This document discusses managing chronic heart failure (CHF) with beta blockers in the era of angiotensin receptor-neprilysin inhibitors (ARNI). It begins by outlining the global prevalence and mortality rates of heart failure, which remain high. It then reviews the mechanisms of benefit of beta blockers in CHF, noting they lower heart rate and mortality risk by blocking sympathetic nervous system overactivation. The document evaluates the efficacy and side effect profiles of various beta blockers, finding bisoprolol to have the lowest rates of adverse events like sexual dysfunction. It concludes by presenting updated treatment algorithms for CHF that incorporate both beta blockers and novel therapies like ARNI, noting ARNI can potentially cause

1. DR JEEWAN MITTAL
MBBS MD (MED) DNB (CARDIO), AFESC
SENOIR CONSULTANT
INTERVENTIONAL CARDIOLOGY AND ELECTROPHYSIOLOGY
AMAR HOSPITAL PATIALA
EX CONSULTANT INTERVENTION CARDIOLOGY
MEDANTA MEDICITY GURGAON
METRO HOSPITAL NOIDA
COLUMBIA ASIA HOSPITAL PATIALA
Managing CHF with beta blockers
in the era of ARNI

2. Flow of the presentation
Role of beta blockers
2
3
BB offers benefits in comorbidities with CHF
4
Magnitude of the problem
1
Comorbidities

3. Global prevalence of HF
~64.3
million
living
with HF
Groenewegen A et al. European journal of heart failure. 2020;22(8):1342-56; Ponikoski P et al Eur Heart J 2016;37:2129-200; Charutvedi V et al. J Pract Cardiovasc Sci 2016;2:28-35
 1% of the general population in India with HF
 Prevalence among >70yrs is rising >10%
 Lifetime risk of HF at age 55 (33% in men & 28% in women

4. Risk for mortality and hospitalization with HFrEF
ESC-HF-LT ASIAN-HF INTER-CHF
Eastern
Europe
Western
Europe
Southern
Europe
Asia-
Pacific
Africa
Middle-
East
Latin-
America
Mortality at 1 year (%) 8 8 7 12 (11-13)a 34 9 9
HF hospitalization at 1 year (%) 13 16 10 15 (14-16)a N/A N/A N/A
aAll cause mortality/hospitalisation per 100 person years
Underlying causes of
death by gender and
LVEF in 463 patients in
the Framingham Heart
Study.
1 year mortality and HF hospitalization in
patients with HFrEF in registries stratified
for geographic region
Registries reported 8-34% mortality and 10-16% HF hospitalization at 1 years in patient with HFrEF
Framingham Heart study also showed that 70-77% of CVD deaths were due to HFrEF
Groenewegen A et al. European journal of heart failure. 2020;22(8):1342-56

5. Heart failure survival rates
23% of Indian patients with heart failure die within a year of
diagnosis
Unadjusted mortality at 1
year by region and cause
The survival rates for HF are worse than for most cancers, e.g. those for bowel, breast or
prostate cancer.2,3
Patients in Africa and India
had the highest mortality
(33·6% & 23·3%
respectively)
Patients in India (hazard
ratio: 2·5) were at highest
hazard of cardiac death
1. Ponikowski P et al. ESC Heart Failure 2014;1:4-25
2. Stewart S et al. Circ Cardiovasc Qual Outcomes 2010;3:573-80
 Mortality with heart failure in India
 22%at 1 year
 42.3% at 5 years

6. Higher discharge HR was associated with a greater risk of all-cause
mortality, cardiovascular death, and hospitalizations for HF
Higher discharge heart rates were associated with greater risk
of mortality at 30 days and at 1 year.1
Habal MV et al. Circ Heart Fail 2014;7:12-20
Association of discharge heart rate with 1-year
cardiovascular death
Association of discharge heart rate with 30-day
cardiovascular death

7. New universal definition of HF: ACC 2021
Ambulatory Hospitalized/
Decompensated
BNP, pg/mL ≥35 ≥100
NT-proBNP, pg/mL ≥125 ≥300
Natriuretic Peptide Levels Supporting Definition of HF
Bozkurt B et al. Journal of cardiac failure. 2021;27(4):387-413.

8. New classification of HF for LVEF: ACC 2021
According to LVEF
This classification is provided for targeting GDMT according to LVEF
indications in different patients
Bozkurt B et al. Journal of cardiac failure. 2021;27(4):387-413.

