Cardiogenic Shock - FINAL.ppt

5/19/2018 Cardiogenic Shock - FINAL.ppt

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Fredric Ginsberg, MDAssistant Professor of Medicine, Robert Wood Johnson Medical School

University of Medicine and Dentistry of New Jersey

Joseph E. Parrillo, MDProfessor of Medicine, Robert Wood Johnson Medical School

University of Medicine and Dentistry of New JerseyHead, Division of Cardiovascular Diseaseand Critical Care Medicine

Director, Cooper Heart InstituteDirector, Cardiovascular and Critical Care Services

Cooper University HospitalCamden, New Jersey

SCCM Online Critical Care Course:

Cardiogenic Shock, Acute CoronarySyn

drome and Congestive

Heart Failure


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Inadequate tissue perfusion resulting from cardiac

dysfunction

Clinical definition - decreased cardiac output and tissue

hypoxia in the presence of adequate intravascularvolume

Hemodynamic definition - sustained systolic BP < 90 mm

Hg, cardiac index < 2.2 L/min/m2, PCWP > 15 mm Hg

Parrillo, J. 2005

Cardiogenic Shock


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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


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Evolution Of The DiseaseFrequently, 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


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Wall motionabnormality

duringocclusion

Wall motionabnormality

From Kloner RA. Am J Med.1986;86:14.

Gradual return offunction (hours to days)

Persistent wallmotion abnormality(despite reperfusionand viable myocytes)

Coronary occlusion

Coronary reperfusion

Return of

function

Clamp

Schematic Diagram of Stunned

Myocardium


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Atherosclerotic narrowing

Wall motion abnormalitydue to chronic ischemia

without infarction

Wall motion abnormality

From Kloner RA. Am J Med. 1986;86:14.

Hibernating Myocardium


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Pre-operative8 Months

Postoperative

CONTROLLVEDV = 128

EF = 0.37

POST NTGLVEDV = 101

EF = 0.51

LVEDV = 104EF = 0.76

Patient Coronary BypassGraft to L.A.D.

Single vessel disease - OccludedL.A.D.

End-DiastoleEnd-Systole

From Rahimtoola SH, et al. Circ. 1992;65:225.

Hibernating Myocardium


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Cell deathSignificant

residualstenosis

Reperfusion

Segments with

myocardialstunning

Segments with

both stunningandhibernation

Segments with

hibernatingmyocardium

Relief ofischemia

Inotropic

supportNo return

of function

Return ofmyocardial function

Ischemic Myocardium


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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


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Reduces afterload and augments diastolic perfusionpressure

Beneficial effects occur without increase in oxygendemand

No improvement in blood flow distal to critical coronarystenosis

No improvement in survival when used alone

May be essential support mechanism to allow fordefinitive therapy

Intra-aortic Balloon Counterpulsation


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Overall 30-Day Survival in the Study

Hochman JS, et al. N Engl J Med. 1999;341:625-34.

Proportion

Alive

0

Days after Randomization

0.6

0.2

0.0

0.8Revascularization (n =152)

Medicaltherapy (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


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46.750.3 54.3

56

63.166.4

0

20

40

60

80

100

%

P = 0.11 P = 0.027 P < 0.03

30 days 6 months 1 year

Revasc

MedRx

SHOCK Trial Mortality


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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 rapidrevascularization (PCI or CABG) if it can be performed

within 18 hours of onset of shock. (Level of Evidence: A)

ACC/AHA Class I Indication


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Despite ACC/AHA recommendation to treat patients < 75

years of age aggressively with early mechanical

revascularization, in 2001, two years after the guidelineswere 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 ofguideline recommended therapy.

Babaev A, et al. Circ. 2002;106(19):1811 (abstract).

National Registry of MI Early

Revascularization is Underutilized in

Cardiogenic Shock


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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 notelevated 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 ClassicParadigm


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Cardiogenic shock IS NOT simply the result of severedepression of LV function due to extensive myocardialischemia/injury.

Depressed Myocardial Contract i l i tycombined withInadequate Systemic Vasoconstr ict ionresulting froma systemic inflammatory response to extensivemyocardial ischemia/injury results in cardiogenic shock .

Pathophysiology of Cardiogenic Shock


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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 MyocardialDepression and Inappropriate

Vasodilatation.


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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 mayinvolve 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.


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Acu te 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 ang ina:

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


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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


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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.


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Therapeutic goal: rapidly break apart

fibrin mesh to quickly restore blood flow

ST-segment elevation MI Non-ST Elevation ACS* Non-ST Elevation MI

+ Troponinor + 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
http://www.acc.org/clinical/guidelines/unstable/unstable.pdfhttp://www.acc.org/clinical/guidelines/unstable/unstable.pdf


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0.00

0.05

0.10

0.15

0.20

0.25

0 3 6 9 12

Probability

ofDeatho

rMI

Placebo

Aspirin 75 mg

Risk ratio 0.5295% 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


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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

BetterUFH

Better

6

14

14

14

Day:

Braunwald. Circulation. 2002;106:1893-2000.


