Download ACE inhibitor therapy for heart failure due to LVSD

Management of Heart
Failure in 2014
Dr CJ Whelan MD FRCP
Consultant Cardiologist and
Honorary Senior Lecturer
Royal Free London NHS Foundation Trust
DIAGNOSIS
Chronic heart failure
A complex syndrome
that can result from
any structural or
functional cardiac
disorder that impairs
the pumping ability
of the heart
HF Clinic Patient
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RS is a 69 yr old gentleman recently referred
to the HF team.
He has a history of LV dysfunction with an EF
of 20% due to IHD.
He has had recent multiple admissions to
hospital with worsening symptoms NYHA IV.
He is now in NYHA III
With PND, orthopnoea and pitting oedema to
his knees
He has LBBB on his ECG with a QRS of 160
ms
Medication

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During last admission beta blocker has
been stopped due to symptomatic
bradycardia.
ACE I has been reduced due to
worsening renal function and
symptomatic hypotension.
Spironolactone has been reduced due
to hyperkalaemia
Further Management

What next?
Treatment



After discussion at the HF MDT,
referred for Biventricular PPM (CRT)
with ICD.
He was brought into a pre assessment
clinic and assessed and counselled by
the HF nurse.
He was admitted for CRT-D the next
week
6 months later
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RS was followed up in the nurse Led HF clinic 2-4 weekly
for assessment and titration of medication.
Beta Blocker was reinstated and he is now tolerating 10
mg Bisoprolol.
His ACE I was reintroduced and slowly titrated - now on
5mg Ramipril
He is tolerating 50 mg Spironolactone
His renal function is normal
He is biventricular paced
He is in NYHA II
An echo was repeated showing an improvement with EF
35-40%
He attends a cardiac rehab exercise class regularly
He has not been admitted to hospital since his CRT-D was
implanted
Case 2

ED is a 67 yr old gentleman
admitted to the medical ward with
a history of breathlessness and
bilateral ankle oedema. He has had
a reduction in exercise tolerance
over the last three months and has
experienced PND and orthopnoea
for a few days prior to admission.
Past Medical History

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STEMI 2008
PPCI to LAD 2008
HTN
Hyperlipidaemia
Arthritis
Drugs on admission
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Atenolol 25 mg od
Perindopril 2 mg od
Simvastatin 40 mg od
Aspirin 75 mg od
Piroxicam 20mg od
Social
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His wife has recently died and he
now lives alone.
He is retired
He has two grown up daughters
living in Manchester and Scotland.
He drinks up to 5 pints of beer every
Friday and Saturday night.
He eats mainly microwave meals
He is a current smoker of 5
cigarettes per day for 50 yrs.
Observations
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BP 160/90 mmHg
HR 100bpm reg Sinus Rhythm
Respirations 22/min
Bilateral basal creps
Third heart sound
His ECG shows SR with anterior q
waves
His Chest x Ray shows Pulmonary
oedema
Further Findings



