Fredric Ginsberg, MD

Assistant Professor of Medicine, Robert Wood Johnson Medical School

University of Medicine and Dentistry of New Jersey

Joseph E. Parrillo, MD
Professor of Medicine, Robert Wood Johnson Medical School
University of Medicine and Dentistry of New Jersey
Head, Division of Cardiovascular Disease
and Critical Care Medicine
Director, Cooper Heart Institute
Director, Cardiovascular and Critical Care Services
Cooper University Hospital
Camden, New Jersey

SCCM Online Critical Care Course:
Cardiogenic Shock, Acute Coronary
Syndrome and Congestive
Heart Failure
Inadequate tissue perfusion resulting from cardiac
dysfunction
Clinical definition - decreased cardiac output and tissue
hypoxia in the presence of adequate intravascular
volume
Hemodynamic definition - sustained systolic BP < 90 mm
Hg, cardiac index < 2.2 L/min/m
2
, PCWP > 15 mm Hg
Parrillo, J. 2005
Cardiogenic Shock
Acute MI
Pump failure
Mechanical complications
Right ventricular infarction
Other conditions
End-stage cardiomyopathy
Myocarditis (fulminant myocarditis)
Myocardial contusion
Prolonged cardiopulmonary bypass
Septic shock with myocardial depression
Valvular disease
Causes of Cardiogenic Shock
Evolution Of The Disease
Frequently, shock develops after presentation for
myocardial infarction.

- SHOCK Registry
At presentation 25% in shock
Within 24 hours 75%
(median delay = 7 hours)

- GUSTO Trial
At presentation 11% in shock
After admission 89%
SHOCK Registry, Circulation. 1995;91:873-81.
GUSTO J Amer Coll Cardiol. 1995;26:668-74.
Cardiogenic Shock
Wall motion
abnormality
during
occlusion
Wall motion
abnormality
From Kloner RA. Am J Med.
1986;86:14.
Gradual return of
function (hours to days)
Persistent wall
motion abnormality
(despite reperfusion
and viable myocytes)
Coronary occlusion
Coronary reperfusion
Return of
function
Clamp
Schematic Diagram of Stunned
Myocardium
Atherosclerotic narrowing
Wall motion abnormality
due to chronic ischemia
without infarction
Wall motion abnormality
From Kloner RA. Am J Med. 1986;86:14.
Hibernating Myocardium
Pre-operative
8 Months
Postoperative
CONTROL
LVEDV = 128
EF = 0.37
POST NTG
LVEDV = 101
EF = 0.51

LVEDV = 104
EF = 0.76
Patient Coronary Bypass
Graft to L.A.D.
Single vessel disease - Occluded
L.A.D.
End-Diastole
End-Systole
From Rahimtoola SH, et al. Circ. 1992;65:225.
Hibernating Myocardium
Cell death
Significant
residual
stenosis
Reperfusion
Segments with
myocardial
stunning
Segments with
both stunning
and
hibernation
Segments with
hibernating
myocardium
Relief of
ischemia
Inotropic
support
No return
of function
Return of
myocardial function
Ischemic Myocardium
Assure oxygenation
Intubation and ventilation if needed
Venous access
Pain relief
Continuous EKG monitoring
Hemodynamic support
Fluid challenge if no pulmonary edema
Vasopressors for hypotension
- Dopamine
- Norepinephrine
Initial Approach: Management
Reduces afterload and augments diastolic perfusion
pressure
Beneficial effects occur without increase in oxygen
demand
No improvement in blood flow distal to critical coronary
stenosis
No improvement in survival when used alone
May be essential support mechanism to allow for
definitive therapy
Intra-aortic Balloon Counterpulsation
Overall 30-Day Survival in the Study
Hochman JS, et al. N Engl J Med. 1999;341:625-34.
P
r
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A
l
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0
Days after Randomization
0.6
0.2
0.0
0.8
Revascularization (n =152)
Medical therapy (n =150)
1.0
0.4
5 10 15 20 25
30
Survival = 53%
Survival = 44%
p = 0.11
Early Revascularization in Acute Myocardial
Infarction Complicated by Cardiogenic Shock
46.7
50.3
54.3
56
63.1
66.4
0
20
40
60
80
100
%
P = 0.11 P = 0.027 P < 0.03
30 days
6 months
1 year
Revasc
Med Rx
SHOCK Trial Mortality
Patients with ST segment elevation MI who have
cardiogenic shock and are less than 75 years of age
should be brought immediately or secondarily transferred
to facilities capable of cardiac catheterization and rapid
revascularization (PCI or CABG) if it can be performed
within 18 hours of onset of shock. (Level of Evidence: A)
ACC/AHA Class I Indication
Despite ACC/AHA recommendation to treat patients < 75
years of age aggressively with early mechanical
revascularization, in 2001, two years after the guidelines
were published, only 41% of patients with cardiogenic
shock complicating AMI were treated with primary PTCA
and only 3.1% underwent early CABG.
These data demonstrate significant underutilization of
guideline recommended therapy.
Babaev A, et al. Circ. 2002;106(19):1811 (abstract).
National Registry of MI Early
Revascularization is Underutilized in
Cardiogenic Shock
Average LVEF is only moderately severely depressed
(30%), with a wide range of EFs and LV sizes noted.
Systemic vascular resistance (SVR) on vasopressors is not
elevated on average (~ 1350), with a very wide range of
SVRs measured.
A clinically evident systemic inflammatory response
syndrome is often present in patients with CS.
Most survivors (85%) have NYHA functional Class I-II CHF
status.
Hochman JS. Circ .2003;107:2998-3002.
Pathophysiology of Cardiogenic Shock
Observations from the SHOCK Trial and
Registry that Challenge the Classic
Paradigm
Cardiogenic shock IS NOT simply the result of severe
depression of LV function due to extensive myocardial
ischemia/injury.
Depressed Myocardial Contractility combined with
Inadequate Systemic Vasoconstriction resulting from
a systemic inflammatory response to extensive
myocardial ischemia/injury results in cardiogenic shock .
Pathophysiology of Cardiogenic Shock
Thus, excess nitric oxide and peroxy
nitrites may be a major contributor to
cardiogenic shock complicating MI.

