Symphatetic Overdrive in CHF : The Role of

Beta Blocker with Focus on Bisoprolol

Yose Ramda Ilhami
 CURICULUM VITAE
Name : Yose Ramda Ilhami
Date of birth : May, 15th 1985
Place of birth : Padang
Religion : Islam
Occupation : Emergency & Acute Cardiac Care Division of Cardiology & Vascular
Medicine of Medicall Faculty of Andalas University

EDUCATIONAL BACKGROUND
2010 : Medical faculty of Gajah Mada University, Indonesia
2014 : Department Cardiology & Vascular Medicine, School of Medicine University of
Andalas, Padang, Indonesia
 • Understanding chronic heart failure (CHF):
Definition, classification, diagnosis, risk
factors/comorbidities, epidemiology
• Pathophysiology of CHF – role of sympathetic overdrive
• CHF – therapeutic options particularly regarding

Overview sympathetic overdrive

• Beta-blockers in the treatment of CHF directed against
sympathetic overdrive
• Bisoprolol in the treatment of stable CHF associated with
sympathetic overdrive
• Summary
 Definition of heart failure
Heart failure can be defined as
è
“an abnormality of cardiac structure or function leading to failure of the heart to deliver oxygen at a rate
commensurate with the requirements of the metabolizing tissues, despite normal filling pressures (or
only at the expense of increased filling pressures).” 1

Clinical definition
Heart failure is a clinical syndrome with typical symptoms and signs resulting from an abnormality of cardiac
structure or function.2-4
È typical symptoms breathlessness, ankle swelling, and fatigue
è
typical signs fluid retention such as pulmonary congestion, elevated
jugular venous pressure, pulmonary crackles, peripheral edema

Many of the signs of (congestive) heart failure may resolve quickly with diuretic therapy 1

1. McMurray JJV, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur Heart J 2012;33:1787-847
2. Ponikowski P, Voors AA, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016;37:2129-200
3. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure. Circulation 2013;128:e240-e327
4. Metra M, Teerlink JR. Heart failure. Seminar. Lancet 2017;390:1981-95
 ACCF/AHA stages of heart failure classification 3

Comparison of ACCF/AHA stages of HF classification and NYHA functional classification 3

ACCF/AHA Stages of Heart Failure (HF) NYHA Functional Classification

A At high risk for HF but without structural

None
heart disease or symptoms of HF

B Structural heart disease but without I No limitation of physical activity. Ordinary physical activity does not cause
signs or symptoms of HF symptoms of HF.

C Structural heart disease with prior or I No limitation of physical activity. Ordinary physical activity does not cause
current symptoms of HF symptoms of HF.

II Slight limitation of physical activity. Comfortable at rest, but ordinary physical

activity results in symptoms of HF.

III Marked limitation of physical activity. Comfortable at rest, but less than ordinary
activity causes symptoms of HF.

IV Unable to carry on any physical activity without symptoms of HF, or symptoms

of HF at rest.

D Refractory HF requiring specialized IV Unable to carry on any physical activity without symptoms of HF, or symptoms
interventions of HF at rest.

ACCF = American College of Cardiology Foundation HF = Heart failure

AHA = American Heart Association NYHA = New York Heart Association

3. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure. Circulation 2013;128:e240-e327

contents
 Diagnosing heart failure1

Swollen limbs
Breathlessness Fatigue
Symptoms

Physical CLINICAL History (e.g.

examination other diseases)
Diagnosis

Heart ultrasound JUDGEMENT

Blood tests
imaging
Heart electrical
activity

“Not all patients with heart failure have the typical symptoms, “For most patients with HF, quality of life can be
and the same symptoms can be experienced by patients who dramatically improved by therapies that relieve
do not have heart failure.”2 symptoms.”2
Graph according to references 2

1. Krum H, Abraham WT. Heart failure. Lancet 2009;373:941-55

2. Ponikowski P, Anker SD, AlHabib KF, et al. Heart failure: preventing disease and death worldwide. ESC Heart Failure 2014;1:4-25
 Modifying risk factors or comorbidities to prevent or affect
prognosis of HF4-6
Myocardial
Coronary infarction Arrhythmias Sudden
thrombosis and loss of muscle death
Myocardial Neurohormon
ischemia al
activation
CHD
Remodelling

