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Acute Decompensated Heart Failure
for Generalists
Eric M. Siegal, M.D.
University of Wisconsin, Madison
Overview
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Evolving definitions
Epidemiology of ADHF
Goals of acute management
Evolving management paradigms:
 Acute vasoactive therapy
 Prevention of SCD
 Biventricular pacing
 Beta-blockers in the hospital
 How “dry” is “dry”?
Why “ADHF”?
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Growing recognition that “CHF” does not adequately
describe a broad spectrum of disease with multiple causes,
presentations and clinical courses.
Describe acuity, severity and underlying pathophysiology:
 “ADHF with severe systolic dysfunction due to
ischemic cardiomyopathy and mitral regurgitation”
 “Compensated NYHA Class II HF with moderate
diastolic dysfunction due to hypertension and diabetes”
Where possible, treatment is tailored to the definition
Epidemiology and Economic Burden of
HF
American Heart Association. Heart Disease and Stroke Statistics – 2005 Update.
Incidence
550,000/year
Prevalence
5.0 million (2.3%)
Hospitalizations
1,000,000 per year
Cost
$27.9 billion
More Medicare Dollars Spent on
HF Than Any Other Diagnosis
Average inpatient Medicare payment
$5,456/patient
Percent of Medicare patients with HF
readmitted within 6 months
44%
American Heart Association. Heart Disease and Stroke Statistics – 2005 Update.
Hunt SA et al. Circulation 2001;104:2996-3007.
Krumholz HM et al. Arch Intern Med. 1997;157:99-104.
Miller LW et al. Cardiol Clin. 2001;19:547-555.
Estimated Direct and Indirect Costs of
HF: $27.9 Billion
American Heart Association. Heart Disease and Stroke Statistics – 2005 Update.
60% of heart failure costs are incurred in the hospital
Hospitalization
$14.7
Nursing Home
$3.6
Lost Productivity/
Morbidity
$2.6
Home Healthcare
$2.2
Providers
$1.9
Drugs/Durables
$2.9
Prevalence of HF Increases With Age
10
Males
Population (%)
8
Females
6
4
2
0
20–24
25–34
35–44
45–54
55–64
Age (yr)
US, 1988–1994
AHA. Heart Disease and Stroke Statistics—2004 Update
65–74
75+
Explosive Increase in HF
AHA.Heart Disease and Stroke Statistics – 2005 Update
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1979 – 2002: Hospital discharges from HF rose from
377,000 to 970,000 per year
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1992 – 2002: Deaths increased 35.3%
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Number of patients with HF is expected to double in 30
years
What is a “Typical” Presentation of
ADHF?
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Median age: 75
HTN: 72%
DM: 44%
COPD: 31%
CKD: 30%
NYHA class at admission:
(N=11,555)
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ADHERE Registry: 10/01-1/04
I:
II:
III:
IV:
2%
11%
40%
47%
What is a “Typical” Presentation of
ADHF?
Blood Pressure at admission (N=104,573)
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<90 mmHg: 2%
90-140 mmHg: 48%
>140 mmHg: 50%
ADHERE Registry: 10/01-1/04
They’re Sicker Than We Think
Mortality risk after 1st hospitalization for ADHF:
(Age, male gender, ischemia and decreased LVEF worsen prognosis)
In-hospital:
3%
30-day: 7.9%
One year: 30%
Five years: 60%
Baker, DW et al. Am Heart J 2003; 146(2): 258-64
Ho KK, et al. Circulation 1993; 88(1): 107-15
Jong P, et al. Arch Int Med 2002; 162(15) 1689-94
Narang R ,et al. Eur Heart J 1996; 17(9) 1390-1403
Comparative Five Year Mortality
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Adenocarcinoma of the colon (IIIB): 36%
COPD (FEV1 30-39% predicted): 53%
ESRD (dialysis-dependent): 60-80%
Summary
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Incidence of ADHF is skyrocketing. Huge strain on
hospitals and health care financing
Patients are extremely sick
There are not enough cardiologists to manage ADHF
Generalists will need to become expert in managing all but
the sickest patients with ADHF
Heart Failure: A Vicious Cycle