NT proBNP is raised on admission at
560pmol/L
Echo carried out the day after
admission shows impaired LV systolic
function with an EF of 20% and severe
AS
He is referred to the HF team.
HF Review
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He is assessed the next day.
Diagnosis LV dysfunction due to IHD and severe
AS
Stop Piroxicam
PLAN: Change Atenolol to Bisoprolol 2.5 mg
titrating up as tolerated, aim for a resting HR of
<70 bpm
Commence Furosemide
Commence Spironolactone 12.5 mg titrating up
to maximum tolerated dosage
Aim to increase perindopril if BP and renal
function will allow to the maximum tolerated
dosage.
Regular bloods for renal function
Life Style advice / Education
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Reduction in salt and advice on changing
his diet from convenience foods
Reduction in alcohol intake
Highlight the importance of compliance of
medication
Explain possible symptoms and the
importance of reporting any changes in
symptoms to the HF team.
Encourage stopping smoking, referral to
cessation, give patches.
Discharge
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Mr Smith is discharged after 4 days on
the medical ward, with a plan for FU in
the HF clinic in 2 weeks.
His U&E s were normal
His HR was 70 bpm on 5 mg of
Bisoprolol
BP 120/80 on perindopril 4 mg
His chest was clear
Follow up
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He was seen two weeks later in the HF
clinic.
His U&Es were checked showing his
creatinine had increased to 161 umol/l
and urea up to 15.4 umol/l
He was reporting symptoms of
increasing lethargy and dizziness
His HR was 50bpm SR BP 100/50
Treatment plan
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Reduce Bisoprolol to 2.5 mg
Reduced Perindopril back to 2 mg
Plan to recheck U&E s in one week
Readmitted with worsening HF
symptoms
Blood renal chemistry deteriorates
further despite stopping ACEI –
creatinine 288 umol/l
Renal review
Ongoing management
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Joint care between HF team and
renal team
Started on haemodialysis
Becomes euvolaemic with
improvement in HF symptoms
Discussed at HF MDT
Further progress
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Referred for consideration of TAVI
in view of severe AS
TAVI performed December 2013
Heart Hospital
Repeat echo March 2014 shows
improvement of LV function to 35%
Now on 8mg perindopril, 7.5mg
bisoprolol and 25mg
spironolactone
In NYHA class II
EPIDEMIOLOGY AND HEALTH
SERVICE IMPACT
Size of the problem
Summary
Common
 Affects 1-2% of the population
 Annual incidence is 0.5-1%
Serious (but improving)
 40% mortality at 1 year, 10% per year thereafter
Increasing
 Ageing population and better treatment of acute MI
Disabling
 Symptoms have enormous impact on quality of life, worse than
many other chronic conditions
Expensive
 Around 2% of NHS budget, 5% of acute admissions,
and 10% of bed occupancy
BMJ, 2002; Eur J Heart Failure, 1999; NICE, 2003; BHF, 2002; DOH 2009
HF GUIDELINES
The NICE algorithm for new diagnosis 2010
Adapted from NICE 2010.
TREATMENT
TREATMENT
Aims of treatment of chronic heart failure

The aims of therapy in heart failure are to:
• Improve life expectancy
• Improve quality of life

The relative importance of these aims varies:
• Between patients
• Over time
NICE, 2003
TREATMENT
Modern management

The therapeutic approach in chronic heart
failure due to systolic dysfunction consists of:
• Non-pharmacological measures
Patient education
 Avoid obesity
 Dietary measures e.g. salt restriction if
prescribed
 Avoid excessive fluid intake
 Smoking cessation
 Exercise/rehabilitation
 Influenza/pneumococcal vaccination

• Pharmacological therapy
• Devices and surgery
ESC, 2008
TREATMENT
Co-morbidities that may impact
on treatment (1)
Co-morbidity
Comments
COPD/asthma/reversible Beta-blockers are contraindicated in
airways disease
patients with reversible airways disease
Renal dysfunction
(serum creatinine > 200
µmol/l)
ACE inhibitors and angiotensin II receptor
blockers may be contraindicated
Adapted from NICE 2003.
NICE, 2003
TREATMENT
Treatment options for chronic heart failure
Drug therapy
 Diuretics
 Neurohormonal antagonists
•
•
•
•
ACE inhibitors
Beta blockers
Mineralocorticoid antagonists
Angiotensin II receptor blockers
 Ivabradine (If channel blocker)
 Digoxin
 Other drugs
•
•
•
•
Amiodarone
Nitrates/Hydralazine
Aspirin
Warfarin
TREATMENT
Diuretic therapy

Rapid relief of congestive symptoms and
fluid retention, improving:
• Breathlessness
• Exercise performance

May be titrated according to need following
initiation of subsequent therapies

No evidence for mortality benefit

No effect on disease progression
“Diuretics should be routinely used for the relief of congestive
symptoms and fluid retention in patients with heart failure, and titrated
(up and down) according to need following initiation of subsequent
heart failure therapies”
NICE, 2003
TREATMENT
Use of oral diuretics
Drug
Initial dose
(mg)
Maximum recommended
daily dose (mg)
0.5–1.0
20–40
5–10
5–10
250–500
100–200
Bendroflumethiazide (bendrofluazide)
Indapamide
Metolazone
2.5
2.5
2.5
5
2.5
10
Potassium-sparing diuretic
+ACEI
2.5
25
Loop diuretics
Bumetanide
Furosemide
Torasemide
Thiazides*
Amiloride
Triamterene
–ACEI
5
50
+ACEI
20
100
–ACEI
40
200
*May be effective when added to loop diuretics when fluid retention is resistant, but can
promote dramatic diuresis and disturbance in fluid balance and electrolytes. Patients must be
closely monitored and specialist advice is required. ACEI=ACE inhibitor
Adapted from NICE et al. 2003.
NICE, 2003
TREATMENT
ACE inhibitor therapy for heart failure
and LVSD
All trials
40
30

