Fredric Ginsberg, MD

1
SCCM Online Critical Care Course Cardiogenic
Shock, Acute Coronary Syndrome and Congestive
Heart Failure

• 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
  JerseyHead, Division of Cardiovascular
  Diseaseand Critical Care MedicineDirector,
  Cooper Heart InstituteDirector, Cardiovascular
  and Critical Care ServicesCooper University
  HospitalCamden, New Jersey

2
Cardiogenic Shock

• 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 15
  mm Hg

Parrillo, J. 2005
3
Causes of 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

4
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. 199591873-81. GUSTO
J Amer Coll Cardiol. 199526668-74.
5
Schematic Diagram of StunnedMyocardium
Clamp
Wall motion abnormality
Wall motion abnormality during occlusion
Coronary occlusion
Coronary reperfusion
Persistent wall motion abnormality (despite
reperfusion and viable myocytes)
Return of function
Gradual return of function (hours to days)
From Kloner RA. Am J Med. 19868614.
6
Hibernating Myocardium
Wall motion abnormality
Atherosclerotic narrowing
Wall motion abnormality due to chronic
ischemia without infarction
From Kloner RA. Am J Med. 19868614.
7
Hibernating Myocardium
8 Months Postoperative
Pre-operative
Patient Coronary Bypass Graft to L.A.D.
Single vessel disease - Occluded L.A.D.
CONTROL LVEDV 128 EF 0.37
POST NTG LVEDV 101 EF 0.51
LVEDV 104 EF 0.76
End-Diastole End-Systole
From Rahimtoola SH, et al. Circ. 199265225.
8
Ischemic Myocardium
Cell death
Significant residual stenosis
Reperfusion
Segments withmyocardialstunning
Segments withboth stunningand hibernation
Segments withhibernatingmyocardium
Inotropicsupport
Relief of ischemia
No returnof function
Return ofmyocardial function
9
Initial Approach Management

• 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

10
Intra-aortic Balloon Counterpulsation

• 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

11
Early Revascularization in Acute Myocardial
Infarction Complicated by Cardiogenic Shock
Overall 30-Day Survival in the Study
1.0
0.8
Revascularization (n 152)
Survival 53
0.6
Proportion Alive
0.4
Medical therapy (n 150)
Survival 44
0.2
p 0.11
0.0
0
5
10
15
20
25
30
Days after Randomization
Hochman JS, et al. N Engl J Med. 1999341625-34.
12
SHOCK Trial Mortality
100
P 0.11
P 0.027
P
80
66.4
63.1

56
54.3
60
50.3
46.7
40
Revasc Med Rx
20
0
30 days
1 year
6 months
13
ACC/AHA Class I Indication

• 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)

14
National Registry of MI Early Revascularization
is Underutilized in Cardiogenic Shock

• Despite ACC/AHA recommendation to treat patients
  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. 2002106(19)1811
(abstract).
15
Pathophysiology of Cardiogenic Shock Observations
from the SHOCK Trial and Registry that Challenge
the Classic Paradigm

• 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 .20031072998-3002.
16
Pathophysiology of Cardiogenic Shock

• 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 .

17
The Overproduction of Nitric Oxide May Cause Both
Myocardial Depression and Inappropriate
Vasodilatation.

• Thus, excess nitric oxide and peroxy nitrites may
  be a major contributor to cardiogenic shock
  complicating MI.

18
LINCS Conclusions

• 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.

