Download Heart Failure Drug Therapy : Digoxin

Congestive Heart Failure
Dr Bernard Silke, MD, DSc, FRCP,
Cardiovascular Physician,
St. James’ Hospital, Dublin 8.
Congestive Heart Failure
Changing population trends
W. Europe
No.
(millions)
5.3
Rate per
million
14000
E. Europe
1.3
13000
USSR
5.6
19000
N. America
5.2
18000
Japan
2.4
19000
Clinical Scenario
JB is 75 and is a retired publican. First presented 12 yr ago
with MI.

A strong family Hx of CVS disease. Father died at age 40
with Stroke. Mother had angina.

Subsequent LVF 5 yr ago with hospitalization. Echo dilated /
asymmetrical contraction / dysynergy.

Ejection Fraction 35%. Effort Dyspnoea

What are the therapeutic options?
Congestive Heart Failure
Incidence per 1000
patient years
Incidence and age
16
Males
12
Females
8
4
Eur Heart J 1999:
20; 421-428.
0
55-64
65-74 75-84
Age group (yr)
85+
Congestive Heart Failure
Changing population trends

< 5% of population

CHF in 1.5% (25-75 yr)
5
4

Clinical CHF - 1%
2

Suspect CHF - 1%
1
0
Suspect
3
Either
abnormality in 1%
LVSD
LV Systolic function
CHF

Congestive Heart Failure
Changing population trends

MI deaths peaked 1985
Rate 215 / 100,000

Between 1985 - 1995
mortality rates decrease
by 33% (215.3 - 144.2)

Numbers of very elderly
predicted to increase by
30% and 57% over next
two decades
10
0
-10
-20
-30
-40
-50
6064
7074
8085
Heart Failure
Definition

Heart unable to meet peripheral blood flow
requirements without a rise in filling volume

Contraction energy is reduced

Stroke volume incompletely expelled

Chamber volume increases
Heart Failure
Natural history
0
Morbidity
Rest symptoms
Pump Failure
100
No symptoms
Mortality
No deaths
100
0
Time from onset
Heart Failure
Therapeutic goals
Normal
A
I
Stroke
Volume
A+V
V
D
CHF
Ventricular Filling Pressure
Heart Failure
Ejection Fraction

Ejection Fraction - % of
EDV ejected each beat

Normal 50 - 75%

Impaired function < 40%

Symptomatic < 30%

If EDV 100 ml

Stroke volume 65 ml

CHF < 40 ml
Heart Failure
Therapeutic implications

Volume overload
Diuretics

Elevated impedance
Vasodilators

Decreased contractility
Inotropes
Heart Failure
Clinical goals

Patient oedema free

Ambulant

Avoid hospitalisation

Optimise quality of life
Heart Failure
Clinical assessment

Peripheral oedema – none to minimal

Paroxysmal nocturnal dyspnoea - infrequent

Posture at night - < 2 pillows

Dyspnoea – absent at rest, activity possible

Nocturia – common and not significant
Heart Failure
Therapeutic groups

Diuretics
Thiazide group, Loop diuretics

Angiotensin converting enzyme inhibitors
Long-acting nitrates
Captopril, Enalapril, Lisinopril, Trandolopril

Inotropes
Digoxin
DIURETICS
Thiazides
Cortex
Inhibit active exchange of Cl-Na
in the cortical diluting segment of the
ascending loop of Henle
K-sparing
Inhibit reabsorption of Na in the
distal convoluted and collecting tubule
Medulla
Loop of Henle
Loop diuretics
Inhibit exchange of Cl-Na-K in
the thick segment of the ascending
loop of Henle
Collecting tubule
Heart Failure
Diuretics : Sites of Action
Glomerulus
Proximal
Tubule
(CAI)
Na/Cl
Distal CT
(Thiazides)
Amiloride
Na
Ascending
Limb
(Loop)
Spironolactone
Na/K
Na/K/Cl
Collecting
Duct
Heart Failure
Diuretics : Sites of Action
Tubular cell
hypertrophy
Sodium load
to distal nephron
increased
Ascending
Limb
(Loop)
Na/K/Cl
Collecting
Duct
Heart Failure
Diuretics : Resistance

Check compliance

Check Na+ intake
Low salt diet
Avoid bread / processed foods

Daily fluid allowance 1L

Check not taking a NSAID

Increased dose of a loop diuretic?

