Acute Coronary

Syndrome
Steven R. Bruhl MD, MS
3rd Year Cardiology Fellow
Internal Medicine Didactics
July 14, 2010
 Goals and Objectives
 Discuss the definition & pathophysiology of
ACS
 Recognize the clinical features of low,
intermediate and high risk ACS
 Be able to identify and treat patients
appropriate for a conservative or invasive
strategy
 Discuss new and controversial
pharmacological treatments
Gold Standard for Treatment of ACS

ACC/AHA 2007 Guidelines for the Management of

Patients With Unstable Angina/Non–ST-Elevation
Myocardial Infarction

http://circ.ahajournals.org/cgi/content/full/102/10/1193
Algorithm for evaluation and management of patients suspected of having ACS.
Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Figure 2.
 ACS Overview

 Overview of ACS
 Assessment of “Likelihood of ACS”
 Early Risk Stratification
 Invasive vs Conservative Strategy
 Pharmacotherapy
 Long-term Therapy/Secondary Prevention
 Scope of the Problem
 5 million ER visits nationwide for CP
 800,000 experience an MI each year
 213,000 die from their event
 ½ of those die before reaching the ER

 Pre-CCU, mortality for MI was >30%

 Fell to 15% with CCU
 With current interventions, in hospital mortality of
STEMI is 6-7%
 Overview of ACS

Acute Coronary
Syndromes*

1.57 Million Hospital Admissions - ACS

UA/NSTEMI† STEMI

1.24 million 0.33 million

Admissions per year Admissions per year

*Primary and secondary diagnoses. †About 0.57 million NSTEMI and 0.67 million UA.
Heart Disease and Stroke Statistics – 2007 Update. Circulation 2007; 115:69–171.
 Acute Coronary Syndrome (ACS)

 Definition: The spectrum of acute ischemia

related syndromes ranging from UA to MI
with or without ST elevation that are
secondary to acute plaque rupture or plaque
erosion.

[----UA---------NSTEMI----------STEMI----]
Pathophysiology of Stable Angina and ACS

Pathophysiology ACS

Decreased O2 Supply

Asymptomatic
•Flow- limiting stenosis
•Anemia
•Plaque rupture/clot

Angina
Increased O2 Demand

O2 supply/demand mismatch→Ischemia

Myocardial ischemia→necrosis
 Pathophysiology of ACS
Evolution of Coronary Thrombosis
Unstable
NSTEMI STEMI
Angina
Non-occlusive
thrombus Complete thrombus
Non occlusive sufficient to cause occlusion
thrombus tissue damage & mild
myocardial necrosis ST elevations on
Non specific ECG or new LBBB
ECG ST depression +/-
T wave inversion on Elevated cardiac
Normal cardiac ECG enzymes
enzymes
Elevated cardiac More severe
enzymes symptoms
 STEMI
 Name 3 situations in which you cannot
diagnose STEMI
 STEMI
 Name 3 situations in which you cannot
diagnose STEMI

 Left Ventricular Hypertrophy

 Chronic or Rate Dependent LBBB

 Paced Rhythm
 Cardiac Catheterization
 Name the only 3 situations that demand
emergent cardiac catheterization.
 Cardiac Catheterization
 Name the only 3 situations that demand
emergent cardiac catheterization.

 STEMI or new LBBB

 ACS with hemodynamic or electrical instability
despite optimal medical management
 Uncontrolled CP despite optimal medical
management
 Diagnosis of ACS

 At least 2 of the
following
 History ( angina or angina
equivalent)
 Acute ischemic ECG changes
 Typical rise and fall of cardiac
markers
 Absence of another identifiable
etiology
Initial Evaluation and management
of Non ST-elevation ACS
Initial Evaluation and Management

•History and Physical

•ECG
•Cardiac Biomarkers

Establish the Likelihood that

Clinical Presentation Risk Stratify for Short-term
Represents an ACS Adverse Outcomes
Secondary to CAD
 Likelihood of ACS by Hx/PE
 History/Examination Suggesting AMI
 Pain in Chest or Left Arm LR 2.7
 CP Radiation
 Right Shoulder LR 2.9 (1.4-6.0)
 Left Arm LR 2.3 (1.7-3.1)
 Both Left & Right Arm LR 7.1 (3.6-14.2)
 Diaphoresis LR 2.0 (1.9-2.2)
 3rd Heart Sound LR 3.2 (1.6-6.5)
 SBP < 80 mm Hg LR 3.1 (1.8-5.2)
 Pulmonary Crackles LR 2.1 (1.4-3.1)

Panju AA. JAMA. 1998;280:1256.

