DIAGNOSTIC ET TRAITEMENT DE LINSUFFISANCE CARDIAQUE

1
DIAGNOSTIC ET TRAITEMENT DE LINSUFFISANCE
CARDIAQUE

• Prof O. Gurné
• UCL Cliniques Univ St Luc

2
Heart Failure (HF) Definition

• A complex clinical syndrome in which the heart is
  incapable of maintaining a cardiac output
  adequate to accommodate metabolic requirements
  and the venous return.

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Etiology and Pathophysiology of Heart Failure
4
Etiology of Heart Failure

• What causes heart failure?
• The loss of a critical quantity of functioning
  myocardial cells after injury to the heart due
  to
• Ischemic Heart Disease
• Hypertension
• Idiopathic Cardiomyopathy
• Infections (e.g., viral myocarditis)
• Toxins (e.g., alcohol or cytotoxic drugs)
• Valvular Disease
• Prolonged Arrhythmias

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Left Ventricular Dysfunction

• Systolic Impaired contractility/ejection
• Approximately two-thirds of heart failure
  patients have systolic dysfunction1
• Diastolic Impaired filling/relaxation

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(EF gt 40 )
(EF lt 40)
70
Diastolic Dysfunction
Systolic Dysfunction
1 Lilly, L. Pathophysiology of Heart Disease.
Second Edition p 200
6
Progress of heart failure
NYHA Class
Ventricular dysfunction
I II III IV
Overt heart failure
Mild
Prevention
Moderate
Severe
Therapy
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Compensatory Mechanisms

• Ventricular Remodeling
• Alterations in the hearts size, shape,
  structure, and function brought about by the
  chronic hemodynamic stresses experienced by the
  failing heart.

Curry CW, et al. Mechanical dyssynchrony in
dilated cardiomyopathy with intraventricular
conduction delay as depicted by 3D tagged
magnetic resonance imaging. Circulation 2000 Jan
4101(1)E2.
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Neurohormonal activation in heart failure
Injury to heart
Neurohormonal activation
Renin angiotensin aldosterone
Sympathetic
Disease progression
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Neurohormonal Responses to ImpairedCardiac
Performance
Initially Adaptive, Deleterious if Sustained
Jaski, B, MD Basics of Heart Failure A
Problem Solving Approach
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Diagnostic of Heart Failure
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Left Ventricular DysfunctionSystolic and
Diastolic

• Physical Signs
• Basilar Rales
• Pulmonary Edema
• S3 Gallop
• Pleural Effusion
• Cheyne-Stokes Respiration

• Symptoms
• Dyspnea on Exertion
• Paroxysmal Nocturnal Dyspnea
• Tachycardia
• Cough
• Hemoptysis

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Right Ventricular FailureSystolic and Diastolic

• Physical Signs
• Peripheral Edema
• Jugular Venous Distention
• Abdominal-Jugular Reflux
• Hepatomegaly

• Symptoms
• Abdominal Pain
• Anorexia
• Nausea
• Bloating
• Swelling

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Current diagnostic algorithm
Patient suspected to have LVD
ECGChest X-rayLung function tests Full blood
countThyroid function testsBiochemistry
Echocardiogram
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Natriuretic Peptides Origin and Stimulus of
Release
ANP Atrial Natriuretic Peptide BNP B-type
Natriuretic Peptide CNP C-type Natriuretic
Peptide
Adapted from Burnett JC, J Hypertens
200017(Suppl 1)S37-S43
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BNP LEVELS IN PATIENTS WITN DYSPNEA
Morrison et al, J Am Coll Cardiol 200239202
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BNP (pg/ml)
600
500
400
300
200
100
0
Pulmponary Asthma COPD Pneumonia
Acute Tbc Lung
Pulmonary fibrosis
bronchitis
cancer Embolism
n 1 11 42
8 14 2
4 3
Types of Lung Disease
Morrison et al, J Am Coll Cardiol 200239202
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ROC Curves for BNP and ED Diagnosis Using All
250 Patients
Sensitivity ()

