level

B-type Natriuretic Peptide (BNP) and Mortality in ACS Patients

Lemos JA,, et al. N Engl J Med. 2001;345:1014-1021.

0

2

4

6

8

10

Mort

alit

y (

%)

0 50 100 150 200 250 300

Days After Randomization

P<.001

Quartile 4(n=630)

Quartile 3(n=632)

Quartile 2(n=632)

Quartile 1(n=631)

>138 pg/ml

Lindahl B, et al.. N Engl J Med. 2000;343:1139-1147.

Predictive Value of hs-CRP for Mortality from ACS in FRISC

SubstudyC

um

ula

tive P

rob

ab

ility

of

Death

(%

)

Months

CRP 2-10mg/l (n=294)

20

10

00 6 12 18 24 30 36 42 48

CRP >10mg/l (n=309)

CRP <2mg/l (n=314)

Invasive

vs

Conservative

Therapeutic Approaches

Invasive vs Conservative Strategy for UA/NSTEMI

UA indicates unstable angina, NSTEMI, non–ST-segment myocardial infarction; ISAR, Intracoronary Stenting and Antithrombic Regimen Trial; RITA, Randomized Intervention Treatment of Angina; VANQWISH, Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital study; MATE, Medicine vs Angioplasty for Thrombolytic Exclusions trial; TACTICS-TIMI18, Treat Angina with Aggrastat® and Determine Cost of Therapy with Invasive or Conservative Strategy; and FRISC, Fragmin during InStability in Coronary artery disease.

TIMI IIIB

2003

Conservative Invasive

VANQWISH

MATE

FRISC II

TACTICS-TIMI 18

VINO

RITA-3

TRUCS

ISAR-COOL

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

Months

4%

20%

16%

12%

8%

TACTICS TIMI 18

1 2 3 4 5 6

15.9%

19.4%Initial Medical Rx

Early Cath + PTCA

Cannon CP, et al. N Engl J Med. 2001;344:1879-1887.

Patients (%)

Cumulative Incidence of the Primary Endpoint of Death, Nonfatal MI, rehospitalization for an ACS within 6 months

TACTICS Trial Results Based on Troponin

Initial Medical Rx Early Cath + PTCA

Negative Troponin

Positive Troponin

5%

10%

15%

20%

25%

P=NS

P<0.001

Cannon CP, et al. N Engl J Med. 2001;344:1879-1887.

Morrow DA, et al. JAMA. 2001;286:2405-2412 and Cannon CP, et al. N Engl J Med. 2001;344:1879-1887.

Benefit of Invasive Strategy by Troponin and ST Changes

Death, MI, or Rehospitalization for ACS at 6 Months

12.4

25.0*

16.0 15.3*

0

5

10

15

20

25

30

TnT – TnT +

CV

Events

(%

)

P=NS

15.1

24.5*

16.6 16.4*

0

5

10

15

20

25

30

No ST change ST change

P=NS

P<.001 P<.001Conservative Invasive

The Primary Composite Ischemic End Point in RITA-3

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. Lancet. 2002;360:743-751.

Meta-Analysis of Trials of Early Cardiac Cath and Revascularization Versus Initial Medical Therapy

Alone in Patients with NSTE-ACS

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. Lancet. 2002;360:743-751.

Cannon C et al. N Engl J Med 2001;344:1879-1887

TACTICS-TIMI18: Rates of Death, Nonfatal MI, or Rehospitalization for an ACS at Six Months,

According to Base-Line Characteristics

Early Invasive Therapy:Class I Recommendations

• Recurrent angina despite rx*

• Elevated cardiac markers*

• New ST-segment depression*

• Positive stress test*

• Symptoms of ischemic CHF, rales, MR

• EF < 40%

• Sustained VT

• Hypotension/hemodynamic instability

• PCI within 6 mos, prior CABG

• High risk score (TIMI, GRACE)

Circulation. 2007;116:e148–e304.

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

early invasive strategy is appropriate

Patient Up Date

• Treated with aspirin, clopidogrel, heparin • Beta-blocker titrated to resting HR ~ 60-70

bpm• High dose statin given• Cardiac catheterization performed.

Cath PCI

What About After Discharge?

Secondary Prevention - Risk Factor Modification

• Smoking Cessation• Achieve optimal weight• Increase physical activity level, cardiac rehab• AHA diet• HTN control to BP <130/85 mm Hg• Statin with goal LDL< 70• Tight glycemic control in diabetics

** Consider referral to cardiac rehab programCirculation. 2007;116:e148–e304.

Long-Term Medical Therapy:Class I Indications

• Aspirin 81 mg/day • Clopidogrel 75 mg QD when ASA intolerant • Combination ASA and

clopidogrel/ticagrelor/prasugrel for 12 months after UA/NSTEMI/STEMI, 1 month BMS and 12 months DES

• Beta-blocker• Lipid-lowering and diet (if LDL>100)• ACE Inhibitor if CHF, LV EF < 40%, HTN, DM• NTG prn with clear instructions on use

Circulation. 2007;116:e148–e304.

Guideline Compliance and Outcomes

Tricoci P Et al. Am J Cardiol 2006;98:S30-S35.

Summary

• Thrombosis is central in the pathophysiology of ACS and mandates antithrombotic and antiplatelet therapy

• All patients with ACS should be treated with aspirin and heparin.

• Consider treatment with Clopidogrel in patients who will be treated conservatively or those likely to undergo PCI

• Use of the TIMI risk score helps identify those patients that benefit from invasive therapies

• Improved adherence to guidelines results in improved outcomes

Recommended Strategy in ACS:Boston Medical Center Guidelines

UA/ NSTEMI

AspirinNitrates

Beta-blockersUFH/LMWH? Clopidogrel

High RiskElevated TroponinRecurrent Ischemia

Dynamic EKG changesTIMI score > 3

Low RiskNormal Troponin on

admission and at 12 hTIMI score <2

Coronary AngiographyPCI/CABG

Stress TestPre-dc