Cotter. Eur Heart J. 2003241287-1295.
19
Acute Coronary Syndromes Definitions

• 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 1061893-2000. www.ac
c.org/clinical/guidelines/unstable/unstable.pdf
20
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21
Pathogenesis of Acute Coronary Syndromes
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 199780 (4A)2B-10B.
22
Structure of Thrombus Following Plaque Disruption
UA/NSTEMIPartially-occlusive thrombus
(primarily platelets)
STEMIOcclusive thrombus (platelets, red blood
cells, and fibrin)
Intra-plaque thrombus
(platelet-dominated)
Intra-plaque thrombus
(platelet-dominated)
Plaque core
Plaque core
UA Unstable Angina NSTEMI Non-ST-segment
Elevation Myocardial Infarction STEMI
ST-segment Elevation Myocardial Infarction
SUDDEN DEATH
White HD. Am J Cardiol 199780 (4A)2B-10B.
23
Diagnostic Algorithm for Acute Coronary Syndrome
Management
Troponinor CK-MB
/or
ST-segment elevation MI
Non-ST Elevation ACS
Non-ST Elevation MI
Therapeutic goal rapidly break apart fibrin mesh
to quickly restore blood flow
Therapeutic goal prevent progression to complete
occlusion of coronary artery and resultant MI or
death
Consider fibrinolytic therapy, if indicated, or
primary percutaneous coronary intervention (PCI)
Consider GP IIb-IIIa inhibitor aspirin
heparin before early diagnostic catheterization
Braunwald E, et al. 2002. http//www.acc.org/clini
cal/guidelines/unstable/unstable.pdf.
24
Risk of MI and Death During Treatment with
Low-Dose Aspirin and IV Heparin in Men with
Unstable CAD
Placebo
Probabilityof Death or MI
Aspirin 75 mg
Risk ratio 0.5295 CL 0.37 - 0.72
0
3
6
9
12
Months
Wallentin LC, et al. J Am Coll Cardiol,
1991181587-93.
25
Low Molecular Weight Heparin (LMWH) vs.
Unfractionated Haparin (UFH) in Non-ST elevation
ACS Effect on Death, MI, Recurrent Ischemia
Day
Trial FRIC (Dalteparin n 1,482) FRAXIS (nadro
parin n 2,357) ESSENCE (enoxaparin n
3,171) TIMI 11B (enoxaparin n 3,910)
?
6
?
14
(p 0.032)
14
?
(p 0.029)
14
?
.75 1.0 1.5
LMWH Better
UFH Better
Braunwald. Circulation. 20021061893-2000.
www.acc.org/clinical/guidelines/unstable/unstable.
pdf
26
Effects of Clopidogrel in Addition to Aspirin in
Patients with ACS without ST-Segment Elevation

14
11.4
Placebo ASA
12
9.3
10
8
Clopidogrel ASA
Death, MI, or Stroke
6
4
20 RRR P
2
0
3
6
9
0
12
Months of Follow-Up
N Engl J Med. 2001345494-502.
27
Platelet Glycoprotein IIb/IIIa Inhibition for
Non-ST elevation ACS Primary Endpoint Results
from the 5 Major Trials
20
Placebo
17.9
GP IIb/IIIa
15.7
14.2
15
12.9
12.8
11.8
11.7
10.3
10
Primary Endpoint
5.6
5
3.8
P 0.04
P 0.01
P 0.004
P 0.48
P 0.33
0
PURSUIT30 days
PRISM48 hrs
PRISM PLUS7 days
PARAGON A30 days
PARAGON B30 days
28
Hospital CareAnti-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. 20021061893-2000. www.ac
c.org/clinical/guidelines/unstable/unstable.pdf
29
Hospital CareClopidogrel Therapy
Aspirin clopidogrel, for up to 1 month
Aspirin clopidogrel, for up to 9 months
Withhold clopidogrel for 5 - 7 days for CABG
Guidelines do not specify initial approach to
using clopidogrel when coronary anatomy is unknown
For patients managed with an early
conservative strategy, and those who are
planned to undergo early PCI
Braunwald. Circulation. 20021061893-2000. www.ac
c.org/clinical/guidelines/unstable/unstable.pdf
30
Hospital CarePlatelet 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
High-risk Age 75 prolonged, ongoing CP
hemodynamic instability rest CP w/ ST ? VT
positive cardiac markers
Braunwald. Circulation. 20021061893-2000. www.ac
c.org/clinical/guidelines/unstable/unstable.pdf
31
Hospital CarePlatelet 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
Braunwald. Circulation. 20021061893-2000. www.ac
c.org/clinical/guidelines/unstable/unstable.pdf
32
Hospital CareAnti-ischemic Therapy (1)
?-blocker (IV?oral) 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
Braunwald. Circulation. 20021061893-2000. www.ac
c.org/clinical/guidelines/unstable/unstable.pdf
33
Hospital CareAnti-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
Braunwald. Circulation. 20021061893-2000. www.ac
c.org/clinical/guidelines/unstable/unstable.pdf
34
ST-segment Depression PredictsHigher Risk of
Mortality in ACS
Cumulative Mortality at 6 Months
ST-segment depression8.9
ST-segment elevation6.8
T-wave inversion3.4
30 60 90 120 150 180
Days from randomization
Savonitto S. J Am Med Assoc. 1999 281 707-711.
35
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36
TIMI Risk Score for UA/NSTEMI7 Independent
Predictors of Higher Risk

