Beta Blockers in Current Cardiovascular Practice

Dr S C Sinha MD DM FACC FSCAI

Consultant CardiologistIndus Hospitals, Visakhapatnam

Do we need Beta-blockers?

• JNC-8

ESC 2013 guidelines on Arterial Hypertension

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

• 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

Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational studyBMJ 2000; 321 doi: http://dx.doi.org/10.1136/bmj.321.7258.412 (Published 12 August 2000)

• 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.

Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39BMJ 1998; 317 doi: http://dx.doi.org/10.1136/bmj.317.7160.713 (Published 12 September 1998)

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)

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

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

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.

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.

ORGAN RECEPTOR TYPE RESPONSE TO STIMULUS

Heart SA Node

Atria

AV node

His-Purkinje system

β1β1

β1

β1

Increased heart rateIncreased contractility and

conduction velocityIncreased conduction velocity

Increased automaticity and system conduction velocity

Ventricles β1 Increased automaticity, contractility, and conduction

velocity

JGA β1 Increase Renin secretion

Physiologic Actions of

Beta-Adrenergic Receptors (β1)

15

Beta blockers around UsAtenolol 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 proteinBinding

10% 12% 30% 95% 98%

Cardio selectivity Selective Selective Selective Β1-β2; 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

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

Bisoprolol: β2/β1 selectivity ratio at human β-receptors in vitroBisoprolol: β2/β1 selectivity ratio at human β-receptors in vitro

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Bisoprolol Metoprolol CarvedilolBetaxolol Atenolol Propranolol

*dose-dependent

Criteria Bisoprolol Atenolol Metoprolol Acebutolol Celiprolol

Plasma eliminationhalf-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 + – – – –

Bisoprolol: Comparison to ß1-selective ß-blockersBisoprolol: Comparison to ß1-selective ß-blockers

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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 + + – –

Bisoprolol: Comparison to non-selective ß-blockersBisoprolol: Comparison to non-selective ß-blockers

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reduction of mortality

ß-blockers without ISA

ß1-selective without ISA

ß-blockers with ISA

non-selective without ISA

ß1-selective with ISA

non-selective with ISA

Secondary prevention of myocardial infarctionwith different types of ß-blockers

Secondary prevention of myocardial infarctionwith different types of ß-blockers

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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.

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

CirculationVolume 103(10):1428-1433

March 13, 2001

Copyright © American Heart Association, Inc. All rights reserved.

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.

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.

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.

Cardiac Insufficiency Bisoprolol Study (CIBIS III) Trial

CIBIS III TrialCIBIS III Trial

Presented atThe European Society of Cardiology

Hot Line Session 2005

Presented by Dr. Ronnie Willenheimer

Monotherapy with beta-blocker bisoprolol (first 6 mos)

10mg O.D.n=505

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.

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 2005Presented at ESC 2005

Monotherapy with ACE-inhibitor enalapril (first 6 mos)10mg B.I.D.

n=505

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

Randomized32% female, mean age 72 years, mean follow-up 1.22 years13% received aldosterone-receptor blocker and 84% diuretic

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

Randomized32% female, mean age 72 years, mean follow-up 1.22 years13% received aldosterone-receptor blocker and 84% diuretic

Combination beta-blocker and ACE-inhibitor therapy (6-24 mos)

Combination beta-blocker and ACE-inhibitor therapy (6-24 mos)

CIBIS III Trial: Per-Protocol (PP) Primary Endpoint

32.4% 33.1%

0%

10%

20%

30%

40%

Beta-blocker bisoprolol ACE-inhibitor enalapril

PP Analysis of death or rehospitalization (%)p = 0.046 for non-inferiority

Presented at ESC 2005Presented at ESC 2005

• 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

CIBIS III Trial: Intent-to-Treat (ITT)CIBIS III Trial: Intent-to-Treat (ITT)

ITT Analysis of death or rehospitalization

Presented at ESC 2005Presented at ESC 2005

• 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)

0

50

100

150

200

Death Hospitalization

# o

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ati

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Beta-blocker bisoprolol

ACE-inhibitor enalapril

p=0.44p=0.44

p=0.86p=0.86

n=65 n=73

n=151 n=157

CIBIS III Trial

0

15

30

45

60

75

# o

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Beta-blocker bisoprolol ACE-inhibitor enalapril

Worsening CHF requiring hospitalization or occuring in-hospital

p = 0.23

Presented at ESC 2005Presented at ESC 2005

• 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

n=63

n=51

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.

• 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 2005Presented at ESC 2005

Beta Blocker Trials in Hypertension

• Primary prevention TrialsANBP(N=3931) Randomized, Prospective Pindolol, Propranolol,

others30% 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

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

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.