non-st-segment elevation acute coronary syndrome (nste-acs

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

From the Committee on Post-Graduate Education, Council on Clinical

Cardiology, American Heart Association

Date Posted: July, 2004.

Non-ST-Segment Elevation Acute Coronary Syndrome

(NSTE-ACS)

Pathophysiology, Epidemiology, Risk Stratification, Evaluation, and

Management

Slides compiled and annotated by Glenn N. Levine, MD, with thanks to many, particularly Christopher P. Cannon, MD.

The content of these slides is current as of July 2004Future revisions will be posted on the

American Heart Association website (www.americanheart.org)

Non-ST-Segment Elevation Acute Coronary Syndrome

• Pathology, Pathophysiology, and Epidemiology• Risk and Risk Stratification• Initial Therapies and Management• Platelets and Anti-Platelet Therapies• Anti-Thrombin Studies and Recommendations• Early Invasive Strategy• Peri- and Post-Discharge Medications and

Management

Pathology, Pathophysiology, and Epidemiology

The Vulnerable Plaque

Reproduced with permission from Falk E, et al. Circulation. 1998;92:657-671.

Large Lipid Core

Thin, Vulnerable, Fibrous Cap

Ruptured Plaque with Occlusive Thrombus Formation

Reproduced with permission from Falk E, et al. Circulation. 1998;92:657-671.

ThrombusFormation

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.

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

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.

ACS PathophysiologyPlaque Rupture, Thrombosis, and MicroembolizationPlaque Rupture, Thrombosis, and Microembolization

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, TNFsCD-40 ligand

MDA Modified LDL

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

MarkerCholesterolLDL

C-Reactive ProteinAdhesion MoleculesInterleukin 6, TNFsCD-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.

Systemic and Focal Plaque Rupture by IVUS in ACS Patients Undergoing PCI

Systemic and Focal Plaque Rupture by IVUS in ACS Patients Undergoing PCI

Adapted from Rioufol G, et al. Circulation. 2002;106:804-808.Slide courtesy of David Kandzari.

Plaque rupture at

site of culprit lesion

Plaque rupture

elsewhere than site of

culprit lesion

Plaque rupture in different

artery than culprit lesion

%

%

%

Analysis of 72 Arteries (n=24 TnI-positive ACS Patients)%

Pla

qu

e ru

ptu

re

37.5

79.070.8

0

25

50

75

100

Frequency of multiple active plaque ruptures beyond the culprit lesion.

Pat

ien

ts (

%)

80% of Patients With 2 Plaques

0

5

10

15

20

25

30

0 1 2 3 4 5

N=24

Frequency of Multiple “Active” Plaques in Patients With ACS

ACS indicates acute coronary syndrome.Adapted from Rioufol G, et al. Circulation. 2002;106:804-808. Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org.

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:

NewTerminology:

Atherothrombosis* is theLeading Cause of Death Worldwide1

*Atherothrombosis defined as ischemic heart disease and cerebrovascular disease.1The World Health Report 2001. Geneva: WHO; 2001. Reprod.with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org.

22.3

19.3

12.6

9.7

9

6.3

0 5 10 15 20 25 30

Atherothrombosis*

Infectious Disease

Cancer

Injuries

Pulmonary Disease

AIDS

Causes of Mortality (%)

3.2 Million Hospital Admissions

Coronary Atherosclerosis

Acute Myocardial Infarction

1,153,000 Admissions

829,000 Admissions

Hospitalizations in the USDue to Atherosclerotic Disease

Cerebrovascular Disease

961,000 Admissions

Vascular Disease

Other IschemicHeart Disease

280,000 Admissions

From Popovic JR, Hall MJ. Advance Data. 2001;319:1-20. Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org.

* 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.