Myocardial Injury
LV dysfunction
Hypotension
Renal hypoperfusion
Activation of RAS and SNS
Oxidative stress, Ischemia
Remodeling
A 2, ADH,
aldosterone
norepi, epi
ANP, BNP
Vasoconstriction, Tachycardia
Sodium/Water Retention
Temporary restoration of BP
and renal perfusion
Heart Failure: A Vicious Cycle
Myocardial Injury
Decreased LV function
Hypotension
Renal hypoperfusion
Activation of RAS and SNS
Oxidative stress
Remodeling
A 2, ADH,
aldosterone
norepi, epi
ANP, BNP
Vasoconstriction,Tachycardia
Sodium/Water Retention
Temporary restoration of BP
and renal perfusion
Pharmacotherapy to Break the Cycle
Myocardial Injury
Decreased LV function
Activation of RAS and SNS
ACE
Angiotensin II
ARB
Aldosterone
Spironolactone,
eplerenone
Vasoconstriction
Na retention
Epi, Norepi
B-blocker
H2O retention
Increased Cardiac
Output
Goals of Acute Management
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Rapidly improve symptoms while preserving organ
function
Restore function to pre-morbid levels
Educate patient and family
Initiate therapies/interventions shown to reduce long-term
mortality
Control costs
Improve quality of life
Reduce mortality
Vasoactive Therapy for ADHF
Parenteral Drugs for ADHF
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Diuretics
Morphine
Vasodilators: nitroglycerin, nesiritide, enalaprilat
Afterload reducers: nitroprusside, hydralazine
Inotropes: dobutamine, milrinone, amrinone, digoxin
What Does the Literature Tell Us?
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Very little
Almost no randomized, placebo-controlled trials of ANY
agent for the management of ADHF.
“Standard of care” is based almost entirely upon expert
opinion and case studies
Conceptual Model For ADHF
Adapted from Stevenson, LW. Eur J Heart Failure 1999; 1: 251-257
Congestion
Hypoperfusion
No
Warm and Dry
Yes
Warm and Wet
No
CI: Nl
PCWP: Nl
CI: Nl
PCWP: High
Cold and Dry
Cold and Wet
Yes
CI: Low
PCWP: Nl
•Fluids
•Inotropes
CI: Low
PCWP: High
•Inotropes
•Vasodilators
•+/- Diuretics
•Diuretics
•Vasodilators
•Diuretics
•Vasodilators
•Inotropes
What About Inotropes?
Abraham WT, et al. JACC 2005;46(1):57-64.
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Retrospective review of 15,230 patients in ADHERE registry
who received milrinone, dobutamine, nitroglycerin or nesiritide
Risk factor and propensity-score adjusted odds ratios for inhospital mortality
Drugs
Mortality: Odds Ratio
NTG vs:
milrinone
dobutamine
0.69 (0.53-0.89)
0.46 (0.37-0.57)
nesritide vs:
milrinone
dobutamine
0.59 (0.48-0.73)
0.46 (0.39-0.56)
More Bad News for Inotropes
Cuffe MS, et al. JAMA 2002; 287:1541-47
OPTIME-CHF Trial:
 Entry criteria: 951 patients with ADHF and systolic dysfxn
who did not require inotropic support.
 Intervention: Milrinone or placebo x 48 hours
 Patients who received Milrinone:
 Trend to increased deaths in-hospital and after 60 days
 Trend to higher incidence of worsening HF,
symptomatic hypotension, new atrial arrhythmias
 Combined endpoint of death or rehospitalization
significantly higher in subgroup with ischemia (36% vs
42%: p=0.01)
Inotropes: Robbing Peter to Pay Paul?
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Pro-arrhythmic
Probably increase mortality in ischemic patients
Ischemic/injured myocardium may “hibernate” as a
protective mechanism
 Inotropes recruit hibernating myocytes and may hasten
cell injury or apoptosis
 Short-term gains appear to be offset by higher mid and
long-term mortality
Vasodilators: Overview
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I.V. vasodilators are a class IB recommendation for
treatment of ADHF
Beneficial effects:
 Decrease pulmonary vascular congestion
 Decrease BP and improve the efficiency of cardiac
work
 Speed symptom relief
 Possibly decrease risk for CCU, mechanical ventilation
 No RCTs
Eur Heart Journal 2005; 26: 384-416
Early Initiation of Vasoactive Therapy:
Clinical Outcomes
Peacock WF, et al. Ann Emerg Med. 2003;42(4):S26.
