Acute Coronary Syndromes

1
Acute Coronary Syndromes

• Edward Catherwood, MD, MS
• Dartmouth-Hitchcock Medical Center
• SBM September 18, 2006

2
Goals of ACS Review

• Epidemiology
• Pathophysiology
• Clinical Presentation and Diagnostic Triad
• Pharmacotherapeutics
• Reperfusion strategies
• DHMC local and regional paradigm
• Secondary prevention

3
Epidemiolgy

• 58 million Americans have one or more types of
  cardiovascular disease
• Approximately 1 million Americans will have a
  new/recurrent myocardial infarction this year
• Coronary heart disease is the single largest
  cause of death in the United States
• Estimated direct/indirect cost
• Coronary heart disease 95.6 billion/year
• Congestive heart failure 20.2 billion/year

1998 Heart and Stroke Statistical Update,
American Heart Association
4
Improvement in Mortality
30
Bed rest
13-15
Defibrillation Hemodynamic monitoring ?-Blockade
5.0- 6.5
Aspirin, PTCA, Lysis
Pre-CCU Era
CCU Era
Reperfusion Era
PTCA, percutaneous transluminal coronary
angioplasty.
5
AMI Cases by Season Men and Women
Adapted from Spencer et al. JACC 1998
6
Rates of Mortality During Hospitalization, by Age
P lt0.001
Vaccarino V, et al. N Engl J Med. 1999
7
National Trends in AMI ManagementHospital
Length of Stay
NRMI 1 NRMI 2 NRMI 3
7.5
6.8
4.6
3.5
Non-transfer-in patients
8
Coronary Thrombus Chicken or Egg
Clot lysis with IC Streptokinase
RCA Clot
9
Plaque Development and Rupture
Occlusive STEMI
Non Occlusive UA / NSTEMI
Embolization
TIMI 2/3 Flow
Vasoconstriction
Edema
Inflammation
TIMI 0 Flow
Tissue level perfusion
Time Dependent Necrosis
Troponin / CK
Arrhythmias / CHF
Death
10
Targeted Therapy in Thrombogenesis
11
Factors Affecting Infarct Size

• Location of unstable lesion
• Total vs. subtotal occlusion
• Presence of collaterals
• Time to reperfusion
• Efficacy of reperfusion
• Reocclusion

A
B
12
Clinical Presentation

• Acute chest pain or pressure (gt20-30 min)
• Substernal localization /- radiation to arms,
  back, throat, jaw
• Accompanying features
• Dyspnea
• Nausea/vomiting
• Diaphoresis
• Weakness
• Atypical syncope, CVA, DKA

13
Initial Chest PainEvaluation
Symptoms Suggestive of ACS
ECG
Definite ACS
Possible ACS
() ECG Normal biomarkers
ST ?
No ST ?
ST-T ?s, chest pain, ? markers
Reperfuse
Observe repeat ECG, markers at 4-8 hrs
No recurrent pain () follow-up studies
Recurrent pain () follow-up studies
Stress test ? LV function if ischemia
() test
Consider Early Invasive Strategy
() test outpt follow-up
14
ECG Findings in ACS
15
ECG Findings in ACS
16
ECG Findings in ACS
17
ECG Findings in ACS
18
Secondary Causes of ACS

• Tachyarrhythmias
• Severe anemia
• Medication withdrawal
• Hyperthyroidism
• Sepsis or other toxic state
• Multisystem organ failure

19
ECG Findings in ACS
20
Cardiac Enzymes
1000
100
10
Relative Marker Increase
Upper Reference Interval
1
0
Hours After Chest Pain Onset
Antman EM. In Braunwald E, ed. Heart Disease A
Textbook in Cardiovascular Medicine, 5th ed.
Philadelphia, Pa WB Saunders 1997.
21
Enzymatic MarkersTime-Dependent Sensitivity
Sensitivity
Hours After Symptom Onset
Hours After Symptom Onset
Hours After Symptom Onset
Winter, Circulation, 1995
22
Troponin Elevation and Risk of Death
23
Clinical Spectrum of Acute Coronary Syndromes
Stable angina
Unstable angina
Non-STE MI
STE MI
None
Positive
Positive
ST-segment elevation
ST-segment depression and/or T-wave inversion
ST-segment depression and/or T-wave
inversion
ECG early
ECG late
No Q
No Q
Q develops
Antman EM. In Braunwald E, ed. Heart Disease A
Textbook in Cardiovascular Medicine, 5th ed.
Philadelphia, Pa WB Saunders 1997.
24
ACC/AHA Guidelines
PTCA, percutaneous transluminal coronary
angioplasty CABG, coronary artery bypass graft
ACE, angiotensin-converting enzyme.Available at
http//www.acc.org/clinical/guidelines and
http//www.americanheart.org.
25
Objective Restoration of Normal Flow
TIMI 1
TIMI 2
TIMI 3
TIMI 0
Occlusion
Penetration
Slow Flow
Normal Flow
9.3
P0.003 vs TIMI 0/1
6.1
plt0.0001 vs TIMI 0/1 plt0.0001 vs TIMI 2
Mortality
3.7
10
16
33
34
44
27
8
4
13
19
9
15
18
29
34
Team 2
Team 2
Team 2
TIM I 1,4 5,10B
German
TIM I 1,4 5,10B
TIM I 1,4 5,10B
German
German
GUSTO 1
GUSTO 1
GUSTO 1
TAM I 1-7
TAM I 1-7
TAM I 1-7
Sample Size of Pooled Analysis 5,498
CM Gibson 1998 in Acute Coronary Syndromes
26
Landmark Trial ISIS 2 (1988)