Metolazone (pulse 2.5 mg) once / twice week
Heart Failure
ACE Inhibitors

Prolong survival in early and established CHF

Improve Quality of Life

Relieve symptomatic congestion

Increase exercise tolerance

Reduce hospitalisation
Heart Failure
Choice of ACE Inhibitor

Captopril - first generation
Short duration of action
Multiple dose administration (50 mg tds)

Enalapril, Lisinopril - second generation
Longer duration of action (once daily)
Increased liklihood of hypotension

Perindopril, Trandolopril - third generation
Vascular selective
Favourable side-effect profile
Lack of first-dose effect
Heart Failure
Benefits of ACEI
0.8
0.7
Placebo
0.6
PROBABILITY 0.5
OF
0.4
DEATH
p< 0.001
p< 0.002
0.3
Enalapril
0.2
0.1
CONSENSUS
N Engl J Med 1987;316:1429
0
0
1
2
3
4
5
6
7
8
MONTHS
9
10 11 12
Heart Failure
Benefits of ACEI
50
p = 0.0036
Placebo
n=1284
40
%
MORTALITY
30
Enalapril
20
n = 2589
CHF
- NYHA II-III
- EF < 35
10
0
SOLVD (Treatment) 0
N Engl J M 1991;325:293
n=1285
6
12
18 24 30
Months
36 42
48
Heart Failure
Contemporary management with ACEI

Considerable variations in ACE prescribing

ACE Inhibitors used in 30 - 60% of CHF cases

Elderly less likely to be treated (21 vs 69%)

Physician perceptions of contra-indication

No documented contra-indications in 35%

Elderly high rate of morbid events

Withhold ACE more complications (p < 0.01)
Am. Heart J. 1998:136;43.
Heart Failure
Survival benefits & dosage (mg / day)

Enalapril
20

Captopril
150

Ramipril
10

Lisinopril
10 / 20

Trandolapril
4

Quinapril
40
Am. Heart J. 1998:136;43.
Heart Failure
Contemporary issues & ACEI

Pharmacodynamic response to ACEI elderly

Valid concerns hypotension / renal dysfunction

Reluctance to adequately dose titrate

Many patients left on initiation dosage

Elderly patients will tolerate ACEI and achieve
target doses if titrated gradually

Suboptimal Rx important due to high morbidity
Am. Heart J. 1998:136;43.
Heart Failure
Contemporary management with ACEI
2%

SPICE registry

Eight countries

Hospital cases

Consecutive 9581

Current practice

USA and Europe
9%
82%
4%
3%
Treated
Intolerant
High risk
Unknown
Recent
Heart Failure
ACEI ADR profile

SPICE registry of 8485 cases

Cough (308 - 4%)

Renal sufficiency (188 - 2%)

Symptomatic hypotension (147 - 2%)

Hyperkalaemia (35)

Rash / pruritus (25)

Angioedema / analyphaxis (19)
DIGOXIN
Na-K ATPase
Na+ K+
K+ Na+
Na-Ca Exchange
Na+
Myofilaments
Ca++
Ca++
CONTRACTILITY
Heart Failure
Drug Therapy : Digoxin

Positive Inotropic

S-A and A-V Nodal actions

Enhanced Automaticity
DIGOXIN
EFFECT ON CHF PROGRESSION
30
Placebo n=93
DIGOXIN
Withdrawal
%
WORSENING
OF CHF
20
p = 0.001
DIGOXIN: 0.125 - 0.5 mg /d
(0.7 - 2.0 ng/ml)
10
EF < 35%
Class I-III (digoxin+diuretic+ACEI)
Also significantly decreased exercise
time and LVEF.
0
RADIANCE
N Engl J Med 1993;329:1
DIGOXIN n=85
0
20
40
60
Days
80 100
Heart Failure
The DIG Study

CHF patients (6800) studied 1991 - 1995

Sinus rhythm; E.F. < 45%

NYHA Class III 33%; Class II < 50%

Background ACEI and/or diuretic (78%)

Digoxin (median 250 ug / day) vs. placebo

Endpoints: mortality and hospitalisation
N. Engl. J. Med. 1997: 336; 525
OVERALL MORTALITY
50
40
30
%
20
Placebo
n=3403
10
0
DIG Study 0
N. Engl. J. Med. 1997: 336; 525
p = 0.8
DIGOXIN
n=3397
12
24
Months
36
48
Heart Failure
The DIG Study

Mortality similar (34.8% vs. 35.1%)

Hospitalisations reduced 22% (16 - 28)

Benefits greatest in those at highest risk
Lower E.F. ( < 25% )
Enlarged hearts
NYHA Class III & IV

Digoxin toxicity
Ventricular fibrillation / tachycardia
Supraventricular dysrhythmia
Second or 3rd degree heart block
N. Engl. J. Med. 1997: 336; 525
Heart Failure
The DIG Study

No substantial change in mortality /morbidity

No ethical mandate for its use

May be prescribed for symptomatic relief

Other drug categories have proven benefit

ACEI and ß-blockers drugs
N. Engl. J. Med. 1997: 336; 575
Heart Failure
Digoxin Therapeutics

Atrial fibrillation with uncontrolled response

Reduce apex rate to 100 or less.

