Transcript 0 - ETSU

Heart Failure
(CHF)
Ram C Sharma, DNB (Med), FRCP (Edin.),
FACC, FSCAI
Associate Professor of Medicine
Div. Of cardiology, Quillen College of Medicine
East Tennessee State University
Johnson City, TN USA
Disclosures: None
Heart Failure
• Definition
• Classification
• Clinical evaluation
• High risk patients
• Diagnosis
• Treatment
• Advanced and emerging therapies
Chronic Heart Failure
• CHF is a progressive disease
• Incidence of heart failure is increasing
worldwide
• Framingham Heart Study: Life time risk of HF
after age 40 is 20%
• HF is 2 times more common in diabetic men and
5 times more common in diabetic women
• HF mortality is increasing, though the overall
CV mortality is declining. Over 55,000 deaths
directly due to HF and in another 262,000 HF
was listed other condition
• From 1994 to 2004 death from HF increased 28%,
CHF: AHA Statistical Update 2011
• Prevalence:
• HF 10/1000
• Mod to severe LVSD 2%
• Mod to severe diastolic dysfunction 6%, mild-mod 21%
• Annual incidence increases with age
• Office and ER visits (2007) 3.4 million
• Annual discharges in 2007 about 1mill, a 175%
increase since 1979 but unchanged since 1997.
• The cost of hospitalizations for heart failure is
twice that for all forms of cancer and myocardial
infarctions combined
• Total annual hospitalization cost $33.2 billion
Mortality
• ADHERE: Inpt. Mortality 4.0%
• OPTIMIZE: 3.8%, 90 d 8.6%
• EuroHeart Failure Survey II (EHJ 2006):
• Median LOS 9 days
• In-hospital morality 6.7%
• UNLOAD (JAAC 2007):
• 200 patients, 45% NHYA IV
• 10% mortality at 90 days
Mortality
• Prognosis from heart failure is poor.
• London Heart Failure Study: 40% of
people died within one year of an initial
diagnosis of heart failure.
• The one-year survival rate for heart
failure is worse than those for breast,
prostate and bladder cancer, better than
those for lung and stomach cancer, and
very similar to that for cancer of the
colon.
Chronic Heart Failure
Common
High economic cost
High morbidity and mortality
Definition
• Heart failure is a complex clinical syndrome that
can result from any structural or functional cardiac
disorder that impairs the ability of the ventricle to
fill with or eject blood.
• HF is not equivalent to cardiomyopathy or to LV
dysfunction; these latter terms describe possible
structural or functional reasons for the
development of HF.
• Instead, HF is defined as a clinical syndrome that
is characterized by specific symptoms (dyspnea
and fatigue) in history and signs (edema, rales) on
the physical examination.
ACC/AHA Heart failure guidelines update 2009
Classification
• Based on systolic LV function
• Systolic vs diastolic
• Left vs right
• Forward vs backward
• Low cardiac output vs high CO
• Current:
• HF with low EF
• HF with preserved EF
ACC/AHA 2005
Clinical Evaluation
• Severity including functional status
• Etiology
• Identify and evaluate noncardiac
disorders and behavior
• Assess volume status
• Identify precipitating factors
• Unusual presentation
Clinical Evaluation
• Symptoms
• Dyspnea
• Fatigue
• Orthopnea, PND
• Exercise intolerance
• Signs: General inspection
• Edema: peripheral, sacral, scrotal
• JVP
• Pulse & BP: p alternans, a fib, low vol, absent pulse
• Rales, signs of pleural effusion
• Third and 4th heart sounds
• Hepatomegaly and ascitis
• Signs of low output state: p cyanosis, cool dry skin, p
alternans.
