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Right Beta Blockers
for the Right Patients
JOHN DOE, MD
SUBTITLE 32 PT ARIAL BOLD ITALICS
Indra Prasetya
Department of Cardiology and Vascular Medicine,Faculty of Medicine Brawijaya University,
Saiful Anwar General Hospital,Malang
DISCLOSURE STATEMENT OF
FINANCIAL INTEREST
• Nothing To Disclose
2003: BB become the most controversial
antiHTNs!!
1980: BB become the most popular antiHTNs after
diuretics. Practolol – First β1 selective.
1963: Therapeutic breakthrough, Propronolol
introduced by J.W.Black
1948: Ahlquist classified adrenergic receptors into α
and β receptors.
1958: Dichloroisoprenaline (DCI) – First BB
•2019: ??????
History
Cardiovascular disease continuum:
From risk factors to irreversible damage
Cardiovascular disease continuum:
The role of sympathetic overdrive
Sympathetic overdrive
Autonomous nervous system –
silent regulator of all bodily functions
Autonomous nervous system –
silent regulator of all bodily functions
Parasympathetic system "rest and digest"
Sympathetic system"fight or flight" "
How to measure activity of sympathetic system
in humans?
• Sympathetic adrenergic neuroimaging• Microneurography• Regional and total norepinephrine spillover• Plasma norepinephrine• Power spectral analysis of heart rate• Heart rate
SYMPATHETIC OVERDRIVE – AN IMPORTANT
RISK FACTOR FOR HYPERTENSION AND
CARDIOVASCULAR COMPLICATIONS
PRESENTING WITH ELEVATED HEART RATE
Dyer AR, et al.: Heart rate as a prognostic factor for coronary heart disease and mortality: findings in three Chicago epidemiologic studies. Am J Epidemiol1980, 112:736–749
Heart rate is associated with mortality
Chicago People Gas Company study, n=1233, 40–59
years
CRUSADE quality improvement initiative. Eur Heart J 2010;31:552–560.
Elevated Heart Rate is a Risk Factor in patients with Heart Disease
CRUSADE Registry (n = 135 164)
Inverse linear relation between RHR and life
expectancy in mammals and humans
Cook S et al. Eur Heart J 2006;27:2387-2393
Heart rate = 25/min
Life span = ?
Heart rate = 25/min
Life span = 150 years
SYMPATHETIC OVERDRIVE IS
COMMON AT INITIAL STAGE OF
HYPERTENSION
Jia Hu, MMa, et al. Association of elevated resting pulse rate with increased risk of hypertension development in children. A prospective study in Suzhou, China. Medicine (2017) 96:32(e7696)
Elevated resting heart rate predicts development of
hypertension in children. Suzhou Study
Jia Hu, MMa, et al. Association of elevated resting pulse rate with increased risk of hypertension development in children. A prospective study in Suzhou, China. Medicine (2017) 96:32(e7696)
Every 10bpm increase in heart rate was associated with a 26% greater risk of hypertension development in boys
Elevated resting heart rate predicts development of
hypertension in children. Suzhou Study
Peter M. Okin et al. All-cause and cardiovascular mortality in relations to changing heart rate during treatment of hypertensive patients with electrocardiographic left ventricular hypertrophy. European Heart Journal (2010) 31, 2271–2279
Heart rate ≥ 84 bpm is associated with increased mortality
LIFE Study
In most studies of hypertension, HR was considered to be elevated when it was higher than 80–85 bpm
Symptomatic tachycardia HR reduction by available drugs (mostly beta-1 selective beta-blockers) should be considered
Tachycardia is frequent alsoin established hypertension (n=38,145)
Heart rate (bpm)
0
5
10
15
20
25
1.43.7
8.0
13.9
19.420.8
0.9 0.5 0.5
% P
atie
nts
<55 55-60
60-65
65-70
70-75
75-80
100-105
105-110
>110
14.5
9.6
4.32.6
80-85
85-90
90-95
95-100
Farinaro E et al, Nutr Metab Cardiovasc Dis 1999:9;196
30%
Julius S, Pascual AV, London R. Role of parasympathetic inhibition in the hyperkinetic type of borderline hypertension. Circulation. 1971; 44: 413-8.