Risk and Risk Stratification

GUSTO IIb: Correlation of 6-Month Mortality With Baseline ECG

Findings in Patients With ACS

Cu

mu

lati

ve M

ort

alit

y (%

)

0

2

4

6

8

10

0 30 60 90 120 150 180

Days From Randomization

T-wave inversion

ST ACS

STEMI with fibrinolytics

GUSTO indicates Global Use of Strategies To Open Occluded Arteries in Acute Coronary Syndromes; ECG, electrocardiogram; ACS, acute coronary syndrome; and STEMI, ST-segment elevation myocardial infarction.Figure adapted with permission from Savonitto S, Ardissino D, Granger CB, et al. Prognostic value of the admission electrocardiogram in acute coronary syndromes. JAMA. 1999;281:707-713. Copyright © 1999, American Medical Association. All rights reserved.


Braunwald Classification of Risk for Patients with Unstable Angina

Feature High Risk

At least 1 of the following features must be present:

Intermediate Risk

No high-risk feature but must have 1 of the following:

Low Risk

No high- or intermediate-risk feature but may have any of the following features:

History Accelerating tempo of ischemic symptoms in preceding 48 hrs

Prior MI, peripheral or cerebrovascular disease, CABG, or prior aspirin use

Character of Pain Prolonged ongoing (>20 min) rest pain

Prolonged (>20 min) rest angina, now resolved, with moderate or high likelihood of CAD

New-onset or progressive CCS Class III or IV angina the past 2 weeks

Clinical Findings •Pulmonary edema•New or worsening MR murmur

•S3 or new/worsening rale

•Hypotension, bradycardia, tachycardia•Age >75 years

Age > 70 years

ECG •Angina at rest with transient ST-segment changes >0.05 mV•New or presumed new BBB•Sustained ventricular tachycardia

•T-wave inversions >0.2 mV•Pathological Q waves

Normal or unchanged ECG during an episode of chest discomfort

Cardiac Markers Elevated (TnT or TnI >0.1 mg/mL)

Slightly elevated (TnT >0.01 but <0.1 ng/mL)

Normal

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

TIMI Risk Score

• Age >65 years• >3 CAD Risk Factors• Prior Coronary Stenosis >50 % • ST deviation• >2 Anginal events <24 hours• ASA in last 7 days• Elevated Cardiac Markers (CK-

MB or troponin)Reproduced with permission from Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA. 2000;284:835-842. Copyright © 2000, American Medical Association. All rights reserved.

The TIMI Risk Score and Incidence of Adverse Ischemic Events in Patients with

NSTE-ACS

Reproduced with permission from Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA.. 2000;284:835-842. Copyright © 2000, American Medical Association. All rights reserved.

4.78.3

13.2

19.926.2

40.9

0

10

20

30

40

50

0/1 2 3 4 5 6/7Number of Risk Factors

Dea

th,

MI,

or

Urg

ent

Rev

ascu

lari

zati

on

(%

)

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

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)

Figure reproduced with permission from Heidenreich PA, Alloggiamento T, Melsop K, et al. The prognostic value of troponin in patients with non-ST elevation acute coronary syndrome: a meta-analysis. J Am Coll Cardiol. 2001;38:478-485. Slide modified with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org.

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

Figure reproduced with permission from de Lemos JA, Morrow DA, Bentley JH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndrome. N Engl J Med. 2001;345:1014-1021.Copyright © 2001, Massachusetts Medical Society. All rights reserved.

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

0

2

4

6

8

10

Mo

rtal

ity

(%)

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)

Figure reproduced with permission from Lindahl B, Toss H, Siegbahn A, et al. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. N Engl J Med. 2000;343:1139-1147. Copyright © 2000, Massachusetts Medical Society. All rights reserved.

