Beta blockers all are not same

NOT ALL BETABLOCKERS ARE SAME
Focus on Bisoprolol
Dr.Nagula Praveen
MD,DM (Cardiology)

Sir James Black
• Nobel Prize in physiology
/medicine 1988

Outline
Hypertension
Heart failure and its management
Beta Blockers
Beta blocker in hypertension
β-blockers (BB) in HF treatment
ß1-selectivity of Various ß-blockers
Bisoprolol
Clinical Pearls
Summary

Beta Blockers
• Beta-blockers refer to a mixed group of drugs with diverse pharmacodynamics and
pharmacokinetic properties.
• They have shown long term beneficial effects on mortality and cardiovascular disease
(CVD) when used in people with heart failure or acute myocardial infarction.
• Beta-blockers were thought to have similar beneficial effects when used as first-line
therapy for hypertension.
Farzam K et al., Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available

Classification Of β Blockers
JAPI Suppl; Dec 2009; 57: 7 – 12

Heart Failure
HF worldwide prevalence is
>37.7 million, in India it is
around 10 millon.
Annual mortality due to HF in
India is ~0.1 mn to 0.16 mn.
The current estimates
about incidence of HF
in India vary widely
from 1.3 to 23 million.
In International CHF Study, it
was found that heart failure
patients in India had one of the
highest mortality rates after
one year of diagnosis at 23%.
1. Indian Heart J. Jan-Feb 2018;70(1):105-127;
2. J Pract Cardiovasc Sci 2016;2:28-35
Epidemiology Of HF

Management Of Heart Failure
Class of drug Example
ACE inhibitors Captopril, Enalapril, Ramipril
ARBs Valsartan, Losartan, Candesartan
ARNI Sacubitril (given with ARB)
Beta blockers Bisoprolol, Metoprolol, Carvedilol
MRA Spironolactone, Eplerenone
Loop Diuretics Furosemide, Torsemide
Thiazide diuretics Hydrochlorothiazide
Other Ivabradine, Digoxin
Interventions: Cardiopulmonary resuscitation – CPR, Cardioversion, PCI, CABG, Pacemaker, Implantable
cardioverter defibrillator (ICD), Left Ventricular Assist Device (LVAD), Heart Transplant
ACE: angiotensin-converting enzyme, ARB: angiotensin receptor blocker, ARNI: angiotensin receptor-neprilysin
inhibitor, MRA: Mineralocorticoid receptor antagonist

High prevalence and poor BP control rate across the India
In 2017, prevalence of hypertension in India is 30.7
Fig. Hypertension awareness, treatment, and
control at different study sites
Am J Hypertens (2017) 30 (4): 373-381.
Fig. Hypertension awareness, treatment,
and control at urban and rural locations

Am J Cardiol 2010;106:1819 –1825
There are valid reasons to question the utility of certain beta blockers in treating hypertension.
Many of the perceptions about beta blockers are derived from data obtained from studies of traditional
agents or combinations of diuretics and blockers.
There are intrinsic differences among beta blocker class. The vasodilatory beta blockers, which have
generally not been included in comparative meta-analyses, lower blood pressure to a similar degree as
other antihypertensive drugs, may provide better central aortic pressure reductions than traditional
blockers, and are associated with neutral or favorable metabolic effects.
When addressing the question of beta blockers’ effectiveness, the answer lies not in global
generalizations but in assessing individual patients and specific beta blocking agents.

For the ischemic patient, be it early or late intervention post-myocardial infarction, or chronic
ischemia in non-surgical and surgical patients, the significant benefits from beta-blockers in
reducing cardiovascular end-points stem from beta-1 blockade.
Likewise for the heart failure patient, on a background of ACE-inhibition, beta-1 blockade (the
common property of carvedilol, metoprolol and bisoprolol) is responsible for the 35% reduction
in all-cause mortality.
Central obesity in younger subjects is linked to endothelial inflammation and
dysfunction, insulin resistance, markedly increased sympathetic nerve activity and
increased cardiac output, heart rate and blood pressure - hemodynamic scenario
ideal for beta-1 blockade
International Journal of Cardiology 120 (2007) 10–27

In younger hypertensives beta-blockers reverse both ECG – and echocardiographic – LVH. High
beta-1 selectivity ensures reversibility of echocardiographic LVH at least as great as the action
of ACE-inhibitors.
Beta-blocker-induced metabolic disturbance (lipids, blood sugar and insulin-resistance) stems
from beta-2 blockade (and possibly beta-3 blockade). Such disturbances are avoided by high
beta-1 selectivity, beta-2/3 intrinsic sympathomimetic activity or alpha blockade.
In trials involving younger/middle-aged overweight hypertensives (MRC mild Hypertension,
IPPPSH, MAPHY, UKPDS), with relatively narrow pulse pressures, first-line beta-blockade has
been more effective than placebo and diuretics, and at least as good as ACE-inhibitors, in
preventing coronary events