Borderline hypertensives present exagerated response to
beta-blockers as compared to normotensives
M Wofford et al. Antihypertensive Effect of a- and b-Adrenergic Blockade in Obese and Lean Hypertensive Subjects. AJH 2001; 14:694–698.
Blood pressure is more sensitive to adrenergic blockade
in obese than in lean hypertensive patients
BETA-BLOCKERS REDUCE
SYMPATHETIC OVERDRIVE IN
HYPERTENSION WITH CLINICAL
BENEFITS
Inhibition of sympathetic overdrive
Alpha2-agonists(moxonidine)
Beta-blockers
Alpha-blockers
Ganglion-blocking drugs(trimetaphane)
Beta-Adrenergic Blockers
Alpha-1
• Vasoconstriction
• Increased peripheral
resistance
• Increased blood pressure
Alpha-2
• Inhibition of norepinepherine
release
• Inhibition of insulin release
Beta-Blockers
Beta-1
• Tachycardia
• Increased lipolysis
• Increased
myocardial
contractility
Beta-2
• Vasodilation (in skeletal vasculature)
• Slightly decreased peripheral
resistance
• Bronchodilation
• Increased muscle and liver
glycogenolysis
• Increased release of glucagon
Properties
Receptor Blockade
Nonselective β blockade
Selective β1 blockade
β+α blockade
Intrinsic sympathomimetic property-ISA
(partial agonistic action)
Membrane stabilising action-MSA
(Local anaesthetic action-Na channel block)
Classification
Properties of β1 Selectivity
Less broncho constriction
Less interference with CHO metabolism less hypoglycemia preferred in diabetics
Less chances of Raynaud's phenomenon
Less deleterious effect on blood lipid profile
Less impairment of exercisecapacity
Less effect on tremor
Properties of ISA
(Intrinsic Sympathomimetic Activity)
Less bradycardia
Less rebound effect on withdrawal
Less deleterious effect on blood lipid profile
Not effective in migraine prophylaxis
Not suitable for secondary prophylaxis of MI
3rd Generation AgentsDrug MSA ISA Beta blockade Other properties
Labetalol Non selective α1 blockade
Carvedilol
+ +
+ Non selective α1 blockade,CCB
Antioxidant
Bucindolol + Non selective α1 blockade,β2,β3 agonism
Increases HDL cholesterol
Celiprolol + β1 selective β2 agonism
NO release
Nebivolol β1 selective •NO release
•Inhibits platelet aggregation
Bevantolol Nonselective α1 blockade
CCB
USES
CARDIOVASCULAR
Hypertension
Angina
Myocardial infarction
Arrhythmia
Cardiomyopathy
CCF
Dissecting aneurysm of aorta
NON - CARDIOVASCULAR
Thyrotoxicosis
Pheochromocytoma
Migraine prophylaxis
Essential tremor
Glaucoma
Anxiety
Portal hypertension
Anti psychotic induced
akathisia
Acute coronary syndrome
• Beta-blockers reduce mortality and reinfarction by 20-25% in those who
have recovered from an infarction [1].
• Oral treatment with beta-blockers should be considered for all ST-
elevation myocardial infarction (STEMI) patients without contraindications
(Class IIa, Level B) [2]. They are indicated if STEMI patients also have
heart failure or LV dysfunction (Class I, Level A) [2].
[1] De Sutter J, Mendes M, Franco OH. Chapter 19 Cardioprotective drugs. In: Gielen S, De Backer G, Piepoli MF, Wood D, editors. The
ESC Textbook of Preventive Cardiology. 2nd ed. United Kingdom: Oxford University Press, 2016.
[2] Steg G, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-
segment elevation. Eur Heart J 2012; 33: 2569–2619.
Stable coronary artery disease
• Beta-blockade is a very effective symptomatic treatment, alone or
combined with another drug, for most of patients with classical angina [1].
• Beta-blockers and/or calcium channel blockers are first-line treatment to
control heart rate and anginal symptoms (Class I, Level A) [3].
[1] De Sutter J, Mendes M, Franco OH. Chapter 19 Cardioprotective drugs. In: Gielen S, De Backer G, Piepoli MF, Wood D, editors. The
ESC Textbook of Preventive Cardiology. 2nd ed. United Kingdom: Oxford University Press, 2016.
