update on -blockers in the management of heart failure
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Update on -Blockers In the Management of Heart Failure
Heart Failure Society of America (HFSA) Practice Guidelines. J Cardiac Fail. 1999;5:357-382.
-Heart Failure Society of America (1999)
“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.”
Definitions of Heart Failure
Braunwald E. Harrison’s Principles of Internal Medicine. 14th ed. 1998:1287-1297. Cohn JN. Circulation. 1988;78:1099-1107.
“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
NYHA Functional CapacityClassification
1994 Revisions to the classification of functional capacity and objective assessment of patients with disease of the heart. Circulation. 1994; 90:644-645.
Class IV:
Class III:
Class II:
Class I: No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or angina.
Unable to carry on any physical activity without discomfort. Symptoms present at rest. With any physical activity, symptoms increase.
Marked limitation of physical activity. Comfortable at rest, but less than ordinary physical activity results in fatigue, palpitation, dyspnea, or angina.
Slight limitation of physical activity. Ordinary physical activity results in fatigue, palpitation, dyspnea, or angina.
American Heart Association. 2001 Heart and Stroke Statistical Update. Dallas, TX.: American Heart Association, 2000; Ho KKL et al. JACC. 1993;22:6A-13A.
• 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
Prognosis in Heart Failure
Pathogenesis and Sequelae of Heart Failure
Adapted from Cohn J. N Engl J Med. 1996;335:490-498.
Coronary arterydisease
Hypertension
Cardiomyopathy
Valvulardisease
Leftventriculardysfunction
Non-cardiacfactors
RemodelingLow
ejectionfraction
Arrhythmia
Death
Pumpfailure
Symptoms:DyspneaFatigueEdema
Chronicheart
failure
• Neurohormonalstimulation
• Endothelialdysfunction
• Vasoconstriction• Renal sodium
retention
Mortality by Baseline Plasma Norepinephrine Level (PNE)
Francis G et al. Circulation. 1993;87(suppl VI):VI-40 - VI-48.
100
80
60
40
20
0 6 12 18 24 30 36 42 48 54 60
Months
Cu
mu
lati
ve M
ort
alit
y (%
)
PNE > 900 pg/mL
PNE > 600 and < 900 pg/mL
PNE < 600 pg/mL
2 YearP < .0001
OverallP < .0001
0
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 and 1 receptorsAm J Hypertens 1998; 11: 23S-37S
PROPERTIES OF -BLOCKERS
Name -1 Selective
-blockade Lipophilic Increases ISA Other ancillary properties
Atenolol Yes No No No No
Acebutolol Disputed No No Disputed No
Bisoprolol Yes No Weak No No
Bucindolol No No Yes Disputed Vasodilator action
Carvedilol No Yes Yes No Antioxidant, effects on endothelial function
Celiprolol Yes No No -2 only No
Metoprolol Yes No Yes No No
Nebivolol Yes No ? No Vasodilation through nitric oxide
Propranolol No No Yes No Membrane stabilizing Effect
Timolol No No Weak No Anti-platelet effects
Xamoterol Yes No No Marked No
Eichhorn EJ, JCF. 2000;6(suppl 1):40-46.
LVEF
Time (months)
Biologic Effect
Pharmacologic Effect
-Blocker Initiated
-Blocker Discontinued
00 11 33 66 88
-Blocker Effects On Ejection Fraction in Heart Failure
Landmark studies reported so far US CARVEDILOL HEART FAILURE STUDY
Total mortality Hospitalization Death/Hospitalization due to CV cause
-70%
-60%
-50%
-40%
-30%
-20%
-10%
0%Total mortality Hospitalization Death/Hospitalization due to CV cause
Ris
k re
ductio
n (
%)
65%
27%
38%
Mild to moderate HF; LVEF < 35%
N = 1094, t = 15.1 mnths
Carvedilol (25-50 mg bid) vs placebo
NEJM 1996; 334 : 1349 - 55
ANZ Multicentre Heart Failure Trial
Placebo Carvedilol % Risk(n=208) (n=207) Reduction
All-cause 26 20 24%mortality (12.5%) (10%)
Risk of hospitalization for 84 64 28%cardiovascular reasons (40%) (31%)
Combined risk of 97 74 29%mortality & hospitalization (47%) (36%)
Lancet 1997; 349: 375-380.
Effect of carvedilol on progressionof congestive heart failure
All randomized patients
Endpoint Placebo Carvedilol (n=134) (n=232)
Primary endpoint 28 (21%) 25 (11%)*
Death due to CHF 4 (3%) 0 (0%)
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.
COPERNICUS (CarvedilOl ProspEctive RaNdomIsed CUmulative Survival Study): Effect on Mortality
11.4%
18.5%
0
2
4
6
8
10
12
14
16
18
20
Carvedilol (n=1156) Placebo (n=1133)
35%
Mo
rta
lity
(%)
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 27%
for CV reasons
Death and hospitalisation 31%
for heart failure
Circulation 2002; 106: 2194-9
BEST Study(Beta-Blocker Evaluation of Survival Trial)
The Beta-Blocker Evaluation of Survival Trial Investigators. N Engl J Med. 2001;344:1659-1667.
