HEART FAILURE Guidelines for the Treatment Facts … · Guidelines for the Treatment of HEART FAILURE ... Stopped due to increase mortality in moxonidine arm? ... Therapies in Heart
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Guidelines for the Treatment of
HEART FAILURE
Leslie W. Miller
University of Minnesota
HEART FAILUREFacts
• 5 million patients with CHF in U.S.
• 550,000 new cases/year
• 300,000 deaths/year
• 4 fold increase in risk mortality
• >10% people over 65 yo will develop HF
End-Stage Congestive Heart FailureScope of Problem
• 1 million hospitalizations/year as #1 Diagnosis,
• 2.5 million as # 2 or 3 Discharge Diagnosis
• Average LOS=5.7 days
• Highest DRG Volume Dx (days X # pts)
• Highest readmission rate
• Number 1 discharge Diagnosis in pts >63 y.o.
• Increasing age of population will double in 15 yrs
HEART FAILUREEstimated Prevalence by Age & Gender
0.3 0.21.3
4.7
8.2
10.1
4.9
0.50.72.1
0.10
2
4
6
8
10
12
20-29 30-39 40-49 50-59 60-69 70-79 >80
Age (Years)
Males Females
10.6
Total = 5 million
% of Population
9
Demographic TrendsElderly U.S. population will double with graying of “baby boomer”generation
0
25
50
75
1990 2000 2010 2020 2030
Projected Elderly
Population Age 65+
(millions)12.6% total US population
31.5 million
65.6 million
21.8% total US population
ACC/AHA Guidelines on Heart FailureDefinition
HF 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.No longer “Congestive” HF, because not all patients have volume overload, but low output
2
Symptomatic HEART FAILUREDiastolic Dysfunction
Ejection Fraction
103
9
3
8
35
3 19
10
0%
20%
40%
60%
80%
100%
Men Women
>.60.50-.59.41-.49.31-.40<.30
(n=40) (n=33)
Vasan et al, JACC ‘99;33(7):1948-55
E.F.
Primary Diastolic Dysfunction
Hypertension is the leading cause
Prevalence Increases in advancing Age
Effects Women > men
ECHO is the best way to make diagnosis
Treatment: control HR and BP
No mortality benefits in Diastolic HF
Rx: Beta Blockers, ARB,ACEI, CCB
Treatment of Heart Failure Changing Goals for Therapy
ERA TARGET THERAPY
60’s Symptoms Diuretic/Digoxin
70’s Hemodynamics Inotropes/Vasodil.
80’s Survival ACEI/β-Blockers
90’s Remodeling ACEI/β-Blockers
2000 Prevention Earlier Dx/Rx
Pathophysiology of CHF
CHF SyndromeRemodeling
Altered Gene Expression
NP’s SNS Cytokines VP
↓ contractility↑ wall stress
ADM ET-1
Ischemia Valve Infection Inflam. Genetic ToxinsHTN
RAAS
ACC/AHA Guidelines on Heart FailureDrug Treatment
Beta Blocker
Digoxin
Diuretic
ACEIHydral/Nitr
ARB
3
Treatment of Heart Failure
Neurohormonal Antagonism
What is the Renin-Angiotensin System (RAS)?Angiotensinogen
Angiotensin I
Angiotensin II
Angiotensin IIReceptors
(Subtype AT 1)
Vasoconstriction
Blood Pressure
Renin
nonACE ACE
Aldosteronesecretion
Sympatheticactivation
Inactive fragments
ChymaseCAGECathepsin G
BradykininSubstance PEnkephalins
Renin
Bradykinin,Substance P
ACE Inhibitor
Angio-tensinogen
Angiotensin IAngiotensin II
Chymase, Cage etc.