IV Vasoactives Started
ED
In-patient Unit
(n = 4096)
(n = 3499)
P Value
Mortality (%)
4.3
10.9
<0.0001
Hospital LOS (days, median)
4.5
7.0
<0.0001
4
20
<0.0001
ICU/CCU time (days, median)
2.1
3.0
<0.0001
Invasive procedure (%)
19
27
<0.0001
Prolonged hospitalization
(>7.1 days, 3rd quartile)
26
49
<0.0001
Transfer to ICU/CCU (%)
Emerman C et al. Ann Emerg Med. 2003;42:S36
Fonarow GC for ADHERE Scientific Advisory Committee. Rev Cardiovasc Med. 2003;4(suppl 7):S21
Choices of I.V. Vasodilators
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Nitroglycerin
Nitroprusside
ACE inhibitors (enalaprilat)
Morphine?
Nesiritide (Natrecor)
Nesiritide: Overview
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Recombinant B-naturetic peptide
BNP is released when myocardium is stretched
Effects:
 Natriuresis / diuresis
 Arterial and venous vasodilatation
 Suppression of RAS and catechols
 Indirect increase of cardiac output
Nesiritide: NSGET Trial
Colucci W, et al. NEJM 2000; 343(4): 246-53
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Open label efficacy trial of 432 patients with ADHF—vast
majority with NYHA III or IV sx
6 hour infusion of nesiritide decreased PCWP and
improved symptoms
No acute difference when compared with standard
vasoactive agents (inotropes, nitroglycerin, nitroprusside)
Not powered to look at outcomes
Conclusion: “Intravenous nesiritide is useful for the shortterm treatment of decompensated CHF”
Nesiritide: VMAC Trial
JAMA 2002; 287(12) 1531-40
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Randomized, placebo-controlled, double-dummy trial. 489
patients, all with NYHA class IV CHF.
Nesiritide vs nitroglycerin vs placebo x 3 hours, followed
by nesiritide or NTG x 24 hours
Outcomes:
 Nesiritide decreased PCWP more effectively than NTG
 Nesiritide offered faster symptom relief
 No difference in outcomes btwn nesiritide and NTG
Not So Fast…
Sackner-Bernstein JD, et al. Circulation 2005. 29;111(12):1487-91.
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Retrospective review of 1,269 patients
Risk of worsening renal function compared to control
therapy (inotrope or no inotrope)
Results:
 High dose nesiritide (<3 mcg/kg/min): (RR 1.54; 95%
CI, 1.19 to 1.98; P=0.001).
 Statistically significant effect also noted with any dose
nesiritide
 No differences in mortality or risk of dialysis
And Then The Kicker…
Sackner-Bernstein et al. JAMA 2005;293(15) 1900-1905.
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Meta-analysis of 3 randomized nesiritide trials (VMAC,
NSGET, PROACTION)
Nesiritide vs non-inotrope controls (vasodilators or
diuretics)
Results: 30 day mortality: 7.2% vs 4.0%, P=0.059
Lots of debate over choices of trials and assumptions made
by the authors
“As this is not an analysis based on an adequately powered
prospective trial but rather an analysis pooling data from
existing trials, our finding should be viewed as hypothesis
generating rather than as conclusive evidence of harm.”
What About the Other
Vasodilators?
Are there better choices than nesiritide?
Nitroglycerin
Advantages
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Effective
High comfort level
Established safety profile
Cost (?)
Disadvantages
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Elkayam U, et al. Circulation 1987;76(3):577-84.