Primary Endpoint All-cause mortality
Design Randomized, placebo-controlled, double-blind trial in 2708 NYHA
Class III or Class IV patients
Follow-up 24 months mean follow-up
Dosing Bucindolol titrated from 3 mg to maximum 100 mg BID as tolerated by patient
Results Nonsignificant relative risk reduction in all-cause mortality (10% , P = .10)
CARDIAC INSUFFICIENCY BISOPROLOL STUDY-II (CIBIS II)
T otal mor tal i ty Al l cause hospital ization CV deaths Combined endpoint Sudden death Hospital ization f or
wor sening HF
-50%
-40%
-30%
-20%
-10%
0%T o ta l mo rta lity A ll c a u se h o sp ita liza tio n C V d e a th s C o mb in e d e n d p o in t S u d d e n d e a th H o sp ita liza tio n fo r w o rse n in g H F
Ris
k r
ed
uc
tio
n
34%
20%
29%
21%
44%
36%Moderate to severe HF, LVEF < 35%
N=2647, t = 1.3 years
Bisoprolol (10 mg od) vs placebo
Lancet 1999; 353 : 9 –13
MEtoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF)
Mortality CV deaths Sudden death Death due to worsening HF
-60%
-50%
-40%
-30%
-20%
-10%
0%M o rta lity C V d e a th s S u d d e n d e a th D e a th d u e to w o rse n in g H F
Risk
red
uctio
n (%
)
34% 38%41%
49%Mild to moderate HF; LVEF < 40%
N = 3991 t = 1 year
Metoprolol CR/XL (200 mg od) vs placebo
Lancet 1999; 353: 2001-2007
Carvedilol Or Metoprolol European Trial COMET
40%
34%
30%32%34%36%38%40%42%
Metoprolol CarvedilolAll-c
au
se m
ort
ality
(%
)
17%
Lancet 2003; 362: 7-13
Cardiovascular mortality was reduced by 20% in carvedilol group as compared to metoprolol group.
35%29%
0%
10%
20%
30%
40%
Metoprolol Carvedilol
20%
Lancet 2003; 362: 7-13
Reduces total mortality by 54.3%
8.1
3.7
0
1
2
3
4
5
6
7
8
9
No
. of d
ea
ths
(%)
ACE Inhibitor + diuretic + digitalis
ACE inhibitor + diuretic + digitalis + Metoprolol extended release Circulation 2000; 101: 378-384
Randomized Evaluation of Strategies for left ventricular Randomized Evaluation of Strategies for left ventricular Dysfunction Pilot Study (RESOLVD)Dysfunction Pilot Study (RESOLVD)
CAPRICORN: Effect on total mortality
15%
12%
0
2
4
6
8
10
12
14
16
Placebo Carvedilol
% m
ort
alit
y
23%
Lancet 2001; 357: 1385-90
CAPRICORN: Effect on combined risk of mortality and cardiovascular hospitalizations
15%
12%
0
2
4
6
8
10
12
14
16
Placebo Carvedilol
All-
caus
e m
orta
lity
or C
V
hosp
italiz
atio
n (%
)
8%
Lancet 2001; 357: 1385-90
Target dose was achieved by more than 70% of patients in both the treatment groups.
75%
78%
73%74%75%76%77%78%79%
Carvedilol (25mgbid)
Metoprolol (50 mgbid)
Pati
en
ts (
%)
Lancet 2003; 362: 7-13
First stable dose of carvedilol achieved in study patients
3.125 mg bd4%
6.25 mg bd13%
12.5 mg bd20%
other3%
50 mg bd4%
25 mg bd57%
Heart 2000; 84:615-619
Low withdrawal rates
15.313.9
0
5
10
15
20P
atie
nt w
ithd
raw
als
(%
)
Lancet 1999; 353: 2001-2007
ACE Inhibitor + diuretic + digitalis
ACE inhibitor + diuretic + digitalis + Metoprolol extended release
Well tolerated when added to standard therapy
Per cent of patients unable to tolerate carvedilol treatment, grouped according to New York Heart Association (NYHA) functional class
3
9
13
22
0
5
10
15
20
25
I (n=59) II (n=201) III (n=254) IV (n=118)
Per
cen
t no
t to
lera
ted
N=808Heart 2000; 84:615-619
NYHA Class
Per cent of patients able to tolerate carvedilol treatment, grouped according to traditional contraindications and precautions in prescribing a -blocker
88 85 86 84
12 15 14 16
020406080
100A
ll p
atie
nts
(n=
795)
CO
PD
/ast
hm
a(n
=89
)
Dia
bet
es(n
=12
7)
PV
D (
n=
58)
Tolerated Not Tolerated
Per
cen
t
Heart 2000; 84:615-619
WHEN TO START TREATMENT?
If no contraindication Early use of blockers risk of adverse reactions
Which to use? Carvedilol Metoprolol extended-release Bisoprolol
How to initiate and titrate blockers doses? Start low, go slow Titration interval = 2-4 weeks 2-3 hours observation period
Titration of blockers in HF
Careful initial unpward dose adjustment
ensures favourable minimizes adverse
clinical management 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 slow upward Maximally tolerated
initial doses dose adjustment target doses
Titration interval: > 2 weeks
Upward titration is delayed until any adverse effects observed with lower doses have resolved
Careful blockers early in treatment may prevent the need for treatment delays during later stages of therapy
Slow upward titration
Improves drug gives time for doctor to
tolerability respond to changes in
patient status by altering
concomitant HF
therapies
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