The Overproduction of Nitric Oxide
May Cause Both Myocardial
Depression and Inappropriate
Vasodilatation.
Nitric oxide synthase inhibition can raise blood pressure
in patients with persistent cardiogenic shock after
percutaneous intervention.
The mechanism of this effect is unknown, but may
involve both an effect on coronary and other organ
perfusion pressure, and potentially an improvement in
cardiac function.
Outcome data are not yet available.
LINCS: Conclusions
Cotter. Eur Heart J. 2003;24:1287-1295.
Acute coronary syndrome:
Constellation of clinical symptoms compatible with
acute myocardial ischemia
ST-segment elevation MI (STEMI)
Non-ST-segment elevation MI (NSTEMI)
Unstable angina

Unstable angina:
Angina at rest (usually > 20 minutes)
New-onset of class III or IV angina
Increasing angina (from class I or II to III or IV)
Braunwald. Circulation 2002; 106:1893-2000.
www.acc.org/clinical/guidelines/unstable/unstable.pdf
Acute Coronary Syndromes: Definitions
Plaque rupture
Platelet adhesion
Platelet activation
Partially occlusive arterial
thrombosis & unstable angina
Microembolization & non-ST-
segment elevation MI
Totally occlusive arterial thrombosis
& ST-segment elevation MI
White HD. Am J Cardiol 1997;80 (4A):2B-10B.
Pathogenesis of Acute Coronary Syndromes
UA/NSTEMI:
Partially-occlusive thrombus
(primarily platelets)
Intra-plaque
thrombus
(platelet-dominated)
Plaque core
STEMI:
Occlusive thrombus (platelets,
red blood cells, and fibrin)
Intra-plaque
thrombus
(platelet-dominated)
Plaque core
SUDDEN
DEATH
UA = Unstable Angina
NSTEMI = Non-ST-segment Elevation Myocardial Infarction
STEMI = ST-segment Elevation Myocardial Infarction
Structure of Thrombus Following Plaque
Disruption
White HD. Am J Cardiol 1997;80 (4A):2B-10B.
Therapeutic goal: rapidly break apart
fibrin mesh to quickly restore blood flow
ST-segment elevation MI Non-ST Elevation ACS* Non-ST Elevation MI
+ Troponin
or + CK-MB
Consider fibrinolytic therapy, if indicated,
or primary percutaneous coronary
intervention (PCI)
Therapeutic goal: prevent progression to
complete occlusion of coronary artery and
resultant MI or death
Consider GP IIb-IIIa inhibitor + aspirin +
heparin before early diagnostic catheterization
&/or
Braunwald E, et al. 2002.
http://www.acc.org/clinical/guidelines/unstable/unstable.pdf.
Diagnostic Algorithm for Acute Coronary
Syndrome Management
0.00
0.05
0.10
0.15
0.20
0.25
0 3 6 9 12
P
r
o
b
a
b
i
l
i
t
y