---
BNP
--- ED diagnosis
AUC
0.884
0.9790


1 - Specificity ()
Dao, Q., Maisel, A. et al. J. American College of
Cardiology, Vol 37, No. 2, 2001
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BNP in LV Dysfunction
N105 N53 N42 N14
Maisel, A., De Maria, A. et al. American Heart
Journal, Vol. 141, No. 3, 2001
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Future diagnostic algorithm
Patient suspected to have LVD
LVD unlikely
BNP
Normal
Increased
Echocardiogram
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Treatment of Heart Failure
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General Measures

• Lifestyle Modifications
• Weight reduction
• Discontinue smoking
• Avoid alcohol and other cardiotoxic substances
• Exercise

• Medical Considerations
• Treat HTN, hyperlipidemia, diabetes, arrhythmias
• Coronary revascularization
• Anticoagulation
• Immunization
• Sodium restriction
• Daily weights
• Close outpatient monitoring

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TRAITEMENT INSUFFISANCE CARDIAQUE
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Digitalis and Inotropic Agents Compounds

• Like the carrot placed in front of the donkey

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Digoxine in heart failure

• DIG trial
• Overall death
• Hospitalization

BUT
Digoxine better ? ? Placebo better
NEJM 1997 336 525-533
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Diuretics, ACE Inhibitors

• Reduce the number of sacks on the wagon

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Studies of Left Ventricular Dysfunction SOLVD
(Treatment Study)
Risk reduction 16 p0.0036
SOLVD Investigators N Engl J Med 1991325293-302
37

• ACE INHIBITORS - IN WHOM AND WHEN?
• Indications
• potentially all patients with heart failure
• 1st line treatment (along with beta-blockers) in
  NYHA class I-IV heart failure
• Contra-indications
• history of angioneurotic oedema
• Cautions
• significant renal dysfunction (creatinine gt 2.5
  mg/dL or 221 µmol/L) or hyperkalaemia (K gt 5.0
  mmol/L)
• symptomatic or severe asymptomatic hypotension
  (SBP lt 90 mmHg)
• Drug interactions to look out for
• K supplements/ K sparing diuretics (including
  spironolactone)
• NSAIDs avoid unless essential
• AT1-receptor blockers

38

• ACE INHIBITORS - HOW TO USE
• start with a low dose
• Increase dose progressively
• aim for target dose or, failing that, the highest
  tolerated dose
• remember some ACE inhibitor is better than no ACE
  inhibitor
• monitor blood chemistry (urea, creatinine, K)
  and blood pressure

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• ACE INHIBITORS - PROBLEM SOLVING
• Asymptomatic low blood pressure
• does not usually require any change in therapy
• Symptomatic hypotension
• if dizziness, light-headedness and/or confusion
  and a low blood pressure occurs, reconsider need
  for nitrates, calcium channel blockers and
  other vasodilators
• if no signs/symptoms of congestion, consider
  reducing diuretic dose
• calcium channel blockers should be
  discontinued unless absolutely essential (eg. for
  angina or hypertension)

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• ACE INHIBITORS - PROBLEM SOLVING (cont.)
• Cough
• cough is common in patients with heart failure,
  many of whom have smoking-related lung disease
• cough is also a symptom of pulmonary oedema which
  should be excluded if a new or worsening cough
  develops
• ACE inhibitor-induced cough rarely requires
  treatment discontinuation 5 10 max
• if a very troublesome cough develops (eg. one
  stopping the patient sleeping) and can be proven
  to be due to ACE inhibition (ie. recurs after ACE
  inhibitor withdrawal and rechallenge)
  substitution with an AT1-receptor blocker can be
  considered