Atherosclerosis Ventricular
LVH Risk factors enlargement
• Hyperlipidemia CHF
HF = Heart failure
CVD = Cardiovascular disease
• Hypertension Death CHD = Coronary heart disease
CHF = Chronic heart failure
• Diabetes
LVH = Left ventricular hypertrophy
Graph adapted from reference 3 • Smoking
1. Dzau VJ, Braunwald E. Resolved and unresolved issues in the prevention and treatment of coronary artery disease: a workshop consensus statement. Am Heart J 1991;121:1244-63
2. Dzau VJ, Antman EM, Black HR, et al. The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes. Circulation 2006;114:2850-70
3. Willenheimer R, Erdmann E. Chairmen’s foreword: beta-blockade across the cardiovascular continuum – when and where to use? Eur Heart J Suppls 2009;11(Suppl A):A1-2
4. Metra M, Teerlink JR. Heart failure. Seminar. Lancet 2017; 390:1981-95
5. Krum H,, Abraham WT. Heart failure. Seminar. Lancet 2015;373:941-55
6. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure. Circulation 2013;128:e240-e327
 Common causes and risk factors for heart failure
Other heart High blood
Rhythm disorders Poor blood supply to lungs
disorders
pressure
Heart muscle Heart Lung Lung disease,
defects problems asthma,
problems
bronchitis,
Coronary heart High blood obstructed
Valve defects
disease pressure in lungs airways
Heart
failure
Anemia Diabetes Kidney disease
Failure to take
preventive Other medical
medication Lifestyle Obesity
conditions
Sleep-
Diet (excessive salt Alcohol or Side effects of disordered
or fluid intake) drug misuse medications
Infections breathing
Thyroid
Chagas disease Rheumatic fever disorders
Graph according to references 1

1. Ponikowski P, Anker SD, AlHabib KF, et al. Heart failure: preventing disease and death worldwide. ESC Heart Failure 2014;1:4-25
 Heart failure survival rates
Despite improvements in care over the past 20 years survival rates for patients admitted to a hospital with
heart failure remain poor across the globe.1

 2-17% of patients die while in a hospital

 17-45% of patients die within 1 year of admission
 the majority dies within 5 years of admission

The survival rates for HF are worse than for most cancers, e.g. those for bowel, breast or prostate cancer. 1

 Using data from a national registry in Sweden the following 5-year mortality rates were found:2
− all cancers on average: 58%
lung cancer: 83%, breast cancer: 23%
lung, colorectal, prostate, bladder are the most common forms of cancer representing 50% of all cancers
− heart failure: 59%

1. Ponikowski P, Anker SD, AlHabib KF, et al. Heart failure: preventing disease and death worldwide. ESC Heart Failure 2014;1:4-25
2. Stewart S, Ekman I, Ekman T, Odén A, Rosengren A. Population impact of heart failure and the most common forms of cancer. Circ Cardiovasc Qual Outcomes 2010;3:573-80
 Neurohormonal and compensatory mechanisms in the pathophysiology of heart failure 1

Poor ventricular function / myocardial damage

(e.g. post myocardial infarction, dilated cardiomyopathy)

Heart failure
Decreased stroke volume and cardiac output

Neurohormonal response

Activation of sympathetic system Renin angiotensin aldosterone system

• Vasoconstriction: increased sympathetic tone, angiotensin II, endothelins, impaired nitric oxide
release
• Sodium and fluid retention: increased vasopressin and aldosterone

Further stress on ventricular wall and dilatation (remodeling)

leading to worsening of ventricular function

Further heart failure

Graph adapted from reference 1

1. Jackson G, Gibbs CR, Davies MK, Lip GYH. ABC of heart failure. Pathophysiology. BMJ 2000;320:167-70
 Sympathetic activation in CHF1
Myocardial damage

Activation of sympathetic nervous system

Renin-angiotensin Increased heart rate

Vasoconstriction Direct cardiotoxicity
system and contractility

Fluid retention Increased wall stress

Increased myocardial oxygen demand

Myocardial hypertrophy Decreased contractility Myocyte damage

Graph adapted from reference 1

1. Jackson G, Gibbs CR, Davies MK, Lip GYH. ABC of heart failure. Pathophysiology. BMJ 2000;320:167-70
 Peripheral neural reflex interactions contribute to the
autonomic imbalance in HF1
Heart failure
Afferents Efferents