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.
Heart Failure
• Beta-blockers have been shown to reduce mortality and heart failure
readmissions in patients with heart failure with a reduced ejection fraction
(HFrEF) [1].
• Beta-blockers are recommended, in addition to ACE inhibitors, for patients
with stable, symptomatic HFrEF (Class I, Level A) [4].
• Bisoprolol, Carvedilol, Metoprolol and Nebivolol are licensed for use in
HFrEF and should be preferred [4].
[1] De Sutter J, Mendes M, Franco OH. Chapter 19 Cardioprotective drugs. In: Gielen S, De Backer G, Piepoli MF, Wood D, editors. The
ESC Textbook of Preventive Cardiology. 2nd ed. United Kingdom: Oxford University Press, 2016.
[4] Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. 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.
Arrhythmia
• Beta-blockers can be used to slow the heart rate in patients with
arrhythmias such as atrial flutter and/or atrial fibrillation [1].
• They are effective in the control of ventricular arrhythmias related to
sympathetic activation, acute coronary syndrome, and heart failure;
including the prevention of sudden cardiac death [1].
[1] De Sutter J, Mendes M, Franco OH. Chapter 19 Cardioprotective drugs. In: Gielen S, De Backer G, Piepoli MF, Wood D, editors. The
ESC Textbook of Preventive Cardiology. 2nd ed. United Kingdom: Oxford University Press, 2016.
Contraindications and side effects• The most frequent side effects of beta-blockers include: hypotension, bradycardia,
bronchospasm, cold extremities, fatigue, headache, sleep disturbances and increased
insulin resistance [1].
• High-degree AV block is an absolute contraindication (if no pacemaker) [1].
• Use cardioselective beta-blockers in case of chronic obstructive pulmonary disease
(COPD); start low and go slow [1].
• Asthma is a relative contraindication for the use of beta-blockers [4]. These drugs
should be used with caution and preferably with specialist advice.
[1] De Sutter J, Mendes M, Franco OH. Chapter 19 Cardioprotective drugs. In: Gielen S, De Backer G, Piepoli MF, Wood D, editors. The
ESC Textbook of Preventive Cardiology. 2nd ed. United Kingdom: Oxford University Press, 2016.
[4] Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. 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.
Take Home Message Beta-blockers are a diverse group of medicines and prescribers should consider their different
properties, along with the presence of co-morbidities, to individualise care for patients with
cardiovascular conditions
When a beta-blocker is initiated, a slow upwards titration of dose is recommended to minimise
adverse effects. Beta-blockers should also be withdrawn slowly, ideally over several months, to
prevent rebound symptoms such as resting tachycardia.
Beta receptor selectivity enhances the beneficial effects of beta blockers and allows treatment
of patients with co-morbidities
New generation of Beta Blocker : β1 selective, NO production, anti oxidative properties.
THANK YOU
BACKUP SLIDES
Treatment strategies and choice of drugs
2013 ESH/ESC Hypertension Guidelines
Drugs to be preferred in specific conditions
2013 ESH/ESC Hypertension Guidelines
Wald and Law. BMJ 2009; b1665
Superior blood pressure and heart rate control with
bisoprolol ADLIB Trial (n=25, age 28 – 55 years)
Deary AJ, et al. Double-blind, placebo-controlled crossover comparison of five classes of antihypertensive drugs. J Hypertens. 2002; 20: 771-7.
60
65
70
80
100
110
120
140
130
90
150
160M
ean
BP
(m
m H
g)
Mean
HR
(/m
in)
Bisoprolol and nebivolol: Blood pressure loweringNEBIS trial
Czuriga I et al.. Comparison of the new cardioselective beta-blocker nebivolol with bisoprolol in hypertension: The nebivolol,
bisoprolol multicenter study (NEBIS). Cardiovascular Drugs and therapy 2003: 17: 257-63
5 mg nebivolol
5 mg bisoprolol
Cardiovascular disease continuum: The role of sympathetic overdrive
Sympathetic overdrive
Arne H. Strand et al. Arterial plasma noradrenaline predicts left ventricular mass independently of blood pressure and body build in men who develop hypertension over 20 years. J Hypertens 2006; 24:905–913
Increased plasma levels of adrenaline predict development of left ventricular hypertrophyTwenty-year follow-up
1984 2004
Cardiovascular disease continuum: The role of sympathetic overdrive
Sympathetic overdrive
Reduction of atherosclerosis during beta-blocker therapy
BCAPS
ELVA
Circulation; 104:1477-1482, 2001.
