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Bisoprolol in Heart Failure

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Development Of Neurohormonal
Antagonists In Treatment Of CHF
AIRE, TRACE CIBIS III
SOLVD
Landmark Trials V-HeFT II SAVE, ISIS-4 SENIORS
COMET
COPERNICUS
CONSENSUS
MERIT-HF
Recognition of CIBIS II
Potential benefit: neurohormonal
vasodilatation activation USCP

CIBIS I
Captopril 1978–80; Swedberg et al.
1975; Sweden Lancet; Br Heart J MDC
Propranolol Waagstein et al.

BB contraindicated:
neg. inotropic effects

1960 1970 1980 1990 2000 2005


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How Well Do Β-blockers Work In HF ?
• ± 34 % reduction in mortality
• Suggested mechanisms also include
reduce remodeling
• β-Blockers may be beneficial
through resensitization of the
down-regulated receptor, improving
myocardial contractility.
• Acts primarily by inhibiting the
sympathetic nervous system.
• Increases beta receptor
sensitivity (up regulation).
• Anti-arrhythmic properties.
• Anti-oxidant properties

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Cardiac Insufficiency Bisoprolol
Studies - The CIBIS Story
1994: CIBIS I study
641 patients NYHA III-IV; study period: 03/1989-02/1993, bisoprolol 1.25 – 5 mg
on top of standard therapy (diuretic + ACEI)  – 20% mortality (p=0.22),
– 32% heart failure hospitalization (p<0.01)

1999: CIBIS II study


2647 patients NYHA III-IV; study period: 11/1995-03/1998, bisoprolol 1.25 – 10
mg on top of
standard therapy (diuretic + ACEI)
 CHF a former contraindication turned into an indication

 2005: CIBIS III study


1010 patients NYHA II-III; study period: 10/2002-05/2005, bisoprolol-first 1.25-
10 mg o.d. vs. enalapril-first 2.5-10 mg b.i.d. bisoprolol-first was significantly
non-inferior to enalapril-first (ITT) with regard to combined primary endpoint
(all-cause mortality and hospitalization) (time-to-event analysis)
 46% significant sudden death reduction during first year (biso-first vs enalapril-
first)
 Bisoprolol another option* for starting CHF therapy
* Option to start CHF therapy with a beta-blocker (bisoprolol) instead of an ACE
inhibitor approved in only some countries.  off-label use in the other countries !
IDN/NONCMCGM/1018/0011
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CIBIS I: Main Results
• Reduction of mortality with bisoprolol in patients ...
... in total (n=641) – 20% p=0.22
... without myocardial infarction – 47% p=0.01
... with dilated cardiomyopathy – 53% p=0.01
... with a ventricular rate of over 80 beats/minute – 42% p<0.05
• Reduction by one NYHA class in patients receiving ...
... bisoprolol 21% p=0.04
... placebo 15%

• Reduction in heart failure decompensation requiring – 32% p<0.01


hospitalisation
• Tolerability/safety of bisoprolol comparable with placebo (no
significant difference in premature dicontinuations)

Lechat Ph at the CIBIS investigators’ meeting at the Journées Européennes de la Société Française de Cardiologie, Paris, 1994

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Conclusion of the authors:
“The beneficial effects of bisoprolol on mortality and hospitalization for worsening
heart-failure were not modified by baseline eGFRBSA. Renal impairment should not
prevent the use of bisoprolol in patients with HF.”

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CIBIS II - Main results at a glance

In the bisoprolol-treated group of patients there was a reduction in

• All-cause mortality (independent of etiology) by 34% (p<0.0001)

• Sudden death by 44% (p<0.0011)

• All-cause hospital admissions by 20% (p<0.0006)

• Hospital admissions due to worsening heart


failure by 36% (p<0.0001)

Permanent treatment withdrawals similar


in both treatment groups 15% (p=0.98)

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CIBIS II: Bisoprolol reduces mortality in CHF
patients at all tolerated dose levels
1
Biso 1.25–3.75 mg/d, n=434
1 Biso 5–7.5 mg/d, n=328
0.9
Survival Probability

0.9
0.8

Survival Probability
0.8
0.7
HR 0.66 (0.48–0.92) 0.7
0.6
0.6 HR 0.33 (0.21–0.51)
0.5
Biso low dose 0.5
0.4 Plac low dose Biso moderate dose
Months 0.4
0.3 Plac moderate dose
Months
0 5 10 15 20 25 0.3
0 5 10 15 20 25
1 Biso 10 mg/d, n=565
its withdrawal 0.9
Survival Probability

