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