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HEART FAILURE
Definition of Heart Failure
Hypertension
Left Low
ventricular ejection
Remodeling Death
dysfunction fraction
Cardiomyopathy
Pump
Valvular failure
disease
• Neurohormonal
stimulation
• Endothelial
dysfunction Non- Symptoms:
• Vasoconstriction cardiac Dyspnea Chronic
• Renal sodium factors Fatigue heart
retention Edema failure
Effects of adrenergic receptors
Receptor Tissue location Effects
In end-stage HF
b1:b2:a1 = 2:1:1
β -Blocker Discontinued
Pharmacologic Effect
LVEF
β -Blocker Biologic
Initiated Effect
0 1 3 6 8
Time (months)
Different Pharmacological Profiles
of Beta-Blockers Studied in
Heart Failure
Class Compound b1/b2 a1 blockade Ancillary
selectivity properties
Nonselective Propranolol 2.1 0 0
Selective b1 Metoprolol 74 0 0
Bisoprolol 119 0 0
Mortality No change
MEtoprolol CR/XL Randomized Intervention Trial in
Congestive Heart Failure (MERIT-HF)
-10%
-20%
Risk reduction (%)
-30%
-40% 34% 38%
-50% 41%
49%
-60%
2
∆
0
Placebo 6.25 mg bid 12.5 mg bid 25 mg bid
Carvedilol
Circulation. 1996;94:2807-2816.
US CARVEDILOL HEART FAILURE STUDY
Total mo rtality Hospitalization Death/Ho spitalizati
0% on due to C V cause
T o ta lm
o rta lity Ho sp ita liza tio n De a th /Ho sp ita liza tio n d u e to CV c a u se
-10%
-20%
Risk reduction (%)
-30% 27%
-40%
38%
-50%
-60%
-70% 65%
NEJM 1996; 334 : 1349 - 55
COPERNICUS Trial (2001)
Design
Multicenter, multinational, randomised, double-blind, placebo-
controlled
Patients
2289 patients with symptoms of heart failure (mixed etiology) and
left ventricular ejection fraction <25%, receiving standard therapy
(diuretic plus ACE inhibitor/angiotensin II-receptor antagonist)
Follow up and primary end point
Mean 10.4 months follow up (stopped early). Primary endpoint all-
cause mortality
Treatment
Placebo or carvedilol 3.125 mg twice daily for 2 weeks, increased
stepwise over several weeks as tolerated to target dose 25 mg
twice daily
COPERNICUS: Carvedilol Prospective Randomized
Cumulative Survival trial
100 100
Placebo
90 80 Carvedilol
80 60
70 40
60 20
50 0
0 3 6 9 12 15 18 21 0 3 6 9 12 15 18 21
Months Months
100% post 100% post MI 90% post MI 39% post MI 55% post MI
MI ≈ 10d prior ≈ 2-3yr prior ≈ 3-4yr prior ≈ 4-5yr prior
≈ 17h
prior
Trial CHAPS CAPRICORN
EF 50% 33 %
1.0
Carvedilol
Proportion surviving
0.8
0.6
Placebo
0.4
0.2 P=0.0101
0
0 20 40 60 80 100 120 140 160 180 200
0.80
Risk Reduction
↓23% Placebo n=984
0.70 (2%, 40%)
0.60 P=0.031
Mortality rates: Placebo 15%; Carvedilol 12%.
0.50
0 0.5 1 1.5 2
Years
0.90
Carvedilol n=975
Proportion Event-free
0.80
Risk reduction Placebo n=984
↓25%
0.70
(4%, 42%)
P=0.024
0.60 Cardiovascular mortality rates:
Placebo 14%; Carvedilol 11%
0
0 0.5 1.0 1.5 2.0
Years
Bisoprolol
Trial CIBIS I (1994) CIBIS II (1999)
-10%
Risk reduction
-20%
20% 21%
-30%
29%
-40% 34% 36%
44%
-50%
Lancet 1999; 353 : 9 –13
Opposite Mortality Trends in
CIBIS trials
50% 48%
44%
45%
40%
34%
35%
30% 26%
25% 20% 21% C IB IS - I
20%
C IB IS - II
15%
10%
5%
0%
All-c a u s e Su d d e n D e a th fr o m
m o r ta lity D e a th p u m p fa ilu r e
Bucindolol
BEST: Beta-blocker Evaluation Survival Trial
Design
Multicenter, randomised, double-blind, placebo-controlled
Patients
2708 patients with NYHA class III/IV heart failure due to primary
or secondary dilated cardiomyopathy, of which 59% were due to
ischemic heart disease, with left ventricular ejection fraction
<35%.