• 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
• 6. ST deviation
• 7. Elevated cardiac markers (CK - MB or troponin)

Antman, et al. JAMA. 2000284835-842.


37
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38
TIMI UA Risk ScorePrimary Endpoint at 6 months
OR 0.55 CI (0.33, 0.91)
CONS
INV
OR 0.75 CI (0.57, 1.00)
Death/MI/ACS Rehosp ()
TIMI Risk Score
of Pts 25 60
15
39
Troponin and ST-Segment Shift PredictBenefit of
Invasive Treatment Strategy
Cannon. J Invas Cardiol. 20031522B.
40
ACC/AHA Guideline Update for the Management of
Patients with Unstable Angina and Non-ST-Segment
Elevation MI

• Class I
• An early invasive strategy in patients with a
  high-risk indicator
• Recurrent angina/ischemia despite intensive
  anti-ischemic rx
• Elevated troponin-T or troponin-I
• New or presumably new ST-segment depression
• 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
• 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. 20021061893-2000. www.ac
c.org/clinical/guidelines/unstable/unstable.pdf
41
2002 ACC/AHA Guidelines for theManagement of
High-risk NSTE ACS
At presentationST-segment depression /or
elevated cardiac troponin
Need to immediately arrest thrombus progression
Need to eliminate occlusive ruptured plaque

• Start immediate
• Aspirin
• Heparin or low-molecular-weight heparin
• GP IIb-IIIa inhibitor