9. Stages of HF: ACC 2021
Bozkurt B et al. Journal of cardiac failure. 2021;27(4):387-413.
New stages of HF suggested addressing some gaps
identified in current classification according to stages

10. McMurray JJV et al. Circulation. 2021;143:875–877.

11. Reduction in all cause mortality with current therapies for heart
failure
European Cardiology Review 2020;15:e22. DOI:https://doi.org/10.15420/ecr.2019.08
Beta-blockers provide the maximum
survival benefit

12. Effects of different beta-blockers on mortality in large placebo-controlled
heart failure studies1-4
Intrinsic sympathomimetic activity (ISA) reduces efficacy (reduction of all-cause mortality)1-4
1. Cruickshank JM. Are we misunderstanding beta-blockers? Int J Cardiol 2007;120:10–27
2. Cruickshank JM. The modern role of beta-blockers in cardiovascular medicine. People’s Medical Publishing House - Shelton, CT, USA; 2011
3. Cruickshank JM. The beta-blocker story. Getting it right. People's Medical Publishing House - Raleigh, NC,USA; 2017
4. Cruickshank J. Expert Opinion. Nebivolol, a third generation beta-blocker. J Symptons Signs 2014;5(3):380-90
Graph adapted from references 1-4
-40
-30
-20
-10
0
10
20
30
40
Change
in
all-cause
death
(%)
p=0.02
p<0.0001 p=0.0062 p=0.0014
Xamoterol
ISA
Bisoprolol
12%
Nebivolol
ISA
34% 34% 35%
10%
Bucindolol
ISA
Metoprolol Carvedilol
28,5%
n.s. = non-significant
p=0.13
n.s.
p=0.21
n.s.

13. 13
• De-escalation/discontinuation of GDMT after heart
failure hospitalization (HFH) associated with
increased risk of all-cause mortality
• For those in whom GDMT must be held/decreased,
improvement tools at discharge and post-discharge
titration clinics may help ensure lifesaving GDMT regimens
remain optimized

14. Beta-blockers in the treatment of
HF

15. 15
Mechanisms of benefit of beta-blockers in heart failure1-4
Benefits of beta-blockers in CHF are mediated via blockade of beta1 receptors1-3
1. Cruickshank JM. Are we misunderstanding beta-blockers? Int J Cardiol 2007;120:10-27
2. Cruickshank JM. The modern role of beta-blockers in cardiovascular medicine. People’s Medical Publishing House - Shelton, CT, USA; 2011
3. Waagstein F. Beta-blockers in congestive heart failure: the evolution of a new treatment concept – mechanisms of action and clinical implications.
J Clin Basic Cardiol 2002;5:215–23
4. Silke B. Beta-blockade in CHF: pathophysiological considerations. Eur Heart J Suppls 2006;8(Suppl C):C13-C18
Reduction of sympathetic tone3,4
 Increase in vagal tone
 Improved autonomic balance/heart rate
variability
 Reduced sudden death
Antiarrhythmic activity1-4
Reduced sudden death
Up-regulation of cardiac
β1-receptors1-4
Modification of remodelling2-4
 Reverse remodeling
 Reduced LV volumes
 Increased LV ejection fraction
Antagonism of stimulatory
β1-receptor autoantibodies2-4
Restoration of Ca2+ release/cardiac
ryanodine receptor function2
 Probably linked to reduced sudden death risk
Inhibition of catecholamine-
induced necrosis/apoptosis/
inflammation (reduced cytokines)2-4
Inhibition of the renin-
angiotensin system1-4
 Reduced renin release
Heart rate reduction1-4
 Reduced cardiac work and oxygen
requirement
 Prolonged diastolic coronary
filling time

16. How often do we reach these dose levels?
Evidence-based beta-blockers
Bisoprolol Carvedilol Metoprolol succinate
1.25 – 10 mg 3.125 – 25 mg BD (<85 kg)
or 50 mg BD (≥85 kg)
12.5/25 – 200 mg

17. Preference for a particular beta-blocker would be dependent on…
Patient
profile
Concomitant
medications
Comorbid
conditions
Drug
profile

18. High ß1-selectivity of Bisoprolol compared with other ß-blockers
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

19. Pharmacokinetics of selected β-blockers
Criteria Bisoprolol Atenolol Metoprolol Carvedilol Nebivolol*
Plasma elimination half-life (h) 10–12 6–8 3–4 6–7 8/27
Absorption (%) > 90 40-60 > 90 85 >95
First-pass effect (%) < 10 – 25-50 60–75 88/4
Bioavailability (%) 90 50 50-75 25 12/96
Protein binding (%) ~30 3 12 98 98
Borchard U. β-Rezeptorenblocker, Klinik und Praxis, Aesopus Verlag 1996
Cruickshank JM. The modern role of beta-blockers in cardiovascular medicine. 2011 PMPH
*Nebivolol demonstrates complicated pharmacokinetics

20.  Bisoprolol – metabolized
primarily by CYP3A4 (~95%)4
 Only minor contribution of
CYP2D64
 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
Metabolism of Bisoprolol & other ß-blockers
4. Horikiri Y, Suzuki T, Mizobe M. Stereoselective metabolism of bisoprolol enantiomers in dogs and humans. Life Sci. 1998;63(13):1097-108.
6. Concor® / Concor® COR Product information (abbreviated prescribing information), Merck KGaA, Darmstadt, Germany; July 2017.

