CHF: Beta BIockers or ACE Inhibitors ?

Focus on CIBIS-III
P Tedjasukmana
Dept of Cardiology
RS Mitra Internasional
Jakarta
CIBIS III
Cardiac Insufficiency Bisoprolol Study
CIBIS III
Cardiac Insufficiency Bisoprolol Study
CBS
Comparison of the ,,. , of initiation of
treatment
with ..,.. ..,.. as monotherapy ,.. .
.. ...... in patients with ... . ,... ^`
CIBIS III
Rationale (1)
CIBIS III
Rationale (1)
W Beta-blockers recommended for the treatment of CHF patients on
standard treatment including diuretics & ACE-inhibitors
1,2
W %reatment sequence based on the chronological sequence of
investigation of the different drug classes for CHF:
ACE-inhibitors already standard treatment when beta-blockers were
investigated
F%. . .. . .-.., ... . . .
..,... .. ~^--...... ., ., ......
.. .. ~^--...... .. ^ ,..
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mortality reduction of about

W ACE-inhibitors + beta-blockers:
further reduction of -
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CIBIS III
Rationale (2)
CIBIS III
Rationale (2)
F .-.., . ,,. .. ~^--...... .. ^
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CIBIS III
RationaIe (3)
CIBIS III
RationaIe (3)
W Sympathetic nervous system is activated earlier than
the RAAS in the CHF disease process
1-3
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W Beta-blockade: more effective suppression of angiotensin
concentrations than achieved by ACE-inhibitors alone
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Angiotensin II Escape During
Long-term ACE Inhibitor Treatment
p<0.001 versus p|aceoo.
8|o||az J, el a|. J 0aro|ovaso Pnarmaoo|. 1982;1:9-9Z2.
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P|acebo 4 h 24 h 1 2 3 4 5
Honths Honths hosp|ta| hosp|ta|
arly vs Late Stage of CHF
CIBIS III
Study design
CIBIS III
Study design
W Prospective, randomised, open, blinded endpoint,
comparative study with two parallel groups
W Multinational, multicentre (approximately 150 study sites in 16
mainly European countries)
W 1000 patients (n=500/group):
NYHA functional class or , aged K 65 years, LVEF A 35%
W Fixed duration of monotherapy (6 months), variable duration
of combination therapy (6-18 months), individual duration: 12-
24 months
6 months 6 to 18 months
week week week week week week week week week week week week
0 10 12 ... 28 30 32 34 36 ...
6months
bisoprolol (mg/d)
enalapril(mg/d)
bisoprolol(mg/d)
Monotherapy Combination therapy
Randomisation
24months
1.25
2.5
3.75
5
7.5
10
1.25
2.5
3.75
5
7.5
10
5
10
20
5
10
20
enalapril(mg/d)
2 4 6 8
CIBIS III
Dose titration
CIBIS III
Dose titration
SurvivaI at 1 year in the intention to treat
sampIe
SurvivaI throughout the study duration in
the intention to treat sampIe
ConcIusions
W UntiI now, the sequence of starting drugs in CHF (i e
diuretic pIus ACE-I, foIIowed by Beta BIocker) has
refIected the situation where ACE-I were the first to
demonstrate their beneficiaI effects.
W CIBIS III shows that Beta bIockade can be safeIy
used to start therapy and,foIIowing the addition of an
ACE-I, wiII produce simiIar efficacy and safety in
chronic management to a regimen in which the ACE-
I precedes Beta BIocker.
W In addition, anaIysis suggested a potentiaI benefit on
survivaI with a 28% mortaIity reduction during the
bisoproIoI monotherapy phase and 31% mortaIity
reduction during the first year of treatment. AIthough
non-significant from a strictIy statisticaI point of
view, these resuIts may argue in favor of initiating
therapy with a Beta bIocker.