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

Adapted from Braunwald E, et al. 2002.
http//www.acc.org/clinical/guidelines/unstable/un
stable.pdf.
42
Ongoing Evaluation in an EarlyConservative
Strategy
Early medical management
Patient stabilizes
Recurrent Symptoms/ischemia Heart
failure Serious arrhythmia
Evaluate LV function
EF ? .40
EF
Stress Test
Not low risk
Low risk
Follow on Medical Rx
Immediate angiography
Braunwald E, et al. 2002. http//www.acc.org/clini
cal/guidelines/unstable/unstable.pdf.
43
ACC/AHA Guidelines for Unstable Angina and
Non-ST-Segment Elevation MI Acute Ischemia
Pathway
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)
Immediate angiography
Recurrent symptoms/ischemia Heart failure
Serious arrhythmia
Evaluate LV Function
EF
Not low risk
Low risk
Braunwald. Circulation. 20021061893-2000. www.ac
c.org/clinical/guidelines/unstable/unstable.pdf
Follow on Medical Rx
44
ACC/AHA Guidelines for the Management of Patients
with Unstable Angina and Non-ST-Segment Elevation
MI
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 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 1061893-2000. www.ac
c.org/clinical/guidelines/unstable/unstable.pdf
45
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
Braunwald. Circulation. 20021061893-2000. www.ac
c.org/clinical/guidelines/unstable/unstable.pdf
46
Recommendations for Revascularization
Cardiac Catheterization
Discharge from Protocol
Coronary Artery Disease
NO
Left Main Disease
CABG
YES
NO
3 Vessel Disease or 2 Vessel Disease
with proximal LAD involvement
1 or 2 Vessel Disease
Left Ventricular Dysfunction or Treated Diabetes
CABG
PCI or CABG, if eligible
YES
NO
PCI or CABG
Smith et al. ACC/AHA PCI Guidelines. J Am Coll
Cardiol 20012239-lxvi.
47
ACC/AHA REVISED GUIDELINES
Recurrent ischemia Trop ST LV
failure/dysf. hemodynamic instability VT
prior CABG ? Enoxeparin. Preferred to UFH
(IIa) ? If coronary arteriography 24 hours
Braunwald E, et al. Circ. 20021061893.
48
ACC/AHA REVISED GUIDELINES
Braunwald E, et al. Circ. 20021061893.
49
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
Braunwald. Circulation 20021061893-2000. www.acc
.org/clinical/guidelines/unstable/unstable.pdf
50
All-Cause Death or Major Cardiovascular Events in
All Randomized Subjects
30
Pravastatin 40 mg (26.3)
25
20
Atorvastatin 80 mg (22.4)
with Event
15
10
16 RR (P 0.005)
5
0
0
3
18
21
24
27
30
6
9
12
15
Months of follow up
Cannon CP, et al. N Engl J Med.
20043501495-1504.
51
Reductions in Major Cardiac End Points
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
All-cause Mortality
MI
Death orMI
Revasc 30 d
UA Requiring Hospitalization
Death/MI/UrgentRevascularization
0.5
1.0
1.5
0.75
1.25
Atorvastatin 80 mg Better
Pravastatin 40 mg Better
Cannon CP, et al. N Engl J Med.
20043501495-1504.
52
Risk Factor Modification
Smoking Cessation Counseling
Dietary Counseling and Modification
Cardiac Rehabilitation Referral
HTN Control (BP
Tight Glycemic Control in Diabetics
Braunwald. Circulation. 20021061893-2000. www.ac
c.org/clinical/guidelines/unstable/unstable.pdf
53
Heart Failure Due toLV Systolic Dysfunction

• Approximately 5 million Americans have heart
  failure (male to female ratio 11)
• 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

Numbers based on 2000 data. American Heart
Association. 2003 Heart and Stroke Statistical
Update. Dallas, Tex AHA 2002.
54
Neurohormonal Activation inHeart Failure
Myocardial injury to the heart (CAD, HTN, CMP,
valvular disease)
Initial fall in LV performance, ? wall stress
Activation of RAS and SNS
Fibrosis, apoptosis,hypertrophy,
cellular/molecular alterations,myotoxicity
Peripheral vasoconstriction Hemodynamic
alterations
Remodeling and progressive worsening of LV
function
Heart failure symptoms
Morbidity and mortality Arrhythmias Pump failure
FatigueActivity altered Chest
congestionEdemaShortness of breath
RAS, renin-angiotensin system SNS, sympathetic
nervous system.
55
LV Remodeling Post Anteroseptal MI
56
Drugs for Heart FailureEnlightened Polypharmacy

• ACE-inhibitors
• 2. Beta-blockers
• Angiotensin receptor blockers
• 4. Aldosterone antagonists
• 5. Loop diuretics
• 6. Nitrates with hydralazine
• 7. Digoxin
• 8. Nesiritide, inotropic agents

57
ACE - Inhibitation and CHF Trials

• SAVE - captopril, 1992. Post-MI (not CHF) with
  EF reduced from 25 to 20
• N Engl J Med. 1992327669.
• SOLVD - enalapril, 1991. CHF pts, class II-III,
  EF reduced from 39 to 35
• N Engl J Med. 1991325293.
• SOLVD - enalapril, 1992. Asymptomatic LV
  dysfunction, EF Non-significant reduction in mortality,
  significant reduction in CHF and hospitalization.
  
