heart failure associate professor rob doughty dept of medicine, the university of auckland &...
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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
• Population-based cohort of 7,983 people age 55
• 30% of individuals age 55 years will develop HF in their remaining life
The Rotterdam StudyThe Rotterdam StudyBleumink GS et al. Euro Heart J 2004;25:1614-19
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 PopulationAging Population
1986 2001
7 6 5 4 3 2 1 0 1 2 3 4 5 6 7
0-4
5-9
10-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
80-84
85-89
90+
Percent
Male Female
7 6 5 4 3 2 1 0 1 2 3 4 5 6 7
0-4
5-9
10-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
80-84
85-89
90+
Percent
Male Female
7 6 5 4 3 2 1 0 1 2 3 4 5 6 7
0-4
5-9
10-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
80-84
85-89
90+
Percent
Male Female
2021
Source: Statistics NZ
Mortality from Cardiovascular Disease
Source: NZ Heart Foundation Technical Report No 82 Jan 2004
Incidence and Prevalence of HF
• 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
Levy D et al. NEJM 2002;347:1397
Trends in Hospitalisations for HFStewart S et al. EHJ 2001;22:209-217
Acute Heart Failure
• Definition• Incidence and prevalence• Hospitalisations• Management
– Patient characteristics– Aetiology – Treatment
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 FailureDefinition of Heart Failure
ESC HF Guidelines EHJ 2005;26:1115-1140
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
Definition of Heart FailureDefinition of Heart Failure
ESC Acute HF Guidelines EHJ 2005;26:384-416
Several Distinct Clinical Conditions
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 HFLow output syndrome with increased JVP,
hepatomegaly and hypotension
ESC Acute HF Guidelines EHJ 2005;26:384-416
Patient Characteristics
Survey of 11,327 HF cases in Europe• Mean age 71 yrs, 47% women• 65% prior diagnosis of HF • 44% prior admission for HFPresentation• 40% acute dyspnoea• 35% exertional dyspnoea / oedema• 19% acute coronary syndrome• 9% atrial fibrillation
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
Patient CharacteristicsPatient CharacteristicsCleland JGF et al. EHJ 2003;24:442-463
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 TrialMebazza A et al. JAMA 2007;297:1883
Proposed Effects of Nesiritide
HemodynamicVasodilation:• Veins• Arteries• Coronary arteries
Neurohormonal• Aldosterone• Endothelin-1• Noradrenaline
Renal• Diuresis• Natriuresis
BNP
Cardiac• Lusitropic• Anti-remodeling• Anti-fibrotic
Nesiritide
• Smaller trials demonstrating short term efficacy
• FDA approval in 2001
• Acute decompensated HF
• Subsequent meta-analyses suggesting potential adverse effects
Nesiritide
GTN
Any iv Vasodilator
NesiritideHauptman PJ, et al. JAMA 2005;296:1877
Data from 491 US hospitals, 385,627 admissions for HF
FUSION II Trial
Week 12Week 12Week 12Week 12
P=0.791HR (95% CI) 1.03 (0.82, 1.30)
0
0.2
0.4
0.6
0.8
1
0 2 4 6 8 10 12 14 16 18 20 22 24Weeks
Even
t Fre
e S
urv
ival
All NesiritideAll Placebo
Out-patient based treatment, nesiritide 1 or 2 weeklyLVEF <40%, Class III/IV HF
Chronic Heart Failure
• SNS• RAAS • Vasopressin• Endothelin-1• ?Urotensin II
CONSTRICTION
DILATATION
• Natriuretic peptides• Nitric oxide• Vasodilatory PGs• Adrenomedullin• Urocortin
Neurohormonal Status in Heart Failure
Annual Mortality (%)