CIinicaI impIications of CIBIS III
W Beta bIockers are at Ieast as important as ACE
inhibitors in patients with CHF and these agents
shouId not be withheId from any patients with
CHF and depressed LVEF, unIess contra
indicated
W The CIBIS III findings may change cIinicaI
practice for the initiation of therapy for CHF. The
resuIts support the initiaI use of bisoproIoI in
patients with systoIic, miId to moderate
symptomatic CHF without signs of reIevant fIuid
retention
%HANK YOU
!ost MI : Beta BIockers
W 1. BBs significantIy reduce post-MI morbidity and
mortaIity: The meta-anaIysis by Yusuf (JAMA
1988;260:2088-2093), based on 25 cIinicaI triaIs incIuding
23,000 pts, showed that BBs vs controI group, significantIy
decreased the risk of death by 22% (p<0.001) and the risk of
sudden death by 32% (95%CI: -4% to -22%), they aIso
significantIy reduced the risk of nonfataI recurrent MI by
27% (p<0.001)
W 2. The benefit of BBs in terms of mortaIity is greater when
treatment is instituted earIy (Goteborg MetoproIoI TriaI
(Lancet 1981;2:823-827), ISIS 1 study (Lancet 1986;2:57-66)
W 3. The absoIute benefit of BBs in terms of mortaIity is
greater in high-risk MI: In the BHAT (JAMA 1982;247:1707-
1714) mortaIity was reduced by aImost 50% in the
subgroup of pts presenting signs of heart faiIure
!ost MI : ACE-is
W 1. !rescribed in addition to conventionaI
treatment, ACE-is significantIy decrease post-MI
mortaIity: CONSENSUS II, GISSI 3, ISIS 4
W 2. Their beneficiaI effect on mortaIity is much
more marked in pts with heart faiIure and/or LV
dysfunction (LVEF < 0,35 to 0.40): The risk of
death was decreased by 19% (!0.019) in the
SAVE study, by 27% (p0.002) in the AIRE study
and by 22% (p0.001) in the TRACE study
!ost MI : The BBs - ACEis combination
is synergistic
W 1. In the SAVE study: The BB-ACEi combination,
used in 34% of pts, had a cummuIative effect on
reduction of mortaIity of 45% vs onIy 31% with
BBs group (N EngI J Med 1992;327:669-677)
W 2. In the TRACE study, the greatest reduction of
mortaIity observed with trandoIapriI was obtained
in the subgroup of pts treated with BBs at the
time of randomization: RR: 0.60 vs 0.78 for the
overaII popuIation (N EngI J Med 1996;334:1546)
W 3. In the AIRE study, retrospective anaIysis of
2,006 pts showed that BBs (prescribed in 20% of
cases) were an independent predictive factor of a
34% reduction of aII cause mortaIity (p0.008) and
a 43% reduction of the risk of deveIoping severe
heart faiIure (p0.002) (J Am CoII CardioI 1998;31
suppI.A:32A)
!ost hoc anaIysis of the DigitaIis Investigation
Group (DIG) triaI
Eur Heart J 2006;27:127-129,178-186
W The primary resuIts of DIG triaI showed that overaII,
digoxin reduced hospitaIisation for decompensated
heart faiIure, but did not effect overaII mortaIity or
hospitaIisation for heart faiIure in patients with EF <
45%
W The post hoc anaIysis invoIved 5548 patients, about
1/3 of whom were on digoxin and the rest were on
pIacebo
W For pts with digoxin IeveIs 0.5 - 0.9 ng/mI, the motaIity
was 29% vs 33% for pIcebo. The aII-cause
hospitaIisation rate was 64% with digoxin vs 67%
pIacebo, hospitaIisation for heart faiIure was 23% with
digoxin vs 33% pIacebo
W For patients with serum digoxin IeveI > 1.0 ng/mI there
was no significant difference in mortaIity vs pIacebo

Hospital Discharges for Heart Failure

eta eta- -lockers. Fundamental in Heart Failure lockers. Fundamental in Heart Failure
Heart disease Heart disease
Risk Risk
Factors Factors
Asymptomatic Asymptomatic
LV Dysfunction LV Dysfunction
Symptoms Symptoms
NYHA NYHA - - IV IV
Symptoms Symptoms
NYHA II NYHA II- -III III
BN! BN!