Precipitants for acute decompensation
•
•
•
•
•
•
Ischemia
Noncompliance: dietary (Na, fluids), meds
Uncontrolled hypertension
Arrhythmias
Acute valvular lesion
Drugs and intoxications
• Alcohol, recreational drugs
• NSAID, steroids, thiozolidinedione, antiplatlet
• Noncardiac conditons
• Fever, sepsis
• Respiratory failure, PE, hypoxia
• Anemia
• Endocrine disorders
Etiology
• It is a common end point for many
cardiovascular and systemic disorders
• It can be caused by :
• Myocyte loss
• Inappropriate work load (volume or pressure
overload)
• Restricted filling
Etiology
• CAD: X 8 NHANES-I
• HTN: Risk of HF
• Men- X 2
• Women- X 3
• Idiopathic
• Familial
• Valvular H D
• Infections:
• Viral, trypanosoma
• Toxins:
• Alcohol, cobalt
•
•
•
•
•
•
Drugs
Tachycardia induced
RV Pacing
Pericardial diseases
Autoimmue
Infiltrative
Drug induced CMP
• Cytotoxic
• Anthracyclin
• Trastuzumab
• Antipsychotics
• Clozapine, Atyp AP
• Other drugs
•
•
•
•
•
•
•
Carbazepines
Tricyclic A
Chloroquine
Hydroxychloroquine
InterferonInterleukin-2
TNF-α antagonists
• Drugs Exacerbating
HF
•
•
•
•
NSAIDs
COX-2 Inhibitors
Thiazolidinediones
Non-dihydropyridiene
Ca channel blockers
xxx
xxxxxxx
Neurohormonal Activation
Leads to:
• Myocyte hypertrophy and interstitial
fibrosis
• Cell apoptosis
• Altered myocardial contractility
• LV dilatation and circular shape
• Endothelial dysfunction
CHF: Summary
•
•
•
•
•
•
•
•
Neurohumoral activation
Increased sympathetic activity- NE level
Decreased vagal activity
Decreased heart rate variability
Impaired arterial baroreflex activity
Increased cytokines level
Endothelial dysfunction
Ventilation , VE , Work of breathing
Pathophysiology
• Hemodynamic changes
• Neurohumoral
• Cellular
Neurohormonal changes
N/H changes
Favorable effect
Unfavor. effect
 HR , contractility,
vasoconst.   V return,
 filling
Arteriolar constriction 
After load  workload
 O2 consumption
 Renin-Angiotensin –
Aldosterone
Salt & water retention VR
Vasoconstriction 
 after load
 Vasopressin
Same effect
Same effect
 interleukins &TNF
May have roles in myocyte
hypertrophy
Apoptosis
Vasoconstriction VR
 After load
 Sympathetic activity
Endothelin
Diagnosis
• Clinical syndrome-clinical diagnosis
supported by abnormal:
• CXR
• Echo
• BNP
• Other tests to elucidate the underlying etiology:
• CBC
• BMP
• ECG and other noninvasive imaging (MRI, stress MPI)
Differential Daignosis
• Pericardial diseases
• Liver diseases
• Nephrotic syndrome
• Protein losing enteropathy
• Peripheral edema of noncardiac
etiology
Framingham Criteria
• Major Criteria:
•
•
•
•
•
PND
JVD
Rales
Cardiomegaly
Acute Pulmonary
Edema
• S3 Gallop
• Positive hepatic Jugular
reflex
• ↑ venous pressure > 16
cm H2O
• Minor Criteria
• LL edema,
• Night cough
• Dyspnea on exertion
• Hepatomegaly
• Pleural effusion
• ↓ vital capacity by 1/3
of normal
• Tachycardia 120 bpm
• Weight loss 4.5 kg over
5 days management
Natriuretic Peptides
• ANP: Atrial natriuretic peptide } NPR-A
• BNP: B-type
} NPR-A
c-GMP
• CNP: C-type
} NPR-B
• HF:
• Relative BNP deficiency: mostly pro-BNP
• Upregulation of phosphodiestsrases
c-GMP degrade
• Cut off in HF: BNP 100pg/ml, NT-proBNP 300pg/ml
• Sensitivity 90%, specificity 70%
• Improved diagnosis: BNP Multinational study, PRIDE
• Cost effective: BASEL (BNP), IMPROVE-HF (NTproBNP)
Elevated BNP
• Wall stress
• Aging
• F>M
• GFR<60 for NT-proBNP
BNP in the Diagnosis of HF
• Higher levels of BNP correlate with
• higher PCW pressures
• in compensated and decompensated patients
• larger LV volumes
• lower ejection fractions
• in symptomatic HF patients
• BNP study (Circ 2002;106: 416-422)
• BNP sensitivity 90% and specificity 73% for
HF
BNP Diagnostic Cut Points for CHF
JACC 2001;37(2):379-85.
• BNP > 400 pg/L – acute CHF present
• BNP 100 pg/L – 400 pg/L
• Diagnostic of CHF with
•
•
•
•
Sensitivity 90%
Specificity 76%
Predictive accuracy 83%
R/O pulmonary embolism, LV dysfunction without
acute CHF or cor pulmonale
• BNP < 100 pg/L – 98% negative predictive
accuracy
BNP: Prognostic Value
• Val-HeFT: High mortality in pts with high
BNP despite therapy
• Also prognostic value in CAD, ACS, and
valvular heart disease.
• Increased risk of sudden death
• CHF mortality/readmissions 15 times
higher when predischarge BNP>700.
• Management of CHF based on serial BNP
is not recommended.
Logheart D. 2004 JACC 43;625-641
Treatment Goals
• Impact the mortality
• Slow the progression of disease
• Decrease hospitalization
• Improve functional status and minimize
the indirect cost of HF
• Improve quality of life
• Prevent heart failure
Principles of Management of
CHF
• Is there decompensation of heart failure?