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• ACE INHIBITORS - PROBLEM SOLVING (cont.)
• Worsening renal function
• some increase in urea (blood urea nitrogen),
  creatinine and K is to be expected after
  initiation if the increase is small and
  asymptomatic no action is necessary
• an increase in creatinine of up to 50 above
  baseline, or 3 mg/dL (266 µmol/L), whichever is
  the smaller, is acceptable
• an increase in K ? 6.0 mmol/L is acceptable
• if urea, creatinine or K rise excessively
  consider stopping concomitant nephrotoxic drugs
  (eg. NSAIDs), other K supplements/ K retaining
  agents (triamterene, amiloride) and, if no signs
  of congestion, reducing the dose of diuretic
• if greater rises in creatinine or K than those
  outlined above persist despite adjustment of
  concomitant medications, halve the dose of ACE
  inhibitor and recheck blood chemistry if there
  is still an unsatisfactory response, check for
  renal artery stenosis

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• ACE INHIBITORS - PROBLEM SOLVING (cont.)
• Worsening renal function (cont.)
• If K rises to gt 6.0 mmol/L or creatinine
  increases by gt100 or to above 4 mg/dL (354
  µmol/L), the dose of ACE inhibitor should be
  stopped
• Blood chemistry should be monitored serially
  until K and creatinine have plateaued
• NB it is very rarely necessary to stop an ACE
  inhibitor and clinical deterioration is likely if
  treatment is withdrawn

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B
lockade of RAS
44
A
NG II levels increase over time despite ACEI
Biollaz et al. J Cardiovasc Pharmacol 19824966
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RALES Study Design
NYHA III or IV heart failure LVEF 35 ACE-I
loop diuretic digoxin
3 years
Spironolactone 25 mg/day (n 822)
Placebo (n 841)

• Primary Endpoint
• Total mortality
• Secondary Endpoint
• Cardiac mortality
• Cardiac hospitalization
• Cardiac mortality or cardiac hosptitalization
• Changes from baseline in NYHA classification

Pitt et al, N Engl J Med, 1999.
History of NYHA IV within 6 months before first
dose
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Randomized Aldactone Evaluation Study (RALES) All
causes mortality
1.00
0.95
0.90
0.85
0.80
0.75
Probability of survival
0.70
Spironolactone
0.65
0.60
Risk reduction 30 95 CI 18-40 plt0.001
0.55
Placebo
0.50
0.45
0.00
0
3
6
9
12
15
18
21
24
27
30
33
36
Months
Pitt B et al. N Engl J Med 199910709-717
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• SPIRONOLACTONE - IN WHOM AND WHEN?
• Indications
• potentially all patients with symptomatically
  moderately severe or severe heart failure
• 2nd line therapy (after ACE inhibitors and
  beta-blockers) in patients with NYHA class III-IV
  heart failure
• Cautions
• significant renal dysfunction (creatinine gt 221
  µmol/L or 2.5 mg/dL)
• significant hyperkalaemia (K gt 5.0 mmol/L)

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• SPIRONOLACTONE - HOW TO USE
• start at 25 mg once daily (12.5)
• check blood chemistry at 1, 4, 8 and 12 weeks 6,
  9 and 12 months 6 monthly thereafter
• if K rises to between 5.5 and 6.0 mmol/L or
  creatinine rises to 2.5 mg/dL (221 µmol/L) reduce
  dose to 25 mg on alternate days and monitor blood
  chemistry closely
• if K rises to gt 6.0 mmol/L or creatinine to gt
  4.0 mg/dL (354 µmol/L), stop
  spironolactone

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E
ffects of Angiotensin II via AT1 receptors
ANGIOTENSINE II
AT1

• Stimulation thirst center
• Vasopressin release
• sympathetic activation

• Vasoconstriction
• Hypertrophy

• Inotrope
• Chronotrope
• Hypertrophy (HVG)
• Fibrosis

• Aldosterone secretion
• Catecholamines secretion

• sodium and water retention
• Vasoconstriction of afferent and efferent
  arterioles