Risk of plaque rupture triples in patients with tachycardia
Cardiovascular disease continuum: The role of sympathetic overdrive
Sympathetic overdrive
Cardiac remodeling: mechanism behind heart failure
Acute myocardialinfarction
Hours - days
Expansion of hypokineticsegment, thining of heart wall
Days - months
Continues remodeling
Jessup i wsp. N Engl J Med. 2003;348:2007-2018
Necrosis Necrosis
Sympathetic system in heart failure
• Sympathetic overactivity
• Decreased cardiac neuronal density
• Reduced beta-receptor density
• Aggrevated norepinephrine release
Inhibition of sympathetic overdrive
Alpha2-agonists(moxonidine)
Beta-blockers
Alpha-blockers
Ganglion-blocking drugs(trimetaphane)
Cohn JN, et al MOXCON Investigators. Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON). Eur J Heart Fail. 2003; 5: 659-67
Higher mortality in heart failure patients treatedwith moxonidine …MOXCON trial
♂
Cohn JN, et al MOXCON Investigators. Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON). Eur J Heart Fail. 2003; 5: 659-67
…despite lower plasma norepinehprine concentrationMOXCON trial
Carvedilol(n=696)
Placebo(n=398)
Survival
0 50 100 150 200 250 300 350 400
1.0
0.9
0.8
0.7
0.6
0.5
RRR = 35%p<0.001
Packer et al (1996)
Lancet (1999)
0 200 400 600 800
1.0
0.8
0.6
0
Bisoprolol(n=1327)
Placebo(n=1320)
p<0.0001
Survival
RRR = 34%
The MERIT-HF Study Group (1999)
Months
Śmiertelność %
0 3 6 9 12 15 18 21
20
15
10
5
0
Placebo(n=1496)
Metoprolol CR/XL(n=1495)
p=0.0062
RRR = 34%
US Carvedilol Study
Beta-blockers reduce mortality in heartfailure due to systolic dysfunction
CIBIS-II MERIT-HF
Days
Days
No reduction in mortality in patients with heart failuretreated with bucindololBEST trial
A Trial Of The Beta-blocker Bucindolol In Patients With Advanced Chronic Heart Failure. The Beta-blocker Evaluation Of Survival Trial Investigators. N Engl J Med 2001;344:1659-67
No reduction in mortality in patients with heart failuretreated with nebivololSENIORS trial
MD Flather et al. Randomized trial to determine the effect of nebivvolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS) Eur Heart J 2005; 26: 215
Cardiovascular disease continuum: How can we stop it?
The Impact Of Sympathetic Overdrive In The Cardiovascular Continuum
• Sympathetic overdive initiates and acceleratescardiovascular continuum
• Heart rate is a sensitive marker of sympatheticoverdrive
• Only cardioselective beta-blockers safely reducesympathetic overdrive with clinical benefits
Heart rate
Contractility
Blood pressure
Less bronchocontriction
Less metabolic effects
Less circulatory side effects
NONSELECTIVE( b1 b2 )
Similar cardiac and nearly similar antihypertensive effects
More marked pulmonary and peripheral effects
Advantages of selective b1-receptor blockade
Smith C,Teitler M. Cardiovasc Drugs Ther 1999;13:123–126
19.6
7.5
6.0 5.7
0.6 0.3
0
2
4
6
8
10
12
14
16
18
20
β2/β
1sele
ctivity r
atio
Bisoprolol Metoprolol CarvedilolBetaxolol Atenolol Propranolol
Bisoprolol: β2/β1 Selectivity Ratio
at Human β-receptors In Vitro
Concor :Setting Standards
Leopold G. J Cardiovasc Pharmacol. 1986;8(Suppl 11): S16-20. Leopold G, Kutz K. Rev Contemp Pharmacother. 1997;8:35-43.