Low Molecular Weight Heparin (LMWH) vs.

Unfractionated Haparin (UFH) in Non-ST elevation

ACS: Effect on Death, MI, Recurrent Ischemia


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0

2

4

6

8

10

12

14

Death,

MI,orStroke

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


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15.7

5.6

17.9

11.7

12.814.2

3.8

12.9

10.311.8

0

5

10

15

20

P

rimaryEndpoint%

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


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I IIa IIb III

Hospital Care

Anti-Thrombotic Therapy

Immediate aspirin

Clopidogrel, if aspirin contraindicated

Aspirin + clopidogrel for up to one month, ifmedical 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




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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



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


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I IIa IIb III

* High-risk: Age >75; prolonged, ongoing CP; hemodynamic instability;

rest CP w/ ST ; VT; positive cardiac markers



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 notplanned

Any GP IIb/IIIa inhibitor for patients already on

ASA + Heparin + clopidogrel, if cath/PCI isplanned


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I IIa IIb III



Hospital Care

Platelet GP IIb/IIIa Inhibitors (2)

Eptifibatide or tirofiban + ASA/Heparin for

patients without continuing ischemia in whomPCI is not planned

Abciximab for patients in whom PCI is not

planned


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I IIa IIb III



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


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I IIa IIb III



Hospital Care

Anti-ischemic Therapy (2)

ACE inhibitor for all ACS pts

Extended-release Ca2+ blocker instead of -

blockerImmediate-release Ca2+ blocker with -blocker

Long-acting Ca2+ blocker for recurrentischemia, if no contraindications and NTG + -blocker used fully


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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


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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.


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20.316.1

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

eath/MI/ACSR

ehosp(%)

TIMI Risk Score

CONS

% of Pts: 25% 60% 15%

INV

OR = 0.75CI (0.57, 1.00)

OR = 0.55CI (0.33, 0.91)

TIMI UA Risk Score:

Primary Endpoint at 6 months


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Cannon. J Invas Cardiol. 2003;15:22B.

Troponin and ST-Segment Shift Predict

Benefit of Invasive Treatment Strategy


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Class I

Anear ly invasivestrategy in patients with ahigh-r iskindicator:

1. Recurrent angina/ischemia despite intensive anti-ischemic rx2. Elevated troponin-T or troponin-I

3. New or presumably new ST-segment depression4. Recurrent angina/ischemia with CHF sx, S3, pulmonary edema, worsening

rales, or new or worsening MR5. High-risk findings on noninvasive stress testing6. Depressed LV systolic function (EF


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Start immediateAspirin

Heparin or low-molecular-weight heparin

GP IIb-IIIa inhibitor

Adapted from Braunwald E, et al. 2002.


At presentationST-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 informationNo clopidogrel within 5-7 days prior to CABG surgeryNo 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


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Recurrent

Symptoms/ischemia

Heart failure

Serious arrhythmia

Patient

stabilizes

EF

.40Stress 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.


Ongoing Evaluation in an Early

Conservative Strategy


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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

angiography12-24 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



ACC/AHA Guidelines for Unstable Angina and Non-

ST-Segment Elevation MI Acute Ischemia Pathway

ACC/AHA G id li f th M t f


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Class I ind icat ions for revascular izat ionwith 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.


ACC/AHA Guidelines for the Management of

Patients with Unstable Angina and Non-ST-

Segment Elevation MI

ACC/AHA G id li f th M t f


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Class IIa indicat ions for revascu lar izat ionwith 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

Patientswith Unstable Angina and Non-ST-

Segment Elevation MI




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Cardiac Catheterization

Coronary Artery Disease

Left Main Disease

Discharge from ProtocolNO

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


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UA/NSTEMI

High Risk *

ASA, Heparin/Enox.,

block., Nitrates, Clopidogrel

RISK STRATIFY

Low Risk

Braunwald E, et al.

Circ. 2002;106:1893.

* Recurrent isch emia; Trop; ST; LV failure/dys f.;hemodynamic instabi l i ty ; VT; pr ior CABG

Eno xepari n. Preferred to UFH (IIa)

If coronary arter iography >24 hours

ACC/AHA REVISED GUIDELINES


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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 PCINormal

Clopidogrel,

IIb/IIIa inhib.Consider Alternative

Diagnosis

Discharge on ASA, Clopidogrel, Statin, ACEI

PCI

ACC/AHA REVISED GUIDELINES


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I IIa IIb III

Braunwald. Circulation 2002;106:1893-2000.


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

All C D th M j C di l


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0 3 18 21 24 27 306 9 12 15

%w

ith

Event

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.


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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


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I IIa IIb III

Risk Factor Modification

Smoking Cessation Counseling

Dietary Counseling and Modification

Cardiac Rehabilitation Referral

HTN Control (BP


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Approximately 5 million Americans have heart failure

(male to female ratio 1:1)

550,000 new cases annuallyHospital 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.

