Bisoprolol in Management of

CHF & Hypertension

Evidence based on Comparative Clinical Trials

Dr.A.SIVARAMAN
MD General Medicine
Consultant Physician
Pondicherry

Disclaimer: Medicine  is a rapidly evolving field, while every effort is made to ensure that the data presented is accurate and up to date. Readers should verify all information and data before MYC CODE: CORBIS/0122/00
treating patients or using any therapies described in this presentation
Outline 01
Heart Failure – Global Burden
• Special Features of Indian HF
patients

02 Beta Blockers, Features & Place in

Therapy

03 Bisoprolol Place in Therapy

04 Bisoprolol: Clinical Evidence

Guideline Recommendations,
05
Take Home Message
 Bisoprolol in Beta Blockers,
Management of 01 Features &
Place in Therapy
CHF &
Hypertension

3
 HEART FAILURE: An Emerging Worldwide Threat
Current Worldwide prevalence of HF is estimated at 64.34 million cases (8.52 per 1,000 inhabitants, 29%
mild, 19% moderate and 51% severe HF), accounting for 9.91 million YLDS (11.61 per 1,000 YLDs).1

International CHF Study revealed that Indian HF patients had one of the highest mortality
rates after one year of diagnosis at 23%3

Prevalence in India
> 10 million2

Annual mortality due to HF in India is ~0.1million to 0.16million3

1. AME Med J 2020;5:15

2. Indian Heart J. Jan-Feb 2018;70(1):105-127
YLDS - Years Lost Due to Disability 3. J Pract Cardiovasc Sci 2016;2:28-35
Special Features of Indian HF patients
HF at a younger age than those in the West

The etiology of HF in India is also different from that

in the West

Prognosis of HF in Indian patients appears

to be worse compared to West

Prevalence of risk factors differs between India

and the West

Different Male to Female ratio compared to west

Indian Heart J. 2018 Jan-Feb; 70(1): 105–127
CVD Tops Mortality Cause in India
CVD is the most common cause of deaths in India in all age groups, either
economically backward or advanced states, in rural as well as urban population and
in both genders

Gupta R. et al. Regional variations in cardiovascular risk factors in India: India heart watch. World J Cardiol 2012 April 26; 4(4): 112-120
 Bisoprolol in Beta Blockers,
Management of 02 Features &
Place in Therapy
CHF &
Hypertension

7
Evolution of β-Blockers

1960
1st Gen
NON-SELECTIVE
• Propranolol

1970
2nd Gen SELECTIVE – NONVASODILATING
• Atenolol
• Metoprolol
• Bisoprolol

3rd Gen

4th Gen

1980-90 2007
NON-SELECTIVE – VASODILATING SELECTIVE –VASODILATING
• Carvedilol • Nebivolol
• Labetalol
β-Blockers - Overview

https://www.animalresearch.info/en/drug-development/drug-prescriptions/bisoprolol-fumarate/
Beta Blockers – Mechanism of Action
• Beta blockers compete with noradrenaline
and adrenaline to bind to β 1 adrenergic
receptor.
• Blocking β 1 adrenergic receptor, fails cAMP
to activate PKA
• PKA doesn’t activate Calcium channels that
allow influx of Ca2+ into the cell
• PKA doesn’t activate myosin phosphorylation
which results in a strogner contraction of
myocardial cells

• Reduction in strong heart muscle contraction

• Lowers Blood Pressure

https://www.animalresearch.info/en/drug-development/drug-prescriptions/bisoprolol-fumarate/
Responses stimulated by β-adrenergic receptors in distinctive tissues

Current Hypertension Reviews, 2019, 15, 22-31

β-Adrenoreceptor Selectivity and presence or absence of ISA

ISA - Intrinsic Sympathomimetic Activity Vascular Health and Risk Management 2021:17 337–348
Pharmacologic Properties of beta – Adrenoceptor blockers

Beta-blocker Propranol Metoprolol Atenolol Carvedilol Bisoprolol

Half Life 2-5 hr 2-5 hr 7-20 hr 7-10 hr 14

Lipid solubility Strong Strong Nil Moderate Moderate

Absorption (%) 90 95 50  ND  > 90

Bioavailability (%) 30 50 40    80
Hepatic metabolism
HM HM No HM 50%
(HM)

