Sympathetic Overdrive In

Hypertension:
The Role of Beta-
Blockers with Focused
on Bisoprolol
Akhtar Fajar Muzakkir
 Sympathetic Overdrive In Hypertension:
The Role of Beta-Blockers with
Focused on Bisoprolol

Akhtar Fajar Muzakkir

 Curriculum Vitae
Akhtar Fajar Muzakkir, MD, FIHA
PERSONAL PROFILE
Full Name : Akhtar Fajar Muzakkir
Place, Date of Birth : Makassar, 25 May 1982
Gender : Male
Marital Status : Married, 2 children
Spouse Name : Melda Warliani, MD, SpKFR
Address : Jl. Sunu Kompleks UNHAS Blok A7, Makassar, 90213
South Sulawesi, Indonesia
Phone/ Mobile : +62 411 453453 / +62 811462710
Email address : akhtarfajarmuzakkir@gmail.com
Current Workplace :
- Department of Cardiology and Vascular Medicine, Faculty of Medicine,
University of Hasanuddin, Makassar, Indonesia
- Pusat Jantung Terpadu (Cardiac Centre), Dr. Wahidin Sudirohusodo
National General Hospital
Workplace address : Jl. Perintis Kemerdekaan Km 10 Tamalanrea, Makassar, Indonesia
Workplace phone /fax: +62 411 586 010 / +62 411 586297; cardiac_mks@yahoo.com
 Curriculum Vitae
Akhtar Fajar Muzakkir, MD, FIHA
FORMAL EDUCATION
• 2017-2018 :Postgraduate Subspecialist/Fellowship Programme in Interventional Cardiology and Intensive & Acute Cardiac Care, National
• Cardiovascular Centre Harapan Kita, Jakarta, Indonesia
• 2009 – 2015 :Postgraduate, Resident Doctor/Specialist in Cardiology and Vascular Medicine, Dr. Soetomo General Hospital, Faculty of
• Medicine, University of Airlangga, Surabaya, Indonesia
• 2000 – 2006 : Undergraduate, Faculty of Medicine, University of Hasanuddin, Makassar, Indonesia
• 1997 – 2000 : High School, SMA Negeri 5, Makassar, Indonesia
• 1994 – 1997 : Junior High School, SMP Swasta Nusantara, Makassar, Indonesia
• 1989 – 1994 : Elementary School, SD Swasta Nusantara, Makassar, Indonesia

NON-FORMAL EDUCATION
• Erasmus+ HEALTH-I Project in Clinical Epidemiology (2018-now)
• Training in Radiation Protection and Safety for Interventional Cardiologist, BAPETEN (Badan Pengawas Tenaga Nuklir), Jakarta, Indonesia (2018)
• Training of Trainer (TOT) Cardiocerebrovascular Disease Prevention in Primary Health Care , Direktorat Pelayanan Kesehatan Rujukan Kementerian
Kesehatan RI (2018)
• ROVUS Lab. (Rotablator and IVUS Course), National Heart Centre Singapore (2018)
• Introductory Course in Interventional Cardiology, National University Heart Centre Singapore (2016)
• Basic Training in Interventional Cardiology, Indonesian Society of Interventional Cardiology, RSUP Adam Malik, Medan, Indonesia (2015)
• Workshop on Transradial Intervention, 7th ISICAM-INALIVE, Jakarta (2015)
• Workshop on Echocardiography Method for Patient Selection and Guidance in Atrial Septal Occluder Procedure, 27th WECOC, Jakarta (2015)
• Regular Workshop on Ethics, Medical Law, and Professional Medical Organization, Batch 22 (IDI Branch Makassar, 2015)
• Basic TEE Workshop, Surabaya (2014)
• Workshop Hospital Health Promotion and Public Relation, Batch 2, RSUD Soetomo Surabaya, 2009
• General Emergency Life Support (GELS), Tim Pengembangan SPGDT dan Pelatihan GELS Tingkat Pusat Departemen Kesehatan Republik Indonesia (2006)
Sympathetic Overdrive : Therapeutic Options in
Hypertension Patients
Pharmacotherapy options for elevated heart rate:1-5 only the beta-blockers
without ISA are associated with the reduction of heart rate by reducing
sympathetic overdrive
Elevated heart rate