• Any precipitating factor. Multiple causative and
precipitating factors may be involved.
• Patients` understanding of his or her condition
• Non pharmacological management
• Lifestyle modification
• Exercise
• Pharmacological management
• Advanced HF: LVAD, Cardiac transplantation
Pathophysiology: Basis for
Treatment
CO
CO
BP
Renal
Perfusion
GFR
NE
Renin
AT II
Aldo
AVP
ET-1
ANP
Cytokines ( IL-6, TNF): Apoptosis
Mitogenic Effect: SMC hyperplasia, Interstitial fibrosis
Oxidative stress, Fetal gene expression
Vasoconstriction, Proarrhythmias
Beta Blockers
Renin Inhibition
ACEI
ARB
Aldosterone
Antagonists
ET-1 R Blockers
X
Diuretics
LV
Remodeling
Digoxin
• William Withering 1785 reported properties of
common foxglove plant (digitalis purpurea)
• Binds extrcytoplasmic a subunit of sarcolemmal
sod pot ATPase & increase intracellular Na and
Ca concentration
• RADIANCE & PROVED: Worsening of HF after
withdrawal of digoxin
• DIG: Trend towards decrease death due to
pump failure but equal increase in sudden
deaths. 4% reduction in hospitalizations. Dig
level 0.6-0.8 ng/ml reduced mortality
RADIANCE NEJM 1993
PROVED JACC 1993
DIG NEJM 1997
derived from plants
Cardiac Glycosides
Strophanus - Ouabain
Digitalis lanata - Digoxin,
Digitoxin
increase force of
myocardial contraction
alters electrophysiological
properties
toxic side-effects
Digoxin most common used
in USA
Digitalis lanata
Mechanism of Action
1.
inhibitor of Na+/K+ ATPase pump
2.
increased [Na+]i
3.
increased Ca2+ influx through Na+/Ca2+ exchanger
4.
new Ca2+ steady-state: increased Ca2+ release during
cardiac action potential
Overall Effect on Cardiac Function
1. Increased cardiac output
2. Increased cardiac efficiency
3. Decrease in heart rate
4. Decrease in cardiac size
Foxglove
Beta Blockers in HF
• Major contribution by Sir James Black for which
he received Noble Prize in 1988.
• Chidsey & Braunwald first reported NE stores in
heart muscles in HF 1965-66
• Contraindicated in heart failure in 1970s.
• First reported in BMJ 1975 by Sweden.
• Swedberg: survial benefit in Lancet 1979.
• Propanolol use in post-MI HF in 1981 NEJM
(Norwegian Multicenter study)
• Bristow: Down regulation of beta receptors in HF
NEJM 1982.
Beta blockers Trials
•
•
•
•
•
•
•
US Carvedilol Trial
CIBIS-II
MERIT-HF
BEST
COPERNICUS
CAPRICORN
COMET
Carvedilol
Bisoprolol
Metoprolol
Bucindilol
Carvedilol, EF <25%
Carvedilol, Post MI
Carvedilol vs. Metoprolol
Beta Blocker Trials in HF
TRIAL
AGENT
HF
class
##
placebo
mortality
mortality reduction
CIBIS-I
Bisoprolol
3,4
641
11
20
USCT
Carvedilol
2-3
1094 10
66
CIBIS-II
Bisoprolol
3-4
2647 13
33
MERIT-HF
Metoprolol 2-4
3991 11
35
Total %
Reduct
COPERNICUS Carvedilol
4
2289 18
38
13370
32%
CAPRICORN
Carvedilol
1
1959 11
23
Post MI
BEAT
Bucindilol
1
343
12
Post MI
21
CAPRICORN: All-Cause and
Cardiovascular Mortality
All-Cause Mortality
0.90
Risk Reduction
23%
0.80
(2%, 40%)
P=.031
CV Mortality
1.00
Proportion Event-Free
Proportion Event-Free
1.00
0.70
0.90
Risk Reduction
25%
0.80
(4%, 42%)
P=.024
0.70
Mortality Rates:
placebo 15%; carvedilol 12%
CV Mortality Rates:
placebo 14%; carvedilol 11%
0
0
0
0.5
1.0
1.5
2.0
2.5
0
0.5
1.0
Years
1.5
Years
Carvedilol (n=975)
Placebo (n=984)
The CAPRICORN Investigators. Lancet. 2001;357:1385-1390. Data on file. GlaxoSmithKline.