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

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

Cu

mu

lativ

e P

rob

ab

ility

of D

ea

th (

%)

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)

Initial Therapies and Management

ACC/AHA Class I Recommendations for Initial Management and

Anti-Ischemic Therapy

• Bed rest• Continuous ECG Monitoring• Supplemental O2 to maintain SaO2 >90%• NTG (IV or PO as dictated clinically)• Beta-blockers (PO and/or IV)• IV Morphine prn pain, anxiety, and/or CHF• IABP for hemodynamic instability• ACEI for persistent hypertension in patients with LV

systolic dysfunction or CHF


Platelets and Anti-Platelet Therapies

Pathogenesis of Acute Coronary

Syndromes:The integral role of

platelets

PlaqueFissure or Rupture

PlateletAggregation

PlateletActivation

PlateletAdhesion

ThromboticOcclusion

Adhesion

The Role of Platelets in Atherothrombosis

Aggregation3

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

1

Activation2

ADP

•Ticlopidine•Clopidogrel

•Heparin•LMW Heparin

•Direct Thrombin Inhibitors

•Aspirin

Epinephrine Collagen ArachidonicAcid

Thrombin

IIb/IIIareceptors

fibrin

The Platelet

•GP IIb/IIIa inhibitors

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.

placebo aspirin heparin ASA+hep0

2

4

6

8

10

12%

Dev

elop

ing

MI

Treatment

Treatment of Unstable AnginaResults 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.

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

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.

Subgroup Placebo Plavix RR

ST Changes 14.3% 11.5% 0.79

No ST Changes 8.7% 7.0% 0.80

Enzyme Elevation 13.1% 10.7% 0.81

No Enzyme Elevation 10.9% 8.8% 0.79

Post-Randomization Revascularization

13.9% 11.4% 0.81

No Post-Random

Revascularization

10.1% 8.1% 0.79

CURE: Primary End Point in Subgroups


Endpoint Placebo Plavix RR P Value

CV Death/ MI/CVA 11.7% 9.28% 0.80 0.00005

CV Death/MI

CVA/Ref Ischemia

19.02% 16.68% 0.88 0.0004

CV Death 5.4% 5.06% 0.92 NA

MI 6.68% 5.19% 0.77 <0.01

Stroke 1.4% 1.2% 0.85 NA

Refract Ischemia 9.4% 8.8% 0.93 NA

Major Bleeding 2.7% 3.6% 1.34 0.03

CURE Secondary End Points


0

5

10

15

2 Days 7 Days 30 Days

RR=43%P=0.006

8.3

4.9

RR=30%P=0.03

11.9

8.7

% P

atie

nts

% P

atie

ntsPlacebo + heparin

Aggrastat + heparin

RR=66%P=0.01

2.6

0.9

PRISM-PLUS: MI/Death Event Rates

Data from PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497.

PURSUIT Primary End Point

Reproduced with permission from the PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. Platelet glycoprotein IIb/IIIa in unstable angina: Receptor Suppression Using Integrilin Therapy. N Engl J Med. 1998;339:436-443. Copyright © 1998, Massachusetts Medical Society. All rights reserved.

PURSUIT Primary Composite End Point%

Wit h

Dea

th o

r M

I

0

2

4

6

8

10

12

14

16

Integrilin

9.1%7.6%

11.6%

10.1%

15.7%14.2%

(n=79) (n=66) (n=118) (n=103)

Not powered for statistical analysis

96 Hrs 7 Days 30 Days

Placebo


P=0.01

P=0.02

P=0.04

Subgroup Analyses from the PURSUIT Study


Meta-Analysis of IV GP IIb/IIIa Inhibitors in NSTE-ACS: Death or MI at 30 Days

PRISMPRISM 7.1%7.1% 5.8%*5.8%* 0.800.80 0.60-1.060.60-1.06

PRISM-PLUSPRISM-PLUS 12.0%12.0% 8.7%8.7% 0.700.70 0.50-0.980.50-0.9813.6%*13.6%* 1.171.17 0.80-1.700.80-1.70

PARAGON-APARAGON-A 11.7%11.7% 10.3%10.3% 0.870.87 0.58-1.290.58-1.2912.3%12.3% 1.061.06 0.72-1.550.72-1.55

PURSUITPURSUIT 15.7%15.7% 13.4%13.4% 0.830.83 0.70-0.990.70-0.9914.2%14.2% 0.890.89 0.79-1.000.79-1.00

PARAGON-BPARAGON-B 11.4%11.4% 10.6%10.6% 0.920.92 0.77-1.090.77-1.09

GUSTO-IVGUSTO-IV 8.0%8.0% (24h)(24h) 8.2%8.2% 1.021.02 0.83-1.240.83-1.24(48h)(48h) 9.1%9.1% 1.151.15 0.94-1.390.94-1.39