ACE Inhibitors – Mechanism of Action
ACE
VasoconstrictionAldosteroneVasopressinSympathetic
tPAProstaglandinsVasodilation
Kininase II
Treatment of Heart FailureHOPE - Secondary Endpoint Results
7.4
16
3.8
9.4
18.4
5.5
0
5
10
15
20
25
% w
ith a
n ev
ent
RamiprilPlacebo
All Heart Failure Any RevascularizationProcedure
New Onset of Diabetes Mellitus
22% Risk Reductionp=0.0005
15% Risk Reductionp=0.0013
31% Risk Reductionp<0.01
4
• Consistent Survival BenefitRelative Risk Reduction 15-20%Absolute Risk 3-4%
• 7-10% intolerance
• No significant change in cardiac ejection fract.
• May not be as effective in Afr.-Americans
• Genotype may influence response
• May be a dose maximum – alternative pathway
Limitations of Medical Rx of HFACE Inhibitors
Pathophysiology of CHF Renin Angiotensin SystemAlternate Pathway – ARB’s
Angiotensin II
Angiotensin I
ATIConstrictionGrowth
ATIIVasodilationAntiprolit.
Renin
ACE(I)
Angiotensinogen
CaspaceCathepsin
Receptor
XARB
X
Val-HeFTStudy Design
HF patients ≥18 yr; EF<40%; NYHA II–IV
Valsartan40 mg bid titrated
to160 mg bid
906 deaths (events reported)
Randomized to
Receiving Standard TherapyACEI, diuretics, digoxin , β-blockers (stratified)
Placebo
J. N. Cohn et. al, J. Card. Fail. 1999; 5: 155-160
0
20
40
60
80
100
0 0.5 1 1.5 2 2.5 3 3.5
CHARM: ADDED TrialCumulative Event Outcome
Candesartann=1272
Placebon=1276
Pro
porti
on w
ith C
ardi
ovas
cula
r Dea
th o
rH
ospi
tal A
dmis
sion
for C
HF
(%)
Years
Lancet 2003;362:767-771
P=0.011
• No significant benefit over ACEI (or difference)
• Addition to ACEI decreases hospitalizations, and
may improve survival
Better tolerated than ACEI’s
• Use of High dose ACEI(>20 mg/d) may lead to
conversion of ANG I-II via alternative pathway
LimitationsARB’s
Sympathetic Activation and Increased Heart Failure Mortality
1.0
0.8
0.6
0.4
0.2
00 10 20 30 40 50 60
Time (Months)
Prob
abili
ty o
f Sur
viva
l
PNE < 400 pg/mL
PNE 400-800 pg/mLPNE > 800 pg/mL
Cohn, JN et al. N Engl J Med 1984; 311:819-824.PNE = Plasma norepinephrine
5
Spill
over
of N
orep
inep
hrin
eto
Pla
sma
(% o
f nor
mal
)
500
300
100
0
1104%
Total Heart Gut &Liver
Lungs Kidney
Norepinephrine Spillover in Heart Failure
Esler et al. Hypertension 1988
1000
Rec
epto
r Den
sity
(fm
ol/m
g)
Non-failing
Failing (IDC)
* P < 0.05 vs. non-failingIDC = Idiopathic Dilated Cardiomyopathy Bristow MR et al. Clin Drug Ther 1989
Adrenergic Receptor Densities in Human LV Myocardium
70
60
50
40
30
20
10
0β1 β2 α1
*
*
Sympathetic activation
Remodelling Effects
Metoprolol
Propranolol
Carvedilol
Antiadrenergic Therapy-βeta Blockade
β2receptors
β1receptors
α1receptors
6
0
5
10
15
20
%
diuretic
digoxin
diuretic
digoxin
ACE-I
diuretic
digoxin
ACE-I
diuretic
digoxin
ACE-I
β blocker
diuretic
digoxin
ACE-I
β blocker
diuretic
digoxin
ACE-I
β blocker
ARB
SOLVD-T (1991)
RRR 21%
MERIT(1999)
RRR 33%
CHARM-Added (2003) (β blocker subgroup)
RRR 30%
Improving survival in CHF1-year mortality
Beta Blockers in CHFRole of Norepinephrine
Moxonidine (Moxcon) Study
Moxonidine: Central acting agent (Clonipin) causes a decrease in norepinephrin
Study: 1,950 patients enrolled (4,500 goal) All on ACE, Dig, Diuretic + Moxonidine vs Placebo
Stopped due to increase mortality in moxonidine arm
? Too rapid a reduction NE
Sympathetic Nervous Blockade Failed MOXCON Trial
0123456789
10111213141516
Death Worse HF MI
% P
atie
nts
CardiovascSAE
Combination
Placebo (n=875)Moxonidine (n=918)
Eur J Heart Fail. 2003 Oct;5(5):659-67 Floras JN. Circulation. 2002;105:1753.