2.0
2.5
Addition of -Blockade to ACEI Reduces
Mortality in Heart Failure
US Carvedilol Trials
Carvedilol (n=696)
0.9
Placebo
(n=398)
65% 
0.8
MERIT-HF
20
P<.001
34% 
Cumulative
Mortality (%)
Probability of
Survival
1.0
0.7
0.0
10
Metoprolol CR/XL
(n=1,990)
5
0
0
100
200
300
0
400
100 200 300 400 500 600
Days
Days
CIBIS-II
Survival
Bisoprolol (n=1,327)
34% 
0.8
Placebo
(n=1,320)
P<.0001
COPERNICUS
100
0.6
Survival (%)
1.0
0.0
Placebo
(n=2,001)
P=.0062
(adjusted)
15
90
Carvedilol (n=1,156)
80
35% 
70
P=.0014
Placebo
(n=1,133)
(adjusted)
60
0
0
200
400
Days
600
800
0
3
6
9
12 15 18 21
Months
Packer M, et al. N Engl J Med. 1996;334:1349-1355. MERIT-HF Study Group. Lancet. 1999;253:2001-2007.
CIBIS-II Investigators. Lancet. 1999;353:9-13. Packer M, et al. N Engl J Med. 2001;344:1651-1658.
COMET: All-Cause Mortality
Carvedilol
(7%, 26%)
30
Mortality (%)
Metoprolol
Tartrate
Risk Reduction
 17%
40
P=.0017
20
“Extrapolation from the survival curves
suggested that [carvedilol] extended median
survival by 1.4 years*... as compared with
metoprolol [tartrate]....Ӡ
10
Mortality rates: metoprolol 40%; carvedilol 34%.
0
0
1
2
3
4
5
Time (years)
Number at Risk
Metoprolol Tartrate
Carvedilol
1,518
1,511
1,359
1,366
1,234
1,259
1,105
1,155
933
1,002
352
383
*95% CI, 0.5 to 2.3.
†Estimated median: carvedilol=8.0 years (95% CI, 7.3 to 8.7); metoprolol tartrate=6.6 years (95% CI, 6.1 to 7.1).
Rates for the composite endpoint of mortality or all-cause hospital admission were 74% (carvedilol) and 76% (metoprolol), RR
6% (95% CI, -2% to 14%, P=.122).
Metoprolol mean dose: 85 mg QD; carvedilol mean dose: 42 mg QD.
Poole-Wilson PA, et al. Lancet. 2003;362:7-13.
Beta blockers in HF
• Long term improvement in symptoms
• Average increase in EF after 6 m of therapy is
about 5%
• Carvedilol may exert a greater effect on EF
than other beta blockers
• Patients with non-ischemic cardiomyopathy
benefit more compared to ischemic
• About 35% risk reduction in mortality
Beta blockers in HF
• Well tolerated. Carvedilol was
significantly less likely to be withdrawn
than placebo in USCT
• Mortality and hospitalizations reduced
even in severe heart failure
• Greater benefit in pts with AF and
hypertension
• Greater benefit in diabetics
Overview of Long Term ACE Inhibitor
Trials Showing Mortality Benefit
Study
Number
Criteria
RRR %
ARR %
NNT
Lives
saved/1000
SOLVD
T/t
2569
LVEF
 35%
16
4.5
22
50
SAVE
2231
LVEF
 40%
19
4.2
24
45
AIRE
2006
Clinical
CHF
27
5.7
18
60
TRACE
1749
LVEF
35%
22
7.6
13
90
ACE Inhibitors Reduce Mortality in
Patients With Heart Failure
MORTALITY
Trial
Chronic CHF
CONSENSUS I
SOLVD (Treatment)
SOLVD (Prevention)
ACEI
Controls
RR (95% CI)
39%
35%
15%
54%
40%
16%
0.73
0.84 (0.74-0.95)
0.92 (0.79-1.08)
20%
17%
35%
5%
25%
23%
42%
6.5%
0.81 (0.68-0.97)
0.73 (0.60-0.89)
0.78 (0.67-0.91)
0.75 (0.40-1.11)
21%
25%
Post-MI
SAVE
AIRE
TRACE
SMILE
Average
The CONSENSUS Trial Study Group. N Engl J Med. 1987;316:1429-1435. The SOLVD Investigators. N Engl J Med. 1991;325:293-302. The SOLVD
Investigators. N Engl J Med. 1992;327:685-691. Pfeffer MA, et al. N Engl J Med. 1992;327:669-677. The Acute Infarction Ramipril Efficacy (AIRE)
Study Investigators. Lancet. 1993;342:821-828. Køber L, et al. N Engl J Med. 1995;333:1670-1676. Ambrosioni E, et al. N Engl J Med. 1995;332:80-85.
ACEI
• Improve natural history of HF through
mechanism other than vasodilation
• Class I indication for stage B-D
• Class I indication for post MI
• Class IIa indication for stage A
• Cough 5% greater than placebo trials
• Angioneurotic edema <1%, greater in
African Americans
Angiotensin II AT1 Receptor
Blockers
(ARB)
• Theoretical advantage over ACEI,
though not proven clinically. Efficacy
similar to ACEI.
