strategies for the use of cardioselective beta blockers in cv continuum
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Strategies for the use of Cardioselective Beta Blockers in CV Continuum
Autonomic Nervous System
Sympathetic System
Receptor Organ Physiological Effects
Β1 receptors Heart Increase heart rate and contractilityIncrease AV-node conduction velocity
Kidneys (juxtaglomerular cells) Increase renin release
Β2 receptors Bronchial smooth muscles Bronchodilation
Uterine smooth muscles Uterine relaxation
Bladder detrusor muscle Relaxation
Eye ciliary muscle Relaxation
GI tract Decrease mortality
Liver Increase glucose metabolism, lipolysis
Vascular smooth muscle Relaxation
Β3 receptors Adipose tissues Promote lipolysis
Outline
Sympathetic Nervous System
Beta Blockers as a Class
Key Beta Blocker Competitors
Therapeutic Comparison
Adverse Event Comparison
Conclusion
1st Generation Non-selective
PindololPropranolol
SotalolTimolol
2nd Generation β1-selective
AcebutololAtenololBetaxololBisoprololCeliprololEsmolol
Metoprolol
3rd GenerationAdditional properties, for
example vasodilationCarvedilol (non-selective)Nebivolol (β1-selective)
Classification of Beta Blockers
Beta blockers are not a homogenous group
Property Implication
Beta selectivity Β1 selective blockers are more cardioselective, reducing B2-associated adverse effects.
Intrinsic sympathomimetic activity
β-blockers with ISA are partial agonists at β-receptors:•at low sympathetic tone (eg, at rest, during sleep), they act as agonists • at high sympathetic tone (eg, during exercise), they act as β-blocker (antagonist)
Advantages:•less effects on metabolism (glucose, lipids)•no bradycardia → use proposed in patients with low baseline heart rate
Disadvantages:•generally lower efficacy (hypertension, secondary prevention of MI
Lipid solubilityAllows drug to cross the blood brain barrier, resulting in moreCentral Nervous System effects
Vasodilatatory property
Blood vessels dilate via:-Nitric oxide generation (Nebivelvol)-Alpha receptor blockade (Carvedilil)
Indications
• Hypertension• Stable angina• Post myocardial infarction• Heart failure• Cardiac arrhythmias
• Glaucoma• Migraine • Anxiety-related symptoms• Hyperthyroidism-related symptoms
Outline
Sympathetic Nervous System
Beta Blockers as a Class
Key Beta Blocker Competitors
Therapeutic Comparison
Adverse Event Comparison
Conclusion
Beta Blockers of Interest
Bisoprolol
Atenolol Carvedilol
Metoprolol (tartrate / SR)
Nebivolol
Cardiovascular Continuum
Outline
Sympathetic Nervous System
Beta Blockers as a Class
Key Beta Blocker Competitors
Therapeutic Comparison
− Hypertension
− Coronary Artery Disease
− Post Myocardial Infarction
− Chronic Heart Failure
Adverse Event Comparison
Conclusion
Indications
Bisoprolol Atenolol Carvedilol Metoprolol Nebivolol
Hypertension X X X X X
Chronic stable angina
X X X
Post-myocardial infarction
X
Heart failure X X X
Characteristics
β1 Selectivity
300:1
1:35 1:35
1:75
Increasingβ1-selectivity
Increasingβ2-selectivity
1.8:1 Propranolol
AtenololBetaxolol
Bisoprolol
1:20Metoprolol
Wellstein A et al. J Cardiovasc Pharmacol 1986;8(Suppl. 11):36–40Wellstein A et al. Eur Heart J 1987;8(Suppl. M):3–8
Brixius K, et al. Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in human myocardium. Br J Pharmacol 2001;133;1330–8
Maack C, et al. Characterization of β1-selectivity, adrenoceptor-Gs-protein interaction and inverse agonism of nebivolol in human myocardium. Br J Pharmacol 2001;132:1817–26
B1 selectivity in myocardium
Bisoprolol Nebivolol
16-20 fold 3-4 fold