If channel inhibitor

IDN/CONCO/0318/0011
Non- (ivabradine)
Beta blockers 4,5
dihydropyridine CCBs (without ISA)3
(verapamil, diltiazem)1 Specific action on the
If channel that
HR control via controls the
Action is not related to SO actions on SO3
but to reducing nerve pacemaker activity in
conduction velocity and sinoatrial node
prolonging repolarization2

Calcium channel blockers(CCBs) Sympathetic overdrive(SO) Intrinsic sympathomimetic activity(ISA) Coronary heart disease(CHD)

The If channel inhibitor, ivabradine, is recommended as a second-line drug in CHD, only if beta-blockers are not
tolerated or additional HR reduction is needed after the maximum dose of beta-blocker6,7

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. Gupta D. A review on calcium channel & its blockers. Int J Pharm Pharm Sci. 2012;4:3842.
3. Egan BM, Basile J, Chilton RJ et al. Cardioprotection: the role of beta-blocker therapy. J Clin Hypertens. 2005;7(7):409–16.
4. DiFrancesco D, Camm JA. Heart rate lowering by specific and selective I(f) current inhibition with ivabradine. Drugs. 2004;64:1757–65.
5. Sulfi S, Timmis AD. Ivabradine: the first selective sinus node I(f) channel inhibitor in the treatment of stable angina. Int J Clin Pract. 2006;60:222–28.
6. Procoralan (ivabradine) Summary of Product Characteristics, revision dated 7 June 2016.
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.
Angiotensin II receptor blockers increase sympathetic activity in young
men with normal blood pressure or mild hypertension1,2
Study investigating the effects of 1 week of treatment with eprosartan 600 mg/day vs. placebo
in 29 young men with normal BP or mild hypertension2
*

IDN/CONCO/0318/0011
**
*p<0.05; **p<0.01 eprosartan vs. placebo

**

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. 3-30
2. Heusser K, Vitkovsky J, Raasch W et al. Elevation of sympathetic activity by eprosartan in young male subjects. Am J Hypertens. 2003;16(8):658–64.
Modulation of sympathetic activation is an important goal of
antihypertensive treatment: effect of different drug classes1

Drug class Effects on peripheral SNS Effects on cardiac SNS

Central sympatholytics Marked reduction Reduction

Alpha-blockers Marked reduction No change

IDN/CONCO/0318/0011
Thiazide diuretics Marked increase No change

Anti-aldosterone agents Reduction No change

Beta-blockers Reduction Marked reduction

Short-acting CA Marked increase Marked increase

Long-acting CA Reduction or no change No change or increase

ACE inhibitors Reduction or no change No change

Angiotensin II receptor blockers* Reduction or no change No change

Angiotensin-converting enzyme (ACE) CA: Calcium antagonists(CA) Sympathetic nervous system(SNS)

*Although laboratory studies suggest that angiotensin II receptor blockers may inhibit the SNS, they have been shown to increase sympathetic activity in young
men with normal or slightly high blood pressure2

1. Grassi G. Sympathetic overdrive in hypertension: clinical and therapeutic relevance. J Cardiol Pract. 2015;13(24):24 November 2015.
2. Heusser K, Vitkovsky J, Raasch W et al. Elevation of sympathetic activity by eprosartan in young male subjects. Am J Hypertens. 2003;16(8):658–64.
Beta-blockers can intervene at many points in the cardiovascular continuum1

Myocardial
Coronary infarction Arrhythmias Sudden
thrombosis and loss of muscle death

