b b BLOCKERS IN BLOCKERS IN HEART FAILURE HEART FAILURE
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bb BLOCKERS INBLOCKERS IN
HEART FAILUREHEART FAILURE
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Definition of Heart FailureDefinition of Heart Failure
Heart failure is the pathophysiological state in
which the heart is unable to pump blood at a
rate commensurate with the requirements of
the metabolizing tissues or can do so only
from an elevated filling pressure.
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Neurohormonal changes in HF
High output failure Low output failure
peripheral vascular resistance Cardiac output
Fullness of the arterial system
Sympathetic Nervous system activity
Vasopresssin Sodium & H20 RAAS
release retention activation
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Coronary arterydisease
Hypertension
Cardiomyopathy
Valvular disease
Left
ventricular
dysfunction
Non-cardiacfactors
Remodeling
Low
ejection
fraction
Arrhythmia
Death
Pump
failure
Symptoms:DyspneaFatigueEdema
Chronicheartfailure
• Neurohormonalstimulation
• Endothelialdysfunction
• Vasoconstriction
• Renal sodiumretention
Pathogenesis and Sequelae of Heart Failure
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Effects of adrenergic receptorsReceptor Tissue location Effects
b1Myocardium Positive chronotropic
Positive inotropic
Stimulates myocyte growth
Myocyte apoptosis
Myocyte toxicity
Activates RAS
b2Bronchial and vascular smooth muscle
Stimulates myocyte growth
Arrhythmia
Positive chronotropic Positiveinotropic
a1Vascular smooth muscle Stimulates myocyte growth
Vasoconstriction
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b Receptors In Younger and non-failing human heart
b1/b2 ratio = 70-80% / 30-20%
In older and failing hearts
b1/b2 ratio = 60-65% / 40-35%
due to selective downregulation of b1 receptors
a1 receptors also upregulated in a failing heart
In end-stage HF
b1:b
2:a
1= 2:1:1
b3 and b4 also exist
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Rationale of using b blockers in HF The failing human heart is adrenergically activated to maintain
cardiac performance over the short term by increasingcontractility and heart rate by increased cardiac adrenergic drive.
Norepinephrine is exceptionally cardiotoxic in a failing heart
producing depletion of ATPs, free radical generation, cytokine
expression and accelerated apoptosis. All these effects aremediated by b receptors (esp. b1
).
In the failing heart, b adrenergic signal transduction is reduced
secondary to desensitization at the level of receptors, inhibitory
G protein and the enzymes adenylyl cyclase and receptor kinase. Thus effective therapeutic strategy would be to add to this
endogenous antiadrenergic strategy.
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Mechanism of action of b blockers in
heart failure
Hemodynamic effects Heart Rate
Improve ventricular coordination
Attenuate sympathetic tone Prevent or reverse
Cellular effects LV dilatation and
Plasma norepinephrine levels hypertrophy
Norepnephrine spillover
Sympathethetic nerve traffic REVERSE
Improves handling of Ca++ at level of SR REMODELLING
Dependency on CHO rather than FA Electrical effects
Ventricular Tachyarrhythmias
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LVEF
Time (months)
Biologic
Effect
Pharmacologic Effect
β -Blocker
Initiated
β -Blocker Discontinued
00 11 33 66 88
β -Blocker Effects On Ejection Fraction in Heart Failure
iff h l i l fil
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Different Pharmacological Profiles
of Beta-Blockers Studied in
Heart Failure
Class Compound b
1 / b
2
selectivity
a1 blockade Ancillary properties
Nonselective Propranolol 2.1 0 0
Selective b1Metoprolol 74 0 0
Bisoprolol 119 0 0
Betablocker-vasodilator
Carvedilol 7.3 +++ Antioxidant
Bucindolol 1.4 +(0) syst.Adrenergic
activity
Nebivolol 293 0 0
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History of use of b blockers
in heart failure 1060s - Braunwald’s group elucidates the importance of
dysfunctional adrenergic activation in CHF. However the
interpretation was that adrenergic support was deficient in
CHF. This view prevailed for 10 to 15 years.
1973 - Single bolus injection of practolol (first
selective b1- blocking agent) was administered to reduce the heart rate of
a 59 year old woman with tachycardia caused by an acute
pulmonary edema owing to dilated cardiomyopathy.
1975 - The traditional dogma that b blockers worsen HFwas first questioned by Waagstein in Sweden. Seven
patients treated with oral practolol experienced an
improvement in their clinical condition.