o
f

D
e
a
t
h

o
r

M
I

Placebo
Aspirin 75 mg
Risk ratio 0.52
95% CL 0.37 - 0.72
Risk of MI and Death During Treatment with
Low-Dose Aspirin and IV Heparin in Men with
Unstable CAD
Wallentin LC, et al. J Am Coll Cardiol, 1991;18:1587-93.
Months
Trial:
FRIC
(Dalteparin; n = 1,482)
FRAXIS
(nadroparin; n = 2,357)
ESSENCE
(enoxaparin; n = 3,171)
TIMI 11B
(enoxaparin; n = 3,910)
.75 1.0 1.5




(p= 0.032)
(p= 0.029)
LMWH
Better
UFH
Better
6
14
14
14
Day:
Braunwald. Circulation. 2002;106:1893-2000.
www.acc.org/clinical/guidelines/unstable/unstable.pdf
Low Molecular Weight Heparin (LMWH) vs.
Unfractionated Haparin (UFH) in Non-ST elevation
ACS: Effect on Death, MI, Recurrent Ischemia
0
2
4
6
8
10
12
14
D
e
a
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h
,

M
I
,

o
r

S
t
r
o
k
e

Clopidogrel
+ ASA
3 6 9
Placebo
+ ASA
Months of Follow-Up
11.4%
9.3%
20% RRR
P < 0.001
N = 12,562
0 12
%
N Engl J Med. 2001;345:494-502.
Effects of Clopidogrel in Addition to Aspirin in
Patients with ACS without ST-Segment Elevation
15.7
5.6
17.9
11.7
12.8
14.2
3.8
12.9
10.3
11.8
0
5
10
15
20
P
r
i
m
a
r
y

E
n
d
p
o
i
n
t

%

Placebo
GP IIb/IIIa
PURSUIT
30 days
PRISM
48 hrs
PRISM
PLUS
7 days
P = 0.04 P = 0.01 P = 0.004
PARAGON A
30 days
P = 0.48
PARAGON B
30 days
P = 0.33
Platelet Glycoprotein IIb/IIIa Inhibition for Non-ST
elevation ACS Primary Endpoint Results from the
5 Major Trials
I IIa IIb III
Hospital Care
Anti-Thrombotic Therapy
Immediate aspirin
Clopidogrel, if aspirin contraindicated
Aspirin + clopidogrel for up to one month, if
medical therapy or PCI is planned
Heparin (IV unfractionated, LMW) with
antiplatelet agents listed above
Enoxaparin preferred over UFH unless
CABG is planned within 24 hours
Braunwald. Circulation. 2002;106:1893-2000.
www.acc.org/clinical/guidelines/unstable/unstable.pdf
I IIa IIb III
* For patients managed with an early conservative strategy, and
those who are planned to undergo early PCI
Guidelines do not specify initial approach to using
clopidogrel when coronary anatomy is unknown
Braunwald. Circulation. 2002;106:1893-2000.
www.acc.org/clinical/guidelines/unstable/unstable.pd
f
Hospital Care
Clopidogrel Therapy
Aspirin + clopidogrel, for up to 1 month *
Aspirin + clopidogrel, for up to 9 months *
Withhold clopidogrel for 5 - 7 days for CABG
I IIa IIb III
* High-risk: Age >75; prolonged, ongoing CP; hemodynamic instability;
rest CP w/ ST ; VT; positive cardiac markers
Braunwald. Circulation. 2002;106:1893-2000.
www.acc.org/clinical/guidelines/unstable/unstable.pdf
Hospital Care
Platelet GP IIb/IIIa Inhibitors (1)
Any GP IIb/IIIa inhibitor + ASA/Heparin for all
patients, if cath/PCI planned
Eptifibatide or tirofiban + ASA/Heparin for high-
risk * patients in whom early cath/PCI is not
planned
Any GP IIb/IIIa inhibitor for patients already on
ASA + Heparin + clopidogrel, if cath/PCI is
planned
I IIa IIb III
Braunwald. Circulation. 2002;106:1893-2000.
www.acc.org/clinical/guidelines/unstable/unstable.pdf
Hospital Care
Platelet GP IIb/IIIa Inhibitors (2)
Eptifibatide or tirofiban + ASA/Heparin for
patients without continuing ischemia in whom
PCI is not planned
Abciximab for patients in whom PCI is not
planned
I IIa IIb III
Braunwald. Circulation. 2002;106:1893-2000.
www.acc.org/clinical/guidelines/unstable/unstable.pdf
Hospital Care
Anti-ischemic Therapy (1)
-blocker (IVoral) if not contraindicated
Non-dihydropyridine Ca2+ antagonist if -
blocker contraindicated and no LV dysfunction,
for recurrent ischemia
ACE inhibitor if BP persists with NTG+ -
blocker, for pts with CHF or diabetes
I IIa IIb III
Braunwald. Circulation. 2002;106:1893-2000.
www.acc.org/clinical/guidelines/unstable/unstable.pdf
Hospital Care
Anti-ischemic Therapy (2)
ACE inhibitor for all ACS pts
Extended-release Ca2+ blocker instead of -
blocker
Immediate-release Ca2+ blocker with -
blocker
Long-acting Ca2+ blocker for recurrent
ischemia, if no contraindications and NTG + -
blocker used fully
30 60 90 120 150 180
10%
8%
6%
4%
2%
T-wave inversion
3.4%
ST-segment elevation
6.8%
ST-segment depression
8.9%
Days from randomization
% Cumulative Mortality at 6 Months
Savonitto S. J Am Med Assoc. 1999; 281: 707-711.
ST-segment Depression Predicts
Higher Risk of Mortality in ACS
1. Age > 65 years
2. > 3 CAD risk factors (elevated cholesterol, + family Hx,
hypertension, diabetes, cigarette smoking)
3. Prior CAD (coronary stenosis > 50%)
4. ASA in last 7 days
5. > 2 anginal events < 24 hours
6. ST deviation
7. Elevated cardiac markers (CK - MB or troponin)
TIMI Risk Score for UA/NSTEMI
7 Independent Predictors of Higher Risk
Antman, et al. JAMA. 2000;284:835-842.
20.3
16.1
19.5
11.8
30.6
12.8
0
5
10
15
20
25
30
35
Low 0-2 Intermed. 3-4 High 5-7
D
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A
C
S

