Transcript Slide 1
Heart Failure
Associate Professor Rob Doughty
Dept of Medicine, The University of Auckland & Green Lane Cardiovascular Service, Auckland City Hospital
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Acute Heart Failure Chronic heart failure
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Pharmacotherapy
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“failed” therapies
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Device-based therapies
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Newer therapeutics
The Rotterdam Study Bleumink GS et al. Euro Heart J 2004;25:1614-19
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Population-based cohort of 7,983 people age
55
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30% of individuals age 55 years will develop HF in their remaining life
Hospital Admissions for Heart Failure
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Incidence and prevalence data are relatively difficult to obtain
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Hospitalisation data are often used as surrogates
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Rely on discharge coding Reasonable reflection of the burden of heart failure
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Used for planning healthcare delivery
Aging Population
4 5 - 4 9 4 0 - 4 4 3 5 - 3 9 3 0 - 3 4 2 5 - 2 9 2 0 - 2 4 15 - 19 10 - 14 5 - 9 0 - 4 9 0 + 8 5 - 8 9 8 0 - 8 4 7 5 - 7 9 7 0 - 7 4 6 5 - 6 9 6 0 - 6 4 5 5 - 5 9 5 0 - 5 4 Male Female 7 6 5 4 3 2 1 0 1 2 3 4 5 6 7 Percent 1986 9 0 + 8 5 - 8 9 8 0 - 8 4 7 5 - 7 9 7 0 - 7 4 6 5 - 6 9 6 0 - 6 4 5 5 - 5 9 5 0 - 5 4 4 5 - 4 9 4 0 - 4 4 3 5 - 3 9 3 0 - 3 4 2 5 - 2 9 2 0 - 2 4 15 - 19 10 - 14 5 - 9 0 - 4 Male Female 7 6 5 4 3 2 1 0 1 2 3 4 5 6 7 Percent 2001 4 5 - 4 9 4 0 - 4 4 3 5 - 3 9 3 0 - 3 4 2 5 - 2 9 2 0 - 2 4 15 - 19 10 - 14 5 - 9 0 - 4 9 0 + 8 5 - 8 9 8 0 - 8 4 7 5 - 7 9 7 0 - 7 4 6 5 - 6 9 6 0 - 6 4 5 5 - 5 9 5 0 - 5 4 Male Female 7 6 5 4 3 2 1 0 1 2 3 4 5 6 7 Percent 2021 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
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Incidence & prevalence strongly age related Incidence
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50’s 2 per 1000, 80’s 40 per 1000 Prevalence
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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
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Definition Incidence and prevalence Hospitalisations Management
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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
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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.
2.
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Acute decompensated HF May be de novo or as decompensated HF Symptoms relatively mild and not 2-4 below Hypertensive AHF Pulmonary oedema and severe respiratory distress Cardiogenic shock High output HF Right-sided acute HF Low output syndrome with increased JVP, hepatomegaly and hypotension
Patient Characteristics
Cleland JGF et al. EHJ 2003;24:442-463
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Survey of 11,327 HF cases in Europe Mean age 71 yrs, 47% women 65% 44% prior diagnosis of HF prior admission for HF
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Presentation 40% 35% 19% 9% acute dyspnoea exertional dyspnoea / oedema acute coronary syndrome atrial fibrillation
Patient Characteristics
Cleland JGF et al. EHJ 2003;24:442-463
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Admission 50% 11 days general medical wards average length of stay
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Death rates: 6.9% during index admission 13.5% at 3 months
Aetiology of Heart Failure
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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
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Levosimendan calcium sensitiser and vasodilator Previous trials showing efficacy
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SURVIVE Levosimendan vs. Dobutamine in patients with acute decompensated HF 1327 patients Primary end point:
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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
BNP Cardiac
• Lusitropic • Anti-remodeling • Anti-fibrotic
Hemodynamic Vasodilation:
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Veins
• Arteries • Coronary arteries
Neurohormonal
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Aldosterone
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Endothelin-1 Noradrenaline Renal
• Diuresis • Natriuresis
Nesiritide
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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 1 0.8
0.6
Week 12 All Nesiritide All Placebo 0.4
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0 0 2 P =0.791
HR (95% CI) 1.03 (0.82, 1.30) 4 6 8 10 12 14 16 18 20 22 24 Weeks
Chronic Heart Failure
Neurohormonal Status in Heart Failure
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SNS RAAS Vasopressin Endothelin-1 ?Urotensin II CONSTRICTION DILATATION
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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
Mortality After Hospital Admission for HF Wasywich C. CSANZ 2007 25 20 15 10 45 40 35 30
12-month 6-month 30-day
5 0 1986 CO NS ENS 198819891990 SO LV D Rx 1992199319941995199619971998 Year RA M LE ERI S T HF 2001200220032004
CHARM Trial Programme: Summary CHARM Alternative ACEi intolerant pt Lancet 2003;362:772
ARB suitable alternative to ACEi
CHARM Added Candesartan + ACEi Lancet 2003;362:767
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
Class TNF blockade Recent “Failed” Phase III HF Trials Drug Trial
Etanercept RENEWAL Packer Circ 2002;106:920