Symptoms Symptoms
ECHO / LV dysfunction ECHO / LV dysfunction
? ?
HEART FAILURE S!ECTRUM
HEART FAILURE S!ECTRUM
Heart Failure is a Neurohormonal Disorder
Norepinephrine Norepinephrine
Angiotensin II Angiotensin II
Hypertrophy, apoptosis, ischaemia, Hypertrophy, apoptosis, ischaemia,
arrhythmia, remodeIIing, fibrosis arrhythmia, remodeIIing, fibrosis
%e vidence: Neuroormonal
Inibiting Drugs Improve Morbidity and
Mortality in Patients Wit CHF
W AC inibitors
CONSENSUS 1, SOLVD P and T,
V-HeFT 2, ATLAS, SAVE, AIRE, TRACE
W Beta-adrenergic blockers
US Carv Progr, CIBIS 2, MERIT-HF, COPERNICUS,
CAPRICORN
W Aldosterone Antagonists
RALES ( Spironolactone)
EPHESUS ( Eplerenone)
. .
1 1
receptors receptors . .
2 2
receptors receptors
Myocyte Myocyte hypertrophy & death, hypertrophy & death,
diIatation, ischaemia & arrhythmia's diIatation, ischaemia & arrhythmia's
- -
1 1
receptors receptors
Cardiac Cardiac
sympathetic activity sympathetic activity
Sympathetic Sympathetic
activity to kidneys activity to kidneys
& bIood vesseIs & bIood vesseIs
Vasoconstriction Vasoconstriction
Sodium retention Sodium retention
CNS sympathetic CNS sympathetic
outfIow outfIow
Adrenergic activation Adrenergic activation
!acker, AHA 2000 !acker, AHA 2000
eta eta- -lockers. Fundamental in Heart Failure lockers. Fundamental in Heart Failure
CONTROL
CONTROL
HEART
FAILURE
HEART
FAILURE
0
0
100
100
200
200
300
300
400
400
500
500
p0.0001
p0.0001
NORADRENALINE !LASMA LEVELES
NORADRENALINE !LASMA LEVELES
pg/mI
pg/mI
SOLVD
Francis GS et al
Circulation 1990;82:1724
SOLVD
Francis GS et al
Circulation 1990;82:1724
n 54 n 151 n 81
p0.02
p0.02
LV
Dysfunction
LV
Dysfunction
Plasma Norepinephrine increases Mortality
eta eta- -lockers. Fundamental in Heart Failure lockers. Fundamental in Heart Failure
!robabiIity !robabiIity
SurvivaI SurvivaI
NA! < 400 NA! < 400 pg/mI pg/mI
NA! 400 NA! 400- -800 800 pg/mI pg/mI
NA! > 800 NA! > 800 pg/mI pg/mI
Months Months
60 60 5 50 0 4 40 0 30 30 20 20 1 10 0 0 0
0 0
0.2 0.2
0.4 0.4
0.8 0.8
1.0 1.0
0.6 0.6
Cohn J, et al. Cohn J, et al.
N N Engl Engl J Med 1984;311:819. J Med 1984;311:819.