+
CNS Heart rate é
Arterial Parasympathetic é
chemoreceptors
- Ach
Arterial
baroreceptors
+
Cardiopulmonary NE é

baroreceptors -
NE é Adverse cardiac
Sympathetic é
effects
Pulmonary
baroreceptors -
é
E Na+ reabsorbtion é
+ é
NE
Muscle Renin é
metaboreceptors é Renalvascular
NE
resistance é
+
Renal nerves
Peripheral vascular
NE é resistance é
Ach = acetylcholine; CNS = central nervous system; E = epinephrine; Na+ = sodium; NE = norepinephrine

Graph adapted from reference 1

1. Floras JS, Ponikowski P. The sympathetic/parasympathetic imbalance in heart failure with reduced ejection fraction. Review. Eur Heart J 2015;36:1974-82
 Increased sympathetic activity (sympathetic overdrive) is associated with increased
heart rate and multiple cardiovascular risk factors 1,2

Sympathetic overactivity
 Hematocrit Increased heart rate

 Plasma volume
Arteriolar  O2 consumption,  Artery wall LV apoptosis
constriction ventricular arrhythmias stress Collagen fibrosis
Venoconstriction
 Muscle blood Endothelial
 Cardiac output LV stiffness
flow dysfunction

Hypertension Insulin resistance Obesity Atherosclerotic LV systolic

plaque dysfunction

Lipid abnormalities Inflammation

Coronary events Heart failure

Sudden death
Graph adapted from references 1-2

1. Adapted from Palatini P. Heart rate and the cardiometabolic risk. Curr Hypertens Rep. 2013;15:253–59.
2. Heusch G. Heart rate and heart failure: not a simple relationship. Circ J. 2011;75:229-36.
 Sympathetic overdrive plays a key role in the pathophysiology of
cardiovascular disease including heart failure1
 Sympathetic nervous activity

Neural release of norepinephrine1

1
Beta1 receptor stimulation 1
Beta1 receptor stimulation
Mechanical
vascular damage
• Pulsatile stress on
vascular system1  Renin release1
 Heart rate1 • Augment atherosclerosis1  Angiotensin1
 Heart rate variability1 • Plaque rupture1  Blood pressure1
 Contractility1 • Risk of cardiac ischemia1  Left ventricular hypertrophy1
 Heart failure1

Graph according to reference 1

1. Egan BM, Basile J, Chilton RJ et al. Cardioprotection: the role of β-blocker therapy. J Clin Hypertens. 2005;7(7):409–16.
 Pathophysiological effects of heart rate within the cardiovascular disease continuum 1
Plaque stability â
Plaque rupture
Oxigene consumption á and thrombosis
Diastole length â
Ischemia Infarction
Coronary perfusion â

Loss of
Coronary heart contractility
disease Heart
rate Dilatation and
„Remodeling“
Artherosclerosis Cardiac hypertrophy é

Oxidative stress á
Heart
Endothelial dysfunction
failure
Tachycardiomyopathy é
Arterial stiffness á
End-stage Oxygen demand á
Risk factors
Microalbuminuria á heart failure Ventricular efficiency â
Ventricular relaxation â

”Increased resting heart rate multiplies risk and interferes at all stages of the cardiovascular disease continuum …” 1
Graph adapted from reference 1

1. Custodis F, Reil JC, Laufs U, Böhm M. Heart rate: A global target for cardiovascular disease and therapy along the cardiovascular disease continuum. J Cardiol
2013;62:183-87
 Cumulative hazard for incident heart failure split by baseline
resting heart rate quartile in the MESA study 1
Nelson-Aalen cumulative hazard estimates
0.04

HR ≥ 70
Cumulative hazard for incident HF

0.03

63 ≤ HR ≤ 69

57 ≤ HR ≤ 62
0.02

HR ≤ 56
0.01

HR = heart rate
HF = Heart Failure
0.00

0 1000 2000 3000 4000

Analysis time
è For the highest resting HR quartile, a more than 3-fold greater adjusted relative risk for incident HF was observed.
è Every increase of 1 bpm increased relative risk for incident heart failure by 4%.
Graph adapted from reference 1