Loading 15 ug / kg in three doses over 24 hr

Maintenance dose 250 to 500 ug / day

Therapeutic concentration 0.8 - 2.0 ng / ml
Heart Failure
ß - blocking Therapy

Reduce heart rate & myocardial contractility

Concern about risk of cardiac depression

In CHF ß - adrenoceptors are downregulated

Cardiac efficiency impaired by compensation

Upregulation during ß - blocking treatment

CIBIS I in 641 CHF - 20% mortality reduction
US Carvedilol Programme
Survival
1.0
Carvedilol
(n=696)
b blockers in
heart failure –
all-cause mortality
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
Packer et al (1996)
Survival
CIBIS-II
1.0
Mortality (%)
20
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
600
Time after inclusion (days)
800
CIBIS-II Investigators (1999)
0
3
6
9
12 15 18
Months of follow-up
21
The MERIT-HF Study Group (1999)
Heart Failure
ß - blocking Therapy

Over 13 000 patients evaluated in placebocontrolled clinical trials

Consistent improvement in cardiac function,
symptoms and clinical status

Decrease in all-cause mortality by 30–35%
(p<0.0001)

Decrease in combined risk of death and
hospitalisation by 25–30% (p<0.0001)
Background
 Angiotensin II type 1 (AT1) receptor blockers
(ARBs) provide a pharmacologically distinct
mechanism of inhibiting the renin-angiotensinaldosterone system
 ARBs offer the potential to produce further
clinical improvements above and beyond ACE
inhibitors as well as an alternative for those
previously intolerant to an ACE inhibitor
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
Study design
Dose-titration and visit schedule
Candesartan/
matching placebo
once daily
32 mg
16 mg
8 mg 32 mg
4 mg 16 mg
8 mg
Time
0w
2w
4w
6w
6m
Visit
1
2
3
4
5
Every 4 months
until study end
31 March 2003
Baseline characteristics
n=2028
Alternative
n=2548
Added
n=3023
Preserved
n=7599
Overall
Mean age (years)
67
64
67
66
Women (%)
32
21
40
32
NYHA class (%)
II
III
IV
Mean LVEF
48
49
3
30
24
73
3
28
60
38
2
54
45
52
3
39
Medical history (%)
myocardial infarction
diabetes
hypertension
atrial fibrillation
61
27
50
25
56
30
48
26
44
28
64
29
53
28
55
27
CHARM Programme
3 component trials comparing
candesartan to placebo
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
30
334 (33.0%)
Candesartan
%
20
10
0
HR 0.77 (95% CI 0.67-0.89), p=0.0004
Adjusted HR 0.70, p<0.0001
0
1
Number at risk
Candesartan 1013
Placebo
1015
2
929
887
3
831
798
3.5 years
434 122
427 126
CHARM-Alternative
Investigator reported CHF hospitalisations
Proportion of
patients (%)
35
30
Number of
episodes
700
p<0.0001
p=0.0001
600
25
500
20
400
15
300
10
200
5
100
0
0
Patients hospitalised
Placebo
Candesartan
Hospitalisations
CHARM-Alternative
Permanent study drug discontinuations
Percent of patients
25
Placebo
Candesartan
21.5
20
19.3
15
10
6.1
5
3.7
2.7
0.9
0
0.3
1.9
0.4
0.2
0
0.1
AE/
lab. abnorm.
Hypotension
Increased
creatinine
Increased
potassium
Cough
Angioedema
p=0.23
p<0.0001
p<0.0001
p=0.0005
p=0.69
p=0.50
CHARM-Alternative
Conclusions