Neurohormonal
Myocardial activation

IDN/CONCO/0318/0011
ischemia

Beta- Remodelling
CHD
blockers

Atherosclerosis Ventricular
LVH enlargement

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

• Diabetes Chronic heart failure (CHF)

• Smoking
Graph adapted from reference 1

1. Adapted from 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.
Why beta1-selectivity is important in the treatment of hypertension
associated with sympathetic overdrive1,2
Primary distribution of beta-receptors and effects of stimulation1

Beta1 receptors Beta2 receptors

 Contractility and heart rate1

IDN/CONCO/0318/0011
Myocardium
 Myocardial necrosis/apoptosis1

Bronchial smooth muscle  Bronchodilation1

Blood vessel smooth

 Vasodilation1
muscle

Kidney  Renin release1

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-blockade may be particularly beneficial in hypertensive patients with
central obesity/diabetes/insulin resistance1

DM2/Obese
Type 2 diabetes mellitus (DM2)

 Insulin resistance
Beta1-blockade

IDN/CONCO/0318/0011
 Insulin/Leptin

 Norepinephrine release

Benefits are
mediated by blockade
of beta1-receptors  PRA  Angiotensin II
Plasma renin activity (PRA)

Beta1-stimulation-induced  BP +  Intra-glomerular
Ventricular
cardiac and coronary damage non-dipping pressure
arrhythmias
( atheroma) at night + nephropathy
Blood pressure (BP)
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. 3-8
 Beta-blockers can reduce mortality in the overweight/obese, high-risk
hypertensive patient with type 2 diabetes1-5
20-year follow up of the United Kingdom Prospective Diabetes Study (UKPDS)4,5

0.8
ACE inhibitor Angiotensin-converting enzyme (ACE)
Proportion with event

Beta-blocker

0.6 *
23% reduction in
death from any
cause in patients
0.4 receiving a
beta-blocker
(*p<0.05) 1
0.2

0
4 8 12 16 20
Graph adapted from reference 1 Years since randomization
1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011; Fig. 3-15
2. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes; UKPDS 38.
BMJ. 1998;317:703–13.
3. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type-2 diabetes: UKPDS 39.
BMJ. 1998:313–20.
4. Holman RR, Paul SK, Bethel MA, Neil HA, Matthews DR. Long-term follow-up after tight control of blood pressure in type-2 diabetes. N Engl J Med. 2008;359:1565–76.
12
5. Coats AJS, Cruickshank JM. Hypertensive subjects with type-2 diabetes, the sympathetic nervous system, and treatment implications. Int J Cardiol. 2014;174:702–9.
Beta-blockers offer additional protection to BP reductions in preventing
recurrent events in patients with a history of CHD1

No of No of Relative risk Relative risk

trials events (95% CI) (95% CI)
Trials of beta-blockers
People with history of CHD 37 2524 0.71 (0.66 to 0.78)

IDN/CONCO/0318/0011
Entry after acute myocardial infarction 27 2155 0.69 (0.62 to 0.76)
Entry after long term coronary heart disease 11 369 0.87 (0.71 to 1.06)

People with no history of CHD 6 851 0.89 (0.78 to 1.02)

p<0.001
Trials of drugs other than beta-blockers
People with history of CHD 37 5834 0.85 (0.79 to 0.91)
People with no history of CHD 24 3217 0.84 (0.79 to 0.90)

All trials except ones of beta-blockers in people 64 9417 0.85 (0.81 to 0.89)
with history of CHD
0.5 0.7 1 1.4 2
Blood pressure(BP) Coronary heart disease(CHD) Treatment better Placebo better

Graph adapted from reference 1

1. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in
the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665. doi:10.1136/bmj.b1665.
Classification of beta-blockers according to their beta1-selectivity1,2

Relative beta1-selectivity Non-selective Beta1-selective

• Atenolol1
• Propanolol1
• Metoprolol1
• Timolol1
No intrinsic sympathomimetic • Bisoprolol1
• Carvedilol1
activity (ISA) • Betaxolol1
• Nadolol1
• Esmolol1
• Sotalol1