Systematic overview of data
from five long-term RCTs

Compared with placebo,
ACE inhibitors reduce:
• Mortality (p<0.0001)
• Readmission (p<0.0001)
• Reinfarction (p<0.0001)

Benefit begins early after
the start of therapy and
persists in the long-term
20
Cumulative
mortality (%)
10
0
0
1
2
3
4
5
Time since randomisation (years)
ACE-1
Placeb0
6391
6372
5378
5279
4204
4025
2457
2364
892
742
Adapted from Elather et al. 2000.
Flather et al, Lancet; 2000
TREATMENT
ACE inhibitor therapy for heart failure
due to LVSD
“All patients with heart failure due to left
ventricular systolic dysfunction should be
considered for treatment with an ACE inhibitor.
ACE inhibitor therapy should be instituted in
patients with heart failure due to left ventricular
systolic dysfunction before beta-blockade is
introduced.”
“ACE inhibitor therapy should be initiated at the
appropriate dose, and titrated upwards at short
intervals (eg every two weeks) until the optimal
tolerated or target dose is achieved.”
NICE, 2003
TREATMENT
Practical recommendations on use of
ACE inhibitors (1)
How to use

Start with a low dose

Seek specialist advice where the patient is on a high dose (eg
furosemide 80mg) of a loop diuretic

Double dose at not less than two weekly intervals

Aim for target dose or the highest tolerated dose

Remember some ACE inhibitor is better than no ACE inhibitor

Monitor blood electrolytes (in particular potassium), urea,
creatinine and blood pressure
If the patient develops a troublesome dry cough which
interferes with sleep and is likely to be caused by an ACE inhibitor,
consider substituting an angiotensin-II receptor blocker
NICE, 2003
TREATMENT
Practical recommendations on use of
ACE inhibitors (2)
Advice to patients

Explain expected benefits

Treatment is given to improve symptoms, to prevent
worsening of heart failure and to increase survival

Symptoms improve within a few weeks to a few months

Advise patients to report principal adverse effects, i.e.
dizziness/symptomatic hypotension, cough.
If the patient develops a troublesome dry cough which
interferes with sleep and is likely to be caused by an ACE inhibitor,
consider substituting an angiotensin-II receptor blocker
NICE, 2003
TREATMENT
Beta-blocker therapy for heart failure
due to LVSD
Bisoprolol pooled (2 trials)
Bucindolol pooled (4 trials)
Carvedilol pooled (5 trials)
Metoprolol pooled (9 trials)
5 small trials
Overall (25 trials)
0.1
0.2
0.5
1
2
5

Pooled data from 25
RCTs (6511 patients and
810 deaths)

Compared with placebo,
beta-blockers reduced
odds of death by 36%
10
Fig 1 Pooled odds ratios (and 95% confidence intervals)
describing the effect of beta blockers on mortality in
patients with heart failure
• (95% CI 25% to 45%)
ACE inhibitors alone
Beta Blockers added