Due to the conflicting results, both Bisoprolol and Nebivolol are considered highly β1 selective
Outline
Sympathetic Nervous System
Beta Blockers as a Class
Key Beta Blocker Competitors
Therapeutic Comparison
− Hypertension
− Coronary Artery Disease
− Post Myocardial Infarction
− Chronic Heart Failure
Adverse Event Comparison
Conclusion
Hypertension – Blood pressure control
Trial BB1 BB2 Relevant outcome SS
BISOMETN = 87 Biso Meto Greater reduction in exercise BP with Biso Yes
NeutalN= 659 Biso Aten
33% greater reduction in 24-hour DBP with Biso 11.6 vs 8.7 mmgHg Yes
Bühler Biso Aten Target pressure response rate in smokers 80% vs 52%
Yes
GrassiN = 205
Nebi AtenMean BP reduction 18.2/14.6 vs 19.1/14.8 mmHg
No
INT-CAR-07N=99
Carve AtenResponder rate (DBP < 90 mmHg) 84 vs 91%
No
NEBISN = 273 Nebi Biso
Mean DBP reduction; Responder rate (DBP < 90 mmHg)15.7 vs 16.0 mmHg; 92 vs 89.6% No
DavidovN = 276
Biso Place Mean reduction in 24-hour SBP/DBP (5, 10, 20 mg vs placebo)8.6/6.3, 8.6/8.8, 10.9/10.1 mmHg vs 3.3/1.6 mmHg
Yes
HofflerN = 1597
Biso PlaceMean SBP/DBP reduction25/16 mmHg
NR
Most head-to-head trials show similar effectsIn 2 separate trials, Bisoprolol is shown to be superior to Atenolol in −Reducing 24-hour DBP−Achieving a higher target pressure response rate in smokers
Generally, the 5 beta blockers show similar blood pressure control
Hypertension – Long term outcome
Clinical outcomes typically include:
− Cardiovascular events
− Cerebrovascular events
− Mortality (cardiovascular)
− Mortality (cerebrovascular)
− Mortality (all cause)
There are no long term clinical outcome studies that compare the 5 beta blockers (or other beta blockers) in the treatment of hypertension
There are long term clinical outcome studies that compare beta blocker (principally atenolol) in patients with hypertension with other classes of antihypertensive drugs
− Angiotensin Converting Enzyme (ACE) Inhibitor
− Angiotensin Receptor Blocker (ARB)
− Calcium Channel Blocker (CCB)
− Diuretics
There are no long term clinical outcome studies that compare the 5 beta blockers in the treatment of hypertension
Coronary Artery DiseaseThere are limited studies that compare the 5 beta blockers in the management
of stable angina
TrialBB1 & dose
BB2 & dose
Relevant outcome SS
Van der Dose 1999N=368
Carve 100 Meto 200 Exercise tolerance No
Dorow 1990 N=40
Biso 5 Aten 50Frequency of anginal attacks64.3% vs 82.8%
No
There has been no study that show significant difference between the 5 beta blockers in the management of stable angina
Bisoprolol is superior to Nifedipine SR in reducing the:
− number of ischaemic episodes.
− total duration of transient ischaemic episodes
− total ischaemic burden [ST-segment depression (mm) multiplied by duration of ST-segment depression (min)]
− number of weekly anginal attacks
− pronounced morning peak of episode frequency, and also the afternoon peak
von Arnim Th, for the TIBBS Investigators. (TIBBS), a multicenter trial comparing bisoprolol and nifedipine. J Medical treatment to reduce total ischaemic burden: Total Ischemic Burden StudyAm Coll Cardiol 1995;25:231–8
Post Myocardial InfarctionThere are limited studies that compare the 5 beta blockers in the management
of stable angina
Trial BB1 & dose
BB2 & dose
Relevant outcome SS
BISOVID Biso Placebo Reduction in angina episodes. QoL improvement. Yes
CAPRICORN 2004N=1959
Carve Placebo Reduction in mortality, nonfatal MI, and the combination of all-cause mortality or nonfatal MI
Yes
Jonsson et al 2005N=232
Carve Aten Left ventricular ejection fraction. Time to first serious cardiovascular event.