• Indicated for patients intolerant to
ACEI
• ACEI + ARB is class IIb in stage C and
D HF
0.3
VALIANT: All-Cause
Mortality
Captopril
Valsartan
Valsartan + Captopril
Probability of Event
0.25
0.2
0.15
0.1
0.05
0
0
6
12
4,909
4,909
4,885
4,428
4,464
4,414
4,241
4,272
4,265
Number at risk
Captopril
Valsartan
Val + Cap
18
24
30
36
4,018
4,007
3,994
2,635
2,648
2,648
1,432
1,437
1,435
364
357
382
Months
Valsartan vs captopril: hazard ratio (HR)=1.00; P=.98. Valsartan + captopril vs captopril: HR=0.98; P=.73.
Pfeffer MA, et al. N Engl J Med. 2003;349:1893-1906.
β-adrenergic receptor antagonists
“β-blockers”
standard therapy for
treatment of CHF
cheap!
reduce sudden death
caused by other drugs
Propranolol
Propranolol: prototype
Carvedilol: combination
effects
Carvedilol
mechanism
still unclear
Mechanism
antagonizes β-adrenergic
receptors on cardiac
myocytes
counterbalances
increased SNS activity in
CHF
prevents development of
arrhythmias
reduces cardiac
remodeling
of Action
Will Additional Neurohormonal
Blockade (or Other Medical Therapy)
Further Improve Survival?
• ACEI/ARB combination (Val-HeFT and
CHARM)
• Aldosterone antagonist (RALES and
EPHESUS)
• Hydralazine/isosorbide dinitrate
combination
(A-HeFT)
Therapeutic
Use
Goal: inhibit aldosterone
negative effects in CHF
aldosterone receptor
antagonists
spironolactone
eplerenone
both antagonists reduce
mortality in patients with
moderate to severe CHF
only use in patients with
normal renal function and
K+ levels
use with K+ sparing
Aldosterone
• Through activation of RAAS
• Independent of ATII from adrenals, heart, and
vasculature. MR are present in endoth and sm cells
• Aldosterone escape, RESOLVED
• Potentiate the effect of other vasoconstrictors
• Endothelial dysfunction, PAI-1, ET-1
• Increase synthesis of collagen I, VSMC hyperplasia
• Increased fibrosis and ventricular arrhythmias
• Cardiomyopathy and interstitial fibrosis in mice
Aldosterone Receptor
Antagonists
Indic- Trial
ation
Drug
used
CHF # of
class Pts.
CHF
RALES
Spironol IIIactone
IV
Post
MI
EPHESU Epleren
S
one
I
Duration RRR%
P(months) Mortalit value
1663 24
25
<0.001
6632 12
15
0.005
RALES: Randomized aldosterone evaluation study
EPHESUS: Eplerenone Post acute MI Heart failure Efficacy and Survival Study
hyperkalemia
Side Effects
agranulocytosis
anaphylaxis
hepatoxicity
renal failure
Spironolactone:
gynecomastia, sexual
dysfunction
Eplerenone: arrhythmia,
myocardial
infarct/ischemia
Diastolic heart failure
•
•
•
•
•
Hypertension
Restrictive cardiomyopathy
Infiltrative cardiomyopathy
Hypertrophic cardiomyopathy
Noncompaction cardiomyopathy
Hear Failure With Preserved
systolic Function
1. Presence of signs or symptoms of
congestive heart failure
2. Normal or mildly abnormal LV
systolic function
3. Evidence of diastolic LV dysfunction.
HF signs and
symptoms
ESC
1998 (10)
NHLBI
2000 (15)
LAHEY
2005 (16)
ESC
2007 (5)
Present
Present
Present
Present
Normal LV systolic
function
LVEF
LVEF
LVEF
>45%
>50%
>50%
LVEDVI< within 72h LVEDVI
102 ml/m2 HF episode <97 ml/m2
LV diastolic
dysfunction
LVEDP >16
mm PCW
>12 mm Hg
E/A <0.5
DT >280 ms
IVRT >105
ms
PVV >0.35
m/s
Ard-Ad >20
ms
LVEDP
>16 mm
Hg
PCW >12
mm Hg
LVEDP >16
mm Hg
PCW >12
mm Hg
E/A <0.5
DT >280 ms
IVRT >105
ms
LAE
LVH
LVEF >50%
LVEDVI
<97 ml/m2
LVEDP >16 mm
Hg
PCW >12 mm Hg
E/E' >15
E/E' >8 + NTproBNP >220
pg/ml
Patients With Heart Failure
and Normal Left Ventricular
Ejection Fraction
I IIa IIb III
Physicians should control systolic and diastolic
hypertension in patients with HF and normal LVEF, in
accordance with published guidelines.