Bisoprolol needs no dose adjustment in patients with
mild to moderate, Renal or Hepatic dysfunction
Plasma concentration profiles after administration of metoprolol
succinate CR and bisoprolol (3/12 subjects were CYP2D6 “poor” metabolizer)
Metoprolol succinate Bisoprolol
Individual plasma concentration profiles of metoprolol and bisoprolol after single administration of one
metoprolol 100 mg controlled release tablet and one bisoprolol 10 mg normal release tablet
BETA-BLOCKERS AND ASTHMA, COPD
Chest; Jan 2003; 123, 1;
J. W. J. Lammers, H. Th. M. Folgering, C. k A. van Herwaarden Ventilatory Effects of Betal-Receptor-Selective Blockade with Bisoprolol and Metoprolol in Asthmatic Patients. Eur J Clin Pharmacol (1984) 27:141-145
Beta-blockers in COPD patients: Reduced mortality
Placebo Bisoprolol 10 mg Bisoprolol 20 mg Metoprolol 100 mg
Frans H. Rutten, Nicolaas P. A. Zuithoff, Eelko Hak, Diederick E. Grobbee, Arno W. Hoes. b-Blockers May Reduce Mortality and Risk of Exacerbations in Patients With Chronic Obstructive Pulmonary Disease. Arch Intern Med. 2010;170:880-887
Beta-blockers in COPD patients: Reduced mortality
Frans H. Rutten, Nicolaas P. A. Zuithoff, Eelko Hak, Diederick E. Grobbee, Arno W. Hoes. b-Blockers May Reduce Mortality and Risk of Exacerbations in Patients With Chronic Obstructive Pulmonary Disease. Arch Intern Med. 2010;170:880-887
Beta-blockers in COPD patients: Reducted mortality
Pulmonary specialists in COPD patients: Reduced survival
BETA-BLOCKERS AND LIPIDS
** **** **
**
**
** ****
*
+10
0
–10
–20
–30
–40
6 12 18 24 30 36 months
Mepindolol 10 mg/day (n = 16)
Bisoprolol 10 mg/day (n = 17)
Propranolol 160 mg/day (n = 15)
Atenolol 100 mg/day (n = 22)
vs. baseline*p<0.05**p<0.01
Δ%
HD
L-c
hole
ste
rol
HDL-cholesterol during treatment with different beta-blockers
Fogari R et al. J Cardiovasc Pharmacol 1990; 16 (Suppl 5): S 76–80
74
HDL-cholesterolTotal cholesterol
5 years4 years3 years2 years1 yearstart
mm
ol/
L
0
1
2
3
4
5
6
7
8
LDL-cholesterolTriglycerides
Frithz G. Cardiovasc Drugs Ther 1993;7(suppl 2):424
Bisoprolol: β1-selectivity and Lipid Metabolism in Long-term Therapy
BETA-BLOCKERS AND DIABETES
William J Elliott, Peter M Meyer. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet 2007; 369: 201–07
Risk of de novo diabetes mellitus during anti-hypertensive therapy
Treatment with valsartan and risk of de novo diabetesmellitus(NAVIGATOR trial)
NEJM 2010
NEJM 2010
Treatment with valsartan and cardiovascular complications(NAVIGATOR trial)
Concomitant therapy and the risk of de novo diabetesNAVIGATOR Trial
Shen L, Shah BR, Reyes EM et al. Role of diuretics, β blockers, and statins in increasing the risk of diabetes in patients with impaired glucose tolerance: reanalysis of data from the NAVIGATOR study. BMJ 2013;347:f6745
Diuretics
1.50
1.40
1.30
1.20
1.10
1.00
0.90
0.80
0.70b-blockers Statins Calcium
antagonists
Haz
ard
rat
io (
95
% C
I)
1.10
1.231.32
0.95
170
160
150
140
130
120
110
100
10
9
8
7
6
A B CA
A: initial value
B: after 2 weeksof bisoprolol
C: after 2 weeksof placebo
B C
(PCB >0.05)
Glucose
(mg
/dL)
HbA1c
(%)
n=20
(PCB >0.05)
ß1-selectivity and glucose metabolism in patients with DM type 2 and concomitant hypertension
Janka HU et al. J Cardiovasc Pharmacol 1986;8(Suppl. 11):96–99
BETA-BLOCKERS AND PAD