• 17,000 patients with STE MI randomized into
  treatment with one of four blinded regimens
• Aspirin
• Streptokinase
• Both
• Neither
• Vascular mortality at 35 days was the primary end
  point.

ISIS-2. Lancet. 1988 ii 349-360
27
ISIS-2 Second International Study of Infarct
Survival

Vascular mortality over 35 days individual
therapies
1029
1016
Cumulative
1000
1000
(12.0)
(11.8)
no. of
vascular
804
800
800
791
(9.4)
deaths
(9.2)
600
600
Placebo
Placebo
infusion
tablets
400
400
SK
Aspirin
Odds reduction
Odds reduction
200
200
25, SD 4
23, SD 4
2Plt0.00001
2Plt0.00001
50
50
0
7
14
21
28
35
0
7
14
21
28
35
Days after randomization
The ISIS-2 collaborative group.
Lancet 1988 ii 34960.
28
ISIS-2 Second International Study of Infarct
Survival

Vascular mortality at 35 days in four treatment
arms and combination
Vascular mortality () at 35 days
Aspirin
Placebo
Streptokinase
8.0
Placebo
13.2
The ISIS-2 collaborative group.
Lancet 1988 ii 34960.
29
Time-Dependent Benefit of Reperfusion Therapy
Adapted from Tiefenbrunn AJ, Sobel BE.
Circulation. 1992852311-2315.
30
Direct Angioplasty

• TIMI 3 Flow 95
• Defines extent of disease
• Avoids lytic risk
• Needs cath lab and trained staff
• Invasive
• Expensive

31
NRMI-2 Primary PCI Door-to-Balloon time vs.
Mortality
P0.01
P0.0007
P0.0003
PNS
PNS
1.62
1.41
1.61
1.15
1.14
N2,230 5,734 6,616
4,461 2,627 5,412
32
Patency and Mode of Reperfusion
90-minute patency
? ED arrival
? Drug administration
Time (minutes)
Adapted from Gibson CM. Ann Intern Med.
1999130841-847.
33
Unstable angina and nonSTE MI TherapyEvidence
for Aspirin
Cairns Lewis Theroux Wallentin Pooled
0
1.0
2.0
Favors Placebo
Favors Aspirin
Relative Risk Death or MI
34
Unstable angina and nonSTE MI Therapy Evidence
for Heparin Use (UFH ASA versus ASA)
Relative Risk of Death or MI
Theroux (n 243) RISC (n 399) Cohen (n
69) Cohen (n 214) Holdright (n 185) Gurfinkel
(n 143) Overall (n 1353)
2.66
6.87
P 0.06
0.5
1
1.5
2
0
ASA UFH Better
ASA Better
Oler A, JAMA 1996
35
CURE Primary Results