No evidence of
heterogeneity between
trial results

Benefit is additional to
that of ACE inhibitors
Combined effect
-8
-6
-4
-2
0
Absolute reduction in mortality in
1 year attributable to treatment (%)
Fig 2 Effect on annual rate of mortality (%) of angiotensin
inhibitors alone, with beta blockers added, and with both
drugs. Risk differences and 95% confidence intervals.
Cleland et al, BMJ, 1999
Adapted from Cleland et al. 1999.
TREATMENT
All patients with heart failure due to LVSD should be
considered for treatment with a beta-blocker (2)
How to use?
 Start with a low dose
 Double dose at not less than two weekly intervals
 Aim for target dose (see above) or, failing that, the highest
tolerated dose
 Remember some beta-blocker is better than no beta-blocker
 Monitor heart rate, blood pressure, clinical status
(symptoms, signs, especially signs of congestion and body
weight)
 Check blood electrolytes, urea and creatinine one to two weeks
after initiation and one to two weeks after final dose titration
NICE, 2003
TREATMENT
When starting a patient on a beta-blocker (1)
Ensure that the patient
 Understands the expected benefits of beta-blockers:
 prevent worsening of heart failure
 improve symptoms (but may take 3-6 months or more)
 increase survival
 Knows that symptoms may deteriorate during initiation / uptitration phase
 Knows that beta-blockers should not be stopped without first
seeking advice
 Understands that any deterioration (tiredness, fatigue,
breathlessness) should be reported as this can be easily
managed by adjusting other drugs
 Is encouraged to weigh themselves each day (after waking,
before dressing, after voiding, before eating)
NICE, 2003
TREATMENT
When starting a patient on a beta-blocker (2)
If patients experience worsening symptoms/signs
 Congestion – double dose of diuretic or halve dose of
beta-blocker
 Fatigue – halve dose of beta-blocker (rarely necessary)
 Review patient in 1-2 weeks; if not improved seek
specialist advice
 Serious deterioration – halve beta-blocker dose or stop
treatment and seek specialist advice
NICE, 2003
TREATMENT
Mineralocorticoid receptor antagonist
(MRA) therapy for heart failure due to
LVSD
Probability
of Survival
1.00

The Randomised Aldactone
Evaluation Study (RALES)

1663 patients with NYHA III or IV
heart failure and ejection fraction
≤35% who were already treated with
ACE inhibitor, diuretic ± digoxin

Spironolactone 25mg od vs placebo,
with patients followed for an average
of 2 years

30% reduction in the risk of death
(p<0.001) and 35% reduction in risk
of hospitalisation (p<0.001) among
patients randomised to
spironolactone
0.95
0.90
RRR=0.30 (0.18-0.40)
0.85
0.80
0.75
Spironolactone
0.70
0.65
0.60
Placebo
0.55
P < 0.001
0.50
0.45
0.00
0
3
6 9 12 15 18 21 24 27 30 33 36
Months
Adapted from Pitt et al. 1999.
Pitt et al, N Engl J Med, 1999
TREATMENT
NICE recommendation on spironolactone
Patients with heart failure due to LV systolic dysfunction
who remain moderately to severely symptomatic despite
optimal therapy should be prescribed spironolactone at a
dose of 12.5 to 50 mg once per day – specialist advice
should be sought
Patients with heart failure taking spironolactone should
have blood potassium and creatinine levels monitored
for signs of hyperkalaemia and/or deteriorating renal
function. If hyperkalaemia is a problem then the dose of
spironolactone should be halved and biochemistry
rechecked
• Symptom improvement occurs within a few weeks to a few months of starting
treatment
• Patients should avoid NSAIDs (including OTC products e.g. ibuprofen)
• Temporarily stop spironolactone if diarrhoea and/or vomiting and contact
physician
• Male patients may develop breast discomfort and/or gynaecomastia
NICE, 2003
TREATMENT
Mineralocorticoid receptor antagonist
therapy for
heart failure after MI
EPHESUS trial
Cumulative
Incidence (%)
40

3313 patients were randomised to eplerenone
25 mg/day and 3319 to placebo (in addition to
‘standard’ medical therapy).

Mean follow-up of 16-months. Among those
taking eplerenone there was:
p=0.008
RR=0.85
35
30
Placebo
25
•
20
(p=0.008)
15
Eplerenone
10
•
5
0
•
0
3 6
9 12 15 18 21 24 27 30 33 36
Months since Randomization

No. at Risk
Placebo
Eplerenone
15% relative risk reduction in all-cause death
3313 3064 2983 2830
3319 3125 3044 2896
2418 1801 1213
2463 1857 1260
709
728
323
336
99
110
2
0
0
0
0
0
13% relative risk reduction in cardiovascular
death or hospitalisation (p=0.002)
21% relative risk reduction in sudden cardiac
death ( p=0.03)
Compared with spironolactone, eplerenone is
less likely to cause gynaecomastia or breast
tenderness, but K+ monitoring is still essential.
Adapted from Pit et al. 2003.
Pitt et al, N Engl J Med, 2003
Primary composite end point
(CV death or hospital admission for worsening HF)
Cumulative frequency (%)
40
HR = 0.82 (0.75–0.90)
Placebo
P < 0.0001
18% RRR
30
Ivabradine
20
10
0
0
6
Swedberg K, et al. Lancet. 2010;376:875-885.
12
18
24
30
Months
New EU license for ivabradine
February 2012
“Ivabradine is indicated in chronic heart failure NYHA II to
IV class with systolic dysfunction, in patients in sinus
rhythm and whose heart rate is ≥ 75 bpm, in combination
with standard therapy including beta-blocker therapy or
when beta-blocker therapy is contraindicated or not
tolerated.”
TREATMENT
Digoxin

