Fredric Ginsberg, MD Fredric Ginsberg, MD Assistant Professor of Medicine, Robert Wood Johnson Medical School University of Medicine and Dentistry of New Jersey Joseph E. Parrillo, MD 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 SCCM Online Critical Care Course: Cardiogenic Shock, Course: Cardiogenic Shock, Acute Coronary Syndrome and Acute Coronary Syndrome and Congestive Congestive Heart Failure Heart Failure
Transcript
Fredric Ginsberg, MDFredric Ginsberg, MDAssistant Professor of Medicine, Robert Wood Johnson Medical School
University of Medicine and Dentistry of New Jersey
Joseph E. Parrillo, MDJoseph E. Parrillo, MDProfessor of Medicine, Robert Wood Johnson Medical School
University of Medicine and Dentistry of New JerseyHead, Division of Cardiovascular Disease
and Critical Care MedicineDirector, Cooper Heart Institute
Director, Cardiovascular and Critical Care ServicesCooper University Hospital
Camden, New Jersey
SCCM Online Critical Care Course: SCCM Online Critical Care Course: Cardiogenic Shock, Acute Coronary Cardiogenic Shock, Acute Coronary
Syndrome and Congestive Syndrome and Congestive Heart FailureHeart 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 - s - sustained systolic BP < 90 mm Hg, cardiac index < 2.2 L/min/m2, PCWP > 15 mm Hg
Parrillo, J. 2005
Cardiogenic ShockCardiogenic 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 ShockCauses 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%
Early Revascularization in Acute Myocardial Early Revascularization in Acute Myocardial Infarction Complicated by Cardiogenic ShockInfarction Complicated by Cardiogenic Shock
46.7 50.354.356
63.166.4
0
20
40
60
80
100
%
P = 0.11 P = 0.027 P < 0.03
30 days 6 months 1 year
RevascMed Rx
SHOCK Trial MortalitySHOCK 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 IndicationACC/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 National Registry of MI Early Revascularization is Underutilized in Revascularization is Underutilized in
Cardiogenic ShockCardiogenic 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 Pathophysiology of Cardiogenic Shock Observations from the SHOCK Trial and Observations from the SHOCK Trial and
Registry that Challenge the Classic Registry that Challenge the Classic ParadigmParadigm
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 ShockPathophysiology of Cardiogenic Shock
Thus, excess nitric oxide and peroxy Thus, excess nitric oxide and peroxy nitrites may be a major contributor to nitrites may be a major contributor to cardiogenic shock complicating MI.cardiogenic shock complicating MI.
The Overproduction of Nitric Oxide The Overproduction of Nitric Oxide May Cause Both Myocardial May Cause Both Myocardial
Depression and Inappropriate Depression and Inappropriate Vasodilatation.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: ConclusionsLINCS: 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)
Risk of MI and Death During Treatment with Risk of MI and Death During Treatment with Low-Dose Aspirin and IV Heparin in Men with Low-Dose Aspirin and IV Heparin in Men with
Unstable CADUnstable 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)
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 1.51.5.75 1.0 1.51.5
Low Molecular Weight Heparin (LMWH) vs. Low Molecular Weight Heparin (LMWH) vs. Unfractionated Haparin (UFH) in Non-ST elevation Unfractionated Haparin (UFH) in Non-ST elevation
ACS: Effect on Death, MI, Recurrent IschemiaACS: Effect on Death, MI, Recurrent Ischemia
0
2
4
6
8
10
12
14
Dea
th,
MI,
or
Str
oke
Clopidogrel + ASA
3 6 9
Placebo + ASA
Months of Follow-Up
11.4%
9.3%
20% RRRP < 0.001
N = 12,562
0 12
%%
N Engl J Med. 2001;345:494-502.
Effects of Clopidogrel in Addition to Aspirin in Effects of Clopidogrel in Addition to Aspirin in Patients with ACS without ST-Segment ElevationPatients with ACS without ST-Segment Elevation
15.7
5.6
17.9
11.712.8
14.2
3.8
12.9
10.311.8
0
5
10
15
20
Pri
mar
y E
nd
po
int
%
Placebo
GP IIb/IIIa
PURSUITPURSUIT30 days30 days
PURSUITPURSUIT30 days30 days
PRISM48 hrsPRISM48 hrs
PRISM PLUS7 days
PRISM PLUS7 days
P = 0.04P = 0.04P = 0.04P = 0.04 P = 0.01P = 0.01P = 0.01P = 0.01 P = 0.004P = 0.004P = 0.004P = 0.004
PARAGON A30 days
PARAGON A30 days
P = 0.48P = 0.48P = 0.48P = 0.48
PARAGON B30 days
PARAGON B30 days
P = 0.33P = 0.33
Platelet Glycoprotein IIb/IIIa Inhibition for Non-ST Platelet Glycoprotein IIb/IIIa Inhibition for Non-ST elevation ACS Primary Endpoint Results from the elevation ACS Primary Endpoint Results from the
* For patients managed with an early conservative strategy, and those who are planned to undergo early PCI* 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 Guidelines do not specify initial approach to using clopidogrel when coronary anatomy is unknownclopidogrel when coronary anatomy is unknown
Guidelines do not specify initial approach to using Guidelines do not specify initial approach to using clopidogrel when coronary anatomy is unknownclopidogrel when coronary anatomy is unknown
TIMI Risk Score for UA/NSTEMITIMI Risk Score for UA/NSTEMI7 Independent Predictors of Higher Risk7 Independent Predictors of Higher Risk
Antman, et al. JAMA. 2000;284:835-842.