Renal excretion (RE)     RE   50% RE

Beta1selectivity* + ++ α, β1β2 ++++

*β1β2 not recommended and may cause postural hypotension

 Bisoprolol in Bisoprolol
Management of 03 Place in Therapy
CHF &
Hypertension

14
Bisoprolol – Mechanism of Action
Adrenalin and noradrenalin

Bisoprolol Binds β1 adrenoreceptor

Stimulations β1 adrenoreceptor

Bisoprolol blocks activation of this Activates signaling

cascade cascade

Contractility of Heart muscle Stimulation of the Heart muscle and Pacemaker cells

Blood pressure
Heart rate
Contractility of the Heart Heart rate

https://www.animalresearch.info/en/drug-development/drug-prescriptions/bisoprolol-fumarate/
 Cardio‐Selective Beta‐
Blocker: Pharmacological
Evidence

Cardiovascular Therapeutics, Volume: 31, Issue: 2, Pages: 76-83, 2012

ß1-selectivity

Bisoprolol
1:75

Atenolol Betaxolol
1:35 1:35
Metoprolol
Increasing β1-selectivity
1:20

No selectivity
1.8:1
Propranolol
Increasing β2-selectivity

300:1
ICI118.551
Ratio of constants of inhibition

1. Wellstein A et al. J Cardiovasc Pharmacol 1986;8(Suppl. 11):36–40

2. Wellstein A et al. Eur Heart J 1987;8(Suppl. M):3–8
3. Goodman and Gilman. The Pharmacologic Basis of Therapeutic 12th edn.
 Bisoprolol in Bisoprolol:
Management of 04 Clinical Evidence
CHF &
Hypertension

18
 Beta-Blocking Effects of Carvedilol and Bisoprolol
Randomised, double-blind, placebo-controlled, cross-over trial
Patient Profile: Twelve healthy male volunteers, age 25–42 years

β-blocking effects of carvedilol under

resting conditions appear to be rather
weak, in subjects with low
sympathetic tone, whereas Bisoprolol
exerts significant β-blockade even at
n = 12
rest

Nearly complete lack of β-blocking efficacy under

resting conditions might be the reason for the weak
side effects of carvedilol resulting from β-blockade,
particularly at rest.

Heart rate during exercise, one of the most relevant parameters to determine clinically
effective β-blockade, was decreased by both carvedilol and Bisoprolol. The effects of 2.5,
5 and 10 mg Bisoprolol (–17 %, –21 % and –25 %) appeared more pronounced than those of
25, 50 and 100 mg carvedilol (–17 %, –18 % and –21 %)

Bisoprolol appears to be more potent than carvedilol as a β-adrenergic

antagonist.
Journal of Clinical and Basic Cardiology 2001; 4 (1), 53-56
Effect on survival and hospitalization of initiating treatment for chronic heart failure with
Bisoprolol followed by Enalapril, as compared with the opposite sequence: results of the
randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III
Patient Profile: Patients with mild to moderate CHF and left ventricular ejection fraction < or =35%,
who were not receiving ACE inhibitor, beta-blocker, or angiotensin receptor blocker therapy,

Beta-blockers are as important as ACE-Is in patients with CHF. Whether started before or after ACE-I, beta-blockers
should not be withheld from any patient with CHF and depressed LVEF, unless contraindicated.

Bisoprolol-first strategy is an attractive option in any stable patient without clinically relevant fluid retention, with depressed
LVEF and NYHA class II or III CHF
JRAAS 2005;6:115-20
Implications of CIBIS

1. Lancet 1999; 353: 9–13

2. JRAAS 2005;6:115-20
 The large-scale placebo-controlled beta-blocker studies in systolic heart
failure revisited: results from CIBIS-II, COPERNICUS and SENIORS-SHF
compared with stratified subsets from MERIT-HF

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

 The large-scale placebo-controlled beta-blocker studies in systolic heart
failure revisited: results from CIBIS-II, COPERNICUS and SENIORS-SHF
compared with stratified subsets from MERIT-HF

Bisoprolol, Carvedilol and Metoprolol CR/XL have

comparable efficacy and tolerability in patients with systolic
HF, irrespective of NYHA class or ejection fraction.
Nebivolol is less effective and is not better tolerated

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

Differences between Bisoprolol and Carvedilol in patients with CHF
& COPD: A Randomized Trial
Patient Population: Elderly patients (73±9 years), predominantly male (81% men). Important co morbidities included ischemic heart disease
and arterial hypertension, patients had average left ventricular fraction of 33±7%, and were in NYHA class II (54%) or III (46%).