• Pindolol1
• Penbutolol1 • Acebutolol1
Intrinsic sympathomimetic
• Carteolol1 • Celiprolol1
activity (ISA)
• Bucindolol1 • Nebivolol*2
• Labetalol1

*Although nebivolol is often characterized as a beta1-selective beta-blocker without ISA,1 the nitric oxide release induced by nebivolol
leading to vasodilatation results from agonism at beta3-receptors, which is an ISA2

1. López-Sendón J, Swedberg K, McMurray J et al. for the Task Force on Beta-blockers of the European Society of Cardiology. Expert consensus document on
14 beta-adrenergic receptor blockers. Eur Heart J. 2004;25:1341-62.
2. Cruickshank J. Nebivolol, a third generation beta-blocker. J Symptoms Signs. 2014;3(5):380-91
 Drug-treatment strategy for
uncomplicated hypertension.
Consider monotherapy in
Initial therapy low-risk grade 1 hypertension
1 pill Dual combination ACEI or ARB + CCB or diuretic or in very old (≥80years)
or frailer patients

Step 2
1 pill Triple combination ACEI or ARB + CCB + diuretic

Step 3 Resistant hypertension

Triple combination Consider referal to a specialist
2 pills + spironolactone Add spironolactone (25-50 mg o.d.) or other centre for further investigation
or other drug diuretic, alpha-blocker or beta-blocker

Beta-blockers
Consider beta-blockers at any treatment step, when there is a
specific indication for their use, e.g. heart failure, angina, post-M,
atrial fibrillation, or younger women with, or planning, pregnancy

15
www.escardio.org/guidelines
 Drug-treatment strategy for
hypertension and CAD

ACEi or ARB
ACEI+orbeta-blocker
ARB + CCB or CCB Consider monotherapy in
Initial therapy or CCB +or
diuretic
ACEI ororARB
beta-blocker
+ low-risk grade 1 hypertension
1 pill Dual combination or in very old (≥80 years)
or
diuretic
beta-blocker + diureticb
(or lop diuretic) or frailer patients

ACEI or ARB + CCB Consider initiating therapy when

Step 2 systolic BP is ≥130 mmHg in
1 pill Triple combination Triple combination
or ACEI or ARB of+ above these very high-risk patients
diuretic (or lop diuretic)b with establish CVD

Step 3 Resistant hypertension

Triple combination Consider referal to a specialist
2 pills + spironolactone Add spironolactone (25-50 mg o.d.) or other centre for further investigation
or other drug diuretic, alpha-blocker or beta-blocker

16
www.escardio.org/guidelines
 Drug-treatment strategy for
hypertension and HFrEF

Initial therapy
ACEI or ARBa + diureticb
(or loop diuretic) + beta-blocker

ACEI or ARBa + diureticb

Step 2 (or loop diuretic) + beta-blocker +
MRAc

When antihypertensive therapy is not require in HFrEF, treatment should be

prescribed accoring to the ESC Heart Failure Guidelines

aConsider an angiotensin receptor/neprilysin inhibitor instead of ACEi or ARB per ESC Heart Failure Guidelines.
bDiuretic refers to thiazide/thiazide-like diuretic. Consider a loop diuretic as an alternative in patients with oedema.
cMRA (spironolactone or eplerenone).

17
www.escardio.org/guidelines
 Drug-treatment strategy for hypertension and AF

ACEI or ARBa + beta-blocker

Initial therapy or non-DHP-CCBa
Dual combination
or beta-blocker + CCB

ACEI or ARB + beta-blocker

Step 2 + DHP CCB or diuretic or
Triple combination
beta-blocker + DHP CCB + diuretic

Add oral anticoagulation when indicated according to the CHA2DS2-VASc score, unless contraindicated.
aRoutine combination of beta-blockers with non-dihydropyridine CCBs (e.g. verapamil or diltiazem)
is not recommended due to a potential marked reduction in heart rate.