0.8
increases risk of
mortality  0.7
HR 0.59 (0.40-0.89)
Better a low 0.6 Simon T et al. Eur Heart J
0.5 2003;24:552–59
dose than no Biso high dose
0.4
dose! Plac high dose
Months
0.3
0 5 10 15 20 25
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CIBIS III - Cardiac Insufficiency
Bisoprolol Study III

Effect On Survival And Hospitalisation


Of Initiation Of Treatment For Chronic Heart Failure
With Bisoprolol Followed By Enalapril
Compared To The Opposite Sequence

• Investigator-initiated, Multicentre, Prospective, Randomised,


Open-label, Blinded Endpoint Evaluation (Probe) Trial
• 1,010 Patients (NYHA II+III), 128 Centres,
20 Countries (Europe, Tunisia, Australia)
• Study Period: 10/2002–05/2005

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CIBIS III:
Worsening Heart Failure Throughout Study (ITT)
Requiring Hospitalisation or Occurring in Hospital:
Sudden Death – First Year
46% significant
reduction of SD

• Initiating CHF treatment with bisoprolol as effective and well-tolerated


as initiating treatment with enalapril
• Bisoprolol-first strategy  trend to improved early survival

• Bisoprolol as another option for starting CHF therapy


• More patients to benefit from early beta-blockade
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CIBIS-ELD study

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CIBIS-ELD: results

• Primary endpoint
• Tolerability, defined as reaching and maintaining guideline-
recommended target doses after 12 weeks of treatment

• None of the BBs was superior with regard to tolerability


(p=0.64):
➢ bisoprolol: 24% (95% CI 20-28) reached endpoint
➢ carvedilol: 25% (95% CI 21-29) reached endpoint

• Overall, 55% of patients tolerated at least half of the target


dose.
• Mean daily doses reached at follow-up were:
▪ bisoprolol 5,0 mg
▪ carvedilol: 23.9 mg in patients ≤85 kg (47.7 mg in patients >85 kg)

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CIBIS-ELD: results

Bisoprolol
induced
➢ a greater reduction of heart rate (adjusted mean difference 2.1 bpm, 95%
CI 0.5-3.6; p=0.008)
➢ more bradycardic adverse events (16% vs. 11%; p=0.02)
➢ more fatigue/drowsiness adverse events (11% vs. 5%; p=0.003)

Carvedilol
led to
➢ a reduction of forced expiratory volume (FEV1; adjusted mean difference
50 ml, 95% CI 4-95; p=0.003
➢ more pulmonary adverse events (10% vs. 4%; p<0.001)
➢ more anemia adverse events (12% vs. 7%; p<0.01)

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CIBIS-ELD:
Conclusion and clinical
implications
• There was no difference in achieved doses and tolerability to
target doses between bisoprolol and carvedilol in elderly
patients with heart failure, although the patterns of adverse
effects differed.

• With both agents, it appears that clinicians should follow an


individualized, slower, titration scheme.

• For patients with low resting heart rates, physicians might


prefer prescription of carvedilol, and for patients with lung
disease, the favourable beta-blocker might be bisoprolol.

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Safety profile of bisoprolol

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Bisoprolol: Beta1-selectivity results in minimal effects on lung
function in patients with stable angina pectoris and chronic
obstructive lung disease1,2
9
AWR (cm H2O/L/s)

b=before dosing
7 N=12
Mean ± SEM
Airway resistance (AWR)
90 Heart rate (HR)
HR (beats/min)

70

50
b 2 4 8 24 b 2 4 8 24 b 2 4 8 24
1 3 6 12 1 3 6 12 1 3 6 12

IDN/CONCO/0318/0011
Placebo Bisoprolol 20 mg Atenolol 100 mg

Graph adapted from reference 1 For complete contraindications, warnings and precautions for use please refer to the abbreviated product information at the end of this presentation.

1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011, Fig. 1-8

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2. Dorow P, Bethge H, Tönnesmann U. Effects of single oral doses of bisoprolol and atenolol on airway function in nonasthmatic chronic obstructive lung disease
and angina pectoris. Eur J Clin Pharmacol. 1986;31:143–7.
IDN/NONCMCGM/1018/0011
Bisoprolol: Beta1-selectivity results in minimal effects on
airways resistance in asthmatic hypertensive patients1,2
1.6 *
N=12
Mean ± SEM
1.2 *p<0.05 vs. placebo2
Change in AWR (cm H2O/L/s)

0.8

IDN/CONCO/0318/0011
0.4

– 0.4 Airway resistance (AWR)

– 0.8
10 mg 20 mg 100 mg
Placebo Bisoprolol Atenolol
Graph adapted from reference 1

For complete contraindications, warnings and precautions for use please refer to the abbreviated product information at the end of this presentation.

