Download ACE INHIBITORS

DIAGNOSTIC ET TRAITEMENT DE
L’INSUFFISANCE CARDIAQUE
Prof O. Gurné
UCL – Cliniques Univ St Luc
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.
Etiology and Pathophysiology of Heart
Failure
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
Left Ventricular Dysfunction
• Systolic: Impaired contractility/ejection
– Approximately two-thirds of heart failure patients
have systolic dysfunction1
• Diastolic: Impaired filling/relaxation
30%
(EF > 40 %)
(EF < 40%)
70%
Diastolic Dysfunction
Systolic Dysfunction
1 Lilly, L. Pathophysiology of Heart Disease. Second Edition p 200
Progress of heart failure
NYHA
Class
Ventricular dysfunction
Overt heart failure
I
Prevention
Mild
II
Moderate
III
Severe
Therapy
IV
Compensatory Mechanisms
Ventricular Remodeling
Alterations in the heart’s 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 4;101(1):E2.
Neurohormonal activation
in heart failure
Injury to heart
Neurohormonal
activation
Renin angiotensin
aldosterone
Sympathetic
Disease progression
Neurohormonal Responses to Impaired
Cardiac Performance
Initially Adaptive, Deleterious if Sustained
Response
Short-Term
Effects
Long-Term
Effects
Salt and Water Retention
Augments Preload
Pulmonary Congestion,
Anasarca
Vasoconstriction
Maintains BP for
perfusion of vital organs
Exacerbates pump
dysfunction (excessive
afterload), increases
cardiac energy
expenditure
Sympathetic Stimulation
Increases HR and
ejection
Increases energy
expenditure
Jaski, B, MD: Basics of Heart Failure: A Problem Solving Approach
Diagnostic of Heart Failure
Left Ventricular Dysfunction
Systolic and Diastolic
• Symptoms
• Physical Signs
– Dyspnea on Exertion
– Basilar Rales
– Paroxysmal
Nocturnal Dyspnea
– Pulmonary Edema
– Tachycardia
– Cough
– Hemoptysis
– S3 Gallop
– Pleural Effusion
– Cheyne-Stokes Respiration
Right Ventricular Failure
Systolic and Diastolic
• Symptoms
• Physical Signs
– Abdominal Pain
– Peripheral Edema
– Anorexia
– Jugular Venous Distention
– Nausea
– Abdominal-Jugular Reflux
– Bloating
– Hepatomegaly
– Swelling
Current diagnostic algorithm
Patient suspected to have LVD
ECG
Chest X-ray
Lung function tests
Full blood count
Thyroid function tests
Biochemistry
Echocardiogram
Natriuretic Peptides: Origin and
Stimulus of Release
Peptide
Primary Origin
Stimulus of Release
ANP
Cardiac atria
Atrial distension
BNP
Ventricular myocardium
Ventricular overload
CNP
Endothelium
Endothelial stress
ANP = Atrial Natriuretic Peptide
BNP = B-type Natriuretic Peptide
CNP = C-type Natriuretic Peptide
Adapted from Burnett JC, J Hypertens 2000;17(Suppl 1):S37-S43
BNP LEVELS IN PATIENTS WITN DYSPNEA
800
700
600
500
400
300
200
100
0
CHF
LVD / NO
CHF
PULMON
Morrison et al, J Am Coll Cardiol 2002;39:202
OTHER
CARD
OTHERS
BNP (pg/ml)
600
500
400
300
200
100
0
Pulmponary Asthma
fibrosis
n=1
11
COPD
Pneumonia
42
8
Acute
bronchitis
14
Tbc
2
Lung
cancer
4
Pulmonary
Embolism
3
Types of Lung Disease
Morrison et al, J Am Coll Cardiol 2002;39:202
Sensitivity (%)
ROC Curves for BNP and ED
Diagnosis Using All 250 Patients
100
90
80
70
60
50
40
30
20
10
0
AUC
0
10
20
30
40
--- BNP
--- ED diagnosis
0.9790
0.884
50
60
70
80
1 - Specificity (%)
Dao, Q., Maisel, A. et al. J. American College of Cardiology, Vol 37, No. 2, 2001
90 100
BNP in LV Dysfunction
1200
1077+/-272
BNP pg/mL
1000
800
567+/-113
600
391+/-89