18
www.escardio.org/guidelines
 Resistant Hypertension

19
www.escardio.org/guidelines
NICE guidelines also recommend beta-blockers as
initial therapy for hypertension in younger people1
Consider beta-blockers in younger people
with evidence of increased sympathetic drive
The NICE evidence review identified four studies that reported beta-blockers and
ACE inhibitors as being more effective at lowering blood pressure in younger
people than calcium channel blockers or thiazide-type-diuretics.

The guidelines do not generally recommend beta-blockers as a preferred initial

treatment option for hypertensive patients, but beta-blockers may be considered
for initial therapy of hypertension in younger people, particularly:

• those with an intolerance or contraindication to ACE inhibitors and

angiotensin II receptor antagonists or
• women of child-bearing potential or
• people with evidence of increased sympathetic drive.

Please refer to abbreviated product information in chapter 7 which may vary by country.
1. NICE Guideline CG127. Hypertension: The clinical management of primary hypertension in adults. August 2011.
Available at: https://www.nice.org.uk/guidance/cg127/evidence/full-guideline-248588317. Last accessed March 2016.

20
Canadian guidelines recommend beta-blockers as an initial antihypertensive
therapy1

IDN/CONCO/0318/0011
Recommendations for individuals with diastolic and/or systolic hypertension
Initial therapy should be monotherapy with:
• a thiazide/thiazide-like diuretic (Grade A)
• a beta-blocker (in patients <60 years of age, Grade B)
• an ACE inhibitor (in non-black patients, Grade B)
• a long-acting calcium channel blocker (CCB) (Grade B) or
• an angiotensin receptor blocker (ARB) (Grade B).

Please refer to abbreviated product information in chapter 7 which may vary by country.

1. Daskalopoulou SS, Rabi DM, Zarnke KB et al. The 2015 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis,
assessment of risk, prevention, and treatment of hypertension. Can J Cardiol. 2015;31(5):549–68.
Bisoprolol in the treatment of hypertension associated
with sympathetic overdrive
Overview of the pharmacokinetics of bisoprolol1-3

Bisoprolol
Absorption >90%3

IDN/CONCO/0318/0011
Bioavailability ~90%1

Plasma protein binding 30%3

Metabolism 50% (inactive)2,3

Plasma elimination half-life 10–12 hours1

1. Leopold G, Kutz K. Bisoprolol: pharmacokinetic profile. Rev Contemp Pharmacother. 1997;8:35-43.

2. Leopold G, Pabst J, Ungethüm W, Bühring K-U. Basic pharmacokinetics of bisoprolol, a new highly beta1-selective adrenoceptor antagonist. J Clin Pharmacol. 1986;26:616-21.
3. Leopold G. Balanced pharmacokinetics and metabolism of bisoprolol. J Cardiovasc Pharmacol. 1986;8(Suppl 11):16–20.
Bisoprolol has a balanced clearance

Bisoprolol has a 'balanced' clearance1,2,3

• 50% renal elimination of unchanged drug
• 50% hepatic metabolism to inactive metabolites – also renally excreted

Metabolism

IDN/CONCO/0318/0011
• Only by oxidation – no subsequent conjugation4,5
• Primarily by CYP3A4 (~95%)4
• Only minor contribution of CYP2D64 ( metabolism not dependent
on CYP2D6 gene polymorphism, formerly debrisoquine-sparteine
polymorphism2)

