Download Update on b-Blockers In the Management of Heart

Update on b-Blockers
In the Management of Heart Failure
“The single most significant addition to the
pharmacological management of heart failure since the
publication of previous guidelines [ACC/AHA] involves
the use of beta-receptor antagonists.”
-Heart Failure Society of America (1999)
Heart Failure Society of America (HFSA) Practice Guidelines. J Cardiac Fail. 1999;5:357-382.
Definitions of Heart Failure
“Heart failure may be considered to be the condition in
which an abnormality of cardiac function is responsible
for the inability of the heart to pump blood at a rate
commensurate with the requirements of the
metabolizing tissues…” E. Braunwald
“Heart failure represents a syndrome in which cardiac
dysfunction is associated with reduced exercise
tolerance, a high incidence of ventricular arrhythmias,
and shortened life expectancy.” J.N. Cohn
Braunwald E. Harrison’s Principles of Internal Medicine. 14th ed. 1998:1287-1297. Cohn JN. Circulation. 1988;78:1099-1107.
NYHA Functional Capacity
Classification
Class I:
Class II:
No limitation of physical activity. Ordinary physical activity does
not cause undue fatigue, palpitation, dyspnea, or angina.
Slight limitation of physical activity. Ordinary physical activity
results in fatigue, palpitation, dyspnea, or angina.
Class III:
Marked limitation of physical activity. Comfortable at rest, but
less than ordinary physical activity results in fatigue, palpitation,
dyspnea, or angina.
Class IV:
Unable to carry on any physical activity without discomfort.
Symptoms present at rest. With any physical activity, symptoms
increase.
1994 Revisions to the classification of functional capacity and objective assessment of patients with disease of the heart.
Circulation. 1994; 90:644-645.
Prognosis in Heart Failure
• In people diagnosed with heart failure, sudden
death occurs at 6 to 9 times the rate of the general
population
• 5-year mortality rate is 50%
• Median survival following onset is 1.7 years for men and 3.2
years for women
American Heart Association. 2001 Heart and Stroke Statistical Update. Dallas, TX.: American Heart Association, 2000;
Ho KKL et al. JACC. 1993;22:6A-13A.
Pathogenesis and Sequelae of Heart Failure
Arrhythmia
Coronary artery
disease
Hypertension
Cardiomyopathy
Left
ventricular
dysfunction
Remodeling
Death
Pump
failure
Valvular
disease
• Neurohormonal
stimulation
• Endothelial
dysfunction
• Vasoconstriction
• Renal sodium
retention
Low
ejection
fraction
Noncardiac
factors
Adapted from Cohn J. N Engl J Med. 1996;335:490-498.
Symptoms:
Dyspnea
Fatigue
Edema
Chronic
heart
failure
Mortality by Baseline Plasma
Norepinephrine Level (PNE)
Cumulative Mortality (%)
100
PNE > 900 pg/mL
80
60
PNE > 600 and < 900 pg/mL
PNE < 600 pg/mL
40
20
2 Year
P < .0001
Overall
P < .0001
0
0
6
12
18
24
30
36
Months
Francis G et al. Circulation. 1993;87(suppl VI):VI-40 - VI-48.
42
48
54
60
Effects of SNS Activation in Heart Failure