400
200
30
0
Normal
N=105
Systolic
Diastolic
N=53
N=42
Maisel, A., De Maria, A. et al. American Heart Journal, Vol. 141, No. 3, 2001
Systolic &
Diastolic
N=14
Future diagnostic algorithm
Patient suspected to have LVD
LVD
unlikely
Normal
BNP
Increased
Echocardiogram
Treatment of Heart Failure
General Measures
Lifestyle Modifications:
Medical Considerations:
• Weight reduction
• Treat HTN, hyperlipidemia,
diabetes, arrhythmias
• Discontinue smoking
• Coronary revascularization
• Avoid alcohol and
other cardiotoxic
substances
• Anticoagulation
• Exercise
• Daily weights
• Immunization
• Sodium restriction
• Close outpatient monitoring
TRAITEMENT INSUFFISANCE
CARDIAQUE
I
DIUR
ACE - INH
INH A II
BB
SPIRO
DIG
II A
IIB
III
IV
Digitalis and Inotropic Agents
Compounds
Like the carrot placed in front of the donkey
Digoxine in heart failure
DIG trial
– Overall death
0.99
– Hospitalization
0.82
Digoxine better 
BUT
 Placebo better
MORTALITY
DIGOXIN
PLACEBO
RR
PVALUE
WORSENING
CHF
11.6 %
13.2 %
0.88
(0.77-1.01)
0.06
OTHER
CARDIAC
15.0 %
13.0 %
1.14
(1.01-1.30)
0.04
NEJM 1997; 336 : 525-533
Diuretics, ACE Inhibitors
Reduce the number of sacks on the wagon
Studies of Left Ventricular Dysfunction –
SOLVD (Treatment Study)
50
40
Mortality
(%)
30
Placebo
Enalapril
20
10
Risk reduction 16%
p=0.0036
0
0
6
12
18
24
30
36
Follow-up (months)
SOLVD Investigators N Engl J Med 1991;325:293-302
42
48
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 > 2.5 mg/dL or 221 µmol/L) or
hyperkalaemia (K+ > 5.0 mmol/L)
• symptomatic or severe asymptomatic hypotension (SBP < 90 mmHg)
Drug interactions to look out for:
• K+ supplements/ K+ sparing diuretics (including spironolactone)
• NSAIDs avoid unless essential
• AT1-receptor blockers
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
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)
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
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
ACE INHIBITORS - PROBLEM SOLVING (cont.)
Worsening renal function (cont.):
• If K+ rises to > 6.0 mmol/L or creatinine increases by >100% 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
Blockade of RAS
LOCAL ANG II SYNTHESIS IS INDEPENDENT OF ACE
ANGIOTENSINOGEN
(LIVER)
CHYMASE
RENIN
INHIBITOR
BRADYKININ
ACE
INHIBITOR
PEPTIDES
AT1 RECEPTOR
BLOCKER
ANGIOTENSIN I
ANGIOTENSIN II
AT1
AT2
A
NG II levels increase over time despite ACEI
180
BLOOD 160
PRESSURE 140
mm Hg 120
100
80
24
PLASMA
ANG II
pg/mL
20
16
12
8
4
0
PLACEBO 4H 24H
HOSPITAL
Biollaz et al. J Cardiovasc Pharmacol 1982;4:966
1
2
3
4
5
6 MONTHS
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
Randomized Aldactone
Evaluation Study (RALES)
1.00
0.95
All causes mortality
0.90
0.85
0.80
0.75
Probability
of survival 0.70
0.65
Spironolactone
0.60
0.55
Risk reduction 30%
0.50
95% CI : 18-40 %
p<0.001
Placebo
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 1999;10:709-717
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 > 221 µmol/L or 2.5
mg/dL)
• significant hyperkalaemia (K+ > 5.0 mmol/L)
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 > 6.0 mmol/L or creatinine to > 4.0
mg/dL
(354 µmol/L), stop spironolactone
Effects of Angiotensin II via AT receptors
1
ANGIOTENSINE II
AT1
• Vasoconstriction
• Hypertrophy
• Stimulation thirst
center
• Vasopressin release
• sympathetic activation
• Inotrope +