 No dose adjustment necessary in mild to moderate liver or kidney impairment6

 Daily dose to be limited to 10 mg in severe liver or kidney impairment6

1. Leopold G, Pabst J, Ungethüm W, Bühring K-U. Basic pharmacokinetics of bisoprolol, a new highly beta1-selective adrenoceptor antagonist. J Clin Pharmacol. 1986;26:616-21.
2. Leopold G. Balanced pharmacokinetics and metabolism of bisoprolol. J Cardiovasc Pharmacol. 1986;8(Suppl 11):16–20.
3. Leopold G, Kutz K. Bisoprolol: pharmacokinetic profile. Rev Contemp Pharmacother. 1997;8:35-43.
4. Horikiri Y, Suzuki T, Mizobe M. Stereoselective metabolism of bisoprolol enantiomers in dogs and humans. Life Sci. 1998;63(13):1097-108.
5. Horikiri Y, Suzuki T, Mizobe M. Pharmacokinetics and metabolism of bisoprolol enantiomers in humans. J Pharm Sci. 1998;87(3):289-94.
6. Concor® / Concor® COR Product information (abbreviated prescribing information), Merck KGaA, Darmstadt, Germany; July 2017.
Bisoprolol: Beta2/beta1 selectivity ratio at human beta-receptors in vitro1,2

Bisoprolol has a 19.6-fold higher affinity for the beta1 receptor

than for the beta2 receptor1

IDN/CONCO/0318/0011
Graph adapted from reference 2

1. Smith C, Teitler M. Beta-blocker selectivity at cloned human beta1- and beta2-adrenergic receptors. Cardiovasc Drugs Ther. 1999;13:123–6.
2. Cruickshank JM. Essential Hypertension. Shelton, CT: People's Medical Publishing House-USA;2013, Fig. 8-28.
Efficacy of Bisoprolol in Hypertension associated with
Sympathetic Overdrive
More effective 24-hour BP control with bisoprolol versus atenolol after
once-daily dosing1,2
Mean change in systolic BP (mmHg) Mean change in diastolic BP (mmHg)

0 Atenolol 0 Atenolol
Bisoprolol Bisoprolol
-5 Night time -5 Night time

IDN/CONCO/0318/0011
-10 -10 **
*
-15 -15
*p<0.05 **p<0.01
-20 -20

10 AM 4 PM 10 PM 4 AM 10 AM 10 AM 4 PM 10 PM 4 AM 10 AM
Dose time: 10 AM Dose time: 10 AM

Randomized, double-blind parallel-group study of 659 patients with mild-to-moderate hypertension (21-84 years) with 24-
hour ABPM measured after 8 weeks’ treatment (bisoprolol 10 mg o.d., n=336, atenolol 50 mg o.d., n=323)
Bisoprolol was significantly more effective in reducing SBP (p<0.05 ) and DBP (p<0.01) during the final 4 hours
of dosing interval
On 24-hour BP monitoring, bisoprolol demonstrated a 33% greater reduction in whole-day average DBP
(11.6 vs 8.7 mmHg, p<0.01)
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. 1-12
2. Neutel JM, Smith DHG, Ram CVS, et al. Application of ambulatory blood pressure monitoring in differentiating between antihypertensive agents. Am J Med. 1993;94:181–7
Efficacy of bisoprolol compared with other antihypertensives (GENRES
Study): Office BP responses1,2
Systolic Diastolic

p<0.001 p<0.08 p<0.001 p<0.001 p<0.13 p<0.001

IDN/CONCO/0318/0011
Prospective, randomized double-blind, cross-over, placebo-controlled study in 208 moderately hypertensive men (aged 35 to 60 years):
bisoprolol 5 mg/day, losartan 50 mg/day, amlodipine 5 mg/day, hydrochlorothiazide (HCT) 25 mg/day.

 Bisoprolol showed the best antihypertensive effect.

Graph adapted from reference 1

1. Cruickshank JM. Essential Hypertension. Shelton, CT: People's Medical Publishing House-USA;2013, Fig. 6-28
2. Hiltunen TP, Suonsyrjä T, Hannila-Handelberg T et al. Predictors of antihypertensive drug responses: initial data from a placebo-controlled, randomized,
cross-over study with four antihypertensive drugs (The GENRES Study). Am J Hypertens. 2007;20:311-8.
Efficacy of bisoprolol vs. nebivolol in the treatment of hypertension (NEBIS)1