Study popukation Pulmonary Forced expiratory volume in 1st

function was moderately second significantly increased
(76%) or severely (24%) in Bisoprolol as compared to
impaired with a FEV1 of Carvedilol
1631±452 ml (60±13% of
predicted).
1750 1734
1698 1704
1700
1650
1600 1561
1550
1500

n = 63 1450
Biso Carve
FEV1 - Baseline FEV1 - Treatment

Bisoprolol induced demonstrable improvement in pulmonary function and caused less adverse events
Respiratory Medicine (2011) 105 S1, S44–S49
 Carvedilol, Bisoprolol, and Metoprolol Use in Patients With
Coexistent Heart Failure and Chronic Obstructive
Patient Profile: Patients with diagnoses of both HF and
COPD

No survival benefit with carvedilol

and metoprolol as recommended by
the HF guidelines.

HRs of bisoprolol were

n = 11,558 statistically significantly lower
in most of subgroups,
suggesting an independent role
of bisoprolol in patient survival.

In Patients with coexisting HF and COPD, a dose–response

survival benefit observed with Bisoprolol use, but not with
Carvedilol or Metoprolol use

Medicine 95(5):e2427
Efficacy & Tolerability of Bisoprolol as first line
antihypertensive in Indian Patients: BRIGHT STUDY
Patient Population: Mild-to-moderate hypertension (WHO stages I and II: mild hypertension—systolic BP (SBP) of 140–
159 mm Hg and diastolic BP (DBP) of 90–99; moderate hypertension—SBP 160–179 mm Hg and DBP 100–109 mm Hg)
who had not received antihypertensive drugs before their screening visit;

n = 186

Bisoprolol provided superior

dynamic HR reduction and
non-inferior dynamic BP
reduction vs. Metoprolol CR in
patients with mild-to-moderate
HTN

BMJ Open 2012;2: e000683. doi:10.1136/ bmjopen-2011-000683

 Effects of Bisoprolol Are Comparable with Carvedilol in Secondary
Prevention of Acute Myocardial Infarction in Patients Undergoing PCI
Patient Profile: Patients who underwent PCI

n = 13,813
MACE-free survival rate was not different between the groups (HR=0.815, 95% CI:0.614-1.081, p=0.156). In the subgroup
analysis, the cumulative incidence of MACEs was lower in the Bisoprolol group in patients having a Killip class of III or IV
than in the carvedilol group (HR=0.512, 95% CI: 0.263-0.998, p=0.049).

Study demonstrated benefit of Bisoprolol in the secondary prevention of acute MI regardless of the presence of heart failure.
Bisoprolol were comparable with carvedilol in the secondary prevention of acute MI in patients who underwent PCI.

Chonnam Med J 2018;54:121-128

Bisoprolol reduces Cardiac Death and Myocardial Infarction in high-risk
patients as long as 2 years after successful major vascular surgery

Patient Population: High-risk patients who were not currently taking beta-blockers were randomized to receive
either oral bisoprolol 5–10 mg daily (n=59) or standard care (n=53).

n = 112
Incidence of cardiac
events during follow-up in
the Bisoprolol group was
12% vs 32% in the
standard care group
(P=0·025).

Peri-operative and long-term post-operative Bisoprolol administration produced a significant, three-fold reduction in
late cardiac death and myocardial infarction rates among high-risk patients after successful major non-cardiac vascular
surgery.
European Heart Journal (2001) 22, 1353–1358
Efficacy & Tolerability of Bisoprolol as first line
antihypertensive in Indian Patients: BRIGHT STUDY
Patient Population: Newly diagnosed with stage I essential HTN as per JNC VII criteria (systolic
blood pressure (SBP) 140-159 mm Hg or diastolic blood pressure (DBP) 90-99 mm Hg)

n = 2161

Response rate of 96.44% was achieved

(BP ≤140 mm Hg and 90 mm Hg) at the
end of 12 weeks treatment with a
median dose of 5 mg/day of Bisoprolol.