The oldest established treatment
for heart failure

Digoxin has a narrow therapeutic
window

Arrhythmias and gastrointestinal
side effects are common
TREATMENT
How useful is digoxin?
The DIG trial




6800 patients with heart failure (EF45%) already on diuretic + ACE inhibitor
Randomised to digoxin or placebo, 250 g/day (mean dose) and followed for
average of 37 months
No difference in total mortality (p=0.80)
28% relative risk reduction in death or hospitalisation due to worsening HF
(p<0.001)
40
40
Mortality
30
from
Any
Cause (%) 20
Death or
30
Hospitalisation
Due to
20
Worsening
Heart
10
Failure (%)
0
Placebo
p=0.80
10
Digoxin
0
0
4 8 12 16 20 24 28 32 36 40 44 48 52
Months
Adapted from DIG 1997.
Placebo
P<0.001
Digoxin
0
4 8 12 16 20 24 28 32 36 40 44 48 52
Months
Adapted from DIG 1997.
DIG, N Engl J Med, 1997
TREATMENT
NICE recommendation on digoxin
• Digoxin is recommended for:
• worsening or severe heart failure due to LV
systolic dysfunction despite ACE inhibitor,
beta-blocker and diuretic therapy
• patients with atrial fibrillation and any degree
of heart failure
 Several drugs can alter the pharmacokinetics of digoxin, especially:
 anti-arrhythmic drugs affecting renal clearance and/or volume
of distribution (verapamil, amiodarone, propafenone and
quinidine)
 drugs increasing its absorption (erythromycin, omeprazole and
tetracycline)
 drugs decreasing its absorption (colestipol, cholestyramine)
NICE, 2003
2012
2012
TREATMENT
Other medical treatments (1)
Anticoagulants
“Anticoagulation is indicated for patients with the
combination of heart failure and atrial fibrillation.”
“In patients with heart failure in sinus rhythm,
anticoagulation should be considered for those with a
history of thromboembolism, left ventricular aneurysm, or
intracardiac thrombus.”
Amiodarone
“The decision to prescribe amiodarone should be made in
consultation with a specialist. The need to continue the
prescription should be reviewed regularly.”
“Patients taking amiodarone should have a routine sixmonthly clinical review, including liver and thyroid function
tests, including a review of side effects.”
NICE, 2003
TREATMENT
Other medical treatments (2)
Aspirin
“Aspirin (75–150 mg once daily) should be prescribed for
patients with the combination of heart failure and
atherosclerotic arterial disease (including coronary heart
disease).”
Calcium channel blockers
‘Amlodipine should be considered for the treatment of comorbid hypertension and/or angina in patients with heart
failure, but verapamil, diltiazem or short-acting
dihydropyridine agents should be avoided”
NICE, 2003
TREATMENT
Other medical treatments (3)
Isosorbide/hydralazine combination
“An isosorbide/hydralazine combination may be used in
patients with heart failure who are intolerant of ACE
inhibitors or angiotensin-II receptor antagonists.”
Inotropic agents
“Intravenous inotropic agents (such as dobutamine,
milrinone or enoximone) should only be considered for the
short-term treatment of acute decompensation of chronic
heart failure. This will require specialist advice.”
NICE, 2003
Statins in chronic heart failure

Two randomised controlled trials — CORONA and
GISSI-HF — have shown no mortality benefit of statin
therapy in patients with chronic heart failure, irrespective
of its aetiology
Kjekshus et al, N Engl J Med 2007;
GISSI-HF investigators, Lancet 2008
ANYTHING NEW?
RELAXIN
CHRONIC DISEASE
MANAGEMENT
Patient self-monitoring

Patients can monitor their volume status by daily
weighing and appropriate adjustment of their diuretic
regimen

Requires education and support

Patients should be taught how to recognise early signs
of decompensation and how to seek professional help

Heart failure nurse usually most appropriate
professional to ‘train’ patient
NICE, 2003
CHRONIC DISEASE
MANAGEMENT
Remote monitoring