Bisoprolol 5 mg
170 Systolic BP
Nebivolol 5 mg
160

150
DBP: Nebivolol -15.7 

IDN/CONCO/0318/0011
Blood pressure (mmHg)

140
6.4 mm Hg vs.
130 Bisoprolol -16.0  6.8
mm Hg, p = 0.82301
120
SBP: Nebivolol -20.5 
110 Diastolic BP 12.9 mm Hg vs.
Bisoprolol -20.0  12.0
100 mm Hg, p = 0.74341
90
Responders: Nebivolol
80
92.0% vs. Bisoprolol
89.6% (DBP ≤ 90 mm
70 Hg or a decrease ≥ 10
0 2 4 6 8 10 12
mm Hg)1

Duration of treatment (weeks)

Graph adapted from reference 1

1. Czuriga I, Riecansky I, Bodnar J et al. Comparison of the new cardioselective beta-blocker nebivolol with bisoprolol in hypertension:
The Nebivolol, Bisoprolol Multicenter Study (NEBIS). Cardiovasc Drugs Ther. 2003;17:257-63.
Bisoprolol showed to be superior to other antihypertensive therapies in
middle-aged hypertensive men (ADLIB study)1,2

160

150
Amlodipine: 5 mg/day
140
BP (mmHg) and heart rate

Doxazosin: 1-4 mg/day

130 Bendrofluazide: 2.5 mg/day

IDN/CONCO/0318/0011
Lisinopril: 2.5-10 mg/day
120
Bisoprolol: 5 mg/day
110

100

90

80

70

60

Placebo Amlodipine Doxazosin Lisinopril Bisoprolol Bendrofluazide

Under randomized, double-blind, cross-over conditions in young/middle-aged (28-55 years) diastolic hypertensive
patients, bisoprolol was the most effective antihypertensive agent compared with the alpha-blocker, doxazosin, the
calcium blocker, amlodipine, the ACE inhibitor, lisinopril, and the diuretic, bendrofluazide, dosed for 6 weeks each.1,2
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. 3-32b
2. Deary AJ, Schumann AL, Murfet H et al. Double-blind, placebo-controlled crossover comparison of five classes of antihypertensive drugs. J Hypertens. 2002;20:771-7.
Control of raised blood pressure is better with bisoprolol than with atenolol,
particularly in smokers1,2
Success rates after 8 weeks of individually-titrated treatment1

Bisoprolol 10-20 mg p<0.05

Atenolol 50-100 mg

IDN/CONCO/0318/0011
Non-smokers (n=69) Smokers (n=25)

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. 3-32a
2. Bühler FR, Berglund G, Anderson OK et al. Double-blind comparison of the cardioselective β-blockers bisoprolol and atenolol in hypertension:
the Bisoprolol International Multicenter Study (BIMS). J Cardiovasc Pharmacol. 1986;8:S122–7.
Bisoprolol was superior to losartan in middle-aged hypertensive patients1,2

SBP DBP Creatinine clearance

IDN/CONCO/0318/0011
Bisoprolol 5 mg/day
Losartan 50 mg/day

Systolic blood pressure (SBP)

Diastolic blood pressure (DBP)
p<0.01

In middle-aged hypertensive patients (mean age 52 years; n=72), bisoprolol was superior to losartan in
controlling blood pressure over 1 year, with no evidence of renoprotection for losartan.1

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. 3-34
2. Parrinello G, Paterna S, Torres D et al. One-year renal and cardiac effects of bisoprolol versus losartan in recently diagnosed hypertensive patients.
Clin Drug Invest. 2009;29:591–600.
Safety Profile of Bisoprolol
 Bisoprolol: Beta1-selectivity results in minimal effects on lung function in
patients with stable angina pectoris and chronic obstructive lung disease1,2
AWR (cm H2O/L/s)

b=before dosing

IDN/CONCO/0318/0011
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 h
1 3 6 12 1 3 6 12 1 3 6 12
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
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.
Bisoprolol: Beta1-selectivity results in minimal effects on airways resistance
in asthmatic hypertensive patients1,2

