beta blockers in hf

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bb BLOCKERS INBLOCKERS IN

HEART FAILUREHEART FAILURE



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.



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



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



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



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



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.



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



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



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



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.



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.



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



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



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



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



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




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



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



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)



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



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%



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




EF 50%

100% post

MI

≈ 17h

prior

Recent


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




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



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



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



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



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


CARDIAC INSUFFICIENCY BISOPROLOL



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



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



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.



• 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



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 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



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



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.



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.



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.



Which is Better ?Which is Better ?

CarvedilolCarvedilol

OR OR

MetoprololMetoprolol



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



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



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



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)



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.



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

beta blockers in hf

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