R
e
h
o
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p

(
%
)

TIMI Risk Score
CONS
% of Pts: 25% 60% 15%
INV
OR = 0.75
CI (0.57, 1.00)
OR = 0.55
CI (0.33, 0.91)
TIMI UA Risk Score:
Primary Endpoint at 6 months
Cannon. J Invas Cardiol. 2003;15:22B.
Troponin and ST-Segment Shift Predict
Benefit of Invasive Treatment Strategy
Class I
An early invasive strategy in patients with a high-risk indicator:

1. Recurrent angina/ischemia despite intensive anti-ischemic rx
2. Elevated troponin-T or troponin-I
3. New or presumably new ST-segment depression
4. Recurrent angina/ischemia with CHF sx, S3, pulmonary edema, worsening
rales, or new or worsening MR
5. High-risk findings on noninvasive stress testing
6. Depressed LV systolic function (EF <40%)
7. Hemodynamic instability
8. Sustained ventricular tachycardia
9. PCI within 6 months
10. Prior CABG

Either early invasive or early conservative strategy if not high risk
Braunwald. Circulation. 2002;106:1893-2000.
www.acc.org/clinical/guidelines/unstable/unstable.pd
f
ACC/AHA Guideline Update for the Management
of Patients with Unstable Angina and Non-ST-
Segment Elevation MI
Start immediate
Aspirin
Heparin or low-molecular-weight heparin
GP IIb-IIIa inhibitor
Adapted from Braunwald E, et al. 2002.
http://www.acc.org/clinical/guidelines/unstable/unstable.pdf.
At presentation
ST-segment depression &/or elevated cardiac troponin
Need to immediately arrest
thrombus progression
Need to eliminate occlusive
ruptured plaque
Send for catheterization & revascularization within 24-48 hours
Cautionary information
No clopidogrel within 5-7 days prior to CABG surgery
No enoxaparin within 24 hours prior to CABG surgery
No abciximab, if PCI is not planned
2002 ACC/AHA Guidelines for the
Management of High-risk NSTE ACS
Recurrent
Symptoms/ischemia
Heart failure
Serious arrhythmia
Patient
stabilizes
EF .40
Stress Test
Not low risk
Follow on Medical Rx
Evaluate LV function
EF < .40
Low risk
Early medical management
Immediate angiography
Braunwald E, et al. 2002.
http://www.acc.org/clinical/guidelines/unstable/unstable.pdf.
Ongoing Evaluation in an Early
Conservative Strategy
ST , positive cardiac markers, deep T-wave inversion, transient ST , or recurrent ischemia
Aspirin, Beta Blockers, Nitrates, Antithrombin regimen, GP IIb-IIIa inhibitor,
Monitoring (rhythm and ischemia)
Early invasive strategy Early conservative strategy
Immediate
angiography
12-24 hour
angiography
Recurrent symptoms/ischemia
Heart failure
Serious arrhythmia
Patient stabilizes
Evaluate LV Function
EF < .40


