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