CCHF
CCHF
!Iasma !Iasma Norepinephrine Norepinephrine
eta eta- -lockers. Fundamental in Heart Failure lockers. Fundamental in Heart Failure
Y BIockers in HF Y BIockers in HF
- - First report: First report: Waagstein Waagstein et aI 1975 et aI 1975
- - Improved Iongevity: Improved Iongevity: Swedberg Swedberg 1979 1979
- - First direct, unequivocaI evidence of mortaIity reduction First direct, unequivocaI evidence of mortaIity reduction
CIBIS II 1997 CIBIS II 1997
- - Consistent evidence, different cIinicaI settings Consistent evidence, different cIinicaI settings
MERIT, CO!ERNICUS, CA!RICORN 1998 MERIT, CO!ERNICUS, CA!RICORN 1998- -2001 2001
- - Appropriate use in cIinicaI practice: A.S.A.!. Appropriate use in cIinicaI practice: A.S.A.!.
eta eta- -lockers. Fundamental in Heart Failure lockers. Fundamental in Heart Failure
Bisoprolol 11.8
Placebo 17.3
SURVIVAL SURVIVAL
CIBIS CIBIS- -II II
CCHF CCHF
NYHA III NYHA III- -IV IV
n2647 n2647
ancet ancet
1999;359:9 1999;359:9- -13 13
p < 0.0001
nnual mortality: bisoprolol = 8.2%; placebo = 12%
Mean follow-up 1.4 years
eta eta- -lockers. Fundamental in Heart Failure lockers. Fundamental in Heart Failure
CIBIS II CIBIS II
CHF CHF
NYHA III NYHA III- -IV IV
MERIT MERIT
CHF CHF
NYHA III NYHA III- -IV IV
CO!ERNICUS CO!ERNICUS
CHF CHF
NYHA NYHA III III- -IV IV
CA!RICORN CA!RICORN
Acute CHF Acute CHF
LVD after AMI LVD after AMI
eta eta- -lockers. Fundamental in Heart Failure lockers. Fundamental in Heart Failure
CIBIS II CIBIS II
CHF CHF
NYHA III NYHA III- -IV IV
MERIT MERIT
CHF CHF
NYHA III NYHA III- -IV IV
CO!ERNICUS CO!ERNICUS
CHF CHF
NYHA NYHA III III- -IV IV
CA!RICORN CA!RICORN
Acute CHF Acute CHF
LVD after AMI LVD after AMI
0 200 400 600 800 0 200 400 600 800
1.0 1.0
0.8 0.8
0.6 0.6
BisoproIoI BisoproIoI
!Iacebo !Iacebo
Days Days
p p<0.0001 <0.0001
SurvivaI SurvivaI
Risk Risk
Reduction34% Reduction34%
CIBIS CIBIS- -II II
Months Months
% MortaIity % MortaIity
0 0 3 3 6 6 9 9 12 12 15 15 18 18 21 21
15 15
10 10
5 5
0 0
!Iacebo !Iacebo
MetoproIoI MetoproIoI
p p0.0062 0.0062
Risk Risk
Reduction34% Reduction34%
MERIT MERIT- -HF HF
100 100
90 90
80 80
60 60
70 70
50 50
24 24 0 0 20 20 16 16 12 12 8 8 4 4 28 28
!Iacebo !Iacebo
CarvediIoI CarvediIoI
Months Months
% SurvivaI % SurvivaI
p p0.00014 0.00014
35% Risk Reduction 35% Risk Reduction
CO!ERNICUS CO!ERNICUS
1 1
0.9 0.9
0.85 0.85
0.7 0.7
0.75 0.75
0.8 0.8
0.95 0.95
0 0 0.5 0.5 1 1 1.5 1.5 2 2 2.5 2.5
CarvediIoI CarvediIoI
!Iacebo !Iacebo
CA!RICORN CA!RICORN SurvivaI SurvivaI
!<0.03 !<0.03
23% Risk Reduction 23% Risk Reduction
years years

Beta-bIockade:
W Renoprotective in patients with CHF,
reduce the risk of worsening renal function which is frequently
observed with ACE-inhibitors
1,2
F ,.. .. .-.., ,. .. .
,... .,.. , .. ..,... .. ~^--
......