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History of use of b blockers in heart
failure
Late 1970s & early 1980s - three separate lines of evidence contributed to a 180-degree turn in the role of adrenergic mechanisms in CHF (1) favorable clinicalresponse to b-blocking agents when administeredchronically; (2) the evidence that the failing human heart
exhibited -adrenergic receptor downregulation and pathway desensitization; and (3) the demonstration of increase in interstitial levels of norepinephrine despite thedecrease in tissue stores. For the next 15 to 20 years, the
prevailing view was that excessively increased adrenergic
drive is harmful to the natural history of the CHF. 1980s - Bristow showed that the adenylate cyclase
response to b blockade was attenuated in patients withheart failure which was later found to be caused by areduction in the b
1receptors.
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History of use of b blockers in heart
failure 1990 - The first double-blind randomized trial on a b
blocker bucindolol was published.
1993 – The first placebo-controlled multicentre trial
with a beta blocker metoprolol (MDC) was published.
1997 - The first b blocker to be approved for treatment
of HF was carvedilol.
During the 24 years between 1973 and 1998 the
consensus for using b blockers to treat heart failure has
changed from being unacceptable to a standard
treatment for heart failure patients.
M t l l
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MetoprololTrial MDC (1993) Merit-HF(1999)
No. of pts. 383 3991
NYHA Class II – 47%
III – 47%
IV – 6%
II – 41%
III – 56%
IV – 3%
EF < 40% < 40 %
Etiology of HF IDCM Mixed
Follow-up 1.5 years 1 yrs (stopped early)
Primary endpoint Death / need for transplant All cause mortality
Molecule Metoprolol tartrate Metoporolol succinate
Starting dose 10 mg/d 12.5 – 25 mg/d
Target dose 100 – 150 mg/d 200 mg/d
Addn t/t ACEI, diuretics, digoxin ACEI, diuretics, digoxin
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Results MDC (1993) Merit-HF(1999)
Change in EF 28 – 34% NR
Exercise tolerance ed at 1yr NR
NYHA Class &
QOL
Improved Improved
Morbidity hospitalization & need for transplant
need for hospitaladmission due to
worsening heart failure
Mortality No change
l l / d i d i i l i
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MEtoprolol CR/XL Randomized Intervention Trial in
Congestive Heart Failure (MERIT-HF)
M o rtal C V d ea S ud d en d D eat h d uw o r s e n i n g
- 6 0 %
- 5 0 %
- 4 0 %
- 3 0 %
- 2 0 %
- 1 0 %
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
R i s k r e
d u c t i o n ( % )
3 4 3 8 %4 1
4 9 %
Lancet 1999; 353: 2001-2007
C dil l
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CarvedilolTrial USCP (MOCHA, PRECISE,
MILD, SEVERE)
ANZ
No. of pts. 1094 415NYHA Class II – 53%
III – 44%
IV – 3%
I – 30%
II – 54%
III – 16%
EF < 35% < 45%Etiology of HF Mixed Ischemic
Follow-up 6.5 mths (stopped early) 20 months
Primaryendpoint
Exercise Tolerance, QOL, disease progression, safety
I - Exercise tolerance
II – Morbidity &Mortality
Starting dose 3.125 – 6.125 BD
Target dose 25 – 50 BD
Addn t/t ACEI, diuretics, digoxin ACEI, diuretics, digoxin
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Carvedilol
Placebo0
1
2
3
4
5
6
7
8
LVEF(E
F
units)
P <. 0 0
1
Circulation. 1996;94:2807-2816.
