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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)
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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
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100
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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
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15
30
45
60
75
# o
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atie
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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.