20.3
16.119.5
11.8
30.6
12.8
0
5
10
15
20
25
30
35
Low 0-2 Intermed. 3-4 High 5-7
Dea
th/M
I/A
CS
Reh
osp
(%
)
TIMI Risk Score
CONS
% of Pts: 25% 60% 15%
INV
OR = 0.75OR = 0.75CI (0.57, 1.00)CI (0.57, 1.00)
OR = 0.55OR = 0.55CI (0.33, 0.91)CI (0.33, 0.91)
TIMI UA Risk Score:TIMI UA Risk Score:Primary Endpoint at 6 monthsPrimary Endpoint at 6 months
Cannon. J Invas Cardiol. 2003;15:22B.
Troponin and ST-Segment Shift PredictTroponin and ST-Segment Shift PredictBenefit of Invasive Treatment StrategyBenefit 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 rx2. Elevated troponin-T or troponin-I3. 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 <40%)7. Hemodynamic instability8. Sustained ventricular tachycardia9. PCI within 6 months10.Prior CABG
Either early invasive or early conservative strategy if not high risk
ACC/AHA Guideline Update for the Management ACC/AHA Guideline Update for the Management of Patients with Unstable Angina and Non-ST-of Patients with Unstable Angina and Non-ST-
Segment Elevation MISegment 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 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 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 the2002 ACC/AHA Guidelines for theManagement of High-risk NSTE ACSManagement of High-risk NSTE ACS
ACC/AHA Guidelines for the Management of ACC/AHA Guidelines for the Management of Patients with Unstable Angina and Non-ST-Patients with Unstable Angina and Non-ST-
Segment Elevation MISegment 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 ACC/AHA Guidelines for the Management of Patients with Unstable Angina and Non-ST-Patients with Unstable Angina and Non-ST-
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 hospitalization2. Class effect
ACE - I and CHF: Meta-analysisACE - 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: RationaleBeta 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)
MetoprololMetoprolol
JAMA .2000;283:1295.
0 0.5 1 1.5 2 2.5
Carvedilol n = 975
Placebo n = 984
Years
Pro
po
rtio
n E
ven
t-fr
ee
23%P = .031
The CAPRICORN Investigators. Lancet. 2001;357:1385–1390.
Risk reduction
Mortality rates: Placebo 15%; Carvedilol 12%
0
1.00
0.90
0.70
0.60
0.80
CAPRICORN:CAPRICORN:Carvedilol in Post-MI patients with Reduced EF:Carvedilol in Post-MI patients with Reduced EF:
All-cause MortalityAll-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:COPERNICUS:Carvedilol in Class III - IV Heart FailureCarvedilol in Class III - IV Heart Failure
N Engl J Med. 2001;344:1651.
P = .0014
All-cause Mortality%
Su
rviv
al
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;344:1651–1658.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%
COPERNICUSCOPERNICUS
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
COMETCOMET
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: SummaryBeta Blockers for CHF: Summary
TrialTrial DrugsDrugs Baseline EFBaseline EFMortality vs. Mortality vs.
ACE-I ACE-I NotesNotes
RESOLVD 1999
Candesartan vs enalapril
Avg 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 increased mortality w/ beta-blocker
Angiotensin Receptor Blockers in CHFAngiotensin 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:Angiotensin Receptor Blockers in CHF:SummarySummary
Study Drug Patients Added therapy
Mortality vs. placebo
Hyper-
kalemia
RALES 1999
spironolactoneClass III
and IV CHFACE-I, no
beta-blocker
Reduced from 46.3%
to 35%
(p < .001)
2%
EPHESUS 2003
eplerenonePost-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 CHFAldosterone 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)
Search for Aggravating MedicalSearch for Aggravating MedicalConditionsConditions
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 PharmacologicPatients Refractory to PharmacologicTherapyTherapy
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 ReferencesSelected 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.