21. Beta-blockers and sexual dysfunction vs. placebo1,2
Beta-blocker
Sexual dysfunction
(% increase vs. placebo)
Reference
Carvedilol 13.5 Fogari R et al. 2001
Propranolol 5.0 MRC-Mild Hypertension 1981 (1985)
Atenolol 3.0 Silvestri A et al. 2003
Bisoprolol and
Nebivolol
0.0
Broekmann CP et al. 1992
Nurmamedova GS et al. 2007, 2012
1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA; 2011
2. Cruickshank JM. Sympathetic overdrive in hypertension and the role of beta-blockers. Lecture during the satellite symposium
‘The role of sympathetic overdrive in hypertension’ of Merck KGaA (Germany) on 18 June 2017, during the congress of the European Society of Hypertension (ESH) in Milan

22. PK variability of a drug for each study was divided into two
categories:
• high (CV>40%) and
• low/moderate (CV<40%)
• Metoprolol displayed the highest PK variability followed by
carvedilol
• Bisoprolol demonstrated lowest pharmacokinetic variability
Pharmacokinetic variability of commonly used beta-blockers
Bisoprolol
Carvedilol
Metoprolol
Nebivolol
Ågesen FN et al. Pharmacol Res Perspect. 2019;00:e00496

23. Pharmacokinetics of Bisoprolol
Flexible dose timing
Absorption >90% after oral dose and not affected by food
Lesser dose required
Systemic bioavailability 90% & First pass metabolism <10%
Convenient once a day dose
Long plasma half life – 10-12 hrs
Lesser drug interactions
30% Plasma protein binding
Lesser chance of central side effects
Less lipid solubility,
Does not or very less amount cross BBB.
Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011; Pg 30
'balanced' clearance & 50% renal and 50% Hepatic No dose adjustment necessary in mild to
moderate liver or kidney impairment

24. Beta-blockers, particularly those without ISA, effectively lower heart rate in
patients with CHF1
Study b-Blocker Baseline HR HR on Rx D HR
CIBIS8 Bisoprolol 83 67 -16
CIBIS II9-11 Bisoprolol 80 69 -11
MERIT-HF12 Metoprolol succinate 82 68 -14
COMET13 Metoprolol tartrate 81 69 -12
US Carvedilol14 Carvedilol 84 71 -13
COPERNICUS15 Carvedilol 83 70.5 -12.5
SENIORS16 Nebivolol 79 69 -10
BEST17 Bucindolol 82 73 -9
Egan BM, et al. J Clin Hypertens 2005;7:409-16

25. Beta-blockers effectively reduce sudden cardiac death in CHF studies1
Study Drug Placebo [%] Verum [%] ARR [%] RRR [%]
CIBIS II6 Bisoprolol 6.3 3.6 2.7 44
CIBIS I + II7 Bisoprolol 6.1 3.8 2.3 37
MERIT-HF4 Metoprolol 6.6 4.0 2.6 41
COPERNICUS8 Carvedilol 6.1 3.9 2.2 36
CAPRICORN9 Carvedilol 7.0 5.2 1.8 26
BEST10 Bucindolol 15.0 13.4 1.6 12
SENIORS11 Nebivolol 6.6 4.1 2.5 38
BBs reduce sudden cardiac death by 30-50% in patients with hypertension, HF, and CHD.
Sudden death is the most common cause of death in patients with HF.
BBs reduce this risk by up to 45%, which is greater than any other class of antihypertensive or antiarrhythmic agents.1
ARR = absolute risk reduction
RRR = relative risk reduction
Egan BM, et al. J Clin Hypertens 2005;7:409-16

26. Effects of beta-blocker treatment in out-clinic patients with regard to
NYHA class
Distribution of NYHA classes at baseline and during follow-up Changes in heart failure symptoms at follow-up visits.
N= 328 patients with HF
Co-morbidities
 Diabetes in 21%
 lipoid metabolism disorders
25%
 thyroid disorders 5.5%
Received Bisoprolol 1.25 to 10
mg
Significant improvement in NYHA class
from baseline (2.4) to (2) at week 7, (1.9)
at week 19 and (1.8) at week 24 (P <
0.001)
Improvement was maintained throughout the
study.
74% of the patients showed an improvement,
21% no change, and 5% a worsening at final
follow up
The European Journal of Heart Failure 2005; 7: 604– 611

