Heart Failure
Associate Professor Rob Doughty
Dept of Medicine, The University of Auckland &
Green Lane Cardiovascular Service,
Auckland City Hospital
• Acute Heart Failure
• Chronic heart failure
– Pharmacotherapy
– “failed” therapies
– Device-based therapies
– Newer therapeutics
The Rotterdam Study
Bleumink GS et al. Euro Heart J 2004;25:1614-19
• Population-based
cohort of 7,983
people age 55
• 30% of individuals
age 55 years will
develop HF in their
remaining life
Hospital Admissions for Heart Failure
• Incidence and prevalence data are
relatively difficult to obtain
• Hospitalisation data are often used
as surrogates
• Rely on discharge coding
• Reasonable reflection of the burden
of heart failure
• Used for planning healthcare delivery
Aging Population
90+
90+
85-89
85-89
Male
Female
90+
Male
Female
85-89
80-84
80-84
80-84
75-79
75-79
75-79
70-74
70-74
70-74
65-69
65-69
65-69
60-64
60-64
60-64
55-59
55-59
55-59
50-54
50-54
50-54
45-49
45-49
45-49
40-44
40-44
40-44
35-39
35-39
35-39
30-34
30-34
30-34
25-29
25-29
25-29
20-24
20-24
20-24
15 - 19
15 - 19
15 - 19
10 - 14
10 - 14
10 - 14
5-9
5-9
5-9
0-4
0-4
0-4
Male
Female
7 6 5 4 3 2 1 0 1 2 3 4 5 6 7
7 6 5 4 3 2 1 0 1 2 3 4 5 6 7
7 6 5 4 3 2 1 0 1 2 3 4 5 6 7
Percent
Percent
Percent
2001
2021
1986
Source: Statistics NZ
Mortality from Cardiovascular Disease
Source: NZ Heart Foundation Technical Report No 82 Jan 2004
Incidence and Prevalence of HF
Levy D et al. NEJM 2002;347:1397
• Incidence & prevalence strongly age
related
• Incidence
– 50’s 2 per 1000, 80’s 40 per 1000
• Prevalence
– 2-3%, increasing to 8-10% in elderly
populations
Trends in Hospitalisations for HF
Stewart S et al. EHJ 2001;22:209-217
Acute Heart Failure
•
•
•
•
Definition
Incidence and prevalence
Hospitalisations
Management
– Patient characteristics
– Aetiology
– Treatment
Definition of Heart Failure
ESC HF Guidelines EHJ 2005;26:1115-1140
1. Symptoms of heart failure (rest or
exercise)
2. Objective evidence of cardiac
dysfunction
and in cases where diagnosis remains in doubt
3. Response to treatment directed at HF
Definition of Heart Failure
ESC Acute HF Guidelines EHJ 2005;26:384-416
Acute heart failure defined as rapid
onset of symptoms and signs,
secondary to abnormal cardiac
function
• With or without previous cardiac disease
• Systolic or diastolic dysfunction, abnormal
rhythm, preload and afterload mismatch
• Often life-threatening
Several Distinct Clinical Conditions
ESC Acute HF Guidelines EHJ 2005;26:384-416
1. Acute decompensated HF
May be de novo or as decompensated HF
Symptoms relatively mild and not 2-4 below
2. Hypertensive AHF
3. Pulmonary oedema and severe
respiratory distress
4. Cardiogenic shock
5. High output HF
6. Right-sided acute HF
Low output syndrome with increased JVP,
hepatomegaly and hypotension
Patient Characteristics
Cleland JGF et al. EHJ 2003;24:442-463
Survey of 11,327 HF cases in Europe
• Mean age 71 yrs, 47% women
• 65%
prior diagnosis of HF
• 44%
prior admission for HF
Presentation
• 40%
acute dyspnoea
• 35%
exertional dyspnoea / oedema
• 19%
acute coronary syndrome
• 9%
atrial fibrillation
Patient Characteristics
Cleland JGF et al. EHJ 2003;24:442-463
Admission
• 50%
general medical wards
• 11 days
average length of stay
Death rates:
• 6.9%
during index admission
• 13.5% at 3 months
Aetiology of Heart Failure
• Heart failure clinical syndrome with