W More effective in reducing sudden cardiac death than ACE-
inhibitors
3-7
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. . .... .. . , ^`
-..,
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CIBIS III
RationaIe (4)
CIBIS III
RationaIe (4)
!atients without worsening HF requiring
hospitaIisation or occuring whiIe in hospitaI in
the intention to treat sampIe
Kesimpulan
W Pemberian bisoprolol dulu tidak inferior dibandingkan dengan
pemberian enalapril dulu pada populasi %% ( p = 0.019)
W %idak ada perbedaan keamanan antara ke 2 strategi,
memperlihatkan pemberian bisoprolol dulu tidak menimbulkan
permasalahan
W Strategi bisoprolol dulu sama efektif dengan strategi enalapril dulu
W CBS menimbulkan pertanyaan mengenai rekomendasi universal
strategi ACE- dulu dalam memulai penanganan gagal jantung
W Bisoprolol dulu dapat meningkatkan survival pada terapi awal,
memungkinkan sejumlah besar pasien mendapatkan manfaat dari
kombinasi BB & ACE_
W Manfaat ini dapat lebih ditingkatkan dengan pengalaman lebih besar
titrasi BB dulu menyebabkan lebih sedikir perburukan gagal jantung
eta eta- -lockers. Fundamental in Heart Failure lockers. Fundamental in Heart Failure
Heart disease Heart disease
Risk Risk
Factors Factors
Asymptomatic Asymptomatic
LV Dysfunction LV Dysfunction
Symptoms Symptoms
NYHA NYHA - - IV IV
Symptoms Symptoms
NYHA II NYHA II- -III III
BN! BN!
Symptoms Symptoms
ECHO / LV dysfunction ECHO / LV dysfunction
? ?
HEART FAILURE S!ECTRUM
HEART FAILURE S!ECTRUM
eta eta- -lockers. Fundamental in Heart Failure lockers. Fundamental in Heart Failure
HY!ERTENSION HY!ERTENSION
MYOCARDIAL ISCHEMIA MYOCARDIAL ISCHEMIA
/ INFARCTION / INFARCTION
HEART FAILURE HEART FAILURE
ARRHYTHMIAS / SUDDEN DEATH ARRHYTHMIAS / SUDDEN DEATH
WHICH DRUG WHICH DRUG
COVERS ALL ?
COVERS ALL ?
eta eta- -lockers. Fundamental in Heart Failure lockers. Fundamental in Heart Failure
Diuretics Diuretics
AIfa BIockers AIfa BIockers
Ca C BIocker Ca C BIocker
TA1 TA1- -i i
ACE ACE- -i i
Y BIockers
Y BIockers
Hypertension Hypertension Ischemia Ischemia
Arrhythmia Arrhythmia
H FaiIure H FaiIure
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
CONSISTENT EFFECT DEMONSTRATED
CONSISTENT EFFECT DEMONSTRATED
EspironoIactone EspironoIactone
+
+
+
+ +
+
+
+
eta eta- -lockers. Fundamental in Heart Failure lockers. Fundamental in Heart Failure
Heart disease Heart disease
Risk Risk
Factors Factors
Asymptomatic Asymptomatic
LV Dysfunction LV Dysfunction
Symptoms Symptoms
NYHA NYHA - - IV IV
Symptoms Symptoms
NYHA II NYHA II- -III III
BN! BN!
Symptoms Symptoms
ECHO / LV dysfunction ECHO / LV dysfunction
? ?
HEART FAILURE S!ECTRUM HEART FAILURE S!ECTRUM
Inotropics Inotropics
Other strategies Other strategies
ACE ACE- -i i
Diuretics Diuretics
Y Y- -BIockers BIockers
EspironoIactone EspironoIactone
ControI of Hypertension ControI of Hypertension
Y Y- -BIockers BIockers
Secondary !revention Secondary !revention
Y Y- -BIockers BIockers
!revent RemodeIing !revent RemodeIing
Y Y- -BIockers BIockers
Last prescribed study drug dose in
reIation to initiation of therapy
CIBIS III
!rimary objectives
CIBIS III
!rimary objectives
W First primary objective:
- nitiation of monotherapy with bisoprololol followed by the addition
of enalapril (combination therapy) is comparable (non-inferior) to
initiation with enalapril in CHF patients in ,... ..-.