Relationship Between LV Remodeling and CV Events Post-MI
0
1
2
3
4
5
6
7
End Diastole End Systole
∆in
LV
Area
at 1
Yea
r (cm
2 )
No Events n=309
CV Events n=111p<0.001
St. John Sutton M et al. Circulation. 1994;89:68–75.
2-D echocardiography obtained at a mean of 11.1 ± 3.2 days after acute MI and 1 year later
p<0.001
0
20
40
60
>4 cm/m2 <4 cm/m2LVEDD
2-Ye
ar M
orta
lity
(%)
P = 0.004
Lee TH et al. Am J Cardiol 1993
Ventricular Remodeling in HF Relationship Between LV Size
and Outcome in CHF
7
∆LV
ESVI
(bip
lane
) [m
l/m2 ]
P values for ∆ BL to M6, M12, M18
Remodeling: CARMEN TrialEffect of ACEI vs BB on LVEDV
Carvedilol & EnalaprilCarvedilolEnalapril
-7
Month 6 Month 12 Month 18Baseline
NS P < 0.002
-6
-5
-4
-3
-2
-1
0
P < 0.05
• Fairly Consistent Survival BenefitRelative Risk Reduction 25-65%Absolute Risk Reduction 7-9%(on top of ACE, Dig, Diuretic)
• Significant increase E.F.• Primarily Class II-III HF, but also Class IV• May be less effective in Afr.-Americans• Class effect, but also unique individual agents
Limitations of Medical Rx of HFBeta Blockers
Use of Evidence-Based Therapies in Heart Failure
LVEF Documented at < 0.40
44.3
10.0
40.9
68.0
31.9
Outpatient HF Medication
Patie
nts
Rec
eivi
ng T
hera
py (%
)
ARB
ß-Blocker
Diuretic
Digoxin
ACE Inhibitor
0
10
20
30
40
50
60
70
80
90
100
Excludes patients with documented contraindications. The ADHERE database. Data from 2300/7883 patients hospitalized with heart failure; prior known diagnosis of systolic dysfunction heart failure; outpatient medical regimen. Collected between July 2001 and July 2002 (unpublished data). 180 US Hospitals.