underlying cause
• Underlying cause often not focused on
• Hypertension & coronary disease
commonest causes
Aetiology of Heart Failure
Fox KF et al. EHJ 2001;22:228-236
Acute HF: Levosimendan
• Levosimendan calcium sensitiser and
vasodilator
• Previous trials showing efficacy
SURVIVE
• Levosimendan vs. Dobutamine in patients
with acute decompensated HF
• 1327 patients
• Primary end point:
– all cause mortality at 180 days
Mebazza A et al. JAMA 2007;297:1883
SURVIVE Trial
Mebazza A et al. JAMA 2007;297:1883
Proposed Effects of Nesiritide
Hemodynamic
Vasodilation:
• Veins
• Arteries
• Coronary arteries
BNP
Cardiac
• Lusitropic
• Anti-remodeling
• Anti-fibrotic
Neurohormonal
•  Aldosterone
•  Endothelin-1
•  Noradrenaline
Renal
• Diuresis
• Natriuresis
Nesiritide
• Smaller trials demonstrating short term
efficacy
• FDA approval in 2001
• Acute decompensated HF
• Subsequent meta-analyses suggesting
potential adverse effects
Nesiritide
Hauptman PJ, et al. JAMA 2005;296:1877
Data from 491 US hospitals, 385,627 admissions for HF
Any iv
Vasodilator
Nesiritide
GTN
FUSION II Trial
Out-patient based treatment, nesiritide 1 or 2 weekly
LVEF <40%, Class III/IV HF
Event Free Survival
1
Week 12
All Nesiritide
All Placebo
0.8
0.6
0.4
P=0.791
HR (95% CI) 1.03 (0.82, 1.30)
0.2
0
0
2
4
6
8
10
12
14
Weeks
16
18
20
22
24
Chronic Heart Failure
Neurohormonal Status in Heart Failure
• SNS
• RAAS
• Vasopressin
• Endothelin-1
• ?Urotensin II
CONSTRICTION
DILATATION
• Natriuretic peptides
• Nitric oxide
• Vasodilatory PGs
• Adrenomedullin
• Urocortin
Neurohormonal Antagonists
Annual Mortality (%)
10
5
0
Diuretics
+ Digoxin
+ ACEi
+ ACEi
+ b-blocker
Cleland meta-analysis; Lechat meta-analysis
Secular Trends in Survival For Patients with HF
Patients with Reduced LVEF
Patients with Preserved LVEF
Owan TE, et al. N Engl J Med 2006;355:251-9
C
O
SE 19
N 86
SU
S
19
8
19 8
SO 1 89
LV 99
D 0
R
19 x
92
19
9
19 3
9
19 4
95
19
9
19 6
97
19
R
M A 98
ER LE
IT S
-H
20 F
0
20 1
02
20
0
20 3
04
N
% Mortality
Mortality After Hospital Admission for HF
Wasywich C. CSANZ 2007
45
40
35
30
12-month
25
6-month
20
15
30-day
10
5
0
Year
CHARM Trial Programme: Summary
CHARM Alternative
CHARM Added
ACEi intolerant pt
Candesartan + ACEi
Lancet 2003;362:772
Lancet 2003;362:767
ARB suitable alternative
to ACEi
Some additive benefit of
addition of ARB to ACEi
but…..beware adverse
effects
Long-Term Effects of Treatment
CONSENSUS I Trial
10-year FU
1-year FU
Recent “Failed” Phase III HF Trials
Class
Drug
Trial
TNF
blockade
Etanercept RENEWAL
Packer Circ 2002;106:920
Vasopeptidase Omapatrilat OVERTURE
inhibition
Mann Circ 2004;1091594
Endothelin
blockade
Bosentan
ENABLE
“Failed” Drugs in Heart Failure
Increase mortality (sudden death) with:
•
•
•
•
•
Milrinone
Flosequinan
Ibopamine
Moxonidine
Class I antiarrhythmics
Emerging Drug Therapies in HF
• Ranolazine (metabolic agent)
• Ivabradine (If channel inhibitor)
• Erythropoietin
• Eplerenone
• HMGcoA reductase inhibitors
• Levosimendan
• Adenosine agonists
• NEP/ECE inhibitors
• AGE cross-link breakers
• Vasopressin antagonists
• Immune modulation therapy
• Nesiritide
• Rosuvastatin
• Copper chelation agents
Vasopressin System
Arterial underfilling
Hyperosmolality
Baroreceptors
• Left atrium
Hypothalamus
• Carotid sinus
• Supraoptic nucleus
• Aortic arch
• Paraventricular nucleus