*
1.6
N=12
Mean ± SEM
Change in AWR (cm H2O/L/s)

1.2 *p<0.05 vs. placebo2

IDN/CONCO/0318/0011
0.8

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
2. Chatterjee SS. The cardioselective and hypotensive effects of bisoprolol in hypertensive asthmatics. J Cardiovasc Pharmacol. 1986;8(Suppl 11):S74–S77.
Bisoprolol has minimal effects on lipids and glucose1,2
Cholesterol (mg/dL) *p<0.05 vs. placebo Triglycerides (mg/dL)
* *

IDN/CONCO/0318/0011
Glucose (mg/dL) HbA1 (%)
*
*

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. 6-13
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.
 Bisoprolol: Beta1-selectivity and lipid metabolism during long-term therapy1-3

% change in plasma HDL-cholesterol

+10

Mepindolol 10 mg/day (n=16)

0
Bisoprolol 10 mg/day (n=17)

IDN/CONCO/0318/0011
-10 Propranolol 160 mg/day (n=15)
** ** ** * Atenolol 100 mg/day (n=22)
** **
-20
** **
**
-30 ** **

-40

6 12 18 24 30 36 months

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

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. 1-9 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.
Bisoprolol has minimal effect on male sexual function1-3

IDN/CONCO/0318/0011
Graph according to reference 1 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.
Blue-Throated Hummingbird
Heart Rate : 250-1200 bpm
Lifespan : 8-12 years
Blue Whale
Heart Rate : 8-10 bpm
Lifespan : 70-90 years
Summary
 Sympathetic overdrive in hypertension:
the role of beta-blockers with a focus on bisoprolol

• Sympathetic overdrive leads to elevated heart rate and BP in HTN

• Sympathetic overdrive elevated heart rate and BP increase the risk of cardiovascular and all-
cause mortality in patients
• The adverse cardiovascular outcomes associated with sympathetic overdrive result from the
neural release of norepinephrine and stimulation of beta1 receptors in the heart and kidneys1,2
• Beta-blockers help to prevent the adverse effects of sympathetic overdrive1 and reduce the
risk of recurrent cardiovascular events and death 6-10
• Beta-blockers are recommended in treatment guidelines:11,12
• as first-line treatments for the relief of angina symptoms11,12
• as first-line treatments for patients with microvascular angina11
• for the prevention of MI or death in all patients with normal LV function after MI or ACS
and all patients with LV systolic dysfunction (EF ≤40%) with heart failure or prior MI12
• HTN patients
• A Fib patients
1. Egan BM, Basile J, Chilton RJ et al. J Clin Hypertens. 2005;7(7):409–16; 2. Palatini P. Curr Hypertens Rep. 2013;15:253–59; 3. Benetos A, Rudnichi A, Thomas F et al.
Hypertension. 1999;33:44–52; 4. Jouven X, Zureik M, Desnos M et al. Cardiovasc Res. 2001;50:373–8; 5. Ho JE, Bittner V, DeMicco DA et al. Am J Cardiol. 2010;105:905-11;
6. Law MR, Morris JK, Wald NJ. BMJ. 2009;338:b1665. doi:10.1136/bmj.b1665; 7. Bauters C, Lemesle G, Meurice T et al. Heart. 2014;100:1757-61; 8. Andersson C, Silane D,
Go AS et al. J Am Coll Cardiol. 2014;64(3):247-52; 9. Kernis SJ, Harjai KJ, Stone GW et al. J Am Coll Cardiol. 2004;43:1773-9; 10. Cucherat M. Eur Heart J. 2007;28:3012-19;
11. Montalescot G, Sechtem U, Achenbach S et al. Eur Heart J. 2013;34:2949-3003; 12. Fihn SD, Gardin JM, Abrams J et al. J Am Coll Cardiol. 2012;60:e44-e164.
42
Thank You