. . .,..... .... .,..` . ,
.
W Second primary objective (if first primary objective is met):
- ..... , ..., .. ..,.. . .,.
...... with enalapril in CHF patients (combined endpoint) at
end of study
CIBIS III
Secondary objectives
CIBIS III
Secondary objectives
W Secondary objectives
W ^.,.. , . .... .,.. at the end of monotherapy
phase
- Necessity of . ..... , . . . due to poor
control of CHF at the end of monotherapy phase
- Comparison of the individual components of the primary
endpoint at
the end of monotherapy and at study end (combination therapy)
- ^.. .. ~~ . at the end of monotherapy and at study
end (combination therapy)
- ^.,.. , , . ..... of both regimens
(P%C*
1
, incidence and type of AEs*
2
)
*
1
Permanent %reatment Cessation *
2
Adverse Events
CIBIS III
Main incIusion criteria
CIBIS III
Main incIusion criteria
W Male or female aged K .
W n- or outpatients with CHF of ~~
W Left ventricular ejection fraction -` A based on
echo- cardiography, determined within 3 months prior to
randomisation
W $.. ^ ... .. , ,... ... within the last 7
days prior to randomisation
W n case of diuretic treatment: drug and dosage to remain
unchanged within the last 7 days prior to randomisation
CIBIS III
Main excIusion criteria (study specific)
CIBIS III
Main excIusion criteria (study specific)
W Uncontrolled hypertension (SBP K 180 mmHg, DBP K 110 mmHg)
W Acute coronary syndrome (UAP, M) before randomisation (3
months)
W Prior (3 months) or planned P%CA or CAB
W Obstructive or restrictive cardiomyopathy
W Ongoing myocarditis
W Hemodynamically significant organic valvular disease requiring
surgery
W Previous heart transplant or currently awaiting heart transplant
surgery
W Congenital heart disease
W Stroke within one month prior to randomisation or stroke with
permanent neurological sequelae within 6 months prior to
randomisation
CIBIS III
Main excIusion criteria (study medication specific)
CIBIS III
Main excIusion criteria (study medication specific)
W Treatment with an ACE-inhibitor or an ARB or a beta-bIocker within 3 months prior
to randomisation
W Heart rate at rest < 60 bpm unIess a pacemaker is functioning
W Sitting systoIic bIood pressure < 100 mmHg at rest
W Hyponatremia < 130 mmoI/I
W HyperkaIemia > 5.5 mmoI/I
W Known stenosis of both renaI arteries
W AV bIock greater than 1st degree without a functioning pacemaker
W Chronic obstructive Iung disease which in the opinion of the investigator wouId
contraindicate bisoproIoI
W Hyper- or hypothyroidism not controIIed by treatment
W !heochromocytoma
W Significant renaI impairment (serum creatinine K 220 3moI / K 2.5 mg/dI)
W Significant hepatic impairment (ALAT or ASAT > 3 times the upper normaI Iimit)
W History of angioneurotic edema
W Mandatory medicaI indication for therapy with an ACE-inhibitor or a beta-bIocker
. . bIockers bIockers
2 2Over 13,000 patients evaIuated in pIacebo Over 13,000 patients evaIuated in pIacebo- -
controIIed cIinicaI triaIs controIIed cIinicaI triaIs
2 2Consistent improvement in cardiac function, Consistent improvement in cardiac function,
symptoms and cIinicaI status symptoms and cIinicaI status
2 2Decrease in aII Decrease in aII- -cause mortaIity by 30 cause mortaIity by 30- -35% 35%
( (p< p<0.0001) 0.0001)
2 2Decrease in combined risk of death and Decrease in combined risk of death and
hospitaIisation by 25 hospitaIisation by 25- -30% ( 30% (p< p<0.0001) 0.0001)