Vascular smooth muscle
AVP
Collecting duct of kidney
V1a receptors
V2 receptors
Vasoconstriction
Water re-absorption
OPC-31260 SR121463
Tolvaptan Lixivaptan
VP-343
FR-161282
OPC-21268
Relcovaptan
Conivaptan
JTV-605
CL-3 85004
Adapted from Sanghi et al Eur Heart J 2005
EVEREST Outcome Trial
Konstam MA, et al. JAMA 2007;297:1319
• Efficacy of Vasopressin Antagonism in Heart failure
Outcome Study with Tolvaptan
• Tolvaptan (30mg/d) vs. placebo
• 4133 patients with LVEF < 40%
• Outcomes:
– All-cause mortality
– CVS death or hospitalisation for worsening HF
• Follow up minimum 60 days, median 9 months
EVEREST Outcome Trial
Konstam MA, et al. JAMA 2007;297:1319
All-Cause Mortality
CVS Death or Hospitalisation for HF
Anaemia and HF
Erythropoietin in HF
Mancini DM, et al. Circulation 2003;107:294
• 26 patients, EPO vs. placebo, 6 months
• End points: Hb and Peak Vo2
Haemoglobin
VO2
Potential Benefits of EPO
• Prevention of apoptosis
• Endothelial progenitor cell mobilisation
• Induction of angiogenesis/
neovascularisation
• Limitation of ischaemia/reperfusion
injury
Biventricular Pacing
• LBBB common in HF patients
• “Dysynchrony” between ventricles
• Biventricular pacing
(cardiac resynchronisation therapy, CRT)
– Pace right and left ventricle (via lead in
coronary sinus)
– Improved cardiac output in severe HF
– Improved quality of life
– Improved survival
Implantable Defibrillators
• Small implantable devices
like pacemakers
• Able to deliver small
electric shock across the heart to
terminate ventricular arrhythmias
• Improved survival in patients with
chronic heart failure
SCD-HeFT: Amiodarone or ICD in CHF
G Bardy et al. NEJM 2005;352:225-37
• 2521 patients with HF, NYHA II/III, LVEF <35%,
ICD vs. amiodarone vs. placebo
• Absolute Risk Reduction at 5yrs = 7.2%
Device-Based Therapy in HF
Cardiac resynchronisation therapy
• Patients with sinus rhythm, wide QRS
on ECG (>120msec), LVEF <35%,
moderate to severe symptom
Implantable defibrillators
• Prophylactic ICD for patients with
LVEF<30% and mild to moderate
symptoms
HF with Preserved LVEF
Inclusion
End-Points
Duration
Drug
CHARM
CHF, age>70
EF>40%
Mortality
Hosp
1 yr
Candesartan
PEP-CHF
CHF, age>70
EF>40%
Mortality
Hosp
2 yrs
Perindopril
I-PRESERVE
CHF, age>60 Mortality
EF>45%
CVS Hosp
2 yrs
Irbesartan
TOP CAT
CHF
EF>45%
3 yrs
Aldo antag
Mortality
Hosp
ACEi in HF with Preserved EF
CHARM Preserved
PEP-CHF
CVS Death or
HF Hospitalisation
Death or
HF Hospitalisation
Yusuf S, et al. Lancet 2003;362:777-781
Cleland JGF, et al. EHJ 2006;27:2338
Treatment Heart Failure with Preserved LVEF
Disease targeted therapy
• Hypertension
– BP target levels
– Prevent / regress LVH
• Atrial fibrillation
– Control rate, anticoagulation
• Coronary artery disease
– Prevention / revascularisation
• Diabetes / metabolic syndrome
• Other
– Anaemia, CRF, arrhythmias (esp. AF)
Diabetes and HF
Haas SJ et al. Am Heart J 2003;146:848
Diabetes worse
Diabetes and HF
• Specific therapies for patients with
diabetes and heart failure
– Metformin and improved outcomes in HF
(PHANTOM Study)
– AGE cross-link breakers in diastolic HF
(Alteon)
– Copper chelation
Summary
• Acute heart failure
– Pathophysiology
– Aetiology
– treament
• Chronic heart failure
– Established therapies
– “Failed” therapies
– Device-based therapies
• Specific patient subgroups
– Disease specific
– Patient specific