 Likelihood of ACS by Hx/PE

 Clinical Examination – Against AMI

 Pleuritic Chest Pain LR 0.2 (0.2-0.3)
 Sharp or Stabbing Pain LR 0.3 (0.2-0.5)
 Positional Chest Pain LR 0.3 (0.2-0.4)
 Reproducible Chest Pain
LR 0.2-0.4

Panju AA. JAMA. 1998;280:1256.

 Risk Stratification by ECG

 Simple, quick, noninvasive tool

 Universally available, cheap
 Correlates with risk and prognosis
 Guides treatment decisions
 Can identify alternative causes
 Risk Stratification by ECG
 ECG Findings and Associated LR for AMI
 New ST-E > 1mm LR 5.7-53.9
 New Q waves LR 5.3-24.8
 Any ST-E LR 11.2 (7.1-17.8)
 New Conduction Defect LR 6.3 ( 2.5-15.7)
 New ST-D LR 3.0-5.2

 NORMAL ECG LR 0.1-0.4

Panju AA. JAMA. 1998;280:1256.

 Risk Stratification by ECG
CAVEATS

 1-8% AMI have a normal ECG

 Only Approx 50% of AMI patients have

diagnostic changes on their initial ECG

Peter J. Zimetbaum, M.D., N Engl J Med 2003;348:933-40.

 Risk Stratification by ECG
CAVEATS cont.
 1 ECG cannot exclude AMI

 Brief sample of a dynamic process

 Small regions of ischemia or infarction may be

missed

Peter J. Zimetbaum, M.D., N Engl J Med 2003;348:933-40.

How Sensitive is the ECG Alone?
How Predictive is NTG response?
 Timing of Release of Various Biomarkers After
Acute Myocardial Infarction

Shapiro BP, Jaffe AS. Cardiac biomarkers. In: Murphy JG, Lloyd MA, editors. Mayo Clinic Cardiology: Concise Textbook. 3 rd ed. Rochester, MN:
Mayo Clinic Scientific Press and New York: Informa Healthcare USA, 2007:773–80.
Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Figure 5.
 Risk Stratification by Troponin
8 7.5 %
7
6.0 %
Mortality at 42 Days

6
5
4 3.4 % 3.7 %
3
2
1.7 %
1.0 %
1
831 174 148 134 50 67
0
0 to <0.4 0.4 to <1.0 1.0 to <2.0 2.0 to <5.0 5.0 to <9.0  9.0

Cardiac troponin I (ng/ml)

 Non ACS causes of Troponin Elevation
1. Trauma (including contusion; ablation; pacing; ICD firings,, endomyocardial biopsy, cardiac
surgery, after-interventional closure of ASDs)
2. Congestive heart failure (acute and chronic)
3. Aortic valve disease and HOCM with significant LVH
4. Hypertension
5. Hypotension, often with arrhythmias
6. Noncardiac surgery
7. Renal failure
8. Critically ill patients, especially with diabetes, respiratory failure
9. Drug toxicity (eg, adriamycin, 5 FU, herceptin, snake venoms)
10. Hypothyroidism
11. Coronary vasospasm, including apical ballooning syndrome
12. Inflammatory diseases (eg, myocarditis, Kawasaki disease, smallpox vaccination,
13. Post-PCI
14. Pulmonary embolism, severe pulmonary hypertension
15. Sepsis
16. Burns, especially if TBSA greater than 30%
17. Infiltrative diseases: amyloidosis, hemachromatosis, sarcoidosis, and scleroderma
18. Acute neurologic disease, including CVA, subarchnoid bleeds
19. Rhabdomyolysis with cardiac injury
20. Transplant vasculopathy
21. Vital exhaustion

Modified from Apple FS, et al Heart J. 2002;144:981-986.