1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011, Fig. 6-9

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2. Chatterjee SS. The cardioselective and hypotensive effects of bisoprolol in hypertensive asthmatics. J Cardiovasc Pharmacol. 1986;8(Suppl 11):S74–S77.

IDN/NONCMCGM/1018/0011
Bisoprolol has minimal effects on
lipids and glucose1,2
Cholesterol (mg/dL) Triglycerides (mg/dL) *
**p<0.05 vs. placebo
260 250
220
200
180
150
140
100 100
Initial value After 2 weeks of After 2 weeks of Initial value After 2 weeks of After 2 weeks of
bisoprolol 10 mg placebo bisoprolol 10 mg placebo
daily daily

*
Glucose (mg/dL) * HbA1 (%)
180 10
160 9
140 8
120 7
100 6
Initial value After 2 weeks of After 2 weeks of Initial value After 2 weeks of After 2 weeks of
bisoprolol 10 mg placebo bisoprolol 10 mg placebo
daily daily

Graph adapted from reference 1 For complete contraindications, warnings and precautions for use please refer to the abbreviated product information at the e

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1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011, Fig. 6-13
2. Janka HU, Ziegler AG, Disselhoff G et al. Influence of bisoprolol on blood glucose, glucosuria, and haemoglobin A1 in noninsulin-dependent diabetics.
J Cardiovasc Pharmacol. 1986;8(Suppl 11):S96–S99.
IDN/NONCMCGM/1018/0011
Bisoprolol: Beta1-selectivity and lipid
metabolism during long-term therapy1-3
+10
% change in plasma HDL-cholesterol

Mepindolol 10 mg/day (n=16)


0
Bisoprolol 10 mg/day (n=17)

-10 Propranolol 160 mg/day (n=15


** ** ** * Atenolol 100 mg/day (n=22)
** **
-20
** **
**
-30 ** **

-40

6 12 18 24 30 36 months
Graph adapted from reference 1

*p<0.05
**p<0.01 vs. baseline

For complete contraindications, warnings and precautions for use please refer to the abbreviated product information at the end of this presentation.

1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011, Fig. 1-9 and Fig. 6-14
2. Fogari R, Zoppi A, Tettamanti F, et al. ß-blocker effects on plasma lipids in antihypertensive therapy: importance of the duration of treatment and the lipid status
before treatment. J Cardiovasc Pharmacol. 1990;16(Suppl 5):S76–S80.
3. Fogari R, Zoppi A. The clinical benefits of β1-selectivity. Rev Contemp Pharmacother. 1997;8:45–54.
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Bisoprolol has minimal effect on male sexual
function1-3
5.0%
Prevalence of overall sexual dysfunction (%)

4.0%
3.9%

3.0%
2.9%

2.0%
2.1%
1.8%
1.0%

0.0%
Placebo Enalapril Amlodipine Bisoprolol
5-40 mg/day 2.5-10 mg/day 5 mg/day
For complete contraindications, warnings and precautions for use please refer to the abbreviated product information at the end
of this presentation.
1. Prisant LM, Weir MR, Frishman WH et al. Self reported sexual dysfunction in men and women treated with bisoprolol, hydrochlorothiazide, enalapril, amlodipine),
placebo or bisoprolol/hydrochlorothiazide. J Clin Hypertens. 1999;1:22-26.
2. Broekman CPM , Haensel SM, van de Ven LLM et al. Bisoprolol and hypertension: Effects on sexual functioning in men. J Sex Marital Ther. 1992;18(4):325-31.
3. Erdmann E. Safety and tolerability of beta-blockers: prejudices and reality. Eur Heart J Suppls. 2009;11(Suppl A):A21-A25.

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Problems

• Beta Blocker Still Underuse.

• Lack Of Awareness To Overcome The Adverse


Effect.

• The Naive To Initiate And Uptitrate Beta


Blocker In Heart Failure.

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IDN/NONCMCGM/1018/0011
Medications Received –
Beta Blockers
100
90
80
70
60 others
50 metoprolol
40 bisoprolol
30 carvedilol
20 no BB
10 ±30%
0
prior during discharge prior during discharge
(2011) (2011) (2011) (2012) (2012) (2012)

BB less prescribed upon discharge?

NCCHK Registry of Heart Failure. Merck


IDN/NONCMCGM/1018/0011
Beta Blocker in Asia

Beta Blocker in Asia 10-50%


Malaysia (10%), Japan (50%)

Guo Y, et al. Current Cardiology Reviews, 2013, 9, 112-122 Merck


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Are We On Target Dose ?