Treatment
Placebo or bucindolol 3 mg twice daily, increased as tolerated over
several weeks to 50 mg twice daily.
• Trial halted early because mortality not significantly
different in bucindolol and placebo groups (30 vs. 33%,
P=0.10)
• Bucindolol group had significantly lower:
— death from cardiovascular causes
— hospitalization due to heart failure
Nebivolol
Undergoing phase III trials.
Shown to improve systolic function in a many small scale
studies.
Initiating & Titrating b blocker
therapy in HF
Appropriate Patients
Based on current evidence, consideration of beta blocker
therapy is appropriate in patients with heart failure who meet
the following criteria :
1. Systolic left ventricular dysfunction (left ventricular ejection
fraction of 40 percent or less).
2. Stable circulation (neither progressive fluid accumulation nor
worsening cardiac output).
3. Patients in NYHA class II or III (? IV), regardless of the
extent of ventricular dysfunction.
4. No contraindications to the use of beta blockers.
Dose Initiation
In patients with clinically stable HF for 2- 4 weeks with
standard therapy.
Start at very low doses
Dose Titration
Patients who tolerate slow upward Maximally
tolerated
initial doses dose adjustment target doses
Bradycardia
The beta blocker dose should be reduced if the decrease in heart rate is
symptomatic or is associated with hypoperfusion or higher than first-degree
atrioventricular block.
Consideration should be given to reducing the digoxin dose or
discontinuing the drug, especially in patients with mild heart failure.
Increased Vascular Congestion
Increased congestion might occur because of the negative inotropic effect
of beta blockers. Congestion often resolves with transient intensification of
diuresis. Rarely, it might necessitate dose reduction or discontinuation of
the beta blocker.
Management of Decompensation
The management of patients with chronic heart failure who deteriorate after
a period of stability on beta blocker therapy.Often, the "decompensation"
occurs because of fluid retention, which may be the consequence of an
inadequate diuretic regimen, poor absorption of diuretic or loop-diuretic
resistance.
On the other hand, if the decompensation is in the form of low cardiac
output in the setting of optimal fluid management, an attempt should be
made to restore stable circulation with short-term intravenous infusion of a
PDE inhibitor while beta blocker therapy is maintained. If this approach
fails, the beta blocker dose should be decreased, or the drug should be
discontinued.
Withdrawal-
Abrupt withdrawal should be avoided.
Reduction/ discontinuation may be warranted if pt. requires
hospitalization or use of IV drugs.
Reinitiation-
OR
Metoprolol
COMET Trial (2003)
3,029 patients with Class III-IV heart failure
Enrolled at 317 centers in 15 European countries
29.0%
30%
20%
10%
0%
All-c a u s e M o rta lity C a rd io v a s c u la r M o rta lityAll-c a u s e Ho s p ita liz a tio n
ACC/AHA Guidelines for the
Evaluation and Management of Chronic
Heart Failure
(2001)
Recommendation 2
Should be considered for patients with left ventricular systolic dysfunction (left
ventricular ejection fraction less than or equal to 40%) who are
asymptomatic (i.e., NYHA Class I) and on standard therapy, including ACE
inhibitors (Strength of Evidence = C).
Using ß-Blockers in Specific Populations
Age:
Subgroup analyses of the major ß-blocker HF trials have shown a
similar benefit in patients 65 years old as seen in the general population.
Gender:
Women represented 20% to 30% of the population in the ß-blocker
HF trials and appear to benefit from ß-blocker therapy except in Merit-HF
trial.
Ethnicity:
There is little information regarding possible ethnic differences in
the response to ß-blockers in HF.
Diastolic HF:
However, the majority of these patients often have HTN, CAD, and/or
atrial fibrillation, conditions for which ß-blockers are indicated.
On-Going Phase III or IV Multicenter Clinical Trials
With ß-Adrenergic Blocking Agents in Chronic HF
Trial Agent PEP Population