1. Beta Blockers in Current
Cardiovascular Practice
Dr S C Sinha MD DM FACC FSCAI
Consultant Cardiologist
Indus Hospitals, Visakhapatnam

2. Do we need Beta-blockers?
• JNC-8

4. ESC 2013 guidelines on Arterial Hypertension

5. Table 16: Major drug combinations used in trials of antihypertensive
treatment in a step-up approach or as a randomized combination

6. Association of systolic blood pressure with macrovascular and microvascular
complications of type 2 diabetes (UKPDS 36): prospective observational study
BMJ 2000; 321 doi: http://dx.doi.org/10.1136/bmj.321.7258.412 (Published 12 August 2000)
• 10 mm Hg reduction in SBP was associated with
• 12% Reduction in Any DM related end-point
• 17% Reduction in DM related Death
• 12% Reduction in All-cause Mortality
• 12% Reduction in Fatal and Non-fatal MI
• 19% Reduction in Fatal and non-fatal Stroke
• 13% reduction in microvascular End-points
• 16% Reduction in Death due to PVD
• 12% Reduction in Heart failure

7. Efficacy of atenolol and captopril in reducing risk of macrovascular
and microvascular complications in type 2 diabetes: UKPDS 39
BMJ 1998; 317 doi: http://dx.doi.org/10.1136/bmj.317.7160.713 (Published 12 September
1998)
• Design: Randomised controlled trial comparing an angiotensin
converting enzyme inhibitor (captopril) with a β blocker
(atenolol) in patients with type 2 diabetes aiming at a blood
pressure of <150/<85 mm Hg.
• Conclusion: Blood pressure lowering with captopril or atenolol
was similarly effective in reducing the incidence of diabetic
complications. This study provided no evidence that either drug
has any specific beneficial or deleterious effect, suggesting that
blood pressure reduction in itself may be more important than
the treatment used.

8. Beta Blockers in various Guidelines
• JNC 8, 2014: Beta blockers not included in first line
• ASH/ISH, 2013: Beta blockers not included in first line
• ESH, 2013: Beta blockers Class IA recommendation
• CHEP, 2014: Recommended in age <60Y(grade B)

10. Pharmacology
• Types of beta adreno-ceptors
• Beta-1
• 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

11. Classification of β-blockers
Non-selective β1-selective
No Intrinsic Sympathomimetic
Activity(ISA)
• Tertalolol
• Propranolol
• Timolol
• Sotalol
• Nadolol
• Atenolol
• Bisoprolol
• Betaxolol
• Esmolol
• Metoprolol
• (Nebivolol)
• Bevantolol
Intrinsic
sympathomimetic
activity (ISA)
• Alprenolol
• Pindolol
• Oxprenolol
• Carteolol
• Penbutalol
• Acebutolol
• Celiprolol
Hydrophilic • Nadolol
• Sotalol
• Atenolol
• Celiprolol
With Alpha blocking activity • Labetalol
• Carvedilol
• Bucindolol

12. Nebivolol
• In a laboratory experiment conducted on biopsied heart tissue,
nebivolol proved to be the most β1-selective of the β-blockers tested,
being approximately 3.5 times more β1-selective than bisoprolol.
However, the drug's receptor selectivity in humans is more complex
and depends on the drug dose and the genetic profile of the patient
taking the medication. The drug is highly cardioselective at
5 mg. However, at doses above 10 mg, nebivolol loses its
cardioselectivity and blocks both β1 and β2 receptors.
• Nebivolol is also not cardioselective when taken by patients with a
genetic makeup that makes them "poor metabolizers" of nebivolol
(and other drugs) or with CYP2D6 inhibitors. As many as 1 in 10
whites and even more blacks are poor CYP2D6 metabolizers and
therefore might benefit less from nebivolol's cardioselectivity
although currently there are no directly comparable studies.

13. Nebivolol : Side-effects
• Bystolic is contraindicated in patients with severe bradycardia,
heart block greater than first degree, cardiogenic shock,
decompensated cardiac failure, sick sinus syndrome (unless a
permanent pacemaker is in place), severe hepatic impairment
(Child-Pugh > B) and in patients who are hypersensitive to any
component of the product.
• FDA warning letter about advertising claims
In late August 2008, the FDA issued a Warning Letter to
Forest Laboratories citing exaggerated and misleading
claims in their launch journal ad, in particular over claims
of superiority and novelty of action.