NCCHK Registry of Heart Failure. Siswanto BB, 2011


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Achievement Of Target Dose
In Beta-blocker Trials
Patients reaching
target dose

CIBIS II (bisoprolol 10 mg o.d.) 42%


MERIT-HF (metoprolol 200 mg o.d.) 64%
COPERNICUS (carvedilol 25 mg b.i.d.) 65%

SENIORS (nebivolol 10 mg o.d.) 68%

CIBIS II Investigators & Committees. Lancet 1999; 353:9-13; MERIT HF Study group.

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Lancet 1999; 353:2001-7; Packer M, et al. N Eng J Med 2001; 344(22):1651-8;
Flather MD. EHJ 2005; 26:215-5.
IDN/NONCMCGM/1018/0011
Adherence to CHF Treatment Guidelines
100
88%
82%
80
63%
Adherence (%)

58%
60

40

20

0
Overall ACE-I Diuretics beta-blockers

The Mahler Survey Investigation, European Heart Journal, 2005 Merck


IDN/NONCMCGM/1018/0011
The Importance Of Adhering To
Guidelines
1.0
cardiovascular hospitalisations
Estimated probability of

0.9

0.8
Low adherence (0-33%)

0.7 Middle adherence (50-67%)

High adherence (100%)


0.6

Log rank test: p=0.002

0.5
0 20 40 60 80 100 120 140 160 180

Days

The Mahler Survey Investigation, European Heart Journal, 2005 Merck


IDN/NONCMCGM/1018/0011
Challenges In Initiating
Beta Blocker

Initiation Of Treatment With A Beta Blocker


May Produce 4 Types Of Adverse Reactions
That Require Attention And Management:

• fluid retention and worsening HF


• Fatigue
• bradycardia or heart block
• hypotension

The Mahler Survey Investigation, European Heart Journal, 2005 Merck


IDN/NONCMCGM/1018/0011
Overcome The Challenges!!!
Fluid retention and worsening HF
Occurrence of fluid retention or worsening HF is not
generally are as on for the permanent withdrawal of
treatment.
Euvolemic state.
Fatigue
Multifactorial and is perhaps the hardest symptom to
address with confidence.
Other causes of fatigue should be considered, including
sleep apnea, over diuresis, or depression.

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Yancy et al. 2013. JACC:e147–239.
ESC Acute and Chronic Heart Failure. 2012.
IDN/NONCMCGM/1018/0011
Overcome The Challenges!!!
Bradycardia or heart block
▪ECG to exclude heart block
▪Consider pacemaker support if severe bradycardia, AV block or SSS early after
starting
▪Review : need, reduction or discontinuing other heart rate slowing drugs e.G
digoxin, amiodarone, diltiazem
▪Reduce dose ( discontinuation rarely necessary)

Hypotension
Administer the β-blocker and acei at different times.
Reduce/stop other agents that reduce bp (nitrate, ccbs).
May also resolve after a decrease in the dose of diuretics in patients who are
volume depleted.
If accompanied by clinical evidence of hypoperfusion, should be decreased or
discontinued.

Yancy et al. 2013. JACC:e147–239.

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ESC Acute and Chronic Heart Failure
The Mahler Survey Investigation, European Heart Journal, 2005
IDN/NONCMCGM/1018/0011
Lee HY, Baek SH. Circ J 2016; 80: 565-571 Merck
IDN/NONCMCGM/1018/0011
Summary
• CHF Still Becomes Major Health Problem Worldwide
• Guidelines Publicized The Importance Of Beta Blocker On Therapeutic
Regiment Of CHF (Class 1A)
• Beta Blocker Therapy Still Underuse, Both Globally And In Indonesia,
Because The Concern Of Adverse Effects After Initiation
• Always Consider Adding Β-blocker To Standard Treatment For HF With
Impaired Systolic Function, Regardless Of Severity
• Do Not With-hold From Patients With Comorbidities (COPD, DM, PAD)
• Avoid In Total AV Block, Severe Poorly Controlled Asthma, And Critical
Limb Ischaemia
• Use Drug Licensed For CHF : Bisoprolol, Carvedilol, Metoprolol, Nebivolol
• Start With Small Dose, Titrate Slowly Every 2 Weeks

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IDN/NONCMCGM/1018/0011
Summary
• Aim to achieve recommended target dose, but accept the
maximum tolerated dose
• Check standing and sitting BP and heart rate, bradycardia in
the absence of symptoms does not require dose reduction
• Try not to stop the β-blocker if the HF deteriorates, try to
adjust other drugs to regain control of symptoms and fluid
balance
• In patients who also have asthma or COPD, monitor
symptoms and peak expiratory flow rates closely

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THANK YOU

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