Vasopeptidase inhibition
Omapatrilat OVERTURE Mann Circ 2004;1091594
Endothelin blockade
Bosentan ENABLE
“Failed” Drugs in Heart Failure
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Increase mortality (sudden death) with: Milrinone Flosequinan Ibopamine Moxonidine Class I antiarrhythmics
Emerging Drug Therapies in HF
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Ranolazine (metabolic agent)
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Erythropoietin
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HMGcoA reductase inhibitors
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Adenosine agonists
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AGE cross-link breakers
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Immune modulation therapy
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Rosuvastatin
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Ivabradine (I
f
channel inhibitor) Eplerenone
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Levosimendan
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NEP/ECE inhibitors
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Vasopressin antagonists
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Nesiritide
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Copper chelation agents
Arterial underfilling
Vasopressin System
Hyperosmolality Baroreceptors
• Left atrium • Carotid sinus • Aortic arch
Hypothalamus
• Supraoptic nucleus • Paraventricular nucleus Vascular smooth muscle
V1a receptors Vasoconstriction AVP
Collecting duct of kidney
V2 receptors Water re-absorption OPC-21268 Relcovaptan OPC-31260 SR121463 Tolvaptan Lixivaptan VP-343 FR-161282 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
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Efficacy of Vasopressin Antagonism in Heart failure Outcome Study with Tolvaptan Tolvaptan (30mg/d) vs. placebo 4133 patients with LVEF < 40% Outcomes:
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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
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26 patients, EPO vs. placebo, 6 months End points: Hb and Peak Vo2 Haemoglobin VO2
Potential Benefits of EPO
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Prevention of apoptosis Endothelial progenitor cell mobilisation Induction of angiogenesis/ neovascularisation
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Limitation of ischaemia/reperfusion injury
Biventricular Pacing
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LBBB common in HF patients “Dysynchrony” between ventricles Biventricular pacing (cardiac resynchronisation therapy, CRT)
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Pace right and left ventricle (via lead in coronary sinus)
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Improved cardiac output in severe HF
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Improved quality of life
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Improved survival
Implantable Defibrillators
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Small implantable devices like pacemakers
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Able to deliver small electric shock across the heart to terminate ventricular arrhythmias
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Improved survival in patients with chronic heart failure
SCD-HeFT: Amiodarone or ICD in CHF G Bardy et al. NEJM 2005;352:225-37
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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
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Cardiac resynchronisation therapy Patients with sinus rhythm, wide QRS on ECG (>120msec), LVEF <35%, moderate to severe symptom
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Implantable defibrillators Prophylactic ICD for patients with LVEF<30% and mild to moderate symptoms
HF with Preserved LVEF
CHARM PEP-CHF Inclusion CHF, age>70 EF>40% End-Points Duration Drug Mortality Hosp CHF, age>70 EF>40% Mortality Hosp 1 yr 2 yrs Candesartan Perindopril I-PRESERVE CHF, age>60 Mortality EF>45% CVS Hosp 2 yrs TOP CAT CHF EF>45% Mortality Hosp 3 yrs Irbesartan Aldo antag
ACEi in HF with Preserved EF
CHARM Preserved CVS Death or HF Hospitalisation PEP-CHF 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
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Disease targeted therapy Hypertension
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BP target levels Prevent / regress LVH Atrial fibrillation
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Control rate, anticoagulation Coronary artery disease
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Prevention / revascularisation Diabetes / metabolic syndrome Other
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Anaemia, CRF, arrhythmias (esp. AF)
Diabetes and HF
Haas SJ et al. Am Heart J 2003;146:848 Diabetes worse
Diabetes and HF
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Specific therapies for patients with diabetes and heart failure
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Metformin and improved outcomes in HF (PHANTOM Study)
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AGE cross-link breakers in diastolic HF (Alteon)
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Copper chelation
Summary
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Acute heart failure
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Pathophysiology Aetiology treament Chronic heart failure
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Established therapies “Failed” therapies Device-based therapies Specific patient subgroups
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Disease specific
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Patient specific