Goodfriend et al. N Engl J Med 19963341649-1654
Jackson and Garrisson. In Hardman et al. eds.
Goodman Gilman s The Pharmacological Basis of
Therapeutics 9th ed. New York McGraw Hill
1996733-758Bauer and Reams Arch Intern Med
19951551361-1368
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Losartan Heart Failure Survival Study ELITE II
Study Design
?60 yrs NYHA II-IV EF ? 40 ACE-I/AIIA
naive or lt7 days in 3 months prior to
entry Standard Rx ( Dig/Diuretics), ß-blocker
stratification
Captopril 50 mg 3 times daily (N1574)
Losartan 50 mg Daily (N1578)
Event Driven (Target 510 Deaths) 2 years
Primary Endpoint All-Cause Mortality Secondary
Endpoint Sudden Cardiac Death and/or
Resuscitated Arrest Other Endpoin All-cause
Mortality/Hospitalizations
Safety and Tolerability
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Losartan Heart Failure Survival Study - ELITE II
Primary Endpoint All-Cause Mortality
1.0
0.8
0.6
Captopril (N1574) 250 Events
Probability of Survival
Losartan (N1578) 280 Events
0.4
Captopril/Losartan Hazard Ratio (95 C.I.) 0.88
(0.75, 1.05) P0.16
0.2
0.0
0
100
200
300
400
500
600
700
Days of Follow-up
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CHARM Programme
3 component trials comparing candesartan to
placebo in patients with symptomatic heart failure
CHARM Added
CHARMPreserved
CHARMAlternative
n2028 LVEF 40ACE inhibitor intolerant
n2548 LVEF 40ACE inhibitor treated
n3025 LVEF gt40ACE inhibitor treated/not
treated
Primary outcome for each trial CV death or CHF
hospitalisation
Primary outcome for Overall Programme All-cause
death
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CHARM Programme
3 component trials comparing candesartan to
placebo in patients with symptomatic heart failure
CHARM Added
CHARMPreserved
CHARMAlternative
n3025 LVEF gt40 ACE inhibitor treated/not
treated
n2028 LVEF 40ACE inhibitor intolerant
n2548 LVEF 40ACE inhibitor treated
Primary outcome CV death or CHF hosp
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CHARM-Alternative Primary outcome CV death or
CHF hospitalisation

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406 (40.0)
Placebo
40
334 (33.0)
30
Candesartan
20
HR 0.77 (95 CI 0.67-0.89), p0.0004Adjusted HR
0.70, plt0.0001
10
0
0
1
2
3
years
3.5
Number at risk Candesartan 1013 929 831 434 122 P
lacebo 1015 887 798 427 126
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CHARM Programme
3 component trials comparing candesartan to
placebo in patients with symptomatic heart failure
CHARM Added
CHARMPreserved
CHARMAlternative
n3025 LVEF gt40ACE inhibitor treated/not
treated
n2028 LVEF 40 ACE inhibitor intolerant
n2548 LVEF 40ACE inhibitor treated
Primary outcome CV death or CHF hosp
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CHARM-Added Primary outcomeCV death or CHF
hospitalisation

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538 (42.3)
Placebo
40
483 (37.9)
30
Candesartan
20
HR 0.85 (95 CI 0.75-0.96), p0.011Adjusted HR
0.85, p0.010
10
0
0
1
2
3
years
3.5
Number at risk Candesartan 1276 1176 1063 948 457
Placebo 1272 1136 1013 906 422
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CHARM Programme
3 component trials comparing candesartan to
placebo in patients with symptomatic heart failure
CHARM Added
CHARMPreserved
CHARMAlternative
n3025 LVEF gt40ACE inhibitor treated/not
treated
n2028 LVEF 40 ACE inhibitor intolerant
n2548 LVEF 40ACE inhibitor treated
Primary outcome CV death or CHF hosp
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CHARM-Preserved Primary outcome CV death or CHF
hospitalisation

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366 (24.3)
Placebo
25
333 (22.0)
20
Candesartan
15
10
HR 0.89 (95 CI 0.77-1.03), p0.118Adjusted HR
0.86, p0.051
5
0
0
1
2
3
years
3.5
Number at risk Candesartan 1514 1458 1377 833 182
Placebo 1509 1441 1359 824 195
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ß-Blockers