Elderly systolic hypertensives tend to have low plasma renin activity, insensitive beta-
receptors, low/normal cardiac output and non-compliant arteries (wide pulse pressure).
Such a haemodynamic scenario is unsuited to certain first-line beta-blockers e.g. atenolol
and propranolol.
First-line low-dose diuretic therapy with second-line beta-blocker therapy, has a track
record at least as good as other combination therapies in reducing cardiovascular
events in the elderly hypertensive, with the added bonus of a 30% reduction in the
risk of bone fractures.
Overweight/obesity in the younger/middle-aged hypertensive, and its
accompanying increased sympathetic nerve activity, is a positive indication for beta-1
blockade and not a relative contra-indication.

2017 The Role of Beta-blockers in Hypertension
Adv Exp Med Biol. 2017;956:149-166.
β-blockers for Hypertension: Are they Going Out of
Style?

BB reduce mortality and morbidity in symptomatic patients with HFrEF, despite treatment with an
ACEI and, in most cases, a diuretic, but have not been tested in congested or decompensated
patients.
There is consensus that BB and ACEIs are complementary, and can be started together as soon as the
diagnosis of HFrEF is made.
There is no evidence favouring the initiation of treatment with a BB an ACEI has been started.
BB should be initiated in clinically stable patients at a low dose and gradually up-titrated to the
maximum tolerated dose.
In patients admitted due to acute HF (AHF) BB should be cautiously initiated in hospital, once the
patient is stabilized.
Beta-blockers are recommended in patients with a history of myocardial infarction and
asymptomatic LV systolic dysfunction to reduce the risk of death
European Heart Journal (2016) 37, 2129–

300:1
1:35 1:35
1:75
increasing
ß1
-selectivity
increasing
ß 2-selectivity
ICI
1.8:1
Propranolol
Atenolol
Betaxolol
Bisoprolol
no
selectivity
Ratio of constants of inhibition
1:20
Metoprolol
Wellstein A et al. J Cardiovasc Pharmacol 1986; 8 (Suppl. 11): 36-40
Wellstein A et al. Eur Heart J 1987; 8 (Suppl. M): 3–8
ß1-selectivity of Various ß-blockers
Cardioselectivity

Bisoprolol
Bisoprolol is a cardioselective β1-blocker.
It is used along with other β 1-blockers to treat multiple heart diseases such as congestive heart failure,
without having the unwanted effect of the β2 receptor blocking, which can affect multiple systems in the
body.
Bisoprolol is considered to be one of the selective agents indicated in the treatment plan of compensated
heart failure, along with carvedilol and metoprolol.
Selective β - blockers are considered the first-line treatment for chronic stable angina.
It is also FDA approved for the treatment of hypertension, post, or recent myocardial infarction (MI).
Bazroon AA et al., Treasure Island (FL): StatPearls Publishing; 2021 Jan-.

Heart Kidney
Heart Rate Force of
Contraction Secretion of Renin
Beta 1
↑ CO ↑ PR
↑ BP
↑ Work Load on Heart
Heart Failure, LVH
Bisoprolol
Mechanism of Action: Bisoprolol

*dose-dependent
Criteria Bisoprolol Atenolol Metoprolol Acebutolol Celiprolol
Plasma elimination
half-life (h)
10 – 12 6 – 9 3 – 4 7 – 13 5
Absorption (%) > 90 50 > 95 70 50
First-pass effect – – + + –
Bioavailability (%) 88 50 50 40 – 60 50*
Protein binding (%) 30 3 12 11 – 25 25
Active metabolites – – – + –
Balanced clearance + – – – –
Borchard U. ß-Rezeptorenblocker, Klinik und Praxis, Aesopus Verlag 1996
Why Bisoprolol??

–16.5
–12.4
–14.2
–9.9
–12.2
–10.9
–13.2
–8.9
p = 0.03
0
–5
–10
–15
–20
day
(6 a.m. – 10 p.m.) (6 a.m. – noon)
night
(10 p.m. – 6 a.m.)
last 4 hours
of dosing interval
(6 a.m. – 10 a.m.)
p = 0.03
p = 0.54
p <0.05
mean
change
in
systolic
blood
pressure
(mm
Hg
)
Atenolol ( n = 96)
Bisoprolol ( n = 107)
S ± SEM
BISOPROLOL Vs ATENOLOL
Neutel JM et al. Am J Med 1993; 94:181–187
ABPM technique were used to compare between the bisoprolol (10 to 20 mg OD) and atenolol (50
to 100 mg) for blood pressure reduction
n=203

p<0.001
p<0.01
0
–2
–4
–6
–8
–10
–12
–14
–16
–12.8
–8.9
–11.5
–7.7
–9.6
–8.5
–10.9
–7.3
p=0.41
p<0.01
mean
change
in
diastolic
blood
pressure
(mm
Hg
)
day
(6 a.m. – 10 p.m.) (6 a.m. – noon)
night
(10 p.m. – 6 a.m.)
last 4 hours
of dosing interval
(6 a.m. – 10 a.m.)
Atenolol (n = 96)
Bisoprolol (n = 107)
S ± SEM
Neutel JM et al. Am J Med 1993; 94:181–187
BISOPROLOL Vs ATENOLOL