NO CHANGE
I IIa IIb III
Physicians should control ventricular rate in patients with HF
and normal LVEF and atrial fibrillation.
NO CHANGE
I IIa IIb III
Physicians should use diuretics to control pulmonary
congestion and peripheral edema in patients with HF
and normal LVEF.
NO CHANGE
68
Patients With Heart Failure and Normal
Left Ventricular Ejection Fraction
I IIa IIb III
Coronary revascularization is reasonable in
patients with HF and normal LVEF and coronary
artery disease in whom symptomatic or
demonstrable myocardial ischemia is judged to
be having an adverse effect on cardiac function.
NO CHANGE
69
HF in African Americans
• HF more likely associated with HTN rather
than CAD
• Higher rate of hospitalization
• Increased mortality
• Higher risk of LVH, stroke, renal failure
• Less responsive to beta blockers and ACEIs
•
CV NO-Superoxide Production in HF:
Implications of NO-Enhancing Effects
Isosorbide
dinitrate
Stimulation
Hydralazine
Nitric
oxide
synthase
Oxidase
Inhibition
Citrulline
O2
L-Arginine
NO
O2
Physiologic
pathway
Physiologic
pathway
Peroxynitrite (ONOO-)
DNA damage
Formation
of cyclic
guanosine
monophosphate
S-nitrosylation:
post-translational
modification of
effector molecules
Cell damage
Oxidized proteins
Inhibition
Adapted from Hare JM. N Engl J Med. 2004;351:2112–2114.
A-HeFT Trial Summary
• Trial in 1,050 AA HF patients
• All patients on standard care and randomized to
placebo (n=532) or HYD/ISDN (n=518)
• Titration to 2 tablets tid = 225 mg HYD/ISDN
• Patients followed up for up to 18 months
• Primary endpoint: combined score of mortality,
hospitalization, and QOL
• 161 US clinical sites
• Study initiated 6/01, terminated 7/19/04 for
significant survival benefit in the fixed-dose
HYD/ISDN group
QOL=quality of life.
Taylor AL, et al. N Engl J Med. 2004;351:2049–2057.
A-HeFT: Overall Survival
100
43% Decrease in Mortality
Survival (%)
Fixed-dose HYD/ISDN
95
90
Placebo
Hazard ratio=0.57
P=.01
85
0
100
200
300
400
500
600
Days Since Baseline Visit Date
HYD/ISDN
518
463
407
359
313
251
13
Placebo
532
466
401
340
285
232
24
Adapted from Taylor AL, et al. N Engl J Med. 2004;351:2049-2057.
Implantable Cardioverter
Defibrillators
• AVID
• MADIT
• MUST
• MADIT II
• COMPANION
MADIT II
N Engl J Med 346:877, 2002
CARDIAC RESYNCHRONIZATION THERAPY:
•CRT devices pace both the ventricles
simultaneously to resynchronize the muscle
contraction and improve the efficiency of the
weakend heart. Particularly useful in patients of HF
with heart block.
• MIRACLE Trial showed that biventricular pacing
improved symptoms and decreased the need for
hospitalization.
Cardiac Resynchronization
Therapy (CRT)
• Atrial-biventricular
stimulation
• Electrical
synchronization 
narrower QRS
• Mechanical
synchronization 
reverse remodeling
M-mode
SPWMD > 130ms
is a marker of
intraventricular
dyssynchrony
Regional phase difference
Another measure of intraventricular dyssynchrony.
CRT Recommendations
I IIa IIb III
•Recommended in patients with LVEF less
than or equal to 35%, sinus rhythm,
NYHA functional class III or ambulatory
class IV symptoms despite recommended
optimal medical therapy, and who have
cardiac dyssynchrony (QRS duration
greater than 0.12 ms) unless
contraindicated
Underlining represents changes from 2001 guidelines.
Hunt SA, et al. ACC/AHA 2005 Practice Guidelines. Available at: http://www.acc.org.
CRT: Areas of Uncertainty
•
•
•
•
•
Atrial fibrillation
RBBB
NYHA Functional Class II symptoms
Not for use as “rescue” therapy
Evaluation of presence/extent of
dyssynchrony
• When QRS is 120 to 150 msec
• In patients with QRS <120 msec
• After BiV placement
RBBB=right bundle branch block; BiV=biventricular.
Mehra MR, Greenberg BH. J Am Coll Cardiol. 2004;43:1145-1148.
SCD-HeFT: Mortality
0.4
HR
1.06
0.77
Amiodarone vs Placebo
ICD Therapy vs Placebo
97.5% CI
0.86–1.30
0.62–0.96
P Value
.53
.007
Mortality Rate
0.3
0.2
Placebo
ICD Therapy
Amiodarone
0.1
0
0
6
12
18
ICD=implantable cardioverter defibrillator.
Bardy GH. N Engl J Med. 2005;352:225-237.