• Limit the donkeys speed, thus saving energy

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US Carvedilol Study
Survival
1.0 0.9 0.8 0.7 0.6 0.5
Carvedilol (n696)
? blockers in heart failure - all-cause
mortality
Placebo (n398)
Risk reduction 65
plt0.001
0
50
100
150
200
250
300
350
400
Days
Packer et al (1996)
Survival
Mortality
CIBIS-II
1.00.80.6 0
20
MERIT-HF
Placebo
Bisoprolol
15
Metoprolol CR/XL
10
Placebo
Risk reduction 34
Risk reduction 34
5
p0.0062
plt0.0001
0
0 200 400
600 800
0
3
6
9
12
15
18
21
Months of follow-up
Lancet (1999)
Time after inclusion (days)
The MERIT-HF Study Group (1999)
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COPERNICUS

• Patient Characteristics
• Symptoms of heart failure at rest or minimal
  exertion for at least 2 months
• LV ejection fraction lt25
• Receiving diuretics and an ACE inhibitor (
  digitalis) ?2 months. Diuretics optimised to
  achieve euvolaemia
• No need for intensive care and no treatment with
  IV inotropic or IV vasodilator therapy within 4
  days of screening

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COPERNICUS
All-cause mortality
100
90
Carvedilol
80
Survival
70
Placebo
p0.00013 35 risk reduction
60
0
0
3
6
9
12
15
18
21
Months
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Flow chart of patients
Randomised 3029
Carvedilol 1511
Metoprolol 1518
Assigned to drug and received at least one tablet
Withdrew consent 10 Lost to follow-up 3
Withdrew consent 18 Lost to follow-up 2
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Primary endpoint of mortality
40
Metoprolol
30
20
Carvedilol
Mortality ()
hazard ratio 0.83, 95 CI 0.74-0.93, P 0.0017
10
0
0
1
2
3
4
5
Time (years)
Number at risk Carvedilol 1511 1367 1259
1155 1002 383 Metoprolol 1518 1359 1234
1105 933 352
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• BETA-BLOCKERS - IN WHOM AND WHEN?
• Indications
• potentially all patients with stable mild and
  moderate heart failure patients with severe
  heart failure should be referred for specialist
  advice
• 1st line treatment (along with ACE inhibitors) in
  patients with stable NYHA class I-III heart
  failure start as early as possible
• Contra-indications
• asthma
• Cautions
• severe (NYHA Class IV) heart failure ( !
  COPERNICUS)
• current or recent (lt 4 weeks) exacerbation of
  heart failure eg. hospital admission with
  worsening heart failure
• heart block or heart rate lt 60 beats/min
• persisting signs of congestion raised jugular
  venous pressure, ascites, marked peripheral
  oedema

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• BETA-BLOCKERS - IN WHOM AND WHEN? (cont.)
• Drug interactions to look out for
• verapamil/diltiazem (should be discontinued)
• amiodarone
• BETA-BLOCKERS - WHERE?
• in the community in stable patients (NYHA class
  IV/severe heart failure patients should be
  referred for specialist advice)
• not in unstable patients hospitalised with
  worsening heart failure
• other exceptions see CAUTIONS

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• BETA-BLOCKERS - HOW TO USE
• start with a low dose
• double dose at not less than 2 weekly intervals
• aim for target dose or, failing that, the highest
  tolerated dose
• remember some beta-blocker is better than no
  beta-blocker
• monitor HR, BP, clinical status (symptoms, signs
  especially signs of congestion) and body
  weight)
• check blood chemistry 1-2 weeks after initiation
  and 1-2 weeks after final dose titration
• a specialist heart failure nurse may assist with
  patient education, follow-up (in person/by
  telephone) and dose up-titration
• when to down-titrate/stop up-titration see
  PROBLEM SOLVING