OverallOverall 11.8%11.8% 10.8%10.8%tt 0.910.91 0.85-0.980.85-0.98

Odds RatioPlacebo IV Gp IIb/IIIa 95% CI

Placebo BetterGp IIb/IIIa Better0 1.0 2.0

Study

P=.015* Without heparin. † With/without heparin. (l), Low dose; (h), High-dose. Adapted with permission from Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndrome: a meta-analysis of all major randomised clinical trials. Lancet. 2002;359:189-198.


GP IIb/IIIa Inhibitor NSTE-ACS Studies Analysis

Risk-Adjusted Mortality at 30 Days

Data from (1) Peterson ED, Pollack CV Jr, Roe MT, et al. Early use of glycoprotein IIb/IIIa inhibitors in non-ST-elevation acute myocardial infarction: observations from the National Registry of Myocardial Infarction 4. J Am Coll Cardiol. 2003;42:45-53 and (2) Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndrome: a meta-analysis of all major randomised clinical trials. Lancet. 2002;359:189-198. Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org.

0.5 2.01.0

NRMI1

Boersma2 0.83-1.010.91

0.79-0.970.88

95% CIOdds Ratio

Odds Ratio for Mortality at 30 Days

GP IIb/IIIa Inhibitor Favored

(aspirin + heparin)

Control Arm Favored

(aspirin + heparin)

GP IIb/IIIa Therapy and Mortality (30 day) in Diabetics with NSTE-ACS

0.5 1.0 1.5 2.00

PARAGON APARAGON BPooled

Relative Risk of Death(versus placebo Rx)

GUSTO IVPRISM-PLUS

PRISMPURSUIT

Mortality:6.2% vs. 4.6%OR=0.74 CI=0.59-0.92 P=0.007

Adapted with permission from Roffi M, et al. Circulation. 2001;104:2767-2771.

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

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


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)

Antithrombin Therapy Studies and Recommendations

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.

ESSENCE Results

30%

25%

20%

15%

10%

09 13

Days After Randomization

17 215

5%

25 29

Unfractionated HeparinEnoxaparin (Lovenox)

Dea

t h, M

I or

Rec

urre

nt A

ngi n

a

P = 0.02Risk Reduction 16.2%

Adapted with permission from Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med. 1997;337:447-452. Copyright © 1997, Massachusetts Medical Society. All rights reserved.

Dea

th,

MI

or

Urg

ent

Rev

ascu

lari

zati

on

Unfractionated HeparinEnoxaparin (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%

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

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

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

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

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


Early Invasive Strategy Studies and Recommendations in Patients with

NSTE-ACS

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.

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

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.

TnT indicates troponin T; and ST, ST segment.Data from (1) Morrow DA, et al. JAMA. 2001;286:2405-2412 and (2) Cannon CP, et al. N Engl J Med. 2001;344:1879-1887. Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org.

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

Eve

nts

(%

)

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

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.

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

in Patients with NSTE-ACS

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.

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


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.

Peri- and Post-Discharge Therapies and Risk Modification

MIRACL:Acute Statin Rx

Cum

ulat

ive

Eve

nts

5%

10%

15%

Time Since Randomization (weeks)4 8 12 16

RR=0.84P=0.048

17.4%

14.8%

PlaceboHigh-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.

PROVE-IT TIMI-22 Trial Primary Results

00 33 1818 2121 2424 2727 303066 99 1212 1515

% with Event

Months of Follow-up

Pravastatin 40mgPravastatin 40mg(26.3%)(26.3%)

Atorvastatin 80mgAtorvastatin 80mg(22.4%)(22.4%)

16% RR16% RR

(P = 0.005)(P = 0.005)

3030

2525

2020

1515

1010

55

00

Courtesy of and reproduced with permission from C.P. Cannon.

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


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


non-st-segment elevation acute coronary syndrome (nste-acs

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