27. Treatment algorithm for GDMT including novel therapies
McMurray JJV et al. Circulation. 2021;143:875–877.

28. Warnings, precautions & adverse events with ARNI
Highlights of prescribing information. Entresto. Revised: 10/2019
With ARNI, hypotension (an adverse event with ARNI) should be
contemplated

29. Alpha & beta-blockade action of Carvedilol
α-blocker
β-blocker
Carvedilol
Vasodilation
Amongst the beta-blockers, Carvedilol
due to its alpha-blocking action can
cause vasodilation/hypotension 
switching such patients to Bisoprolol
has been shown to be beneficial

30. Switching from carvedilol to bisoprolol ameliorates adverse effects in
heart failure patients with dizziness or hypotension
Changes in dizziness and hypotension at pre-switch, and
after-switch.
Conclusion:
Switching form
carvedilol to
bisoprolol may help
with continuation of
beta-blocker
treatment as well as
dosage increase in
patients with adverse
symptoms or signs,
allowing them to
reach the target
dose.

31. Proportion of patients rated as NYHA class I
(no symptoms) or II heart failure increased,
and that of those with class III or IV heart
failure decreased during the interval from
baseline to the 6-month follow-up visit
NYHA functional class was significantly improved from before to 6
months after switching

32. HF & comorbidities

33. In heart failure,
97.5% patients have comorbidities

34. Some co-morbid conditions where selection/efficacy of β-blockers
plays an important role
Atrial fibrillation
up to 35%
comorbid AF and CHF1
Diabetes
44% of patients
hospitalized for CHF
have DM2
COPD
COPD in CHF ranges
from 10% to 40%3
CKD
~20%-74% of CHF
patients have concomitant
CKD4
1. Lubitz SA, et al. Heart Fail Clin. 2010 Apr; 6(2): 187–200.
2. Kenny HC, et al. Circulation Research. 2019;124:121–141.
3. Cardiology in Review 2020;28: 20–25
4. Molnar AO, et al. Nephrol Dial Transplant. 2019 Sep 8. pii: gfz167. doi: 10.1093/ndt/gfz167.

35. Comparative effects of Carvedilol Vs Bisoprolol for severe CHF
Special reference to AF
Survival of patients with AF in the
2 treatment groups
Cardiac event-free patients of patients with
AF in the 2 treatment groups
Bisoprolol had favorable effects in HF patients with AF
Konishi M et al. Circ J 2010; 74: 1127–1134

36. Increasing Bisoprolol dose was associated with lower mortality in
patients with Diabetes
3.5% per mg/day
8.9% per mg/day
Klaus K, et al. Diabetes Care 2018, 41 (1) 136-142.
Kaplan-Meier curves show 5-year all-cause mortality according to the dose of b-blocker in patients with and
without diabetes
(P< 0.004)
(P< 0.001)

37. 1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive
pulmonary disease. 2020 Report. GOLD website: www.goldcopd.org
2. Quaderi SA, Hurst JR. The unmet global burden of COPD. Global Health Epidemiol Genomics 2018; 3, e4: page 1 of 3, doi:10.1017/gheg.201
COPD remains a growing but neglected global epidemic.
COPD is under-recognized, under-diagnosed and under-treated resulting
in millions of people continuing to suffer from this preventable and treatable condition. 1
OUTLOOK:
Despite recent trends in reducing
COPD mortality rates and successes
in anti-smoking efforts in Western
countries, the demographic impact
of ageing in an ever-expanding
world population, joined with other
factors such as high rates of
smoking and air pollution in
Asia, will ensure that COPD will
continue to pose an ever-increasing
problem well into the 21st century.2
Global burden of COPD – the unmet burden
500 1k 1.5k 2k 2.5k 3k 3.5k
Graphic: IMHE - Institute for Health Metrics and Evaluation GBD 2017 © 2020 University of Washington
COPD - both sexes, all ages, 2017, disability-adjusted life years (DAILY) per 100,000