Dysfunction/death of cardiac myocytes

Provokes myocardial ischemia

Provokes arrhythmias

Impairs cardiac performance
These effects are mediated via stimulation
of b and a1 receptors
Am J Hypertens 1998; 11: 23S-37S
PROPERTIES OF b-BLOCKERS
Name
b-1
Selective
a-blockade
Lipophilic
Increases ISA
Other ancillary
properties
Atenolol
Acebutolol
Bisoprolol
Bucindolol
Carvedilol
Yes
Disputed
Yes
No
No
No
No
No
No
Yes
No
No
Weak
Yes
Yes
No
Disputed
No
Disputed
No
No
No
No
Vasodilator action
Antioxidant, effects on
endothelial function
Celiprolol
Metoprolol
Nebivolol
Yes
Yes
Yes
No
No
No
No
Yes
?
b-2 only
No
No
No
No
Vasodilation through
nitric oxide
Propranolol
No
No
Yes
No
Membrane stabilizing
Effect
Timolol
Xamoterol
No
Yes
No
No
Weak
No
No
Marked
Anti-platelet effects
No
b-Blocker Effects
On Ejection Fraction in Heart Failure
b-Blocker Discontinued
Pharmacologic Effect
LVEF
b-Blocker
Biologic
Effect
Initiated
0
1
3
6
Time (months)
Eichhorn EJ, JCF. 2000;6(suppl 1):40-46.
8
Landmark studies reported so far
US CARVEDILOL HEART FAILURE STUDY
Tot al mort alit y
0%
To ta lm
o rta lity
Hospit alizat ion
Deat h/ Hospit alizat i
on due t o CV cause
Ho s
p ita liz
a tio n
De a th /Ho s
p ita liz
a tio n d u e to CVc a u s
e
Risk reduction (%)
-10%
-20%
-30%
27%
-40%
38%
-50%
Mild to moderate HF; LVEF < 35%
N = 1094, t = 15.1 mnths
-60%
Carvedilol (25-50 mg bid) vs placebo
-70%
65%
NEJM 1996; 334 : 1349 - 55
ANZ Multicentre Heart Failure Trial
Placebo
(n=208)
Carvedilol
(n=207)
% Risk
Reduction
26
(12.5%)
20
(10%)
24%
Risk of hospitalization for
cardiovascular reasons
84
(40%)
64
(31%)
28%
Combined risk of
mortality & hospitalization
97
(47%)
74
(36%)
29%
All-cause
mortality
Lancet 1997; 349: 375-380.
Effect of carvedilol on progression
of congestive heart failure
All randomized patients
Endpoint
Placebo
(n=134)
Primary endpoint
28 (21%)
Carvedilol
(n=232)
25 (11%)*
Death due to CHF
4 (3%)
Hospitalization due to worsening CHF
8 (6%)
9 (4%)
Increase in CHF medication
16 (12%)
16 (7%)
* Placebo vs. carvedilol, p = 0.008
Drugs of Today 1998; 34 (Suppl B): 1-23.
0 (0%)
COPERNICUS (CarvedilOl ProspEctive RaNdomIsed
CUmulative Survival Study): Effect on Mortality
20
18
18.5%
Mortality (%)
16
14
12
10
8
35%
11.4%
6
4
2
0
Carvedilol (n=1156)
Placebo (n=1133)
NEJM 2001; 344: 1651-8
COPERNICUS: Effect on combined risk of death and
hospitalisations
Parameter
% risk reduction with carvedilol
Death or hospitalisation
24%
for any reason
Death and hospitalisation
for CV reasons
27%
Death and hospitalisation
for heart failure
31%
Circulation 2002; 106: 2194-9
BEST Study
(Beta-Blocker Evaluation of Survival Trial)
Primary Endpoint
Design
Follow-up
Dosing
Results
All-cause mortality
Randomized, placebo-controlled,
double-blind trial in 2708 NYHA
Class III or Class IV patients
24 months mean follow-up
Bucindolol titrated from 3 mg to
maximum 100 mg BID as
tolerated by patient
Nonsignificant relative risk reduction in
all-cause mortality (10% , P = .10)
The Beta-Blocker Evaluation of Survival Trial Investigators. N Engl J Med. 2001;344:1659-1667.
CARDIAC INSUFFICIENCY BISOPROLOL STUDY-II (CIBIS II)
T ot al mor t al i t y A l l c aus e hos pi t al i z at i on
CV deat hs Combi ned endpoi nt Sudden deat h
Risk reduction
0%
Hos pi t al i z at i on f or
wor s eni ng HF
-10%
-20%
20%
21%
-30%
29%
-40%
34%
Moderate to severe HF, LVEF < 35%
Bisoprolol (10 mg od) vs placebo
-50%
36%
N=2647, t = 1.3 years
44%
Lancet 1999; 353 : 9 –13
MEtoprolol CR/XL Randomized Intervention Trial in
Congestive Heart Failure (MERIT-HF)
Risk reduction (%)
M ortality
CV deaths
Sudden death
0%
Death due to
worsening HF
-10%
-20%
-30%
-40%
-50%
-60%
34%
38%
Mild to moderate HF; LVEF < 40%
N = 3991 t = 1 year
41%
49%
Metoprolol CR/XL (200 mg od) vs placebo
Lancet 1999; 353: 2001-2007
All-cause mortality (%)
Carvedilol Or Metoprolol European Trial COMET
42%
40%
38%
36%
34%
32%
30%
40%
17%
34%
Metoprolol
Carvedilol
Lancet 2003; 362: 7-13