EF > .40 Stress Test
Not low risk Low risk
Follow on Medical Rx
Braunwald. Circulation. 2002;106:1893-2000.
www.acc.org/clinical/guidelines/unstable/unstable.pdf
ACC/AHA Guidelines for Unstable Angina and Non-
ST-Segment Elevation MI Acute Ischemia Pathway
Class I indications for revascularization with PCI or
CABG

1. CABG for 50% stenosis of the left main coronary artery

2. CABG for 3 vessel CAD

3. CABG for 2 vessel CAD including proximal LAD stenosis & EF < 50%

4. PCI or CABG for 1 or 2 vessel CAD, no proximal LAD,
large area of viability, high-risk noninvasive test

5. PCI for patients with multivessel CAD, normal EF, no diabetes

6. IV platelet GP IIb/IIIa inhibitor in ACS patients undergoing PCI

Braunwald. Circulation 2002; 106:1893-2000.
www.acc.org/clinical/guidelines/unstable/unstable.pdf
ACC/AHA Guidelines for the Management of
Patients with Unstable Angina and Non-ST-
Segment Elevation MI
Class IIa indications for revascularization with PCI or
CABG

1. Repeat CABG for patients with multiple saphenous vein graft stenoses,
especially if LAD graft

2. PCI for focal saphenous vein graft lesions or multiple lesions if poor surgical
candidate

3. PCI or CABG for patients with 1 or 2 vessel CAD, not proximal LAD, but
moderate area of viability and ischemia

4. PCI or CABG for patients with 1 vessel CAD with proximal LAD

5. CABG with Internal Mammary artery for patients with multivessel CAD and
diabetes
ACC/AHA Guidelines for the Management of
Patients with Unstable Angina and Non-ST-
Segment Elevation MI
Braunwald. Circulation. 2002;106:1893-2000.
www.acc.org/clinical/guidelines/unstable/unstable.pdf
Cardiac Catheterization
Coronary Artery Disease
Left Main Disease
Discharge from Protocol NO
CABG
1 or 2 Vessel
Disease
PCI or CABG,
if eligible
3 Vessel Disease
or 2 Vessel Disease with
proximal LAD involvement
Left Ventricular Dysfunction
or Treated Diabetes
CABG
PCI or CABG
YES
NO
NO
YES
Smith et al. ACC/AHA PCI Guidelines. J Am Coll
Cardiol 2001:2239-lxvi.
Recommendations for Revascularization
UA/NSTEMI
High Risk
*
ASA, Heparin/Enox.,
block., Nitrates, Clopidogrel


RISK STRATIFY
Low Risk
Braunwald E, et al.
Circ. 2002;106:1893.

* Recurrent ischemia; Trop; ST; LV failure/dysf.;
hemodynamic instability; VT; prior CABG
Enoxeparin. Preferred to UFH (IIa)

If coronary arteriography >24 hours
ACC/AHA REVISED GUIDELINES
Braunwald E, et al.
Circ. 2002;106:1893.
LMCD, 3VD+LV Dys.,
or Diab. Mell.
CABG
High Risk
Cor. Arteriography
1 or 2VD, Suitable
for PCI
Normal
Clopidogrel,
IIb/IIIa inhib.
Consider Alternative
Diagnosis
Discharge on ASA, Clopidogrel, Statin, ACEI
PCI
ACC/AHA REVISED GUIDELINES
I IIa IIb III
Braunwald. Circulation 2002;106:1893-2000.
www.acc.org/clinical/guidelines/unstable/unstable.pdf
Discharge/Post-discharge Medications
ASA, if not contraindicated
Clopidogrel, when ASA contraindicated
Aspirin + Clopidogrel, for up to 9 months
-blocker, if not contraindicated
Lipid agents (statins) + diet
ACE Inhibitor: CHF, EF < 40%, DM, or HTN
0 3 18 21 24 27 30 6 9 12 15
%

w
i
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E
v
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t