Typical equipment for telemonitoring

Remote monitoring of
patients’ clinical status
(telemonitoring) can improve
access to health care
Facilitates earlier detection of
deterioration
Acceptable and easy to use
by patients
Likely to become part of a
modern heart failure
management programme
Riley, Heart, 2009
TREATMENT
Other treatment options
Surgery and devices

Cardiac resynchronisation therapy (CRT)

Implantable cardioverter defibrillator (ICD)

Coronary revascularisation (PCI/CABG)

Transplantation

Left ventricular assist device (LVAD)

Other invasive therapies
• Valve repair/replacement
• Left ventricular aneurysmectomy
NICE, 2003
CHRONIC DISEASE
MANAGEMENT
Treatment monitoring checklist
Follow-up interval should be a maximum of six months
NICE, 2010
CHRONIC DISEASE
MANAGEMENT
Side-effects of drugs commonly used
in the treatment of heart failure (2)
Digoxin
 Common: nausea
 Serious:
life threatening arrhythmias
Angiotensin II receptor blockers
 Common: hypotension including postural
 Serious:
worsening renal function, renal infarction in renal artery
stenosis
Amiodarone
 Common: photosensitivity, nausea, thyroid dysfunction, sleep
disturbance, corneal microdeposits
 Serious:
thyrotoxic storm, pro-arrhythmia, pulmonary/hepatic
fibrosis
NICE, 2003
CHRONIC DISEASE
MANAGEMENT
Side-effects of drugs commonly used
in the treatment of heart failure (1)
Diuretics
 Common: postural hypotension, gout, urinary urgency
 Serious:
electrolyte imbalance (hypokalaemia, hypomagnesia,
hyponatraemia), arrhythmia
ACE inhibitors
 Common: cough, hypotension including postural
 Serious:
worsening renal function, renal infarction in renal artery
stenosis, angio-oedema
Beta-blockers
 Common: tiredness, bradycardia, coldness
 Serious:
asthmatic attack, exacerbation of heart failure, heart
block
Spironolactone
 Common: gynaecomastia, tiredness, rashes;
 Serious:
hyperkalaemia, hyponatraemia
NICE, 2003
CHRONIC DISEASE
MANAGEMENT
Improving adherence to drug therapy

Non-adherence with treatment is associated
with a high risk of readmission to hospital

Non-adherence may be reduced by:
• Simplifying drug dosing regimens
• Educating patients/carers about medicines,
and the reasons for taking them
NICE recommendation: Dosing regimens should be kept
as simple as possible, and the healthcare professional
should ensure that the patient and carer are fully informed
about their medication
NICE, 2003 & 2009
CHRONIC DISEASE
MANAGEMENT
Depression: common and important

Consider depression in all patients with heart failure

Studies suggest a prevalence of depression of around
30% in non-hospitalised patients with heart failure

Diagnosis is more common in those with physical
symptoms and poorer physical functioning

Depressive symptoms are strongly linked with a
worse outcome
Rumsfeld et al, 2003; Friedman et al 2001, Jiang et al, 2004
CHRONIC DISEASE
MANAGEMENT
End of life issues




Palliative care aims to improve the quality of life
for terminally ill patients and to help family and
carers by:
• Providing symptom control
• Providing psychological and social support
• Planning for the future and providing end of life
care
Specialist palliative care in cancer:
• Improves symptom control
• Reduces time spent in hospital
• Improves patient and carer choice and
satisfaction
• Reduces overall costs
Anecdotal evidence suggests benefit in heart
failure
Providing palliative care is complex
NICE, 2003
CHRONIC DISEASE
MANAGEMENT
Initiatives in end of life care


First National End of Life Care
strategy
‘Better Together’ palliative care
service for heart failure patients
set up by British Heart
Foundation and Marie Curie
Cancer Care
CHRONIC DISEASE
MANAGEMENT
Communication is essential for good
discharge planning

Patients with heart failure should generally be discharged
from hospital only when their clinical condition is stable
and their management plan is optimised

The timing of discharge should take into account both
patient and carer wishes and the level of care and support
that can be provided in the community
The primary care team, patient and carer must be aware
of the management plan
Clear instructions should be given as to how the
patient/carer can access advice particularly in the high
risk period immediately following discharge


NICE, 2003
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