1. Opdahl A, Venkatesh BA, Fernandes VRS, et al. Resting heart rate as predictor for left ventricular dysfunction and heart failure. MESA (Multi- Ethnic Study of
Atherosclerosis). J Am Coll Cardiol 2014;63:1182-89
 HR as a prognostic risk factor in patients with coronary artery disease
and left ventricular systolic dysfunction1
Heart rate ≥ 70 bpm
Subanalysis of the placebo group in the BEAUTIFUL study 1 Heart rate < 70 bpm

15 15
Percentage with event CV death HF hospitalization
P = 0.0041 P < 0.0001
10 10

5 5

Years Years
0 0
Number at risk 0.5 1.0 1.5 2.0 0.5 1.0 1.5 2.0
HR ≥ 70 bpm 2693 2580 2405 1537 639 2693 2480 2265 1436 593
HR< 70 bpm 2745 2670 2510 1578 722 2745 2628 2445 1516 683

10 8
Hospitalization for MI Coronary revascularization
Percentage with event

P = 0.0066 6 P = 0.037

5 4

2
Years Years
0 0
Number at risk 0.5 1.0 1.5 2.0 0.5 1.0 1.5 2.0
HR ≥ 70 bpm 2693 2548 2347 1493 617 2693 2552 2347 1483 624
HR < 70 bpm 2745 2653 2467 1542 703 2745 2649 2463 1537 703

Graph adapted from reference 1

1. Fox K, Ford I, Steg PG, et al., on behalf of the BEAUTIFUL investigators. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular
systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet 2008;372:817-21
Neurohormonal antagonists are the backbone of medical
treatment of HF3

Three neurohumoral antagonists*

 an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB),
 a beta-blocker (BB), and
 a mineralocorticoid receptor antagonist (MRA)
− have been shown to improve survival in patients with HFrEF
− are recommended for every patient with HFrEF unless contraindicated
HFrEF =or not
Heart failure with reduced ejection fraction

tolerated.1, 2

There is consensus that

 ACEIs and BBs are complementary and

 should both be started together as soon as possible after diagnosis of HFrEF is made.
1, 2

1. McMurray JJV, Adamopoulos S, Anker SD, et al. for the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the ESC. Developed in
collaboration with the HFA of the ESC. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur Heart J 2012;33:1787-1847
2. Ponikowski P, Voors AA, Anker SD, et al. for the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC).
Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart
failure. Eur Heart J 2016;37:2129-2200
3. Metra M, Teerlink JR. Heart failure. Seminar. Lancet 2017;390:1981-95
Therapeutic algorithm for a patient with symptomatic HFrEF 1
 Pharmacotherapy options for elevated heart rate1-9

Elevated heart rate

If channel inhibitor
Non-dihydropyridine
calcium channel blockers (ivabradine)2,5,8,9
(verapamil, diltiazem)1,3,6 Beta blockers
(without ISA, e.g. bisoprolol)4 Specific action on the
Use contraindicated in If channel that controls
heart failure because both HR control via actions on SO4
the pacemaker activity
drugs have been shown to be in sinoatrial node
unsafe in HFrEF7,8
SO = Sympathetic overdrive
HFrEF = Heart failure with reduced ejection fraction ISA = Intrinsic sympathomimetic activity

Graph according to references 1,2,4-6,8,9

1. Palatini P, Benetos A, Julius S. Impact of increased heart rate on clinical outcomes in hypertension: implications for antihypertensive drug therapy. Drugs 2006;66(2):133–44
2. Cook S, Togni M, Schaub MC, Wenaweser P, Hess OM. High heart rate: a cardiovascular risk factor? Eur Heart J 2006;27:2387-93
3. Gupta D. A review on calcium channel & its blockers. Int J Pharm Pharm Sci 2012;4:3842
4. Egan BM, Basile J, Chilton RJ et al. Cardioprotection: the role of β-blocker therapy. J Clin Hypertens 2005;7(7):409–16
5. DiFrancesco D, Camm JA. Heart rate lowering by specific and selective I(f) current inhibition with ivabradine: …. Drugs 2004;64:1757–65
6. Habib GB. Reappraisal of heart rate as a risk factor in the general population. Eur Heart J Suppls 1999;1(Suppl H):H2-H10
7. Montalescot G, Sechtem U, Achenbach S et al. 2013 ESC guidelines on the management of stable coronary artery disease. Eur Heart J 2013;34:2949-3003
8. Ponikowski P et al. for the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Eur Heart J
2016;37:2129-2200
9. Kapoor JR, Heidenreich PA. Role of heart rate as a marker and mediator of poor outcome for patients with heart failure. Curr Heart Fail Rep 2012;9:133-38
 cardiovascular continuum2
Beta-blockers can intervene at many points in the
cardiovascular
Myocardial continuum1
infarction
Coronary Arrhythmias Sudden
thrombosis and loss of muscle death