Months of follow up
Pravastatin 40 mg
(26.3%)
Atorvastatin 80 mg
(22.4%)
16% RR
(P = 0.005)
30
25
20
15
10
5
0
All-Cause Death or Major Cardiovascular
Events in All Randomized Subjects
Cannon CP, et al. N Engl J Med. 2004;350:1495-1504.
2-Year Event Rates
RR Atorva 80 Prava 40
28% 2.2% 3.2%
30% 1.1% 1.4%
13% 6.6% 7.4%
18% 8.3% 10.0%
14% 16.3% 18.8%
29% 3.8% 5.1%
14% 19.7% 22.3%
0.5 1.0 1.5
All-cause Mortality
Death or
MI
MI
Revasc >30 d
UA Requiring
Hospitalization
0.75 1.25
Atorvastatin 80 mg Better Pravastatin 40 mg Better
CHD-related Death
Death/MI/Urgent
Revascularization
Cannon CP, et al. N Engl J Med. 2004;350:1495-1504.
Reductions in Major Cardiac End Points
I IIa IIb III
Risk Factor Modification
Smoking Cessation Counseling
Dietary Counseling and Modification
Cardiac Rehabilitation Referral
HTN Control (BP <130/85 mm Hg)
Tight Glycemic Control in Diabetics
Braunwald. Circulation. 2002;106:1893-2000.
www.acc.org/clinical/guidelines/unstable/unstable.pdf
Approximately 5 million Americans have heart failure
(male to female ratio 1:1)
550,000 new cases annually
Hospital discharges 1,000,000 annually
80% of men and 70% of women under the age of 65 with
HF will die within eight years
Heart Failure Due to
LV Systolic Dysfunction
Numbers based on 2000 data.
American Heart Association. 2003 Heart and Stroke Statistical
Update. Dallas, Tex: AHA; 2002.
Myocardial injury to the heart (CAD, HTN, CMP, valvular disease)
Morbidity and mortality
Arrhythmias
Pump failure
Peripheral vasoconstriction
Hemodynamic alterations
Heart failure symptoms
Remodeling and progressive
worsening of LV function
Initial fall in LV performance, wall stress
Activation of RAS and SNS
Fibrosis, apoptosis,
hypertrophy, cellular/
molecular alterations,
myotoxicity
Fatigue
Activity altered
Chest congestion
Edema
Shortness of breath
Neurohormonal Activation in
Heart Failure
RAS, renin-angiotensin system; SNS, sympathetic
nervous system.
1 week 3 months
EDV 137 mL ESV 80 mL
EF 41%
EDV 189 mL ESV 146 mL
EF 23%
Apical 4 Chamber View
LV Remodeling Post Anteroseptal MI
1. ACE-inhibitors
2. Beta-blockers
3. Angiotensin receptor blockers
4. Aldosterone antagonists
5. Loop diuretics
6. Nitrates with hydralazine
7. Digoxin
8. Nesiritide, inotropic agents
Drugs for Heart Failure
Enlightened Polypharmacy
SAVE - captopril, 1992. Post-MI (not CHF) with EF < 40%,
f/u 42 mos, 2,231 pts. Mortality reduced from 25% to 20%
N Engl J Med. 1992;327:669.
SOLVD - enalapril, 1991. CHF pts, class II-III, EF < 35%,
f/u 41 mos, 2,569 pts. Mortality reduced from 39% to 35%
N Engl J Med. 1991;325:293.
SOLVD - enalapril, 1992. Asymptomatic LV dysfunction,
EF < 35%, f/u 37 mos, 4,228 pts. Non-significant reduction
in mortality, significant reduction in CHF and
hospitalization.
N Engl J Med. 1992;327:685.