Cleland meta-analysis; Lechat meta-analysis
DiureticsDiuretics
+ Digoxin+ Digoxin
+ ACEi+ ACEi + ACEi + ACEi
+ + blockerblocker
0
5
10
Neurohormonal Antagonists
Secular Trends in Survival For Patients with HFSecular 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
Mortality After Hospital Admission for HF
0
5
10
15
20
25
30
35
40
45
12-month
6-month
30-day
Year
% M
ort
alit
y
Wasywich C. CSANZ 2007
CHARM AlternativeACEi intolerant ptLancet 2003;362:772
ARB suitable alternative to ACEi
CHARM AddedCandesartan + ACEiLancet 2003;362:767
Some additive benefit of addition of ARB to ACEi but…..beware
adverse effects
CHARM Trial Programme: SummaryCHARM Trial Programme: Summary
Long-Term Effects of Treatment
1-year FU
10-year FU
CONSENSUS I Trial
Recent “Failed” Phase III HF Trials
Class Drug Trial
TNF Etanercept RENEWALblockade
Vasopeptidase Omapatrilat OVERTUREinhibition
Endothelin Bosentan ENABLEblockade
Packer Circ 2002;106:920
Mann Circ 2004;1091594
Increase mortality (sudden death) with:• Milrinone • Flosequinan • Ibopamine • Moxonidine• Class I antiarrhythmics
“Failed” Drugs in Heart Failure
Emerging Drug Therapies in HF
• Ranolazine (metabolic agent)
• Erythropoietin
• HMGcoA reductase inhibitors
• Adenosine agonists
• AGE cross-link breakers
• Immune modulation therapy
• Rosuvastatin
• Ivabradine (If channel inhibitor)
• Eplerenone
• Levosimendan
• NEP/ECE inhibitors
• Vasopressin antagonists
• Nesiritide
• Copper chelation agents
Adapted from Sanghi et al Eur Heart J 2005
Baroreceptors
• Left atrium
• Carotid sinus
• Aortic arch
Arterial underfilling
Hyperosmolality
• Supraoptic nucleus
• Paraventricular nucleus
Hypothalamus
V2 receptorsV1a receptors
Vasoconstriction Water re-absorption
AVP
OPC-21268Relcovaptan
OPC-31260 SR121463Tolvaptan LixivaptanVP-343 FR-161282Conivaptan
JTV-605CL-3 85004
Vascular smooth muscle Collecting duct of kidney
Vasopressin System
EVEREST Outcome TrialKonstam 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
All-Cause Mortality CVS Death or Hospitalisation for HF
EVEREST Outcome TrialKonstam MA, et al. JAMA 2007;297:1319
Anaemia and HF
Erythropoietin in HFMancini 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
• 2521 patients with HF, NYHA II/III, LVEF <35%, ICD vs. amiodarone vs. placebo
• Absolute Risk Reduction at 5yrs = 7.2%
G Bardy et al. NEJM 2005;352:225-37
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 LVEFHF with Preserved LVEF
Inclusion End-Points Duration Drug
CHARM CHF, age>70 Mortality 1 yr CandesartanEF>40% Hosp
PEP-CHF CHF, age>70 Mortality 2 yrs PerindoprilEF>40% Hosp
I-PRESERVE CHF, age>60 Mortality 2 yrs IrbesartanEF>45% CVS Hosp
TOP CAT CHF Mortality 3 yrs Aldo antagEF>45% Hosp
ACEi in HF with Preserved EFACEi in HF with Preserved EF
Yusuf S, et al. Lancet 2003;362:777-781
CHARM PreservedCVS Death or
HF Hospitalisation
PEP-CHFDeath or
HF Hospitalisation
Cleland JGF, et al. EHJ 2006;27:2338
Treatment Heart Failure with Preserved LVEFTreatment 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 worse
Diabetes and HFHaas SJ et al. Am Heart J 2003;146:848
• 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
Diabetes and HF
Summary
• Acute heart failure– Pathophysiology– Aetiology– treament
• Chronic heart failure– Established therapies– “Failed” therapies– Device-based therapies
• Specific patient subgroups– Disease specific– Patient specific