b BLOCKERS IN

HEART FAILURE
Definition 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.
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
Pathogenesis and Sequelae of Heart Failure
Arrhythmia
Coronary artery
disease

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

b1 Myocardium Positive chronotropic

Positive inotropic
Stimulates myocyte growth
Myocyte apoptosis
Myocyte toxicity
Activates RAS

b2 Bronchial and vascular Stimulates myocyte growth

smooth muscle Arrhythmia
Positive chronotropic Positive
inotropic
a1 Vascular smooth muscle Stimulates myocyte growth
Vasoconstriction
 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:b2:a1 = 2:1:1

 b3 and b4 also exist

Rationale of using b blockers in HF
 The failing human heart is adrenergically activated to maintain
cardiac performance over the short term by increasing
contractility 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 are
mediated 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.
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
 β -Blocker Effects
On Ejection Fraction in Heart Failure

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

Betablocker- Carvedilol 7.3 +++ Antioxidant

vasodilator

Bucindolol 1.4 +(0) syst.

Adrenergic
activity
Nebivolol 293 0 0
 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 HF
was first questioned by Waagstein in Sweden. Seven
patients treated with oral practolol experienced an
improvement in their clinical condition.
 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 clinical
response to b-blocking agents when administered
chronically; (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 the
decrease 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 with
heart failure which was later found to be caused by a
reduction in the b1 receptors.
 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.
 Metoprolol
Trial MDC (1993) Merit-HF(1999)
No. of pts. 383 3991
NYHA Class II – 47% II – 41%
III – 47% III – 56%
IV – 6% 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
 Results MDC (1993) Merit-HF(1999)
Change in EF 28 – 34% NR

Exercise tolerance ed at 1yr NR

NYHA Class & Improved Improved

QOL

Morbidity hospitalization & need for need for hospital

transplant admission due to
worsening heart failure

Mortality No change
 MEtoprolol CR/XL Randomized Intervention Trial in
Congestive Heart Failure (MERIT-HF)

M o rt alit y C V d eat hs S ud d en d eat h D eat h d ue t

0% M o rta lity C V d e a th s
w o rs ening H
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

-10%
-20%
Risk reduction (%)

-30%
-40% 34% 38%
-50% 41%
49%
-60%

Lancet 1999; 353: 2001-2007

 Carvedilol
Trial USCP (MOCHA, PRECISE, ANZ
MILD, SEVERE)
No. of pts. 1094 415
NYHA Class II – 53% I – 30%
III – 44% II – 54%
IV – 3% III – 16%
EF < 35% < 45%
Etiology of HF Mixed Ischemic
Follow-up 6.5 mths (stopped early) 20 months
Primary Exercise Tolerance, QOL, disease I - Exercise tolerance
endpoint progression, safety II – Morbidity &
Mortality
Starting dose 3.125 – 6.125 BD
Target dose 25 – 50 BD
Addn t/t ACEI, diuretics, digoxin ACEI, diuretics, digoxin
 Results USCP (1996) ANZ (1997)

Change in EF significant - MOCHA & 28.4% - 33.5%

PRECISE

Exercise tolerance No improvement – No clear changes

MOCHA & PRECISE

NYHA Class & No significant effect No significant effect

QOL

Morbidity 27% Hospitalization 23% hospitalization

48% disease progression 28% CV hosp.

Mortality 65% in mortality 24% all-cause mortality

MOCHA 73%
 Effect of Carvedilol on Left
Ventricular Ejection Fraction
8
< .001
7 P
LVEF (EF units)

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

All-cause mortality All-cause hospitalisation

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

35% relative risk reduction 24% relative risk reduction

N Engl J Med 2001; 344 :165

COPERNICUS: Effect on combined risk of
death and hospitalizations

Parameter % risk reduction with

carvedilol
Death and hospitalization for 27%
CV reasons

Death and hospitalization for 31%

heart failure

Circulation 2002; 106: 219

 Recent Remote
Myocardial Infarction Myocardial Infarction

ANZ US Program COPERNICUS

EF 28% EF 23% EF 20%

90% post MI 39% post MI 55% post MI

≈ 2-3yr prior ≈ 3-4yr prior ≈ 4-5yr prior
 Recent Remote
Myocardial Infarction Myocardial Infarction

CHAPS CAPRICORN ANZ US Program COPERNICUS

EF 50% EF 33% EF 28% EF 23% EF 20%

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

No. of pts. 157 2600

EF 50% 33 %

Follow-up 6 months 15 months

Primary endpoint Death due to CV cause / any All cause mortality

CV event

Target dose 12.5 BD 25 BD

Post MI 17 hrs 10 days

 CHAPS: Primary Endpoint

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

Days after randomization

 CAPRICORN
All-Cause Mortality
1.00

0.90 Carvedilol n=975

Proportion Event-free

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

The CAPRICORN Investigators. Lancet. 2001;357:1385-1390.

 CAPRICORN
Cardiovascular Mortality
1.00

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)

No. of pts. 641 2647

NYHA Class III – 95% III – 83%
IV – 5% IV – 17%

EF < 35% < 35%

Etiology of HF Mixed Mixed
Follow-up 23 months 14 mths (stopped early)
Primary All-cause mortality All-cause mortality
endpoint

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
STUDY-II (CIBIS II)
A l l c aus e hos pi tal i z ati on
T otal mor tal i ty C V deathsC ombi ned endpoi Sudden deathH os pi tal i z ati on f o
nt

0% T o ta lm o rta lity A lc a u se h o sp ita liza

w or s eni ng H F
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 rw o rse n in g H F

-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%.

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 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

Therefore in patients with advanced heart failure and left

ejection fraction <35%, bucindolol conferred no overall survival
benefit.

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

Titration interval: > 2 weeks

 Upward titration is delayed until any adverse effects observed
with lower doses have resolved
 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 symptoms
of increased congestion or hypoperfusion. Patients should be
evaluated before any dose increase.
 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 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-

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.

Dosing Guidelines

Beta Blocker Initial Dose Target Dose

Metoprolol XL 12.5–25 qd 200 mg qd

Bisoprolol 1.25 mg/day 10 mg/day

Carvedilol 3.125 mg bid 25–50 mg bid

Which is Better ?
Carvedilol

OR

Metoprolol
 COMET Trial (2003)
3,029 patients with Class III-IV heart failure
Enrolled at 317 centers in 15 European countries

Carvedilol Metoprolol tartrate

(target dose 25 mg twice daily) (target dose 50 mg twice daily)
 (n = 1,511)  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

European Heart Failure Meeting 2003

 COMET Trial : Primary
Endpoint Analysis
50% C arved ilo l 73.9% 76.4%
M eto p ro lo l
39.5%
40%
33.9% 35.0%

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)

Beta-blockers should be prescribed to all

patients with stable HF due to left
ventricular 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
β -Adrenergic Receptor Blockers (1999)
Recommendation 1
Should be routinely administered to clinically stable patients with left
ventricular 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).
 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

CHRISTMAS Cravedilol Hibernating Ischemic

Myocardium CMY

CARMEN Carvedilol Remodeling NYHA I-II

EMPOWER Enoximone + Mortality + NYHA III-IV

Metoporolol Morbidity