No
Mrdovic et al 2007N=313 Carve Meto
Time to composite adverse effects. Time to composite hard effects. No
Yusuf et al 1985BB with
ISABB without
ISAReduction in post-MI mortality.Greater reduction in BBs without ISA Yes
There has been no consistent differences between beta blockers found in patients with myocardial infarction
Heart Failure
TrialMortality reduction
Sudden death
reduction
Progressive heart failure
reduction
NYHA class improvement
QoL improvement
CIBISBisoprolol
Yes Yes Not proven Yes Not significant
COPERNICUSCarvedilol
Yes Yes ? Not proven Not significant
MERIT-HFMetoprolol SR Yes Yes Yes Not proven Yes
SENIORSNebivolol
Not significant
Not significant
No evidence Not significant No evidence
Bisoprolol, Metoprolol succinate and Carvedilol have each reduced total mortality by about 35%
Nebivolol is superior to placebo in reducing the risk of primary composition outcome of all-cause mortality or cardiovascular hospital admission. However, when the primary outcome was examined individually, there is no significant difference between nebivolol and placebo
4 beta blockers have been shown to reduce mortality in HF
Heart FailureThere are limited studies that compare the 5 beta blockers in the management
of heart failure
Trial BB1 BB2 Main Findings
CIBIS-ELD 2011 Biso Carve
• Comparable overall tolerability to target doses• Bisoprolol: greater reduction in heart rate and more bradycardic adverse events• Carvedilol: greater reduction in forced expiratory volume and more pulmonary adverse events
COMET 2003 CarveMeto
tartrate• Carvedilol extends survival compared with metoprolol
Top Perderson et al 2007
Carve Meto tartrate
• Metoprolol: higher risk of new onset diabetes in HF patients
Masanori et al 2010 Biso Carve• Both equally effective in improving severe heart failure• Bisoprolol: defibrillate more patients with AF to sinus rhythm
Marazzi et al 2010 Biso Carve• Bisoprolol is more effective than carvedilol in decreasing the incidence of post-discharge AF after CABG in patients with decreased left ventricular function
Carvedilol is superior to Metoprolol tartrate in reducing all-cause mortality
Bisoprolol is superior to Carvedilol in defibrillating AF and in decreasing post-discharge AF after CABP in patients with heart failure
Outline
Sympathetic Nervous System
Beta Blockers as a Class
Key Beta Blocker Competitors
Therapeutic Comparison
Adverse Event Comparison
Conclusion
Sexual Dysfunction
Beta-blockerBeta-blocker Sexual dysfunctionSexual dysfunction - % increase vs placebo- % increase vs placebo ReferenceReference
CarvedilolCarvedilol 13.513.5 Fogari R et al 2001Fogari R et al 2001
AtenololAtenolol 3.03.0 Silvestri A et al 2003Silvestri A et al 2003
BisoprololBisoprolol 0.00.0 Broekman CP et al 1992Broekman CP et al 1992
Baseline
47.8 51.6 47.752.7 52.0 50.9
10203040505560
0
Sco
re (
units
– o
ut o
f 10
0)
Placebo Bisoprolol
6 mo.12 mo. Baseline6 mo.12 mo. CIBIS-II
Bisoprolol is associated with a lower risk of sexual dysfunction
Lipid Metabolism
** **** **
***
6 12 18 24 30 36months
Bisoprolol 10 mg/day (n=17)
Atenolol 100 mg/day (n=22)
vs baseline *p<0.05
**p<0.01
∆ %
HD
L-ch
oles
tero
l+10
0
-10
-20
-30
-40
Fogari R et al. J Cardiovasc Pharmacol 1990;16 (Suppl 5):S76–80
Bisoprolol has been shown to have minimal effect on a patient’s long term diabetic profile
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