Use of beta-blockers was associated with a 53% significant reduction in the incidence of new coronary events
Freedom from MALE was significantly higher in the bisoprolol-treated group than in the carvedilol group
84
Soga Y et al. J Atheroscler Thromb 2014;21:691-702
MALE = major adverse limb events incl. any repeated revasularization [any endovascular procedure, any surgical revision or the use of thrombectomy or thrombolysis] and major amputation
BETA-BLOCKERS AND ERECTILE DYSFUNCTION
0
0,5
1
1,5
2
2,5
3
3,5
4
Amlodipine
(n=103)
Bisoprolol
(n=389)
Bisoprolol/HCTZ
(n=333)
Enalapril (n=102) HCTZ (n=134) Placebo (n=150)
%
Self-reported erectile dysfunction during 6-14 weeksof antihypertensive therapy
Prisant LM et al.: Self-reported sexual dysfucntion in men and women treated with bisoprolol, hydrochlorothiazide, enalapril, amlodipine, placebo, or bisoprolol/hydrochlorothiazide. J Clin Hypertens 1999; 1: 22
0
5
10
15
20
25
30
35
% patients
3,1%
Complaints on erectile dysfunction and knowledge on the type of drug and side effects
„Blinded”
Silvestri A. et al. Eur Heart Journal 2003, 24: 1928-32
0
5
10
15
20
25
30
35
3,1%
15,6%
% patients
„Blinded” Known drug
Silvestri A. et al. Eur Heart Journal 2003, 24: 1928-32
Complaints on erectile dysfunction and knowledge on the type of drug and side effects
0
5
10
15
20
25
30
35
3,1%
15,6%
31,2%
% patients
„Blinded” Known drug Known drug and SE
Complaints on erectile dysfunction and knowledge on the type of drug and side effects
Silvestri A. et al. Eur Heart Journal 2003, 24: 1928-32
Patients who reported erectile dysfunction respondedsimilarly to sildenafil and placebo
Silvestri A. et al. Eur Heart Journal 2003, 24: 1928-32
Ko DT i wsp., JAMA 2002; 288: 351-7
Beta-blocker therapy was not associated with a significant absolute annual increase in
risk of reported depressive symptoms (6 per 1000 patients;95% CI [-7 to 19])
Beta-blockers were associated with a small significant annual increase in risk of reported
fatigue (18 per 1000 patients; 95% CI, [5-30])
Beta-blockers were also associated with a small, significant annual increase in risk of
reported sexual dysfunction (5 per 1000 patients; 95% CI, [2-8])
None of the risks of adverse effects differed significantly by degree of -blocker lipid
solubility
The risk associated with reported fatigue was significantly higher for early-generation
than for late-generation beta-blockers (P=.04).
ADVANCES IN MEDICINE 2013 June 29-30, 2013 Hong Kong
Ko DT i wsp., JAMA 2002; 288: 351-7
Beta-blocker therapy was not associated with a significant absolute annual increase in
risk of reported depressive symptoms (6 per 1000 patients;95% CI [-7 to 19])
Beta-blockers were associated with a small significant annual increase in risk of reported
fatigue (18 per 1000 patients; 95% CI, [5-30])
Beta-blockers were also associated with a small, significant annual increase in risk of
reported sexual dysfunction (5 per 1000 patients; 95% CI, [2-8])
None of the risks of adverse effects differed significantly by degree of -blocker lipid
solubility
The risk associated with reported fatigue was significantly higher for early-generation
than for late-generation beta-blockers (P=.04).
The conventional wisdom that beta-blocker therapy is associated with substantial risks of depressive symptoms, fatigue, and sexualdysfunction is not supported by data from clinical trials.