Despite prior intolerance to another inhibitor of the
renin-angiotensin-aldosterone system, candesartan
was well tolerated
In patients with symptomatic chronic heart failure
and ACE-inhibitor intolerance, candesartan
reduces cardiovascular mortality and morbidity
Cardioprotective Effects of Valsartan
as Seen in the Valsartan-Heart Failure
Trial (Val-HeFT)
Jay N. Cohn, MD
Professor of Medicine
University of Minnesota Medical School
Minneapolis, Minnesota, USA
Study Overview
5010 patients
18 years; EF <40%; NYHA II-IV; LVIDd >2.9 cm/m2
Receiving background therapy
ACE inhibitors (92.7%), diuretics (85.8%),
digoxin (67.3%), b-blockers (35.6%)
Randomized to
Valsartan
40 mg bid titrated to
160 mg bid
Cohn JN et al. Eur J Heart Fail. 2000;2:439-446.
Placebo
Patients’ Baseline
Characteristics
Valsartan
(n = 2511)
Placebo
(n = 2499)
Mean age (y)
62.4
63.0
Gender, male (%)
79.9
80.0
Race (%)
White
89.8
90.9
NYHA Class (%)
II
III
IV
62.1
36.1
1.7
61.4
36.3
2.2
Ejection fraction (%)
26.6
26.9
Background therapy (%)
Diuretic
Digoxin
b-Blocker
ACE inhibitor
85.8
67.1
34.5
92.6
85.2
67.6
35.3
92.8
Cohn JN et al. N Engl J Med. 2001;345:1667-1675.
Primary and Secondary Efficacy
Endpoints*

Combined all-cause mortality and
morbidity (time to event)

Hospitalization for heart failure

Signs and symptoms of heart failure

NYHA functional class (change from
Hospitalization for heart failure
Sudden death with resuscitation
baseline)
Need for intravenous inotropes/vasodilators
for worsening HF


Echocardiographic indices of left
ventricular function (LVEF and LVIDd
All-cause mortality (time to event)
— change from baseline)

Quality of life score (Minnesota Living
With Heart Failure score)
* For
the trial to be positive, one of the primary endpoints had to reach
statistical significance (P < 0.02532).
Cohn JN et al. N Engl J Med. 2001;345:1667-1675.
Mortality and Morbidity Analyses
Primary Endpoint Analyses
Events
Valsartan
(n = 2511)
Placebo
(n = 2499)
Combined all723
cause mortality and (28.8%)
morbidity
All-cause
mortality
495
(19.7%)
Reduction
RR
P Value
801
(32.1%)
13.2%
0.87
(0.77-0.97)
0.009*
484
(19.4%)
–
1.02
(0.88-1.18)
0.80
*Log-rank test.
Cohn JN et al. N Engl J Med. 2001;345:1667-1675.
Effect of Valsartan on Morbidity
Endpoint*
100
Valsartan
Placebo
95
90
13.2% Risk Reduction
P = 0.009
85
Probability of
Event-Free
Survival
80
75
70
65
0
0
3
6
9
12
15
18
21
24
27
Months
*All-cause mortality, sudden death with resuscitation, hospitalization for worsening heart failure, or
therapy with IV inotropes or vasodilators.
Cohn JN et al. N Engl J Med. 2001;345:1667-1675.
30
All-Cause Mortality:
Kaplan-Meier Analysis (Val-HeFT)*
1.0
Valsartan
Placebo
0.9
Proportion
Survived
0.8
0.7
0.6
0.5
0
Patients at Risk
Months
0
Valsartan
2511
Placebo
2499
3
6
9
12
15
18
21
24
27
Time Since Randomization (mo)
6
2389
2370
12
2279
2260
18
1779
1784
*P value (log-rank): 0.801; hazard ratio (Cox model): 1.017.
Cohn JN et al. N Engl J Med. 2001;345:1667-1675.
24
1201
1196
30
439
440
30
Mortality by ACE Inhibitor/Beta Blocker
Subgroups
n
ACEI ACEI +
BB BB +
366
4644
3260
1750
ACEI - BB ACEI - BB +
ACEI + BB ACEI + BB +
226
140
3034
1610
Favors Valsartan
0.2
0.4
Data on file, Novartis Pharma AG.
Cohn JN et al. N Engl J Med. 2001;345:1667-1675.
0.6
0.8
1.0
Favors Placebo
1.2
1.4
1.6
1.8
2.0
HF-Related Hospitalizations*
100
Valsartan
Placebo
95
90
85
Event-Free
Probability
80
75
27.5% Risk Reduction
70
P < 0.00001
65
0
0
3
6
HF = heart failure.
*First hospitalization.
Cohn JN et al. Circulation. 2000;102:2672b.
9
12
15
Months
18
21
24
27
30