Haasis R et al. Eur Heart J 1987; 8 (Suppl M): 103–113
0
20
40
60
80
100
90%
SBP HR RPP
66%
93%
54%
92%
60%
%
Bisoprolol: 24 H Efficacy In Comparison To Metoprolol
(BISOMET Study)
The effects of the beta blockers on systolic blood pressure, heart rate and rate-pressure product during exercise, 24 h and
3h at rest after administration (p.a.) were compared with the values obtained in the baseline exercise test (El)
Bisoprolol 10 mg
Metoprolol
n = 87
Under Exercise Conditions

180
160
140
120
100
80
90
80
70
60
50
mm Hg SBP
n.s.
DBP
2-4 weeks 0 + 2 + 4 weeks
placebo ß-blocker
p < 0.01
p < 0.05
HR
beats/min
Bisoprolol (n = 44)
Metoprolol (n = 43)
n.s.= not significant
*
*
* *
*
* *
*
*
*
*
BISOMET Study
Haasis R et al. Eur Heart J 1987; 8 (Suppl M): 103–113
At rest

Comparison of Bisoprolol to a metoprolol for control heart rate and blood pressure in mild
to moderate hypertensive patients (CREATIVE Study)
Bisoprolol provided superior dynamic HR reduction and non-inferior dynamic BP reduction vs. metoprolol
. No new safety concerns were found.
n=186
Treatment duration: 12 weeks
Hypertens Res. 2017 Jan;40(1):79-86

Comparing Beta-Blocking Effects of Bisoprolol, Carvedilol and Nebivolol
• Beta-blocking effi cacy of bisoprolol, carvedilol and nebivolol both at rest and during exercise. In addition, we
also determined potential effects of beta-blockade on quality of life (QOL).
Hemodynamic Effects
-Compared to baseline, heart rate during exercise was decreased at 3hr by bisoprolol (–24%), carvedilol
(–17%) and nebivolol (–15%)
- At the end of 1 week of chronic administration by bisoprolol (–14%), carvedilol (12 h!; –15%) and
nebivolol (–13%)
Quality of Life
Total QOL with carvedilol was slightly but significantly lower than that with placebo, nebivolol and
bisoprolol in all cases.
Cardiology 2006;106:199–206

CIBIS II – Cardiac Insufficiency Bisoprolol Study
• Double-blind, placebo-controlled, randomised trial
• 2,647 patients included (NYHA III + IV)
• Bisoprolol administered on top of standard therapy
(diuretic + ACE inhibitor)
• Study Objective
• Primary objective
• All-cause mortality
Lancet. 1999 Jan 2;353(9146):9-13.
• Secondary objectives
Cardiovascular mortality
Hospital admissions
Cardiovascular mortality or cardiovascular hospital
admissions
Permanent treatment withdrawal

Survival
 34% reduction in all-cause mortality with bisoprolol
1.0
0.8
0.6
0
0 200 400 600 800
Time after inclusion (days)
Survival
Bisoprolol: 156 deaths (n = 1327)
Placebo: 228 deaths (n = 1320)
log rank test, p < 0.0001
Lancet. 1999 Jan 2;353(9146):9-13.
Lancet. 1999 Jan 2;353(9146):9-13.

Analysis of time to death
Patients
Unknown cause
of death
Non-cardio-
vascular deaths
Other cardio-
vascular deaths
Myocardial
infarction
Pump
failure
Sudden
death
0.45
(0.27 – 0.74)
0.75
(0.37 – 1.50)
1.17
(0.67 – 2.03)
0.85
(0.31 – 2.34)
83
6%
p=0.0011
48
4%
36
3%
0.56
(0.39 – 0.80)
0.74
(0.48 – 1.14)
Hazard ratio:
(95% CI)
p=0.17
p=0.75
p=0.58
p=0.41
p=0.0012
Bisoprolol (n = 1327)
Placebo (n = 1320)
0
20
40
60
80
100
47
4%
7
1%
8
1%
28
2% 23
2%
14
1%
18
1%
23
2%
49
4%
Lancet. 1999 Jan 2;353(9146):9-13.