Combined Sensitivities for ACS
Early Invasive

Conservative
 Unstable angina/NSTEMI cardiac
care
 Evaluate for conservative vs. invasive strategy
based upon:
 Likelihood of actual ACS
 Risk stratification by TIMI risk score

 ACS risk categories per AHA guidelines

Low High
Intermediate
 TIMI Risk Score
Predicts risk of death, new/recurrent MI, need for urgent revascularization within 14 days
 TIMI Risk Score

T: Troponin elevation (or CK-MB elevation)

H: History or CAD (>50% Stenosis)
R: Risk Factors: > 3 (HTN, Hyperlipidemia, Family Hx, DM II, Active Smoker)
E: EKG changes: ST elevation or depression 0.5 mm concordant leads
A2:Aspirin use within the past 7 days; Age over 65
T: Two or more episodes of CP within 2 hours
 Deciding between Early Invasive vs a Conservative Strategies

Definitive/Possible ACS
Initiate ASA, BB, Nitrates,
Anticoagulants, Telemetry

Early Invasive Strategy Conservative Strategy

• TIMI Risk Score >3 •Hemodynamic instability
•Elecrical instability
• New ST segment
•Refractory angina
•TIMI Risk Score <3 (Esp. Women)
deviation
•PCI in past 6 months •No ST segment deviation
• Positive biomarkers
•CABG •Negative Biomarkers
•EF <40%

Remains Stable
Recurrent Signs/Symptoms ↓
Coronary angiography Heart failure Assess EF and/or Stress Testing
(24-48 hours) Arrhythmias ↓
EF<40% OR Positive stress
Go to Angiography
Specifics of Early Hospital Care

Anti-Ischemic Therapy
Anti-Platelet Therapy

Anticoagulant Therapy
 Early Hospital Care
Anti-Ischemic Therapy
 Class I
 Bed/Chair rest and Telemetry
 Oxygen (maintain saturation >90%)
 Nitrates (SLx3 Oral/topical. IV for ongoing iscemia, heart
failure, hypertension)
 Oral B-blockers in First 24-hours if no contraindications.
(IV B-blockers class IIa indication)
 Non-dihydropyridine Ca-channel blockers for those with
contraindication fo B-blockers
 ACE inhibitors in first 24-hours for heart failure or
EF<40% (Class IIa for all other pts) (ARBs for those
intolerant)
 Statins
 Early Hospital Care
Anti-Ischemic Therapy
 Class III
 Nitrates if BP<90 mmHg or RV infarction
 Nitrates within 24-hrs of Sildenafil or 48 hrs of Tadalafil
 Immediate release dihydropyradine Ca-blockers in the
absence of B-Blocker therapy
 IV ACE-inhibitors
 IV B-blockers in patients with acute HF, Low output state
or cardiogenic shock, PR interval >0.24 sec, 2nd or 3rd
degree heart block, active asthma, or reactive airway
disease
 NSAIDS and Cox-2 inhibitors
 Early Hospital Care
Anti-Platelet Therapy
 Class I
 Aspirin (162-325 mg), non enteric coated
 Clopidogrel for those with Aspirin
allergy/intolerance (300-600 mg load and 75 mg/d)
 GI prophylaxis if a Hx of GI bleed

 GP IIb/IIIa inhibitors should be evaluated based on

whether an invasive or conservative strategy is
used
 GP IIb/IIIa inhibitors recommended for all
diabetics and all patient in early invasive arm
 Early Hospital Care
Anticoagulant Therapy
 Class I
 Unfractionated Heparin
 Enoxaparin

 Bivalarudin

 Fondaparinux

 Relative choice depends on invasive vs

conservative strategy and bleeding risk
 Early Hospital Care
Statin Therapy

 MIRACL Trial
Inclusion Criteria
 3086 patients with Non ST ACS
 Total cholesterol <270 mg/dl

 No planned PCI

 Randomized to Atorvastatin vs Placebo

 Drug started at 24-96 hours

 Statin Evidence: MIRACL Study
Primary Efficacy Measure
Placebo 17.4%
15
14.8%
Cumulative Incidence (%)

Atorvastatin
10

Time to first occurrence of:

• Death (any cause)
• Nonfatal MI
5
• Resuscitated cardiac arrest
• Worsening angina with new Relative risk = 0.84
objective evidence and P = .048
urgent rehospitalization 95% CI 0.701-0.999
0
0 4 8 12 16
Time Since Randomization (weeks)

Schwartz GG, et al. JAMA. 2001;285:1711-1718.

