Strategies for the use of cardioselective beta blockers in cv continuum

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






Conclusion

Beta Blockers of Interest

Bisoprolol

Atenolol Carvedilol

Metoprolol (tartrate / SR)

Nebivolol

Cardiovascular Continuum

Outline





− Hypertension

− Coronary Artery Disease

− Post Myocardial Infarction

− Chronic Heart Failure


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





− Hypertension

− Coronary Artery Disease

− Post Myocardial Infarction

− Chronic Heart Failure


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






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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Strategies for the use of cardioselective beta blockers in cv continuum

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