Main results at a glance
• All-cause mortality (independent of aetiology) 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)
In the bisoprolol-treated group of patients there was
a reduction in
Lancet. 1999 Jan 2;353(9146):9-13.

Study Conclusions
• CIBIS II successfully demonstrated that ß1-selective bisoprolol given in addition to standard therapy
–
• Reduces significantly all-cause mortality and
• All-cause hospitalisation in CHF patients
• Bisoprolol is the first ß-blocker which has proven its efficacy in a single large-scale CHF study with all-
cause mortality as primary objective
• Bisoprolol was as well tolerated as placebo with a permanent treatment withdrawal rate of 15% in
both groups
Lancet. 1999 Jan 2;353(9146):9-13.

Monotherapy with beta-blocker
bisoprolol (first 6 mos) 10mg O.D.
n=505
 Primary Endpoint: Time-to-the-first-event of combined all-cause mortality and all-cause hospitalization
throughout study.
 Secondary Endpoint: Combined primary endpoint at end of monotherapy phase; individual components of
primary endpoint at study end and at end of monotherapy phase.
CIBIS III Trial
Presented at ESC 2005
Monotherapy with ACE-inhibitor enalapril (first
6 mos) 10mg B.I.D.
n=505
1010 patients > 65 years with mild to moderate CHF (NYHA class II or III) and LV ejection fraction < 35% in 3
months prior to randomization, clinically stable CHF for 7 days
Randomized
32% female, mean age 72 years, mean follow-up 1.22 years
13% received aldosterone-receptor blocker and 84% diuretic
Combination beta-blocker and
ACE-inhibitor therapy (6-24 mos)
Circulation. 2005 Oct 18;112(16):2426-35.
Circulation. 2005 Oct 18;112(16):2426-35.

CIBIS III Trial Summary
• Among patients with newly diagnosed mild to moderate heart failure, a strategy
of initial treatment with the beta-blocker bisoprolol did not meet the criteria for
non-inferiority in the per-protocol population for death or hospitalization
compared with a strategy of initial treatment with the ACE-inhibitor enalapril.
• Non-inferiority was met in the intent-to-treat population.
• Current guidelines recommend first-line therapy with an ACE-inhibitor after initial
heart failure diagnosis, followed by addition of beta-blocker.
Presented at ESC 2005
Circulation. 2005 Oct 18;112(16):2426-35.

Outcomes of major randomized, placebo-controlled trials in patients with heart
failure and reduced ejection fraction
Am J Cardiovasc Drugs (2017) 17:361–373

Journal of Internal Medicine, 2014, 275; 134–143

Design and results of the main clinical trials of beta-blockers in heart failure
CV, cardiovascular; HF, heart failure; LVEF, left ventricular ejection fraction; NNT, number needed to treat; NS, not significant; NYHA,
New York Heart Association. All studies analyzed beta-blockers vs placebo, except COMET (carvedilol vs metoprolol tartrate). All risk
reductions are significant, unless otherwise indicated.
* LVEF was not an inclusion criterion, but 36% of patients had a LVEF > 35%; the patients included were older than 70 years of age.
Rev Esp Cardiol. 2019;72(10):844–852

Clinical Pearls
Essential hypertension
• Meta analysis has shown that Atenolol does NOT
reduce cardiovascular mortality and morbidity or MI
in patients with uncomplicated HTN (n=17671)
• In another meta analysis (n=105951), β blockers
when compared to other antihypertensive agents do
not reduce MI or mortality and have shown ↑ risk of
stroke in elderly (> 60 yrs) by 16%
• β blockers reduce risk of MI and mortality in patients
with essential HTN with ACS, post MI with
symptomatic/ asymptomatic LV dysfunction
Heart failure
• Bisoprolol, metaprolol (SR) and carvedilol
all have been shown to
- reduce symptoms of HF
-↑ QOL scores in HF
- ↓ risk of death (RRR 30%)
- combined risk of death and
hospitalizations (RRR 40%)

Summary
All beta blockers are majorly approved for the treatment of heart failure and hypertension.
They produce unique nitric oxide–mediated vasodilatory effects, lacks intrinsic sympathomimetic activity,
and possess a tolerability profile.
For heart attack survivors, people with angina, or those with heart failure, beta blockers are a must-use
medication because they have been proven to help prevent stroke and other cardiovascular problems.
β‐Blockers have improved survival and are one of the cornerstones in the treatment of ischemic heart
disease; they exert an antianginal effect by reducing the myocardial workload and oxygen demand.
The effects of β‐blockers have been extensively investigated in patients with AMI and the current practice
guidelines also recommend the use of β‐blockers in all patients after AMI unless contraindicated

Beta blockers all are not same

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