Rapid tachyphylaxis
Frequently underdosed
Requires titration in
CCU/IMCU
Dose-limiting sx (20%)
Limited data
Nitroprusside
Advantages
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Afterload reduction
Fine titration
Useful adjunct to
inotropes in cardiogenic
shock
Disadvantages
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ICU and arterial line
Thiocyanate toxicity (esp
in renal/hepatic
insufficiency)
No randomized trials
Nesiritide
Advantages
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Faster than NTG
Easy dosing (no CCU)
Few side effects
Theoretical hemodynamic
and neurohormonal
advantages
Disadvantages
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Safety concerns:
 Mortality
 Renal function
Cost: $380/day
Conclusions
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Inotropes may increase mortality and are unnecessary for
the vast majority of class III-IV ADHF
IV vasodilators are underutilized, especially in “wet”
patients with preserved BP who do not respond to diuretics
Early initiation of vasodilators may improve outcomes
If you stick with nitroglycerin:
 Rapid dose escalation is often necessary
 Side effects may limit titration and efficacy
 Patients must go to CCU or ICU
Jury is still out on nesiritide
Vasodilator Algorithm
Class III or IV ADHF
AND
preserved BP
Immediate
Immediate or early
Expectant
Poor response
to diuretics
Impending resp.
failure
Chest pain
ADHF and HTN
(? first-line)
Prevention of Sudden Cardiac
Death
Implantable CardioverterDefibrillators (ICDs)
ICDs: Rationale
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Sudden cardiac death (SCD) is the second most common
cause of death in patients with HF (after pump failure)
Antiarrhythmics are ineffective if not outright dangerous
Despite Proven Benefit, ICDs are
Underutilized
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4.6 million managed care and Medicare patients
analyzed for diagnosis of SCD and previous MI or
CHF.
Estimated 736 to 1,140 ICD candidates per million
population.
Actual implantations: 416 per million population
Probably even worse for primary prevention
Ruskin JN, et al. J Cardiovasc Electrophysiol. 2002;13(1):38-43.
Primary Prevention Trials
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MADIT-I
MADIT-II
CABG Patch
MUSTT
DINAMIT
CAT
AMIOVERT
ICDs: MADIT-I
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196 patients enrolled
Entry criteria:
Prior MI, NSVT, LVEF <35%, EPS: Inducible
sustained VT not suppressed with procainamide
Intervention: ICD vs amiodarone
Average survival at 4 years:
 ICD: 3.7 years
 Conventional therapy: 2.8 years
Moss AJ, et al. NEJM 1996; 335: 1933
MUSTT
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704 patients enrolled
Entry criteria:
Prior MI, Inducible VT, LVEF <40%
Intervention: No therapy vs EPS-guided antiarrhythmic tx
(drug or AICD)
Outcomes:
 Death at 2 years: 12% vs 18%
 Death at 5 years: 25% vs 32 %
 Mortality reduction due to ICDs, not medication
Buxton AE, et al. Circulation 2002; 106: 2466
MADIT-II
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1232 patients enrolled
Entry criteria:
 MI >30 days prior to enrollment, LVEF<30%
 No EPS done. Presence of VT not an entry criterion
Intervention: ICD vs conventional therapy
Outcomes:
 Prematurely terminated
 Mortality 14.2% (ICD) vs 19.8% (no ICD)
 Sudden death 3.8% vs 10.0%
Moss AJ, et al. NEJM 2002; 346:877
SCD-HeFT
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2521 patients enrolled
Entry criteria:
 LVEF <35%: ischemic and nonischemic CMP
 NYHA II or III CHF
Intervention: ICD, amiodarone or placebo
Outcomes:
Five year mortality:
 ICD: 29%
 Placebo and amiodarone: 36%
 Benefit only seen with LVEF <30%
Bardy, et al. NEJM 2005; 352:225
More for Everyone!
Increasingly broad indications for ICDs:
 Ischemic CMP with inducible VT
 Ischemic CMP with or without VT
 Nonischemic CMP
Who Should Get an ICD?
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Nonischemic cardiomyopathy:
 NYHA class II to III sx
 LVEF < 35%
Ischemic cardiomyopathy:
 NYHA class II to III sx
 LVEF < 35%
 At least 40 days post-MI (DINAMIT)
 No reversible ischemia
 No recent revascularization
Bardy GH et al. NEJM 2005. 20;352(3):225-37.