24
30
36
Months of Follow-Up
42
48
54
60
MIRACLE
RRR 40%
N Engl J Med 346:1845-1853, 2002
ICD Recommendations
•Recommended as secondary prevention to prolong
I IIa IIb III
survival in patients with current or prior symptoms of HF
and reduced LVEF who have a history of cardiac arrest,
VF, or hemodynamically unstable VT
•Recommended for primary prevention to reduce total
mortality by a reduction in SCD in patients with ischemic
heart disease who are at least 40 days post-MI, with LVEF
less than or equal to 30%, and with NYHA functional class
II or III symptoms*
I IIa IIb III
•Recommended for primary prevention to reduce total
mortality by a reduction in SCD in patients with
nonischemic cardiomyopathy, LVEF less than or equal to
30%, and NYHA functional class II or III symptoms*
Underlining represents changes from 2001 guidelines.
ICD Recommendations*
I IIa IIb III
I IIa IIb III
• Reasonable in patients with ischemic
cardiomyopathy who are at least 40 days postMI, with LVEF less than or equal to 30%, and
with NYHA functional class I symptoms
• Reasonable in patients with LVEF of 30% to 35%
of any origin with NYHA functional class II or
III symptoms
• Might be considered in patients without HF who
*For patients undergoing chronic optimal medical therapy with reasonable expectation of
have
nonischemic
cardiomyopathy and an LVEF
survival with good functional
status >1
year.
Underlining represents changes
2001 guidelines.
lessfrom
than
or equal to 30%, with NYHA functional
Hunt SA, et al. ACC/AHA 2005 Practice Guidelines. Available at: http://www.acc.org.
class I symptoms
Major Trials of CRT
Trial
# of
pts
Condition
Result
COMPAN NHYA IIIION
IV, EF<35,
QRS >120
1520
CRT vs ICD,
no pacing
All C M &
H
MIRACLE NHYA IIIIV, <35,
>130 ICD
indicate
369
CRT + ICD
vs ICD
Improved
QOL,
NHYA
class
III-IV, <35,
819
>150, 120150 dysynch
CRT vs no
pacing
AC M & H
(unplanne
d)
RETHINQ III-IV, <35,
172
<130
Asynchrony
(TDI)
CRT vs no
pacing
No
increase in
mVO2 at
6m
CARE-HF
Inclusion
criteria
CARE-HF: CRT Long-Term
Outcomes
Primary Endpoint
All-Cause Mortality or
Hospitalization for Major
Cardiovascular Event
P<.001
60%
Secondary Endpoint
All-Cause Mortality
P<.002
55%
50%
40%
39%
30%
30%
20%
20%
10%
0%
CRT
Control
CRT
Control
Cleland JG, et al. N Engl J Med. 2005;352:1539-1549.
•Median LVEF was 25%
•Of the 409 patients
randomized to the CRT
device, 95% had a successful
implantation
•The primary endpoint of allcause mortality or
hospitalization for a major CV
event occurred less frequently
in the CRT group than in the
medical therapy alone group
(HR 0.63, 95% CI 0.51-0.77)
•The major sec. endpoint of allcause mortality was also
lower in the CRT group (HR
0.64, 95% CI 0.48-0.85)
Indications
Advanced Heart Failure
• CRT and ICD
• Ventricular assist devices
• Heart transplantation
Surgical Treatment of Heart
Failure
• CABG
• MV Repair
• LV aneurysm resection
• Surgical remodelling: Dor, Batista
• LVAD
• Transplantation
Prevention of HF
• Prevention and treatment of:
• HTN
• DM
• CAD
• Metabolic syndrome
HR 0.36
N Engl J Med 2008;358:1887-1898.
Frequently Asked Questions
• Q: How much salt should I take
• A: 2-3 gm per day
Frequently Asked Questions
• Should I prescribe statins in nonishemic
cardiomyopathy?
• CORONA (Controlled Rosuvastatin Multinational
Trial
• 5011 pts, ischemic, NHYA II-IV, 10 mg rosuvastatin
• 32.8 m medial F/U
• No benefit in CV D/MI or coronary events
• GISSI-HF (Gruppo Italiano per lo Studio della
Sopravvivenza nell’Infarcto Miocardico-HF)
• 4575 pt, 60% nonischemic, 10 mg rosuvastatin
• 3.9 yr F/U, No diff in death or CV hospitalization
Frequently Asked Questions
Evidence Based HF Therapy
Post-MI
LV Dysfunction
Mild
HF
Moderate
HF
Severe
HF
AIRE/SAVE
(ramipril/captopril)
SOLVD Treatment
(enalapril)
CONSENSUS
(enalapril)
CAPRICORN
(carvedilol)
US Carvedilol/MERIT
(carvedilol/metoprolol)
COPERNICUS
(carvedilol)
EPHESUS
(eplerenone)
CHARM/Val-HeFT
(candesartan/valsartan)
RALES
(spironolactone)
CRT and/or ICD
JCAHO: Quality-of-Care
(QoC) Indicators for HF
HF-1:
Discharge instructions
1. Daily weights
2. 2-g sodium diet
3. Activity Rx
4. What to do if symptoms worsen
5. Follow-up appointment
6. List of medications
HF-2:
Assessment of LV function
HF-3:
ACEI at discharge for appropriate patients
HF-4:
Smoking cessation advice/counseling
JCAHO=Joint Commission on Accreditation of Healthcare Organizations.