14. Physiologic Actions of
Beta-Adrenergic Receptors (β1)
ORGAN RECEPTOR TYPE RESPONSE TO
STIMULUS
Heart
SA Node
Atria
AV node
His-Purkinje system
β1
β1
β1
β1
Increased heart rate
Increased contractility and
conduction velocity
Increased conduction velocity
Increased automaticity and
system conduction velocity
Ventricles β1 Increased automaticity,
contractility, and conduction
velocity
JGA β1 Increase Renin secretion

15. 15

18. Beta blockers around Us
Atenolol Metoprolol Bisoprolol Carvedilol Nebivolol
Plasma t1/2(h) 6-7 3-7 9-12 6 10
Lipid Solubility 0 + + + +++
First-pass effect 0 ++ 0 ++ +++
Elimination Kidney Liver Liver/Kidney Liver Liver/Kidney
Plasma protein
Binding
10% 12% 30% 95% 98%
Cardio selectivity Selective Selective Selective Β1-β2; 휶 Selective
Bioavailability 40% 50% 88% 30% 12-96%
Β1 blockade potency 1.0 1.0 10.0 10.0 10.0
Interpatient variation
in plasma levels
4-fold 10-fold 0 5-10 fold 7-fold

19. Beta blockers around Us
• Renal failure
• Dose adjustment required for Atenolol, Bisoprolol, Nebivolol
• Safe: Metoprolol, Carvedilol
• Diabetes Mellitus
• Carvedilol+ ACEI/ARB superior to Metoprolol + ACEI/ARB
• Hypoproteinemia

20. Bisoprolol: β2/β1 selectivity ratio at human β-receptors in vitro
Smith C and Teitler M. Cardiovasc Drugs Ther 1999; 13: 123-126
19,6
7,5
6 5,7
0,6 0,3
20
18
16
14
12
10
8
6
4
2
0
ß2/ß1 selectivity ratio
Bisoprolol Betaxolol Metoprolol Atenolol Carvedilol Propranolol

21. Bisoprolol: Comparison to ß1-selective ß-blockers
Criteria Bisoprolol Atenolol Metoprolol Acebutolol Celiprolol
Plasma elimination
half-life (h)
*dose-dependent
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

22. Bisoprolol: Comparison to non-selective ß-blockers
Criteria Bisoprolol Pindolol Propranolol Carvedilol
Plasma elimination
half-life (h)
10 – 12 3 – 4 3 – 4 7
Absorption (%) > 90 90 > 90 85
First-pass effect – – + +
Bioavailability (%) 88 90 30 25
Protein binding (%) 30 60 93 98
Active metabolites – – + +
Balanced clearance + + – –
Borchard U. ß-Rezeptorenblocker, Klinik und Praxis, Aesopus Verlag 1996

23. Secondary prevention of myocardial infarction
with different types of ß-blockers
reduction of
mortality
–30
–20
–10
%
ß-blockers without ISA
ß1-selective
without ISA
ß-blockers with ISA
non-selective
without ISA
ß1-selective
with ISA
non-selective
with ISA
Yusuf S et al. Progress Cardiovasc Diseases 1985; 5: 335–371

24. Data from a large multicenter cohort (N=2024) examined 1-year survival following acute myocardial infarction by β blocker and diabetic
status. Survival from the time of hospital discharge to 1 year was significantly better for patients both with and without diabetes taking
β blockers (p<0.001 for both comparisons). One-year mortality following discharge was 17% vs. 10% for diabetic patients compared
with nondiabetic patients; 10% vs. 23% for diabetic patients taking β blockers compared with diabetic patients not taking β blockers;
and 7% vs. 13% for nondiabetic patients taking β blockers compared with nondiabetic patients not taking β blockers. Adapted from Eur
Heart J. 1990;11:43–50.

25. Heart Rate and Cardiac Rhythm Relationships With
Bisoprolol Benefit in Chronic Heart Failure in CIBIS II Trial
by Philippe Lechat, Jean-Sébastien Hulot, Sylvie Escolano, Alain Mallet, Alain
Leizorovicz, Marie Werhlen-Grandjean, Gilbert Pochmalicki, and Henry Dargie
Circulation
Volume 103(10):1428-1433
March 13, 2001
Copyright © American Heart Association, Inc. All rights reserved.

26. CIBIS II survival curves in patients with sinus rhythm at baseline.
Lechat P et al. Circulation. 2001;103:1428-1433
Copyright © American Heart Association, Inc. All rights reserved.