ICDs: Other Recommendations
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Unclear whether or not ICDs are beneficial in patients with
NYHA class IV HF
Waiting period after MI is controversial
Amiodarone doesn’t improve survival, but does appear to
decrease number of shocks in patients with ICDs
Patients who meet criteria should at least be referred to a
cardiologist for further evaluation
Mechanical Resynchronization
Cardiac Resynchronization Therapy
(CRT)
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What it is:
Using biventricular pacing to re-synchronize LV and RV
contraction in patients with HF and IVCD
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Rationale:
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IVCD and LBBB worsen HF by causing ventricular
dyssynchrony
Patients with HF and IVCD/BBB have increased sx and
worse outcomes than patients with normal ventricular
conduction.
Dual-chamber pacing is associated with poor outcomes.
Biventricular Pacer
Coronary sinus (LV) lead
RV lead
CRT: Outcomes
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Meta-analysis of 3216 patients
Increased likelihood of improving at least one NYHA class
(58% vs 37%)
Reduced hospitalization for CHF (RR 0.65) for patients
with NYHA III or IV CHF
Reduced mortality (RR 0.79) due to fewer deaths from
progressive HF
McCalister FA, et al. Ann Int Med 2004; 141:381-390.
CRT: CARE-HF Trial
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Randomized, controlled trial of 813 patients
Entry criteria:
 IVCD
 NYHA III or IV CHF
 LVEF <35%
Outcomes:
 Decreased mortality: 8.1% vs 13.9% at 29 months
 At 90 days: Improved quality of life (NYHA class 2.1
vs 2.7)
Cleland JGF, et al. NEJM 2005; 352(15):1539-1549
CRT: Recommendations
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Indicated for patients with LBBB or IVCD and:
 LVEF < 35%
 Sinus rhythm
 NYHA III-IV symptoms despite optimal medical mgmt
These patients are also candidates for ICD placement and
should be considered for a dual-function device.
J Am Coll Cardiol. 2005 Sep 20;46(6):1116-43.
Neurohormonal Modulation in
the Hospital
Acute Use of Beta Blockers:
Cognitive Dissonance?
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Chronic use of beta blockers clearly shown to decrease
mortality
All studies initiated therapy in patients with stable patients,
most of whom had class II-III CHF
Starting beta-blockers in decompensated patients is risky.
But…
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Initiation of beta blockers a quality measure, especially
post-MI
If we don’t start therapy in the hospital, will the ball get
dropped?
Dose-Response Effect of Carvedilol
MOCHA: six-month crude mortality as deaths per randomized patientsx100
Bristow, MR et al. Circulation 1996;94:2807-2816
Beta Blockers Are Not Equal
Four beta-blockers shown to decrease mortality in systolic
HF:
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Carvedilol
Metoprolol
Bisoprolol
Bucindolol
COMET Trial: Carvedilol vs Metoprolol
Poole- Wilson PA, et al. Lancet 2003; 362: 7-13
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Multicenter, randomized, controlled trial of 3,029
patients—mean study duration: 58 months
Entry criteria:
 NYHA II- IV CHF
 LVEF <35%
 Previous admission for ADHF
Intervention:
 Metoprolol (target dose: 50 mg bid)
 Carvedilol (target dose: 25 mg bid)
COMET: Mortality
50%
39.50%
33.90%
40%
30%
Metoprolol
Carvedilol
20%
10%
0%
Metoprolol
Carvedilol
Huge Cost Differential
One month supply at doses per COMET Trial:
AWP (drugstore.com)
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Metoprolol tartrate (50 mg bid) $12.09
Carvedilol (25 mg bid) $95.00
Beta Blockers: Bottom Line
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Most of the benefit from carvedilol occurs at low dose
It’s probably reasonable to start beta-blockers in-house,
especially if patient is hypertensive
In non-hypertensive and elderly patients: Start low and
titrate slowly
Metoprolol is good, but carvedilol is better
Many patients cannot afford carvedilol
Conclusions
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Acute and chronic HF may be the single most common
inpatient dx managed by hospitalists/internists
Economic burden is huge and growing
Consider vasodilators in patients with ADHF, preserved
BP.
Inotropes should be reserved for patients with hypotension
and evidence of end-organ hypoperfusion.
Think ICD in any patient with symptomatic HF, EF <35%
and no reversible etiology.
Think CRT for patients with EF <35%, IVCD and sx not
improved with medical therapy
Choose the right beta-blocker and titrate slowly in-house