Effect of Carvedilol on Left
Ventricular Ejection Fraction
25 mg bid6.25 mg bid 12.5 mg bid
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US CARVEDILOL HEART FAILURE STUDY
Total mortali Hospitalizatio Death/Hospitaliz
on due to C V cau
-70%
-60%
-50%
-40%
-30%
-20%
-10%
0% Totalmortality Ho spitalization Death/Hospitalization du e toCVc ause
R i s
k r e d u c t i o n ( %
)
65%
27%
38%
NEJM 1996; 334 : 1349 - 55
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Design
Multicenter, multinational, randomised, double-blind, placebo-controlled
Patients
2289 patients with symptoms of heart failure (mixed etiology) andleft 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
TreatmentPlacebo or carvedilol 3.125 mg twice daily for 2 weeks, increasedstepwise over several weeks as tolerated to target dose 25 mgtwice daily
COPERNICUS Trial (2001)
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COPERNICUS: Carvedilol Prospective RandomizedCumulative Survival trial
Months
0 3 6 9 181512 21
50
80
70
60
90
100
All-cause mortality
Months
0 3 6 9 181512 21
0
60
40
20
80
100
All-cause hospitalisation
N Engl J Med 2001; 344 :165
35% relative risk reduction 24% relative risk reduction
Placebo
Carvedilol
COPERNICUS Effect on combined risk of
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COPERNICUS: Effect on combined risk of
death and hospitalizations
Circulation 2002; 106: 21
Parameter % risk reduction withcarvedilol
Death and hospitalization for CV reasons
27%
Death and hospitalization for heart failure
31%
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Recent
Myocardial Infarction
EF 28%
90% post MI≈ 2-3yr prior
EF 23%
39% post MI
≈ 3-4yr prior
EF 20%
55% post MI
≈ 4-5yr prior
ANZ US Program COPERNICUS
Remote
Myocardial Infarction
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EF 50%
100% post
MI
≈ 17h
prior
Recent
Myocardial Infarction
EF 33%
100% post MI
≈ 10d prior
EF 28%
90% post MI
≈ 2-3yr prior
EF 23%
39% post MI
≈ 3-4yr prior
EF 20%
55% post MI
≈ 4-5yr prior
CHAPS CAPRICORN ANZ US Program COPERNICUS
Remote
Myocardial Infarction
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Trial CHAPS CAPRICORN
No. of pts. 157 2600
EF 50% 33 %
Follow-up 6 months 15 months
Primary endpoint Death due to CV cause / anyCV event
All cause mortality
Target dose 12.5 BD 25 BD
Post MI 17 hrs 10 days
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0 20 40 60 80 100 120 140 160 180 20
0
0.2
0.4
0.6
0.8
1.0
P
roportion
su
rv
iving
Carvedilol
P=0.0101
Placebo
Days after randomization
CHAPS: Primary Endpoint
CAPRICORN
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CAPRICORN All-Cause Mortality
0 0.5 1 1.5 2
Years
Proportion
Ev
en
t-free
↓23%
(2%, 40%)
P =0.031
Risk Reduction
0.50
1.00
0.90
0.70
0.60
0.80
The CAPRICORN Investigators. Lancet . 2001;357:1385-1390.
Mortality rates: Placebo 15%; Carvedilol 12%.
Carvedilol n=975
Placebo n=984
CAPRICORN
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CAPRICORNCardiovascular Mortality
↓25%
P =0.024
Risk reduction
(4%, 42%)
Proportion
Even
t-free
0 0.5 1.0 1.5 2.0
Carvedilol n=975
Placebo n=984
0
1.00
0.90
0.70
0.60
0.80
Years
Cardiovascular mortality rates:
Placebo 14%; Carvedilol 11%
Bi l l
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BisoprololTrial CIBIS I (1994) CIBIS II (1999)
No. of pts. 641 2647
NYHA Class III – 95%
IV – 5%
III – 83%
IV – 17%
EF < 35% < 35%Etiology of HF Mixed Mixed
Follow-up 23 months 14 mths (stopped early)
Primaryendpoint
All-cause mortality All-cause mortality
Starting dose 1.25 mg/d 1.25mg/d
Target dose 5 mg/d 10 mg/d
Addn t/t ACEI, diuretics, digoxin ACEI, diuretics, digoxin
CARDIAC INSUFFICIENCY BISOPROLOL
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CARDIAC INSUFFICIENCY BISOPROLOL
STUDY-II (CIBIS II)
T otal mor ta l i A l l cause hosp i ta l i za C V deathC ombi ned endpo Sudden dea Hospi ta l iz at ion f
wors ening HF
-50%
-40%
-30%
-20%
-10%
0% T o ta lmo rta lity A llc 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 f o rw o rse n in g H F
R i s
k r e d u c t i o n
34%
20%
29%
21
44%
36
Lancet 1999; 353 : 9 –13
O it M t lit T d i
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Opposite Mortality Trends in
CIBIS trials
20%
34%
21%
44%48%
26%
0%5%
10%
15%
20%
25%30%
35%
40%
45%
50%
All -cause
mortal i ty
S u d d e n
D e a t h
D e a t h from
pu mp fa i lure
C IB IS -
C IB IS -
B i d l l
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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 primaryor secondary dilated cardiomyopathy, of which 59% were due toischemic heart disease, with left ventricular ejection fraction<35%.
Follow up and primary endpoint
Primary endpoint: all-cause mortality. Mean 24 months follow up
Treatment
Placebo or bucindolol 3 mg twice daily, increased as tolerated overseveral weeks to 50 mg twice daily.
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• Trial halted early because mortality not significantlydifferent 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
Therefore in patients with advanced heart failure and leftejection fraction <35%, bucindolol conferred no overall survivalbenefit.
NebivololNebivolol
Undergoing phase III trials. Shown to improve systolic function in a many small scale
studies.
Initiating & Titrating b blocker
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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.