Neurohormonal
Myocardial activation
ischemia

Sympathetic
CHD overdrive Remodelling
---------------
Beta-blockers
Atherosclerosis Ventricular
LVH enlargement

Risk factors
CHF
• Hyperlipidemia LVH = Left ventricular hypertrophy)
Death CHD = Coronary heart disease
• Hypertension CHF = Chronic heart failure

• Diabetes
• Smoking
1. Willenheimer R, Erdmann E. Beta-blockade across the cardiovascular continuum – when and where to use? Eur Heart J Suppls 2009;11(Suppl A):A1–2
2. Grassi G, Seravelle G, Mancia G. Sympathetic activation in cardiovascular disease: evidence, clinical impact and therapeutic implications. Review. Eur J Clin Invest
2015;45(12):1367–75
 Mechanisms of benefit of beta-blockers in heart failure1-4
Reduction of sympathetic tone3,4
 Increase in vagal tone
 Improved autonomic balance/heart rate
variability
 Reduced sudden death
Antiarrhythmic activity1-4
Reduced sudden death
Up-regulation of cardiac β1-
receptors1-4
Modification of remodelling2-4
 Reverse remodeling
 Reduced LV volumes
 Increased LV ejection fraction
Antagonism of stimulatory β1-
receptor autoantibodies2-4
Heart rate reduction1-4
 Reduced cardiac work and oxygen
requirement
 Prolonged diastolic coronary filling time
Inhibition of the renin-angiotensin
system1-4
 Reduced renin release
Inhibition of catecholamine-induced
necrosis/apoptosis/ inflammation
(reduced cytokines)2-4
Restoration of Ca2+ release/cardiac ryanodine
receptor function2
 Probably linked to reduced sudden death risk
 Blockade of adrenergic receptors by BBs investigated in CHF 1-
4

Sympathetic activation
Noradrenaline = norepinephrine (NE)
(noradrenaline)

β1 β2 1
receptors receptors receptors
Bisoprolol
Nebivolol
Metoprolol

Bucindolol Additional clinical benefits from

blocking β2- and  1-receptors are

Carvedilol not to be expected.1,2,4

Detrimental effects
Benefits are mediated by blockade of β1-receptors1,2,4
1. Cruickshank JM. Are we misunderstanding beta-blockers. Review. Int J Cardiol 2007;120:10–27
2. Bristow MR, Feldman AM, Adams KF, JR, Goldstein S. Selective versus nonselective -blockade for heart failure therapy: are there lessons to be learned from the COMET trial? J Card Fail 2003;9:444–53
3. Cruickshank J. Expert Opinion. Nebivolol, a third generation beta-blocker. J Symptons Signs 2014;5(3):380-90
4. Waagstein F. Beta-blockers in congestive heart failure: the evolution of a new treatment concept – mechanisms of action and clinical implications. J Clin Basic Cardiol 2002;5:215–23
 HF guidelines recommend beta-blockers as standard
therapy
ESC 2016 HF Guidelines 1

recommend a beta-blocker
• bisoprolol
• carvedilol
• metoprolol succinate (CR/XL)
• nebivolol*
in addition to an ACE inhibitor (or ARB if ACE inhibitor not tolerated), for stable, symptomatic HFrEF patients
(symptomatic = NYHA II-IV, HFrEF = LVEF <40%) to reduce the risk of HF hospitalization and death.’ (I-A)
*Indicates a treatment not shown to reduce cardiovascular or all-cause mortality in patients with heart failure (or shown to be non-inferior to a treatment
that does). Nebivolol indicated to elderly ≥70 years only.