ACE - Inhibitation and CHF Trials
Captopril, enalapril, ramipril, quinapril, lisinopril
32 trials, 7,105 patients, FC II - III
2 mortality trials
Combined - total mortality reduced 21.9% to 15.8%, and
total mortality plus CHF hosp reduced 32.6% to 22.4%.
Summary:
1. Improvement in risk of death or MI or CHF hospitalization
2. Class effect

ACE - I and CHF: Meta-analysis
JAMA. 1995;273:1450.
Catecholamine levels are increased in CHF
Higher levels correlate with worse disease severity
Catecholamines contribute to myocyte hypertrophy and
necrosis (apoptosis)
More ischemia, arrhythmia, vasoconstriction, and LV
dilatation

Beta Blockade: Rationale
MERIT - HF: Metoprolol tartrate
Preceded by two previous trials in CHF (MDC,
RESOLVD)
3,991 pts, mean f/u 12mos, class II - III
Mean EF 28%
Results - stopped early as total mortality + all cause
hospitalization was reduced 38% to 32% (p = .00012)
and total mortality reduced 10.8% to 7.2 % (p < .0001)


Metoprolol
JAMA .2000;283:1295.
0 0.5 1 1.5 2 2.5
Carvedilol
n = 975
Placebo
n = 984
Years
P
r
o
p
o
r
t
i
o
n

E
v
e
n
t
-
f
r
e
e

23%

P = .031
The CAPRICORN Investigators. Lancet. 2001;357:13851390.
Risk reduction
Mortality rates: Placebo 15%; Carvedilol 12%
0
1.00
0.90
0.70
0.60
0.80
CAPRICORN:
Carvedilol in Post-MI patients with Reduced EF:
All-cause Mortality
Inclusion - EF < 25%, class III - IV, euvolemic
2,289 pts, mean f/u 10.4 mos, stopped early
Mortality 18.5% (placebo) vs. 11.4% with carvedilol 35%
reduction (p < .00013)
No difference in withdrawal rates
Mortality curves diverge w/in three weeks, thus beneficial
effects are not delayed and can occur at low dose

COPERNICUS:
Carvedilol in Class III - IV Heart Failure
N Engl J Med. 2001;344:1651.
P = .0014

All-cause Mortality
%

S
u
r
v
i
v
a
l

Carvedilol
Placebo
0 3 6 9 12 15 18 21
Months
100
90
80
60
70
0
Packer M et al. N Engl J Med. 2001;344:16511658.
Coreg (carvedilol) Prescribing Information. GlaxoSmithKline,
Research Triangle Park, NC. Mar 2003.
Risk reduction
35%
(19%, 48%)
n = 1156
n = 1133
Mortality rates: Placebo 19.7%; Carvedilol 12.8%
COPERNICUS
First head-to-head mortality study comparing two beta-
blocking agents in CHF - carvedilol vs. short-acting
metoprolol titrate
3,029 pts, class II - III, EF < 35%, 80% male, 99%
Caucasian
Carvedilol compared to metoprolol reduced annual
mortality from 10.0% to 8.3% and prolonged median
survival by 1.4 years

COMET
Lancet. 2003;362:7.
Ischemic or non-ischemic CMP
All symptomatic CHF patients
Class II - IV
Hemodynamically stable and euvolemic
Even in compensated patients as there is a high
likelihood of symptom progression in 12 months
Beneficial effects are in addition to effects of other
therapies
Beta Blockers for CHF: Summary
Trial Drugs Baseline EF
Mortality vs.
ACE-I
Notes
RESOLVD
1999
Candesartan vs
enalapril
Avg 27%
6.1 vs. 3.7
(p = NS)
ELITE II 2000
Losartan vs.
captopril
< 40%
17.7 vs. 15.9
(p = NS)
ValHeft 2001 Valsartan < 40%
19.9 vs. 19.4
(p = NS)
33% decreased
mortal if not on
ACE-I
CHARM 2003 Candesartan
Small decrease
in mortality
when added to
ACE-I
No increased
mortality w/
beta-blocker
Angiotensin Receptor Blockers in CHF
ARBs should be used in patients intolerant of ACE
inhibitors.
ARBs can be added on in patients receiving ACE-
inhibitors and beta blockers with a small added benefit.
Increased risk of hypotension, hyperkalemia, and renal
insufficiency when added on to ACE-I and beta-blocker
therapy.