38. Beta blocker use in patients with COPD and CHF with low ejection
fraction
 A randomized, open-label, triple-crossover trial
 N =35
 NYHA (I–III) patients with coexistent COPD
studied respiratory and hemodynamic function
changes after switching between carvedilol,
metoprolol, and bisoprolol.
 FEV1 was highest with bisoprolol (2.0 L),
followed by metoprolol (1.94 L), and lowest in
carvedilol (1.85 L)
 A randomized open label study
 bisoprolol Vs carvedilol
 N=63
 Beta blocker naive patients with CHF +
moderate-to-severe COPD
 a significant increase in FEV1 in the bisoprolol
arm (1.56 ± 0.41 to 1.70 ± 0.52 L; P = 0.046)
but not in the carvedilol arm
Mtisi TF et al. Cardiology in Review 2020;28: 20–25
Prevalence of COPD as a comorbidity in CHF patients ranges from 10% - 40%

39. Association Between Beta-Blockers and All-Cause Mortality in
Patients With COPD and Concurrent CHF in Observational Cohort
Studies
Only high-dose bisoprolol showed a significant
difference in all-cause mortality in patients with
CHF + COPD compared to metoprolol and
carvedilol.
Bisoprolol significantly reduced the risk of
rehospitalization due to CHF and/or COPD
exacerbation (HR = 0.38; 95% CI, 0.15–0.98; P
= 0.046).
BBs showed lower all-cause mortality hazard
ratio (HR) = 0.78
CHF and/or COPD exacerbation was higher in
patients treated with carvedilol (58%) compared
with bisoprolol (17.6%, P = 0.033)
HDB, high-dose bisoprolol; LDB, low-dose bisoprolol
Mtisi TF et al. Cardiology in Review 2020;28: 20–25

40. HF with AF Bisoprolol Vs Carvedilol
Bisoprolol provides favorable effects in patients with atrial
fibrillation Vs Carvedilol
Konishi M et al. Circ J 2010; 74: 1127–1134

41. Sinagra G et al. Pharmacological Research 2020; 156;104785
Flowchart of optimized β-blocker treatment

42. Title of Presentation | DD.MM.YYYY
42
Conclusions
Relative to metoprolol initiation, carvedilol initiation was associated with higher 1-year all-cause and
cardiovascular mortality. One potential mechanism for these findings may be the increased occurrence
of intradialytic hypotension after carvedilol (vs metoprolol) initiation.

43. Beta blocker Dialyzability and Mortality in Older Patients Receiving
Hemodialysis
Weir MA et al. J Am Soc Nephrol 26: 987–996, 2015
Group β-blockers
high-dialyzable (n=3294) metoprolol (70%), atenolol (27%), or acebutolol (3%)
low-dialyzable (n=3294) bisoprolol (97%) or propranolol (3%)
40% higher risk of mortality with highly
dialyzable β-blockers

44. Bisoprolol is associated with a lower risk of all-cause mortality,
MACEs in HF patients undergoing Haemodialysis
All-cause mortality Major adverse cardiovascular events
Both low-dose bisoprolol (1.25–<10 mg/day) or high-dose bisoprolol (10 mg/
day) were associated with a lower risk of all-cause mortality, MACEs and heart failure
20% lower risk of all-
cause mortality
13% lower risk of
MACEs
Ping-Hsun Wu et al. Clinical Kidney Journal 2021;14(3): 983–990

45. The beneficial effects of bisoprolol on mortality and hospitalization for
worsening heart failure were not modified by baseline eGFR(BSA)
Castagno D et al et al. Eur J Heart Fail. 2010 Jun;12(6):607-16
<45
mL/min
45-60
mL/min
60-75
mL/min
>75
mL/min
Patients were divided into four sub-
groups according to baseline eGFR (BSA)
The effect of bisoprolol on the outcome of our post hoc global safety outcome of all-
cause mortality or all-cause hospitalization was consistent across each eGFR(BSA)
category and unmodified by baseline renal function (p=0.81)
Bisoprolol in patients with HF and Renal Impairment (CIBIS-II) (subgroup analysis)
Renal impairment should not prevent the use
of bisoprolol in patients with HF

46. 46 Title of Presentation | DD.MM.YYYY

47.  β-blockers are the cornerstone in the treatment of HFrEF
 Bisoprolol, Carvedilol and Metoprolol succinate are evidenced based β-blockers for the treatment of
HFrEF
 Bisoprolol has the highest β1-selectivity amongst the proven beta blockers, an advantageous PK profile
& has proven efficacy in the landmark CIBIS studies
 Amongst the beta-blockers, Carvedilol due to its alpha-blocking action can cause
vasodilation/hypotension  switching such patients to Bisoprolol has been shown to be beneficial
 In patients with COPD, atrial fibrillation and receiving long term hemodialysis (CKD Stage V), Bisoprolol
appears to be the preferred molecule
Summary