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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 Maximallytolerated
initial doses dose adjustment target doses
Titration interval: > 2 weeks Upward titration is delayed until any adverse effects observed
with lower doses have resolved
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Patient Education Potential for temporary worsening of symptoms
Clinical response may not be apparent for up to 3 months
Weight monitoring daily
Report symptoms ASAP
Monitoring Side Effects Up to 15 percent of patients might not tolerate beta blocker
therapy.
Patients should be monitored closely for signs and symptomsof increased congestion or hypoperfusion. Patients should beevaluated before any dose increase.
Management of Side Effects
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Management of Side Effects Hypotension
Symptomatic hypotension or hypoperfusion usually occur within 24-48 hrs.
of first dose or first increment. In less serious situations, hypotension might
be prevented by the administration of a once-daily ACE inhibitor taken at a
different time than the beta blocker.
At times, a temporary decrease in the dose of ACEI / Diuretics might be
necessary.
If hypoperfusion or symptomatic hypotension persists, the dose of the beta blocker must be reduced, or the drug must be discontinued.
Bradycardia
The beta blocker dose should be reduced if the decrease in heart rate issymptomatic 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.
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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 bemade 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.
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Withdrawal-Abrupt withdrawal should be avoided.
Reduction/ discontinuation may be warranted if pt. requireshospitalization or use of IV drugs.
Reinitiation-
If discontinuation < 72 hrs reinitiate at previous dose
If >72 hours but < 7 days reinitiate at 50% of previous dose.
If > 7 days restart therapy at the initial dose.
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Which is Better ?Which is Better ?
CarvedilolCarvedilol
OR OR
MetoprololMetoprolol
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Carvedilol
(target dose 25 mg twice daily) (n = 1,511)
Carvedilol
(target dose 25 mg twice daily) (n = 1,511)
Metoprolol tartrate
(target dose 50 mg twice daily) n = 1,518)
Metoprolol tartrate
(target dose 50 mg twice daily) n = 1,518)
Endpoints (mean follow-up 58 months): Primary – 1) All-cause mortality and 2) All-cause mortality or all-
cause hospitalization Secondary – Composite of all cause mortality or cardiovascular
hospitalization; Composite of cardiovascular death, non-fatal acute
MI, or heart transplantation; Worsening of heart failure;
Cardiovascular death; NYHA class
Endpoints (mean follow-up 58 months): Primary – 1) All-cause mortality and 2) All-cause mortality or all-
cause hospitalization Secondary – Composite of all cause mortality or cardiovascular
hospitalization; Composite of cardiovascular death, non-fatal acute
MI, or heart transplantation; Worsening of heart failure;
Cardiovascular death; NYHA class
COMET Trial (2003)COMET Trial (2003)
European Heart Failure Meeting 2003European Heart Failure Meeting 2003
3,029 patients with Class III-IV heart failure
Enrolled at 317 centers in 15 European countries
3,029 patients with Class III-IV heart failure
Enrolled at 317 centers in 15 European countries
COMET Trial : PrimaryCOMET Trial : Primary
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COMET Trial : Primary
Endpoint Analysis
COMET Trial : Primary
Endpoint Analysis
33.9
29.0
39.5
35.0
76.473.9
0%
10%
20%
30%
40%
50%
All-cause M orta lity Card iovasc ular M orta lityAll-cause Hosp ita lizat io
CarvedilolMetoprolo
ACC/AHA Guidelines for the
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ACC/AHA Guidelines for the
Evaluation and Management of Chronic
Heart Failure
(2001)
Beta-blockers should be prescribed to all
patients with stable HF due to leftventricular systolic dysfunction unless they
have a contraindication to their use or have
been shown to be unable to tolerate
treatment with these drugs.
HFSA Practice Guidelines
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Recommendation 1
Should be routinely administered to clinically stable patients with leftventricular systolic dysfunction (left ventricular ejection fraction less than
or equal to 40%) and mild to moderate heart failure symptoms (i.e., NYHA
Class II-III, Appendix A) who are on standard therapy, which typically
includes ACE inhibitors, diuretics as needed to control fluid retention, and
digoxin
(Strength of Evidence = A).
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).
HFSA Practice Guidelines
β -Adrenergic Receptor Blockers (1999)
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Using ß-Blockers in Specific Populations
Age:
Subgroup analyses of the major ß-blocker HF trials
have shown asimilar 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-HFtrial.
Ethnicity:
There is little information regarding possible ethnic differences inthe 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.
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On-Going Phase III or IV Multicenter Clinical Trials
With ß-Adrenergic Blocking Agents in Chronic HF
Trial Agent PEP Population
CHRISTMAS Cravedilol Hibernating
Myocardium
Ischemic
CMY
CARMEN Carvedilol Remodeling NYHA I-II
EMPOWER Enoximone +Metoporolol
Mortality +Morbidity
NYHA III-IV
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