Cardiovascular mortality was reduced by 20% in
carvedilol group as compared to metoprolol
group.
20%
Lancet 2003; 362: 7-13
Randomized Evaluation of Strategies for left ventricular
Dysfunction Pilot Study (RESOLVD)
9
8.1
No. of deaths (%)
8
7
Reduces total mortality by 54.3%
6
5
4
3.7
3
2
1
0
ACE Inhibitor + diuretic + digitalis
ACE inhibitor + diuretic + digitalis + Metoprolol
extended release
Circulation 2000; 101: 378-384
CAPRICORN: Effect on total mortality
23%
16
15%
% mortality
14
12%
12
10
8
6
4
2
0
Placebo
Carvedilol
Lancet 2001; 357: 1385-90
All-cause mortality or CV
hospitalization (%)
CAPRICORN: Effect on combined risk of
mortality and cardiovascular hospitalizations
16
8%
15%
14
12%
12
10
8
6
4
2
0
Placebo
Carvedilol
Lancet 2001; 357: 1385-90
Target dose was achieved by more than 70% of
patients in both the treatment groups.
Patients (%)

79%
78%
77%
76%
75%
74%
73%
78%
75%
Carvedilol (25mg
bid)
Metoprolol (50 mg
bid)
Lancet 2003; 362: 7-13
First stable dose of carvedilol achieved in study patients
6.25 mg bd
13%
3.125 mg bd
4%
50 mg bd
4%
12.5 mg bd
20%
other
3%
25 mg bd
57%
Heart 2000; 84:615-619
Well tolerated when added to standard therapy
Patient withdrawals (%)
20
Low withdrawal rates
15.3
15
13.9
10
5
0
ACE Inhibitor + diuretic + digitalis
ACE inhibitor + diuretic + digitalis + Metoprolol extended release
Lancet 1999; 353: 2001-2007
Per cent of patients unable to tolerate carvedilol treatment, grouped
according to New York Heart Association (NYHA) functional class
Per cent not tolerated
25
22
20
13
15
9
10
5
3
0
I (n=59)
II (n=201)
III (n=254)
NYHA Class
IV (n=118)
N=808
Heart 2000; 84:615-619
86
12
15
84
14
Tolerated
16
PVD (n=58)
85
Diabetes
(n=127)
88
COPD/asthma
(n=89)
100
80
60
40
20
0
All patients
(n=795)
Per cent
Per cent of patients able to tolerate carvedilol treatment, grouped according
to traditional contraindications and precautions in prescribing a b-blocker
Not Tolerated
Heart 2000; 84:615-619
WHEN TO START TREATMENT?
If no contraindication
 Early use of b blockers risk of adverse reactions
Which to use?
 Carvedilol
 Metoprolol extended-release
 Bisoprolol
How to initiate and titrate b blockers doses?
 Start low, go slow
 Titration interval = 2-4 weeks
 2-3 hours observation period

Titration of b blockers in HF
Careful initial unpward dose adjustment
ensures favourable
clinical management

minimizes adverse
events
Eligible candidates: Non hospitalized patients with
HF (NYHA class II or III), stable with standard HF
therapy
Dose Initiation
 In patients with clinically stable HF for 2-weeks with
standard therapy (ACEI + diuretics)
 At very low doses
Dose Titration
Patients who tolerate
initial doses
slow upward
dose adjustment
Maximally tolerated
target doses
Titration interval: > 2 weeks


Upward titration is delayed until any adverse effects observed
with lower doses have resolved
Careful b blockers early in treatment may prevent the need for
treatment delays during later stages of therapy
Slow upward titration
Improves drug
tolerability
gives time for doctor to
respond to changes in
patient status by altering
concomitant HF
therapies