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• BETA-BLOCKERS - ADVICE TO PATIENT
• explain expected benefits (see WHY?)
• emphasise that treatment given as much to prevent
  worsening of heart failure as to improve
  symptoms beta-blockers also increase survival
• if symptomatic improvement occurs, this may
  develop slowly, 3 - 6 months or longer
• temporary symptomatic deterioration may occur
  (estimated 20 - 30 of cases) during
  initiation/up-titration phase

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• BETA-BLOCKERS - ADVICE TO PATIENT (cont.)
• advise patient to report deterioration (see
  PROBLEM SOLVING) and that deterioration
  (tiredness, fatigue, breathlessness) can usually
  be easily managed by adjustment of other
  medication patients should be advised not to
  stop beta-blocker therapy without consulting
  their physician
• patients should be encouraged to weigh themselves
  daily (after waking, before dressing, after
  voiding, before eating) and to increase their
  diuretic dose should their weight increase,
  persistently (gt 2 days), by gt1.5 2.0 kg

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• BETA-BLOCKERS - PROBLEM SOLVING
• Worsening symptoms/signs (eg. increasing
  dyspnoea,
• fatigue, oedema, weight gain)
• if increasing congestion, double dose of diuretic
  and/or halve dose of beta-blocker (if increasing
  diuretic does not work)
• if marked fatigue (and/or bradycardia see
  below) halve dose of beta-blocker (rarely
  necessary)
• review patient in 1-2 weeks if not improved seek
  specialist advice
• if serious deterioration halve dose of
  beta-blocker or stop this treatment (rarely
  necessary) seek specialist advice

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• BETA-BLOCKERS - PROBLEM SOLVING (cont.)
• Low heart rate
• if lt 50 beats/min and worsening symptoms halve
  dose beta-blocker or, if severe deterioration,
  stop beta-blocker (rarely necessary)
• review need for other heart rate slowing drugs
  eg. digoxin, amiodarone, diltiazem
• arrange ECG to exclude heart block

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• BETA-BLOCKERS - PROBLEM SOLVING (cont.)
• Asymptomatic low blood pressure
• does not usually require any change in therapy
• Symptomatic hypotension
• if dizziness, light-headedness and/or confusion
  and a low blood pressure occur, reconsider need
  for nitrates, calcium channel blockers and other
  vasodilators
• if no signs/symptoms of congestion, consider
  reducing diuretic dose
• NOTE Beta-blockers should not be stopped
  suddenly unless absolutely necessary (there is
  a risk of a rebound increase in myocardial
  ischaemia/infarction and arrhythmias) ideally
  specialist advice should be sought before
  treatment discontinuation

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Treatment of Heart Failure

• How could we do better than better perhaps one
  day ?

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HEART FAILURE - TREATMENT

• MEDICAL THERAPY
• TECHNICAL DEVICE
• Biventricular pacing
• Défibillateur implantable
• Assist devices
• Artificial heart
• Bridge to transplant
• Permanent
• GENE / CELLULAR THERAPY

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Cardiac Resynchronization Therapy

• Increase the donkeys (heart) efficiency

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BIVENTRICULAR PACING in CHF
Conventional target population

• High functional class (NYHA III or IV)

• Prolonged QRS ( gt 150 ms)

• PR interval gt 150 ms

• Dilated LV with EF lt0.35

• Relative clinical stability

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Effect of Multidisciplinary Intervention in
Treatment of Heart Failure
Structure of heart failure clinic
Cardiologist
GP
Nursing
In-hospital patient
Out-patient
Dietician
Social services
Physiotherapist
Home nursing
(4) Lancet 1998 352 SI15-SI18
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EXEMPLE EDUCATION DU PATIENT

• DEBUTE A LHOPITAL
• POURSUIVI A LA MAISON

• Connaissance de sa pathologie
• Relation avec sa médication
• Relation avec son hygiène de vie, son régime
• Connaissance des signes précoces de
  décompensation
• Ex prise du poids