Neurohormonal Activation in


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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.


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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

Drugs for Heart Failure


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1. ACE-inhibitors

2. Beta-blockers

3. Angiotensin receptor blockers

4. Aldosterone antagonists

5. Loop diuretics

6. Nitrates with hydralazine

7. Digoxin8. Nesiritide, inotropic agents

Drugs for Heart Failure

Enlightened Polypharmacy

ACE I hibit ti d CHF T i l


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SAVE -captopril, 1992. Post-MI (not CHF) with EF < 40%,

f/u 42 mos, 2,231 pts. Mortality reduced from 25% to 20%

NEngl 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

ACE I d CHF M t l i


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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%, andtotal 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.

B t Bl k d R ti l


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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

M t l l


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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 causehospitalization was reduced 38% to 32% (p = .00012)and total mortality reduced 10.8% to 7.2 % (p < .0001)

Metoprolol

JAMA .2000;283:1295.

CAPRICORN:


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0 0.5 1 1.5 2 2.5

Carvedilol

n = 975

Placebo

n = 984

Years

ProportionE

vent-free

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

COPERNICUS:


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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.

COPERNICUS


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P = .0014

All-cause Mortality

%S

urvival

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

COMET


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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.

Beta Blockers for CHF: Summary


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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 othertherapies

Beta Blockers for CHF: Summary

Angiotensin Receptor Blockers in CHF


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Trial Drugs Baseline EFMortality vs.

ACE-I

Notes

RESOLVD

1999

Candesartan vs

enalaprilAvg 27%

6.1 vs. 3.7

(p = NS)

ELITE II 2000Losartan 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 increasedmortality w/

beta-blocker

Angiotensin Receptor Blockers in CHF

Angiotensin Receptor Blockers in CHF:


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ARBs should be used in patients intolerant of ACEinhibitors.

ARBs can be added on in patients receiving ACE-

inhibitors and beta blockers with a small added benefit.Increased risk of hypotension, hyperkalemia, and renalinsufficiency when added on to ACE-I and beta-blockertherapy.

Angiotensin Receptor Blockers in CHF:

Summary

Aldosterone Blockers in CHF


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Study Drug PatientsAdded

therapy

Mortality

vs. placebo

Hyper-

kalemia

RALES

1999spironolactone

Class III

and IV CHF

ACE-I, no

beta-blocker

Reduced

from 46.3%

to 35%

(p < .001)

2%

EPHESUS

2003eplerenone

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: Summary


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Aldosterone blockers should be used in patients withchronic heart failure with low EF (spironolactone) and inpatients post-MI and heart failure with EF < 40% ordiabetes mellitus (eplerenone)

Contraindications - renal insufficiency (creat > 2.5 mg%)or hyperkalemia (over 5.0)

Patients on aldosterone blockers must have renalfunction and electrolytes carefully and frequently

monitored

Aldosterone Blockers: Summary

Digoxin and CHF: Dig Trial


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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 fordig toxicity

Summary - use digoxin for symptomatic benefit, notmortality benefit

Digoxin and CHF: Dig Trial

N Engl J Med. 1997; 336:525.

Vasodilators and CHF


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V-HeFT I - 1986: preceded use of ACE-I and betablockers 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.

Vasodilator Therapy: A-Heft


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Therapy with ISDN and hydralazine added on tostandard 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-monthfollowup (p = 0.02)

Vasodilator Therapy: A-Heft

N Engl J Med. 2004;351:2049.

A-Heft: Kaplan-Meier Estimates of Overall


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A Heft: Kaplan Meier Estimates of Overall

Survival

NESERITIDE (BNP)


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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)

Intravenous Inotropic Agents


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ACC/AHA Guidelines (Circ. 2001;104:2996.)

1. For symptomatic systolic dysfunction (Stage C):Class III (i.e., NOT ind icated)- Long term intermittent use of aninfusion 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 inotropicagent for pal l ia tion of symp toms (level of evidence C)

Class III (NOT ind icated)- Routine intermittent infusions (level ofevidence B)

Intravenous Inotropic Agents

Search for Aggravating Medical


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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

Patients Refractory to Pharmacologic


77/79

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

y g

Therapy

Selected References


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1. Hochman JS, Sleeper LA, Webb JG, et al. Early

revascularization in acute myocardial infarction complicatedby cardiogenic shock. N Eng J Med. 1999;341:625-634.

2. Clopidogrel in Unstable Angina to Prevent Recurrent EventsTrial Investigators. Effects of clopidogrel in addition toaspirin 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/AHAguideline update for the management of patients withunstable angina and non-ST segment elevation myocardialinfarction-2002: summary article. A report of the ACC/AHA

Task Force on Practice Guidelines. Circulation.2002;106:1893-1900.

Selected References

Selected References


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4. McMurray JJ, Ostergren J, Swedberg K, et al, CHARMInvestigators 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

Documents

Cardiogenic Shock - FINAL.ppt