Saluresis and Diuresis
Complications of Diuretic Therapy for Heart Failure
↑ Distal Ca++Reabsorption
↓ Plasma Volume
↓ Uric AcidClearance
Diuretic Therapy
↓ Cardiac Output ↓ Renal Blood Flow
Hyponatremia
↑ PRA
↓ GFR
↑ ProximalReabsorption
↑ Aldosterone
Kaliuresis
Hypokalemia
Glucose IntoleranceHypocalcemiaHyperuricemia
↓ CalciumClearance
Pre-renalAzotemia
PosturalHypotension
↓ Renal Reabsorption of Na (and Mg) Hypomagnesemia
SLIDE NOT FINISHED
8
The RALES Trial: Effect ofSpironolactone on Survival in CHF
Months
Prob
abili
ty o
f Sur
viva
l
Number at riskPlacebo 841 775 723 678 628 592 565 483 379 280 179 92 36Spironolactone 822 766 739 698 669 639 608 526 419 316 193 122 43
Total mortality↓ 30% (p < 0.001)
Pitt B, et al. N Engl J Med 1999; 341:709-717
Spironolactone
Placebo
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
0.000 3 6 9 12 15 18 21 24 27 30 33 36
DIG Study
Sudden death
Pump failure
Cardiovascular
All cause mortality
Cause of Death
1.12
0.86
1.03
1.00
Risk Ratios
0.13(0.96-1.31)
(0.76-0.99)
(0.95-1.12)
0.92(0.93-1.09)
P valueConfidence Intervals
NP’s
BNP(ventricle)
DNP(kidney)
Pathophysiology of CHFNatriuretic Peptides
ANP(atria)
CNP(endothelium)
rhBNPD
R I
MKRG
S SS
SGLG
FC CS SG
SGQVMK V L R
RH
KPS
Effects of NesiritideVASODILATION
CARDIACINDEX
PreloadAfterloadPCWPDyspnea
HEMODYNAMIC
CARDIACNo increase in HRNot proarrhythmic
AldosteroneEndothelinNorepinephrine
SYMPATHETIC AND NEUROHORMONAL SYSTEMS
RENAL
NATRIURESISDIURESIS
Fluid volumePreloadDiuretic usage
[Hb]<11.8g/dL (n=102)
[Hb] 11.8-13.2g/dL (n=107)
[Hb] 13.3-14.4g/dL (n=114)
[Hb] >14.4g/dL (n=113)
6004002000
1.0
.9
.8
.7
.6
.5
.4
Time (days)
Dea
th o
r Urg
ent T
rans
plan
t
Data courtesy Dr. G. Fonarow (UCLA) adjusted for age, sex, BMI, LVEF, LVEDD, SCr, etiology, DM
The Effect of Anemia on Survival in CHF Patients Outside the Clinical Trial Setting
Hb quartiles
9
Effect of Anemia Treatment on Regression of LVH*
*Portoles et al. Am J Kidney Dis. 1997;29:541-548. 2. Casale et al. Ann Intern Med. 1986;10:173-178.
130
150
170
190
Baseline 6 mo
LVM
I (g/
m2 )
*
P < .05N = 11
LVMI
20
25
30
35
40
Hct
(%)
Hct
P < .001N = 11
*Note: Normal LVMI2 = 125 g/m2
Pathophysiology of CHFMediators of Vascular Tone
VasodilatorsOld
Beta Adrenergic Recept.
NewNatriuretic Peptides Nitric OxideAdrenomedullinBradykinin
VasoconstrictorsOldAlpha Adrenergic Recept.
NewEndothelinAngiotensin II
↔
• Age -ELITE , HOPE• Race –ACEI, Beta Blockers, Hydral/Nit• Gender –DIG Trial• Etiology-PRAISE (CCB) • Dose- ATLAS• Genomics-BETA 2AR, iNOS, ACE I/D• Pharmacogenomics-Metoprolol
Limitations of Drug Therapy for HFFactors Affecting Outcome
• Many issues that effect the response to a given oral HF drug
• ACEI’s, ARB’s, and BB’s remain the most consistent drugs to favorably alter survival
• Most promising new drugs have not been shown to have a survival benefit
• Device therapies will likely play a significant role in HF therapy in the future
Limitations of Oral HF TherapySummary
Stem Cell Therapy in AMI:TOPCARE Study
Assmus et al, Circulation 2002;106:3009-17
Intracoronary Infusion
20 pts3-6 days post MI
9 pts: Bone marrowaspiration
11 pts: 250 cc peripheral blood drawn
Mononuclear cellsisolated
Ex vivo EPC expansionin cell culture (3 days)
10
TOPCARE-AMI
4 Month Follow-up:• Improved EF• Improved wall motion• Reduced end-systolic
diameter
No change in matched reference group
No difference b/w BM or PB groups
No Placebo group
Assmus et al, Circulation 2002;106:3009-17
Baseline 4-months
University of Frankfurt
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