Angiotensin Receptor Blockers in CHF:
Summary
Study Drug Patients
Added
therapy
Mortality
vs. placebo
Hyper-
kalemia
RALES
1999
spironolactone
Class III
and IV CHF
ACE-I, no
beta-blocker
Reduced
from 46.3%
to 35%
(p < .001)
2%
EPHESUS
2003
eplerenone
Post-MI w/
EF < 40% or
diabetes
ACE-I and
beta-blocker
Reduced
from 14.6%
to 8.5%
(p = .008)
5.5%
Aldosterone Blockers in CHF
Aldosterone blockers should be used in patients with
chronic heart failure with low EF (spironolactone) and in
patients post-MI and heart failure with EF < 40% or
diabetes mellitus (eplerenone)
Contraindications - renal insufficiency (creat > 2.5 mg%)
or hyperkalemia (over 5.0)
Patients on aldosterone blockers must have renal
function and electrolytes carefully and frequently
monitored

Aldosterone Blockers: Summary
1997, CHF with EF < 45%, NSR, class I - III
6,800 pts, 94% ACE - I, little beta-blocker, f/u 37 mos
Total and CV mortality - no significant differences
Decreased need for hospitalization for CHF, 2% hosp for
dig toxicity
Summary - use digoxin for symptomatic benefit, not
mortality benefit
Digoxin and CHF: Dig Trial
N Engl J Med. 1997; 336:525.
V-HeFT I - 1986: preceded use of ACE-I and beta
blockers for CHF
Placebo vs. prazosin vs. combined isosorbide dinitrate
(avg. 136 mg) with hydralazine (avg. 270 mg)
642 pts, EF < 45%
All cause mortality improvement only with ISDN +
Hydralazine (p = .04)
Recommend - use for pts unable to take ACE-I or ARBs.
Vasodilators and CHF
N Engl J Med. 1986;314:1547.
Therapy with ISDN and hydralazine added on to
standard CHF therapy
1,050 black patients; class III - IV heart failure, EF < 45%
76% on ACE-I/ARB, 74% on beta-blocker
Mortality reduced from 10.2% to 6.2% at 10-month
followup (p = 0.02)

Vasodilator Therapy: A-Heft
N Engl J Med. 2004;351:2049.
A-Heft: Kaplan-Meier Estimates of Overall
Survival
Inpatient intravenous infusion
Arterial and venodilator
Natriuresis and diuresis
No tolerance or proarrhythmia
Associated with hypotension
Rapid fall in PCWP
No adverse effect on mortality
NESERITIDE (BNP)
ACC/AHA Guidelines (Circ. 2001;104:2996.)
1. For symptomatic systolic dysfunction (Stage C):
Class III (i.e., NOT indicated) - Long term intermittent use of an
infusion of a positive inotropic drug (level of evidence C)
2. For refractory end-stage CHF (Stage D):
Class IIb - Continuous intravenous infusion of a positive inotropic
agent for palliation of symptoms (level of evidence C)
Class III (NOT indicated) - Routine intermittent infusions (level of
evidence B)


Intravenous Inotropic Agents
Ischemia, arrhythmias, conduction abnormalities
Worsening valve regurgitation
Hypertension, bilateral renal artery stenosis
Anemia, thyroid disease, infection, renal failure,
obstructive sleep apnea, medication noncompliance
Search for Aggravating Medical
Conditions
Resynchronization therapy to improve heart failure
(biventricular pacemaker)
Revascularization if documented ischemia
ICD implant to reduce risk of sudden arrhythmic death
Surgery - CABG, valve repair, transplant
Patients Refractory to Pharmacologic
Therapy
1. Hochman JS, Sleeper LA, Webb JG, et al. Early
revascularization in acute myocardial infarction complicated
by cardiogenic shock. N Eng J Med. 1999;341:625-634.
2. Clopidogrel in Unstable Angina to Prevent Recurrent Events
Trial Investigators. Effects of clopidogrel in addition to
aspirin in patients with acute coronary syndrome without ST
segment elevation. N Eng J Med. 2001;345:494-502.
3. Braunwald E, Antman EM, Beasley JW. ACC/AHA
guideline update for the management of patients with
unstable angina and non-ST segment elevation myocardial
infarction-2002: summary article. A report of the ACC/AHA
Task Force on Practice Guidelines. Circulation.
2002;106:1893-1900.


Selected References
4. McMurray JJ, Ostergren J, Swedberg K, et al, CHARM
Investigators and Committees. Effects of candesartan in
patients with chronic heart failure and reduced left
ventricular systolic function taking angiotensin converting
enzyme inhibitors: the CHARM-added trial. Lancet.
2003;362:767-771.
5. Packer M, Coats AJ, Fowler MB, et al, Carvedilol
Prospective Randomized Cumulative Survival Study Group.
Effect of carvedilol on survival in severe chronic heart
failure. N Eng J Med. 2001;344:1651-1658.
Selected References