Bisoprolol is an effective and safe option to control BP & can be used as first-line antihypertensive in Indian
patients.
BMJ Open 2012;2: e000683. doi:10.1136/ bmjopen-2011-000683
Selective β1-Antagonism with Bisoprolol Is Associated with Fewer Postoperative
Strokes than Atenolol or Metoprolol

Patient Population: 50 yearr or more having non-cardiac, non-neurologic surgery were involved

• Perioperative metoprolol increases postoperative stroke.

The mechanism may be related to attenuated β2-
Metoprolol: ------- Blue adrenoreceptor-mediated cerebral vasodilatation. n = 44,092
Atenolol: ----- Green
Bisoprolol : ------ Red • The authors therefore conducted a cohort to study whether
the highly β1-specific β-blocker (Bisoprolol) was associated
with a reduced risk of postoperative stroke compared with
less selective β-blockers (metoprolol or atenolol)
In a propensity-adjusted cohort study on approximately 2,500
patients undergoing noncardiac, nonneurologic surgery with
perioperative β-blockade, those receiving the β1-selective
agent, bisoprolol, had a five-fold reduced risk of stroke compared
with those receiving nonselective β-blockers

Metoprolol and atenolol is associated with increased risks of post-operative stroke, compared with Bisoprolol

Anesthesiology 2013; 119:777-87

 Respiratory effect of beta-blockers in people with asthma and
cardiovascular disease: population-based nested case
Patient Profile: Cohort consisted of 35,502 people identified with active asthma and CVD

n = 35,502

Cardioselective beta-blocker exposure consisted mainly of atenolol (7.9%) and Bisoprolol (5.4%), whilst non-
selective beta-blocker exposure consisted mainly of Sotalol (0.6%) and Carvedilol (0.4%)

Cardioselective beta-blockers prescribed to people with asthma and CVD were not associated with a
significantly increased risk of moderate or severe asthma exacerbations and potentially could be used more widely
BMC Medicine (2017) 15:18
Bisoprolol for the treatment of symptomatic patients with obstructive
hypertrophic cardiomyopathy (HCM)
Patient Profile: HCM with LVOT gradient ≥50mmHg and Study Design: Retrospective study
NYHA Class II-III symptoms
Overall grp/
Intervention

Sample Size N=92

Dose increased every
Patients received 2 weeks to achieve 1) LVOT gradient <
30mmHg
Bisoprolol starting at target LVOT of <30 Primary endpoint
2) NYHA ≥ 1 class
16 (17%)
1.25mg daily. mmHg or maximum
improvement

tolerated dose 33 (36%)

1) Proportion of 57 (62%)
patients with LVOT
gradient <30mmHg
or < 50mmHg
Secondary 2) Patients with ≥ 1
30(33%)
endpoint NYHA class
improvement
Treatment with Bisoprolol was well-tolerated and effective in 3) Change from
baseline in LVOT 28±14
relieving obstruction and improving symptoms in a significant gradient mmHg
42%
proportion of patients with symptomatic obstructive HCM. reduction

European Heart Journal Supplements, Vol. 23, Issue Supplement G, December 2021 1. LVOTO: left ventricular outflow tract obstruction
 Bisoprolol in Guideline
Management of 05 Recommendations,
Take Home Message
CHF &
Hypertension

33
 Recommendations
Guideline

1. Circulation. 2017;136(6): e137–e161.

2. Eur Heart J. 2016;37(27):2129–2200.
3. Eur Heart J. 2018;39(2):119–177.
4. Eur Heart J. 2018;39:3021–3104
Take Home Message

Use bisoprolol with RAS inhibitor (Add

diuretic if required) for CHF with reduced
Ejection Fraction
Heart
01 failure
02 • Initiate long-term oral treatment of
Bisoprolol within the first 24 hours after
IHD or onset of ACS
ACS • For NSTEMI Continue during and after
HTN hospitalization
• Initiate in stabilized heart failure

03

Bisoprolol is preferred for

hypertensive patients with HFrEF
THANK YOU
MYC CODE: CORBIS/0122/004