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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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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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slide1
Heart Failure

Associate Professor Rob Doughty

Dept of Medicine, The University of Auckland &

Green Lane Cardiovascular Service,

Auckland City Hospital

slide2
Acute Heart Failure
  • Chronic heart failure
    • Pharmacotherapy
    • “failed” therapies
    • Device-based therapies
    • Newer therapeutics
slide3

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
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
Aging Population

2021

2001

1986

Source: Statistics NZ

slide6

Mortality from Cardiovascular Disease

Source: NZ Heart Foundation Technical Report No 82 Jan 2004

incidence and prevalence of hf
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 hf
Trends in Hospitalisations for HF

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

acute heart failure
Acute Heart Failure
  • Definition
  • Incidence and prevalence
  • Hospitalisations
  • Management
    • Patient characteristics
    • Aetiology
    • Treatment
definition of heart failure
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

definition of heart failure11
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

several distinct clinical conditions
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

patient characteristics
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

patient characteristics14
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

aetiology of heart failure
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 failure16
Aetiology of Heart Failure

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

acute hf levosimendan
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
SURVIVE Trial

Mebazza A et al. JAMA 2007;297:1883

proposed effects of nesiritide
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
nesiritide
Nesiritide
  • Smaller trials demonstrating short term efficacy
  • FDA approval in 2001
  • Acute decompensated HF
  • Subsequent meta-analyses suggesting potential adverse effects
slide21

Nesiritide

Any iv Vasodilator

Nesiritide

GTN

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

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

fusion ii trial
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

neurohormonal status in heart failure
Neurohormonal Status in Heart Failure
  • SNS
  • RAAS
  • Vasopressin
  • Endothelin-1
  • ?Urotensin II

DILATATION

  • Natriuretic peptides
  • Nitric oxide
  • Vasodilatory PGs
  • Adrenomedullin
  • Urocortin

CONSTRICTION

neurohormonal antagonists
Neurohormonal Antagonists

Annual Mortality (%)

10

5

0

+ ACEi

+ b-blocker

Diuretics

+ Digoxin

+ ACEi

Cleland meta-analysis; Lechat meta-analysis

slide26

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

slide28

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
Long-Term Effects of Treatment

CONSENSUS I Trial

10-year FU

1-year FU

recent failed phase iii hf trials
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

failed drugs in heart failure
“Failed” Drugs in Heart Failure

Increase mortality (sudden death) with:

  • Milrinone
  • Flosequinan
  • Ibopamine
  • Moxonidine
  • Class I antiarrhythmics
emerging drug therapies in hf
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
vasopressin system
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

slide34

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
slide35

EVEREST Outcome Trial

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

All-Cause Mortality

CVS Death or Hospitalisation for HF

slide37

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

potential benefits of epo
Potential Benefits of EPO
  • Prevention of apoptosis
  • Endothelial progenitor cell mobilisation
  • Induction of angiogenesis/ neovascularisation
  • Limitation of ischaemia/reperfusion injury
biventricular pacing
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
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
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
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
slide44

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

slide45

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

slide46

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)
slide47

Diabetes and HF

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

Diabetes worse

slide48

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
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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