ACCF/AHA 2013 HF Guidelines2

recommend the use of 1 of the 3 beta-blockers proven to reduce mortality
• bisoprolol
• carvedilol
• sustained release metoprolol succinate
for all patients with current or prior symptoms of HFrEF, unless contraindicated, to reduce morbidity and
mortality. (I-A) ( do not recommend nebivolol)2
 Only beta-blockers proven to reduce mortality should be used for CHF treatment! 2

1. Ponikowski P, Voors AA, Anker SD, et al. for the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the
special contribution of the Heart Failure Association (HFA) of the ESC. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016;37:2129-2200
2. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task
Force on Practice Guidelines. Circulation 2013;128:e240-e327
 Beta-blockers, particularly those without ISA,
effectively lower heart rate in patients with CHF 1

Study  -Blocker Baseline HR HR on Rx D HR

CIBIS8 Bisoprolol 83 67 -16

CIBIS II9-11 Bisoprolol 80 69 -11

MERIT-HF12 Metoprolol succinate 82 68 -14

COMET13 Metoprolol tartrate 81 69 -12

US Carvedilol14 Carvedilol 84 71 -13

COPERNICUS15 Carvedilol 83 70.5 -12.5

SENIORS16 Nebivolol 79 69 -10

BEST17 Bucindolol 82 73 -9

1. Egan BM, Basile J, Chilton RJ, et al. Cardioprotection: the role of -blocker therapy. J Clin Hypertens 2005;7:409-16
 Why beta1-selectivity is important in the treatment of
cardiovascular diseases associated with sympathetic overdrive 1,2
Primary distribution of beta-receptors and effects of stimulation 1

Beta1 receptors Beta2 receptors

 Contractility and heart rate1
Myocardium  Myocardial  Myocardial
necrosis/apoptosis1 necrosis/apoptosis1

Bronchial smooth muscle  Bronchodilation1

Blood vessel smooth

muscle  Vasodilation1

Kidney  Renin release1

è Highly selective beta1-blockers inhibit sympathetic activity in the heart and kidney, preserve beta2-mediated
vasodilation, and reduce the risk of adverse effects mediated by blockade of beta2 receptors in the lungs and peripheral
tissues2

1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011
2. Egan BM, Basile J, Chilton RJ et al. Cardioprotection: the role of beta-blocker therapy. J Clin Hypertens. 2005;7(7):409–16.
 Beta1-selectivity of different beta-blockers: bisoprolol is a highly selective
beta1-blocker1-5
Ratio of constants of inhibition (ci/β1 to ci/β2)
Bisoprolol
1:75

Atenolol Betaxolol
1:35 1:35
Increasing beta1-selectivity Metoprolol
1:20
No selectivity
1.8:1
Propranolol
Increasing beta2-selectivity

300:1 Comparisons between the beta1-selectivity of bisoprolol

ICI 118,551 with that of nebivolol have reported inconsistent results.4,5

Graph adapted from reference 1

1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011, Fig. 1-5
2. Wellstein A, Palm D, Belz G. Affinity and selectivity of the β-adrenoceptor antagonists in vitro. J Cardiovasc Pharmacol. 1986; 8 (Suppl. 11): 36–40.
3. Wellstein A, Palm D, Betz GG et al. Reduction of exercise tachycardia in man after propranolol and bisoprolol in comparison to beta-adrenoceptor
occupancy. Eur Heart J. 1987; 8 (Suppl. M): 3–8.
4. Maack C, Tyroller S, Schnabel P et al. Characterization of beta1-selectivity, adrenoceptor-Gs-protein interaction and inverse agonism of nebivolol in human
myocardium. Br J Pharmacol. 2001;132:1817–26.
5. Brixius K, Bundkirchen A, Bölck B et al. Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in human
 CIBIS II: Survival1
1.0

Bisoprolol: 156 deaths (n=1327)

0.8
Survival

è 34% reduction in
all-cause mortality
Placebo: 228 deaths (n=1320) with bisoprolol

0.6 (HR 0.66, 95% CI 0.54081) log rank test, p<0.0001

0
0 200 400 600 800
Time after Inclusion (Days)

Graph adapted from reference 1

1. CIBIS II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:913
 CIBIS II - Main results at a
glance1
• 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)

1. CIBIS II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:913
 • The activation of neurohormonal systems
(sympathetic nervous system, renin-angiotensin
system) and compensatory mechanisms play
the principal role in the pathophysiology of
heart failure

Take Home • β1-receptor antagonist are cornerstone in HF

treatment by their action in many phase of
Message cardiovascular continuum
• Bisoprolol (Concor®) is a highly sensitive β1-
receptor antagonist and very effective
treatment for HF patient and even in specific
and high risk population