14
11.4
Placebo ASA
12
9.3
10
8
Clopidogrel ASA
Death, MI, or Stroke
20 RRR P lt 0.001 N 12,562
6
4
2
0
3
6
9
0
12
Months of Follow-Up
N Engl J Med. 2001
36
GP IIb/IIIa Inhibition for Non-ST-Elevation ACS
30-Day Death or Nonfatal MI
n
Trial
Risk Ratio 95 CI
Placebo
GP IIb/IIIa
7.1
PRISM
5.8
3,232
PRISM PLUS
11.9
10.2
1,915
PARAGON A
11.7
11.3
2,282
PURSUIT
15.7
14.2
9,461
PARAGON B
11.4
10.5
5,165
GUSTO-IV ACS
8.0
8.7
7,800
0.92 (0.86, 0.995) p 0.037
11.5
10.7
Pooled
29,855
0.5
1.0
1.5
Placebo Better
GP IIb/IIIa Better
Boersma, Lancet 2002
37
Initial Chest PainEvaluation
Symptoms Suggestive of ACS
Definite ACS
Possible ACS
() ECG Normal biomarkers
ST ?
No ST ?
Reperfuse
ST-T ?s, chest pain, ? markers
Observe repeat ECG, markers at 4-8 hrs
No recurrent pain () follow-up studies
Recurrent pain () follow-up studies
Stress test ? LV function if ischemia
() test
Consider Early Invasive Strategy
() test outpt follow-up
38
NonSTE AntMI LAD PCI
39
Non-STE IMI RCA PCI
40
FRISC-II Mortality at One-Year Invasive Vs.
Conservative Management Strategies
.04
Non-Invasive (n 1235)
.03
Probability of Death
.02
Invasive (n 1222)
.01
Invasive Noninvasive RR (95 CI) 2.2
4.0 0.56 (0.35 - 0.89) p 0.018
0
360
180
90
30
0
Wallentin, Lancet 2000
41
TACTICS-TIMI 18 Study Design
PCI/ CABG
Early Invasive
Angio
Medical Rx
UA/ NSTEMI
ASA, Hep,Tirofiban
Endpoints
Early Conservative
Medical Rx
Baseline Troponin
ETT
ischemia
Cath/ PCI/ CABG
Chest pain
Randomize
-24 hrs
Hour 0
6 mos
4- 48 108
hrs hrs
42
Cardiac Events at 30 Days
P value
CONS ()
OR
No. Pts 1o Endpoint Death/MI Death MI Rehosp
ACS
1106 10.5 7.0 1.6 5.8 5.5
0.67 0.65 1.40 0.51 0.61
0.009 0.02 0. 29 0.002 0.018
43
Invasive vs. Conservative Treatment in Unstable
Coronary Syndromes (ICTUS)

• 1200 patients with nonSTE acute MI (elevated
  troponin)
• Daily aspirin, enoxaparin and clopidogrel
• Selective invasive arm applied for recurrent
  ischemia or significant ischemia in predischarge
  ETT

Endpt Composite death, nonfatal MI, recurrent
unstable angina within one year.
deWinter RJ et al. NEJM. 2005 3531095-1104.
44
Invasive vs. Conservative Treatment in Unstable
Coronary Syndromes (ICTUS)
deWinter RJ et al. NEJM. 2005 3531095-1104.
45
DHMC ACS Protocol

• STE MI DHMC ER or local Direct PCI
• STE MI outside within 2 hours Facilitated PCI
  (Half-dose lytic and receptor blocker)
• STE MI outside beyond 2 hours Full-dose lytic
• STE MI ineligible for lytics Direct PCI
• Non-STE MI medically refractory Urgent PCI
• Non-STE MI Early invasive strategy within 48
  hours

46
Case Presentation
60 yo man, retired high school teacher, complains
of severe anterior chest pressure awakening him
from sleep two hours before arrival in the
ER. His wife states that he appeared ashen and
short of breath during the discomfort. He
mentions no prior episodes of similar pain. PMH
Mild labile hypertension, Rx with
hydrochlorothiazide No history of DM,
hyperlipidemia SH Smoker of 1ppd since age 22.
FH Negative for premature CAD.
47
Physical exam
WD, WN 60 yo man, moderate distress from residual
chest pain. VS BP 114/72 P reg 50 Resp 12
Afebrile HEENT No neck vein distension Lungs
Clear Cardiac Regular rhythm, normal S1 and S2,
soft mitral insufficiency murmur at the apex. No
S3 Abdomen Soft, nontender, no organomegaly or
bruits Extremities All pulses preserved. No
edema.
48
Laboratory data
CBC shows a normal hemoglobin and platelet count
WBCs mildly elevated Renal function, electrolytes
and clotting parameters all normal Initial
troponin and CPK are normal CXR Normal cardiac
silhouette, no CHF, infiltrates, effusion or bony
abnormalities.
49
Electrocardiogram
50
Treatment Paradigm

• Administer aspirin
• Establish IV lines, obtain blood studies
• Supplemental oxygen if needed
• Treat for pain with analgesic and/or anxiolytic
• Start antithrombin, beta blocker (if appropriate)
• Screen for reperfusion therapy options
• Expedite reperfusion strategy

51
Emergency cardiac catheterization
52
Emergency cardiac catheterization
53
Emergency cardiac catheterization
54
Evidence-based care
Counseling
Medications

• Smoking cessation
• Diet and exercise
• Education on atherosclerotic process
• Contingencies for recurrent events
• BLS training for family

• Aspirin/Clopidogrel
• Nitro sl prn
• Beta-blocker
• Lipid-lowering agent
• ACEI