 Statin Evidence: MIRACL Study
Fatal and Nonfatal Stroke
2
Cumulative Incidence (%)

1.5
Placebo

1
Atorvastatin

0.5
Relative risk = 0.49
P = .04
95% CI 0.24-0.98
0
0 4 8 12 16
Time Since Randomization (weeks)
Waters DD, et al. Circulation. 2002;106:1690-1695. S24
 PROVE-IT Trial
All-Cause Death or Major CV Events
in All Randomized Subjects
30
Pravastatin 40mg
25 (26.3%)

20
%
Atorvastatin 80mg
with 15 (22.4%)
Event
10
16% RR
5 (P =
0.005)
0
0 3 6 9 12 15 18 21 24 27 30
Months of Follow-up
 Summary of PROVE-IT Results
In patients recently hospitalized within 10 days for an
acute coronary syndrome:
 “Intensive” high-dose LDL-C lowering (median LDL-C 62
mg/dL) compared to “moderate” standard-dose lipid-lowering
therapy (median LDL-C 95 mg/dL) reduced the risk of all cause
mortality or major cardiac events by 16% (p=0.005)
 Benefits emerged within 30 days post ACS with continued benefit
observed throughout the 2.5 years of follow-up
 Benefits were consistent across all cardiovascular endpoints,
except stroke, and most clinical subgroups
Invasive vs Conservative
Strategies
 Invasive vs Conservative Strategy
Clinical Trials
ISAR-
COOL

VANQWISH (98) ICTUS (05) RITA-3 (02)

MATE VINO

TIMI IIIB (94) TRUCS

TACTICS-
TIMI 18 (01)
Weight of FRISC II (99)
the evidence

Conservative Invasive
Strategy Favored No difference Strategy Favored
N=920 N=2,874 N=7,018
How Early is Early?
 Secondary Prevention
Class I Indications
 Aspirin
 Beta-blockers: (all pts, slow titration with moderate to
severe failure
 ACE-Inhibitors: CHF, EF<40%, HTN, DM
(All pts-Class IIa) ARB when intolerant to ACE.
(Class IIa as alternative to ACEI)
Aldosterone blockade: An ACEI, CHF with either
EF<40% or DM and if CrCl>30 ml/min and K<5.0
mEq/L
 Statins
 Standard Risk Factor Management
 Long-Term Antithrombotic Therapy at Hospital
Discharge after UA/NSTEMI
New UA/NSTEMI
Patient Groups at
Discharge

Medical Therapy Bare Metal Stent Drug Eluting

without Stent Group Stent Group

ASA 75 to 162 mg/d indefinitely ASA 162 to 325 mg/d for at least 1 ASA 162 to 325 mg/d for at
(Class I, LOE: A) month, then 75 to 162 mg/d least 3 to 6 months, then 75 to
indefinitely (Class I, LOE: A) 162 mg/d indefinitely
& (Class I, LOE: A)
&
Clopidogrel 75 mg/d at least 1 &
Clopidogrel 75 mg/d for at least 1
month (Class I, LOE: A) and up
month and up to 1 year Clopidogrel 75 mg/d for at
to 1 year (Class I, LOE: B)
(Class I, LOE:B) least 1 year (Class I, LOE: B)

Indication for
Anticoagulation?

Yes No
Add: Warfarin (INR 2.0 to 2.5) Continue with dual antiplatelet
(Class IIb, LOE: B) therapy as above

Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Figure 11. INR = international normalized ratio; LOE = level of evidence.
 Secondary Prevention
Class III

 Hormone Replacement Therapy

 Antioxidants (Vit C, Vit E)
 Folic Acid
New and Controversial
Drug Therapies
Early Treatment with Clopidogrel
Shortcomings of the CURE Trial
 Conducted primarily at centers without routine
use of early invasive strategy
 Only 462 (3.7%) patients enrolled from the
U.S.
 44% had catheterization during index
hospitalization
 Adverse event reduced only in nonfatal MI set
 Major Bleeding rate of 9.6% among patients
who were administered clopidogrel within 5
days of CABG
 Clopidogrel
Bleeding Risk and CABG

 “In hospitals in which patients with

UA/NSTEMI undergo rapid diagnostic
catheterization within 24 hours of admission,
clopidogrel is not started until it is clear that
CABG will not be scheduled within the next
several days. However, unstable patients
should receive clopidogrel or be take for
immediate angiography.”
Clopidogrel vs. Prasugrel
 Prasugrel-Key Facts

 Contraindicated in pts with prior TIA/Stroke

 Not recommended for patients >75 years
 5 mg maintenance dose suggested in patients
<60 Kg, though this dose has not been studied
 Summary
 ACS includes UA, NSTEMI, and STEMI
 Management guideline focus
 Immediate assessment/intervention (MONA+BAH)
 Risk stratification (UA/NSTEMI vs. STEMI)
 RAPID reperfusion for STEMI (PCI vs.
Thrombolytics)
 Conservative vs Invasive therapy for UA/NSTEMI

 Aggressive attention to secondary prevention

initiatives for ACS patients
 Beta blocker, ASA, ACE-I, Statin
Questions?