http://www.jcaho.org/nms/core+measures/information+on+inal+specification.htm. Accessed June 22, 2004.
Patients Treated (%)
100
Performance Indicators for
Heart Failure Patient Care
(JCAHO)
83
90
73
80
70
60
50
40
36
29
30
20
10
0
HF-1
Complete
Discharge
Instructions
HF-2
LVF Measured
or Scheduled
HF-3
ACEI at
Discharge for
LVSD
HF-4
Smoking
Cessation
LVF=left ventricular function; LVSD=left ventricular systolic dysfunction.
ADHERE Registry 2001-2003 HF-1: n=28,776; HF-2: n=34,397; HF-3: n=12,725; HF-4: n=5,475.
Fonarow GC. J Card Fail. 2003;9:S79.
100
75
50%
50
20%
25
Mortality (%)
Hospital Readmission Rate (%)
100
Outcomes in Patients
Hospitalized
With HF
75
50%
50
25
0
30
Days
6
Months
Mean LOS: 6.2 days
LOS=length of stay.
Fonarow GC, et al. J Card Fail. 2003;9:S79.
Jong P, et al. Arch Intern Med. 2002;162:1689.
33%
12%
0
30
Days
12
Months
5
Years
Institutional HF Discharge
Medication Program Reduces
Readmissions and Mortality
100
95
Pre-intervention (n=11,038)
Treatment Rates (%)
Post-intervention (n=8,045)
65
50
HR=0.80
P<.0001
46
38
HR=0.77
P<.0001
23
18*
0
ACEI Rx
Readmissions
1-year Mortality
Intermountain Health Care: 10 hospitals pre-intervention 1/96-12/98, n=11,038; post-intervention 1/99-3/00, n=8,045.
Pearson TA. Circulation. 2001;104:II-838.
-Blocker Users (%)
Outpatient Adherence to Blocker Therapy Post–Acute
MI
80
Discharged on -blockers
60
40
Not discharged on -blockers
20
0
0
30
90
180
270
Days Since Discharge
Prescription data on 846 patients surviving acute MI were studied by the Tennessee Quality
Improvement Organization.
Butler J, et al. J Am Coll Cardiol. 2002;40:1589-1595.
365
Patients Treated With BB (%)
Comparative Percentages of
Patients With HF Receiving a Blocker
100
91
75
67
50
27
25
16
0
Usual Care
Provider/Patient
Notification
Nurse
Facilitator
IMPACT-HF
Carvedilol
Predischarge
Initiation
BB= -blocker.
Ansari M, et al. Circulation. 2003;1107:2799-2804. Gattis W, et al. J Am Coll Cardiol. 2004;43:1534-1541.
Novel Therapies
• Vasopressin antagonists
• Conivaptan (V1a, V2)
• Tolvaptan (V1a): EVEREST no diff in mortality but improved
dysnea, weight and edema
• Endothelin antagonists: VERITAS
• Adenosine antagonists: Rolofylline
• Ularitide: Increase urine and decrease renin, ald &
AT2. Being tested in URGENT trial
• Levosimendan: Ca sensitizer
• REVIVE II
• RUSSLAN vs placebo decrease mortality at 14 days
• LIDO & CASINO vs dobutamine
Novel Therapies
• Istaroxime: Inhibits N-K ATPase, increase
activity of SECA. HORIZON-HF
• Metabolic modulators
• Perhexiline, ranolazine, L-carnitine
• Sildenafil
• Gene Therapy
• B-adrenergic signaling system
• Calcium-handling system
• Apoptosis pathways
Anticytokine Therapy
• TNF
• TACE, TNFR1 &2
• Activation of kinases, amplification of
inflammatory response (IL1, IL6, MCP-1,
PDGF,TGFb, PAI-1,PAF etc)
• High level of TNF in CHF with cachexia, cardiac
remodeling,
• Pentoxyfilline, amiodarone, simvastatin, etanercept
Levine NEJM 1990
Endothelin Receptor
Antagonists
• 4 peptides, vasoconstriction and cell
proliferation.
• Bosentan (ET a/b): REACH1, ENABLE
• ETa antagonists have theoretical
advantage