• Chronotrope +
• Aldosterone secretion
• Hypertrophy (HVG)
• Catecholamines secretion
• Fibrosis
• sodium and water retention
• Vasoconstriction of afferent and efferent arterioles
Goodfriend et al. N Engl J Med 1996;334:1649-1654
Jackson and Garrisson. In: Hardman et al. eds. Goodman & Gilman ’s The Pharmacological Basis of Therapeutics 9th ed. New
York: McGraw Hill: 1996;733-758
Bauer and Reams Arch Intern Med 1995;155:1361-1368
Losartan Heart Failure Survival Study
ELITE II
Study Design
60 yrs; NYHA II-IV; EF  40%
ACE-I/AIIA naive or <7 days in 3 months prior to
entry
Standard Rx (± Dig/Diuretics), ß-blocker
stratification
Captopril
50 mg 3 times
daily (N=1574)
Event Driven
(Target 510 Deaths)
~ 2 years
Losartan
50 mg Daily
(N=1578)
Primary Endpoint: All-Cause Mortality
Secondary Endpoint: Sudden Cardiac Death and/or Resuscitated
Arrest
Other Endpoin: All-cause Mortality/Hospitalizations
Safety and Tolerability
Losartan Heart Failure Survival Study ELITE II Primary Endpoint: All-Cause
Mortality
Probability of Survival
1.0
0.8
0.6
Captopril (N=1574)
Losartan (N=1578)
250 Events
280 Events
0.4
Captopril/Losartan Hazard Ratio (95% C.I.):
0.88 (0.75, 1.05) P=0.16
0.2
0.0
0
100
200
300
400
500
Days of Follow-up
600
700
CHARM Programme
3 component trials comparing candesartan
to placebo in patients with symptomatic heart failure
CHARM
Alternative
CHARM
Added
CHARM
Preserved
n=2028
n=2548
n=3025
LVEF 40%
ACE inhibitor
intolerant
LVEF 40%
ACE inhibitor
treated
LVEF >40%
ACE inhibitor
treated/not treated
Primary outcome for each trial: CV death or CHF hospitalisation
Primary outcome for Overall Programme: All-cause death
CHARM Programme
3 component trials comparing candesartan
to placebo in patients with symptomatic heart failure
CHARM
Alternative
CHARM
Added
CHARM
Preserved
n=2028
n=2548
n=3025
LVEF 40%
ACE inhibitor
intolerant
LVEF 40%
ACE inhibitor
treated
LVEF >40%
ACE inhibitor
treated/not treated
Primary outcome:
CV death or CHF hosp
CHARM-Alternative: Primary outcome CV
death or CHF hospitalisation
50
%
406 (40.0%)
Placebo
40
334 (33.0%)
30
Candesartan
20
HR 0.77 (95% CI 0.67-0.89), p=0.0004
Adjusted HR 0.70, p<0.0001
10
0
0
Number at risk
Candesartan 1013
Placebo
1015
1
2
929
887
831
798
3
3.5 years
434 122
427 126
CHARM Programme
3 component trials comparing candesartan
to placebo in patients with symptomatic heart failure
CHARM
Alternative
CHARM
Added
CHARM
Preserved
n=2028
n=2548
n=3025
LVEF 40%
ACE inhibitor
intolerant
LVEF 40%
ACE inhibitor
treated
LVEF >40%
ACE inhibitor
treated/not treated
Primary outcome:
CV death or CHF hosp
CHARM-Added: Primary outcome
CV death or CHF hospitalisation
50
%
Placebo
40
30
538 (42.3%)
483 (37.9%)
Candesartan
20
HR 0.85 (95% CI 0.75-0.96), p=0.011
Adjusted HR 0.85, p=0.010
10
0
0
Number at risk
Candesartan 1276
Placebo
1272
1
2
1176
1136
1063
1013
3
3.5 years
948 457
906 422
CHARM Programme
3 component trials comparing candesartan
to placebo in patients with symptomatic heart failure
CHARM
Alternative
CHARM
Added
CHARM
Preserved
n=2028
n=2548
n=3025
LVEF 40%
ACE inhibitor
intolerant
LVEF 40%
ACE inhibitor
treated
LVEF >40%
ACE inhibitor
treated/not treated
Primary outcome:
CV death or CHF hosp
CHARM-Preserved: Primary outcome
CV death or CHF hospitalisation
%
30
Placebo
25
366 (24.3%)
333 (22.0%)
20
Candesartan
15
10