27. CIBIS II survival curves in patients with atrial fibrillation at baseline.
Lechat P et al. Circulation. 2001;103:1428-1433
Copyright © American Heart Association, Inc. All rights reserved.

28. One-year mortality with SD (Kaplan-Meier estimate) according to baseline heart rate and study
treatment group.
Lechat P et al. Circulation. 2001;103:1428-1433
Copyright © American Heart Association, Inc. All rights reserved.

29. CIBIS III Trial
Cardiac Insufficiency Bisoprolol Study (CIBIS III) Trial
Presented at
The European Society of Cardiology
Hot Line Session 2005
Presented by Dr. Ronnie Willenheimer

30. CIBIS III Trial
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
Monotherapy with beta-blocker
bisoprolol (first 6 mos)
10mg O.D.
n=505
Monotherapy with ACE-inhibitor enalapril
(first 6 mos)
10mg B.I.D.
 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.
Presented at ESC 2005
n=505
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)

31. CIBIS III Trial: Per-Protocol (PP) Primary Endpoint
PP Analysis of death or rehospitalization (%)
p = 0.046 for non-inferiority
32.4% 33.1%
40%
30%
20%
10%
0%
Beta-blocker bisoprolol ACE-inhibitor enalapril
• The per-protocol primary endpoint of
death or rehospitalization did not differ
by treatment group (HR 0.97, 95% CL
0.78-1.21), and
• In the per-protocol group , non-inferiority
criteria, trended to be significant, but
significance was not met
• Baseline characteristics were similar
between the two treatment groups:
•Ischemic heart disease
present in 62% of patients
•Mean LVEF of 28.8% NYHA
heart failure classification was
evenly divided by class II and III
•Adverse even rate was similar
between two treatment groups
Presented at ESC 2005

32. CIBIS III Trial: Intent-to-Treat (ITT)
ITT Analysis of death or rehospitalization
• In the intent-to-treat group, non-inferiority
criteria was met (HR 0.94,
95% CL 0.77-1.16, p=0.019)
• There was no difference in the
individual components of death (n=65
vs n=73, HR 0.88) or hospitalization
(n=151 vs n=157, HR 0.97) among the
intent-to-treat group
• At the end of the monotherapy phase,
there was no difference in the primary
endpoint (HR 1.02, p=0.90)
Presented at ESC 2005
200
150
100
50
0
p=0.44
p=0.86
Death Hospitalization
# of patients
Beta-blocker bisoprolol
ACE-inhibitor enalapril
n=65
n=73
n=151 n=157

33. CIBIS III Trial
75
60
45
30
15
0
# of patients
Worsening CHF requiring hospitalization or
occuring in-hospital
p = 0.23
Beta-blocker bisoprolol ACE-inhibitor enalapril
• Worsening CHF requiring
hospitalization or occurring in-hospital
was non-significantly
higher in the bisoprolol group
(HR 1.25)
• Study drug discontinuation
during the monotherapy arm
occurred in 6.9% of the
bisoprolol-first strategy and
9.7% of the enalapril-first
strategy
Presented at ESC 2005
n=63
n=51

34. 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

41. Beta Blocker Trials in Hypertension
• Primary prevention Trials
ANBP(N=3931) Randomized, Prospective Pindolol, Propranolol,
others
30% RRR
MRC(N=17,354) Randomized, Prospective Propranolol 40% reduction in Stroke
HAPPHY(N=6569) Comparative Atenolol/Metoprolol Vs
Thiazides
NS
IPPPSH (N=6357) RCT Oxeprnolol vs others NS
UKPDS39(N=1148) RCT Atenolol Vs captopril NS

42. Beta Blocker Trials in Hypertension
• Secondary Prevention Trials
BHAT(N=3837) Propranolol,
Post MI
RCT 26% RRR
SHEP (N=4736) Atenolol Placebo controlled 36% reduction in
stroke;26% reduction in
CVD
STOP-Hypertension
(N=1627)
Atenolol, Metoprolol,
Pindolol
38% reduction in stroke
and other primary end-points

43. Conclusion
• “Despite some setbacks, Beta blockers still come closest to
providing all-purpose cardiovascular therapy, with the
conspicuous absence of any benefits for lipid problems.” L
H Opie, Drugs For The Heart, 7 Ed.
• Since there is a plethora of beta-blockers, evidence- based
selection needed for a specific condition.
• Bisoprolol, is closest to being an ideal beta-blocker due to its
various superior pharmacological profile.