• N Engl J Med. 1992327685.

58
ACE - I and CHF Meta-analysis

• 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

JAMA. 19952731450.
59
Beta Blockade Rationale

• 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

60
Metoprolol

• 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

JAMA .20002831295.
61
CAPRICORNCarvedilol in Post-MI patients with
Reduced EFAll-cause Mortality
1.00
Carvedilol n 975
0.90
Risk reduction

• 23

0.80
Proportion Event-free
Placebo n 984
P .031
0.70
0.60
Mortality rates Placebo 15 Carvedilol 12
0
0
0.5
1
1.5
2
2.5
Years
The CAPRICORN Investigators. Lancet.
200135713851390.
62
COPERNICUSCarvedilol in Class III - IV Heart
Failure

• Inclusion - EF
• 2,289 pts, mean f/u 10.4 mos, stopped early
• Mortality 18.5 (placebo) vs. 11.4 with
  carvedilol 35 reduction (p
• No difference in withdrawal rates
• Mortality curves diverge w/in three weeks, thus
  beneficial effects are not delayed and can occur
  at low dose

N Engl J Med. 20013441651.
63
COPERNICUS
All-cause Mortality
100
Carvedilol
90
n 1156
Risk reduction ? 35 (19, 48)
80
Survival
Placebo
P .0014
70
n 1133
Mortality rates Placebo 19.7 Carvedilol 12.8
60
0
Packer M et al. N Engl J Med. 200134416511658.
Coreg (carvedilol) Prescribing Information.
GlaxoSmithKline, Research Triangle Park, NC. Mar
2003.
64
COMET

• 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 99 Caucasian
• Carvedilol compared to metoprolol reduced annual
  mortality from 10.0 to 8.3 and prolonged median
  survival by 1.4 years

Lancet. 20033627.
65
Beta Blockers for CHF Summary

• 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

66
Angiotensin Receptor Blockers in CHF
67
Angiotensin Receptor Blockers in CHFSummary

• 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.

68
Aldosterone Blockers in CHF
69
Aldosterone Blockers Summary

• 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 (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

70
Digoxin and CHF Dig Trial

• 1997, CHF with EF
• 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

N Engl J Med. 1997 336525.
71
Vasodilators and CHF

• 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
• All cause mortality improvement only with ISDN
  Hydralazine (p .04)
• Recommend - use for pts unable to take ACE-I or
  ARBs.

N Engl J Med. 19863141547.
72
Vasodilator Therapy A-Heft

• Therapy with ISDN and hydralazine added on to
  standard CHF therapy
• 1,050 black patients class III - IV heart
  failure, EF
• 76 on ACE-I/ARB, 74 on beta-blocker
• Mortality reduced from 10.2 to 6.2 at 10-month
  followup (p 0.02)

N Engl J Med. 20043512049.
73
A-Heft Kaplan-Meier Estimates of Overall Survival
74
NESERITIDE (BNP)

• 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

75
Intravenous Inotropic Agents

• ACC/AHA Guidelines (Circ. 20011042996.)
• 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)

76
Search for Aggravating MedicalConditions

• Ischemia, arrhythmias, conduction abnormalities
• Worsening valve regurgitation
• Hypertension, bilateral renal artery stenosis
• Anemia, thyroid disease, infection, renal
  failure, obstructive sleep apnea, medication
  noncompliance

77
Patients Refractory to PharmacologicTherapy

• 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

78
Selected References

• Hochman JS, Sleeper LA, Webb JG, et al. Early
  revascularization in acute myocardial infarction
  complicated by cardiogenic shock. N Eng J Med.
  1999341625-634.
• 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. 2001345494-502.
• 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. 20021061893-1900.

79
Selected References

• 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.
  2003362767-771.
• 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. 20013441651-1658.