HR 0.89 (95% CI 0.77-1.03), p=0.118
Adjusted HR 0.86, p=0.051
5
0
0
Number at risk
Candesartan 1514
Placebo
1509
1
2
1458
1441
1377
1359
3
3.5 years
833 182
824 195
ß-Blockers
Limit the donkey’s speed, thus saving energy
US Carvedilol Study
 blockers in
heart failure all-cause mortality
Survival
1.0
Carvedilol
(n=696)
0.9
Placebo
(n=398)
0.8
Risk reduction = 65%
0.7
p<0.001
0.6
0.5
0 50 100 150 200 250 300 350 400
Days
Mortality %
20
Survival
CIBIS-II
1.0
Packer et al (1996)
MERIT-HF
Placebo
Bisoprolol
15
0.8
Metoprolol CR/XL
10
Risk reduction = 34%
Placebo
Risk reduction = 34%
5
0.6
p=0.0062
p<0.0001
0
0
0
200
400
Time after inclusion (days)
600
800
Lancet (1999)
0
3
6
9
12 15
Months of follow-up
18
21
The MERIT-HF Study Group (1999)
COPERNICUS
Patient Characteristics
• Symptoms of heart failure at rest or minimal
exertion for at least 2 months
• LV ejection fraction <25%
• 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
COPERNICUS
All-cause mortality
100
% Survival
90
80
Carvedilol
70
Placebo
p=0.00013
35% risk reduction
60
0
0
3
6
9
12
Months
15
18
21
Flow chart of patients
Randomised
3029
Carvedilol
Metoprolol
Assigned to drug
and received at least one tablet
1511
1518
Withdrew consent 10
Lost to follow-up
3
Withdrew consent 18
Lost to follow-up 2
Primary endpoint of mortality
40
Metoprolol
Mortality (%)
30
20
Carvedilol
hazard ratio 0.83,
95% CI 0.74-0.93, P = 0.0017
10
0
0
Number at risk
Carvedilol
1511
Metoprolol
1518
1
2
3
4
5
1002
933
383
352
Time (years)
1367
1359
1259
1234
1155
1105
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 (< 4 weeks) exacerbation of heart failure eg.
hospital admission with worsening heart failure
• heart block or heart rate < 60 beats/min
• persisting signs of congestion – raised jugular venous pressure,
ascites, marked peripheral oedema
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
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 uptitration
• when to down-titrate/stop up-titration – see PROBLEM
SOLVING
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/uptitration phase
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 (> 2 days), by >1.5 – 2.0 kg
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
BETA-BLOCKERS - PROBLEM SOLVING
(cont.)
Low heart rate:
• if < 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
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
Treatment of Heart Failure
How could we do
better than better …
perhaps one day ?
HEART FAILURE TREATMENT
• MEDICAL THERAPY
• TECHNICAL DEVICE
–
–
–
–
Biventricular pacing
Défibillateur implantable
Assist devices
Artificial heart
• Bridge to transplant
• Permanent
• GENE / CELLULAR THERAPY
Cardiac Resynchronization
Therapy
Increase the donkey’s (heart) efficiency
BIVENTRICULAR PACING in CHF
“Conventional” target population
• High functional class (NYHA III or IV)
• Prolonged QRS ( > 150 ms)
• PR interval > 150 ms
• Dilated LV with EF <0.35
• Relative clinical stability
... % of CHF patients reflect these findings !
Effect of Multidisciplinary Intervention
in Treatment of Heart Failure
Structure of heart failure clinic
Cardiologist
GP
Nursing
In-hospital patient
Out-patient
Dietician
Physiotherapist
(4) Lancet 1998; 352 : SI15-SI18
Social
services
Home
nursing
EXEMPLE :
EDUCATION DU PATIENT
• DEBUTE A L’HOPITAL
• 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