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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.

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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

    • Pharmacotherapy

    • “failed” therapies

    • Device-based therapies

    • Newer therapeutics


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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


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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


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Aging Population

2021

2001

1986

Source: Statistics NZ


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Mortality from Cardiovascular Disease

Source: NZ Heart Foundation Technical Report No 82 Jan 2004


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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


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Trends in Hospitalisations for HF

Stewart S et al. EHJ 2001;22:209-217


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Acute Heart Failure

  • Definition

  • Incidence and prevalence

  • Hospitalisations

  • Management

    • Patient characteristics

    • Aetiology

    • Treatment


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Definition of Heart Failure

  • Symptoms of heart failure (rest or exercise)

  • Objective evidence of cardiac dysfunction

    and in cases where diagnosis remains in doubt

  • Response to treatment directed at HF

ESC HF Guidelines EHJ 2005;26:1115-1140


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Definition of Heart Failure

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

ESC Acute HF Guidelines EHJ 2005;26:384-416


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Several Distinct Clinical Conditions

  • 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

ESC Acute HF Guidelines EHJ 2005;26:384-416


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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 HF

    Presentation

  • 40% acute dyspnoea

  • 35% exertional dyspnoea / oedema

  • 19% acute coronary syndrome

  • 9% atrial fibrillation

Cleland JGF et al. EHJ 2003;24:442-463


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Patient Characteristics

Admission

  • 50% general medical wards

  • 11 days average length of stay

    Death rates:

  • 6.9% during index admission

  • 13.5% at 3 months

Cleland JGF et al. EHJ 2003;24:442-463


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Aetiology of Heart Failure

  • Heart failure clinical syndrome with underlying cause

  • Underlying cause often not focused on

  • Hypertension & coronary disease commonest causes


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Aetiology of Heart Failure

Fox KF et al. EHJ 2001;22:228-236


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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


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SURVIVE Trial

Mebazza A et al. JAMA 2007;297:1883


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Proposed Effects of Nesiritide

  • Hemodynamic

  • Vasodilation:

    • Veins

    • Arteries

    • Coronary arteries

  • Neurohormonal

    •  Aldosterone

    •  Endothelin-1

    •  Noradrenaline

  • Renal

    • Diuresis

    • Natriuresis

  • BNP

    • Cardiac

      • Lusitropic

      • Anti-remodeling

      • Anti-fibrotic


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    Nesiritide

    • Smaller trials demonstrating short term efficacy

    • FDA approval in 2001

    • Acute decompensated HF

    • Subsequent meta-analyses suggesting potential adverse effects


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    Nesiritide

    Any iv Vasodilator

    Nesiritide

    GTN

    Hauptman PJ, et al. JAMA 2005;296:1877

    Data from 491 US hospitals, 385,627 admissions for HF


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    FUSION II Trial

    1

    Week 12

    All Nesiritide

    0.8

    All Placebo

    0.6

    Event Free Survival

    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

    16

    18

    20

    22

    24

    Weeks

    Out-patient based treatment, nesiritide 1 or 2 weekly

    LVEF <40%, Class III/IV HF



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    Neurohormonal Status in Heart Failure

    • SNS

    • RAAS

    • Vasopressin

    • Endothelin-1

    • ?Urotensin II

    DILATATION

    • Natriuretic peptides

    • Nitric oxide

    • Vasodilatory PGs

    • Adrenomedullin

    • Urocortin

    CONSTRICTION


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    Neurohormonal Antagonists

    Annual Mortality (%)

    10

    5

    0

    + ACEi

    + b-blocker

    Diuretics

    + Digoxin

    + ACEi

    Cleland meta-analysis; Lechat meta-analysis


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    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



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    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


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    Long-Term Effects of Treatment

    CONSENSUS I Trial

    10-year FU

    1-year FU


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    Recent “Failed” Phase III HF Trials

    ClassDrugTrial

    TNFEtanercept RENEWAL

    blockade

    VasopeptidaseOmapatrilat OVERTURE

    inhibition

    EndothelinBosentan ENABLE

    blockade

    Packer Circ 2002;106:920

    Mann Circ 2004;1091594


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    “Failed” Drugs in Heart Failure

    Increase mortality (sudden death) with:

    • Milrinone

    • Flosequinan

    • Ibopamine

    • Moxonidine

    • Class I antiarrhythmics


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    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


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    Vasopressin System

    V1a receptors

    V2 receptors

    Arterial underfilling

    Hyperosmolality

    • Baroreceptors

    • Left atrium

    • Carotid sinus

    • Aortic arch

    Hypothalamus

    • Supraoptic nucleus

    • Paraventricular nucleus

    AVP

    Collecting duct of kidney

    Vascular smooth muscle

    Vasoconstriction

    Water re-absorption

    OPC-31260SR121463TolvaptanLixivaptanVP-343FR-161282

    OPC-21268Relcovaptan

    ConivaptanJTV-605CL-3 85004

    Adapted from Sanghi et al Eur Heart J 2005


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    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


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    EVEREST Outcome Trial

    Konstam MA, et al. JAMA 2007;297:1319

    All-Cause Mortality

    CVS Death or Hospitalisation for HF



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    Erythropoietin in HF

    • 26 patients, EPO vs. placebo, 6 months

    • End points: Hb and Peak Vo2

    Mancini DM, et al. Circulation 2003;107:294

    Haemoglobin

    VO2


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    Potential Benefits of EPO

    • Prevention of apoptosis

    • Endothelial progenitor cell mobilisation

    • Induction of angiogenesis/ neovascularisation

    • Limitation of ischaemia/reperfusion injury


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    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


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    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


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    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


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    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


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    HF with Preserved LVEF

    Inclusion End-Points Duration Drug

    CHARM CHF, age>70 Mortality 1 yr Candesartan EF>40% Hosp

    PEP-CHF CHF, age>70 Mortality 2 yrs Perindopril

    EF>40% Hosp

    I-PRESERVE CHF, age>60 Mortality 2 yrs Irbesartan

    EF>45% CVS Hosp

    TOP CAT CHF Mortality 3 yrs Aldo antag

    EF>45% Hosp


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    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


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    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)


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    Diabetes and HF

    Haas SJ et al. Am Heart J 2003;146:848

    Diabetes worse


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    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


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    Summary

    • Acute heart failure

      • Pathophysiology

      • Aetiology

      • treament

    • Chronic heart failure

      • Established therapies

      • “Failed” therapies

      • Device-based therapies

    • Specific patient subgroups

      • Disease specific

      • Patient specific


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