The risk was not associated with lipid-solubility but low b1-selectivity
Erectile dysfunction and treatment with different beta-blockers (MR NOED study)
Brixius K et al.. Clin Exp Pharmacol Physiol 2007; 34: 327-31
metoprolol
nebiwolol
BETA-BLOCKERS AND STROKE
Systolic blood pressure and risk of stroke (Prospective Cohort Study Collaboration)
120 160
256
64
16
4
1
Systolic BP (mmHg)
Age (years)
80-89
70-79
60-69
50-59
40-49
Lancet 2002; 360: 1903
Stro
ke d
eath
s
200
Hypertensive therapy: effects calculated on BP reduction
SBP difference (mmHg)
CA/placebo
ACE/plac
Better/worse
ARB/other
ACE/CA
CA/DBB
ACE/DBB
Lancet 2003; 362: 1527-35.
0.25
0.50
0.75
1.00
1.25
1.50
-10 -8 -6 -4 -2 0 2 4
• Atenolol (once daily) was used in 80% of clinical trials
• Atenolol (once daily) is a weak antihypertensive drug
• Risk of stroke is mostly related to blood pressure level
Beta-blockers and stroke prevention
Evidence-based on clinical trials
Beta-blockers reduce risk of stroke
Hypertensive treatment lowers cardiovascular risk in young and middle-aged population
Musini VM et al. Pharmacotherapy for hypertension in adults aged 18 to 59 years (Review). 2017, Issue 8. Art. No.: CD008276.
BETA-BLOCKERS AND ACC/AHA AND
NICE GUIDELINES
Isam Al-Karkhi et al. Comparisons of automated blood pressures in a primary health care setting with self-measurements at the office and at home using the Omron i-C10 device. Blood Press Monit 2015: 20: 98-103
Difference between automated BP readings and mesurement by medical personel(SMOB, self-measurement by the patient at the office)
141,0±18/85,4±9,9 - 140,3±18/86,3±9,5
Dahlöf B et al.Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005; 366: 895–906
ASCOT BPLA trial: unmet primary clinical endpoint
Dahlöf B et al.Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005; 366: 895–906
ASCOT BPLA trial: unmet primary clinical endpoint
Why atenolol?
Why once daily?
Why 50 mg?
Bisoprolol
Atenolol ± SEM
(mm
Hg
)
SBP DBP HR
0
– 5
–10
–15
–20
–13.4
p<0.01
–3.7
–12.7
–13.8
–16.3
–5.7
p=0.001
p=0.13
Dm
ea
n B
P f
rom
24-h
r m
onitori
ng 0
– 5
–10
–15
–20
Bisoprolol and atenolol in hypertensive subjects > 60
Neutel JM et al. Am J Cardiol 1993; 72: 41–46
Db
ea
ts/m
in
Bryan Williams, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 2015 September 21, 2015
Bisoprolol – most effective in reduction of diastolic blood pressure (PATHWAY-2)
Bryan Williams, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 2015 September 21, 2015
Bisoprolol was most effective in patients with high-renin resistant hypertension (PATHWAY-2)
RR Holman et al.. Long-Term Follow-up after Tight Control of Blood Pressure in Type 2 Diabetes.N Eng J Med. 2008;359:1565-76
UKPDS at 20-year follow up: significant reduction in mortality in patients treated with beta-blocker
• No data on basal heart rate
• Heart rate as an indicator of higher doses = more severe hypertension
• Heart rate < 50/min is not normal (!)
• Mostly (78% patients) studies with atenolol
• Relationship not observed in placebo studies
• Outcomes in the trials mostly affected by BP difference
• Beta-blocker are not given in hypertensive pts according to HR
Beta-blocker-induced heart rate lowering and cardiovascular outcomes
Objections
S Bangalore, et al. Beta-Blocker Use and Clinical Outcomes in Stable Outpatients With and Without Coronary Artery Disease. JAMA. 2012;308(13):1340-1349
In patients with prior MI use of beta-blockers was not associatedwith a lower risk of composite cardiovascular eventsPropensity score analysis of data from REACH Registry
• Mostly (78% patients) studies with atenolol
• Observational study
• 36% patients on beta-blockers
• 74% without beta-blockers
• Unobserved confounding by atrial fibrillation, renal dysfunction, COPD
• Comparing current users with nonusers and past users
In patients with prior MI use of beta-blockers was not associatedwith a lower risk of composite cardiovascular eventsPropensity score analysis of data from REACH Registry
Chocolate Consumption, Cognitive Function, and Nobel Laureates
Franz Messerli. N Eng J Med. 2012; 167: 1562-4
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