CURRENT STATUS OF BETA BLOCKER USE IN CARDIOVASCULAR DISEASES

History

• Beta-blockers were first developed by Sir James Black at the imperial chemical industries in the United Kingdom in 1962.

• They are considered one of the most important contributions to clinical medicine and pharmacology in the 20th century.

• Sir James Black was awarded the Nobel prize in 1988 for advances in medicine.

Today’s talk will include

• The pertinent clinical pharmacology of beta-blockers

• Their clinical use in cardiovascular medicine.

CLASSIFICATION

Actions of beta receptor stimulation

Beta 1 VS Beta 2 Selectivity

300:1

1:35 1:35

1:75

increasing ß1-selectivity

increasing ß2-selectivity

ICI 118.551

1.8:1 Propranolol

Atenolol Betaxolol

Bisoprolol

no selectivity

Ratio of constants of inhibition

1:20

Metoprolol

1-selectivity of various -blockers

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

Summary of use of beta blockers in cardiovascular diseases

ACTIONS OF BETA BLOCKERS

Mechanism of β-blocker benefitsin ischemic heart disease

• Reduction in myocardial oxygen requirements via a decrease in heart rate, blood pressure and ventricular contractility.

• Slowing of the heart rate prolongs coronary diastolic filling period.

• Redistribution of coronary flow toward vulnerable sub-endocardial regions.

Mechanism of β-blocker benefitsin ischemic heart disease

• Increases threshold to ventricular fibrillation.

• Reduction in infarct size and reduction in the risk of cardiac rupture.

• Reduction in the rate of reinfarction.

• Regression of the atheromatous process.

• Atheromatous plaque stabilisation (rupture less likely).

β-Blockers and atheromatous plaqueregression/progression/vulnerability stability

Decrease in coronary atheromatous plaque volume by BB

(as assessed by intracoronary ultrasound) over 1 year (independent of statins, ACE inhibitors, other drugs, low-density lipoprotein concentration, and heart rate). ns, not

significant; sig, significant.

Sipahi I, Tuzcu EM, Woski KE, et al. Ann Intern Med 2007;147:10–18

MECHANISM OF BETA BLOCKERS IN HEART FAILURE

• Upregulation of β receptors and improved β adrenergic signaling.

• Reducing the hyperphosphorylation of calcium release channels of sarcoplasmic reticulum and normalizing their function

• Bradycardia (↑ coronary blood flow and decreased myocardial oxygen demand).

• Protection from catecholamine myocyte toxicity.• Suppression of ventricular arrhythmias.• Anti-apoptosis. β2 receptors, which are relatively increased, are

coupled to inhibitory G protein & block apoptosis.• Inhibition of RAAS. When added to prior ACE-I or ARB,

metoprolol augments RAAS inhibitors

β-Blockers and the inflammatory process

The effect of monotherapy antihypertensive treatments upon plasma C-reactive

protein levels. ACE/ARB, angiotensin-converting enzyme/ ACE receptor blocker;

CCB, calcium channel blocker.

Palmas W, Ma S, Psaty B, et al. Am J Hypertens 2007;20:233–41

Reduction in Vascular markers with BB

JNC 7 recommendations

Beta blockers for hypertension

• In the 1980s, beta-adrenergic receptor blockers (beta blockers) became the most popular form of antihypertensive therapy after diuretics, reflecting their relative effectiveness and freedom from many bothersome side effects

• Because beta blockers reduce mortality in patients post–myocardial infarction or heart failure (i.e., secondary prevention), it was assumed they would also provide special protection against initial cardiac events (i.e., primary prevention).

Beta blockers for hypertension….any benefit in primary prevention??? NO

• In multiple large RCTs, the use of a beta blocker (particularly atenolol) provided no more protection against the first myocardial infarction (MI) than other drugs and was associated with a statistically significant 16% increase in the incidence of stroke.

• rationale—beta blockers lower brachial systolic BP equally but do not lower aortic pressure as well as other drugs. They reduce heart rate and increase peripheral resistance, so that the arterial wave reflection from the periphery returns during systole rather than during diastole.

This is how braunwald’s textbook summarizes the use of betablockers in hypertension

• “Beta blockers are specifically recommended for hypertensive patients with concomitant coronary disease, particularly after a myocardial infarction, congestive heart failure, or tachyarrhythmias.”

• “If a beta blocker is chosen, the agents that are more cardioselective offer the likelihood of fewer perturbations of lipid and carbohydrate metabolism and, because of fewer side effects (except for bradycardia), better adherence to therapy.”

• “Long-acting formulations are better for once-daily dosing.”

Page 945 braunwald’s textbook of medicine 9th edition

Copyright © The American College of Cardiology. All rights reserved.

From: Cardiovascular Protection Using Beta-Blockers: A Critical Review of the Evidence

J Am Coll Cardiol. 2007;50(7):563-572. doi:10.1016/j.jacc.2007.04.060

Proposed Use of Beta-Blockers for Hypertension

In patients with uncomplicated hypertension, beta-blockers should not be used as first-line agents. However, in patients with uncontrolled hypertension on various other antihypertensive agents and in those with complicated hypertension, beta-blockers should be considered in the armamentarium of treatment. CHF = chronic heart failure; MI = myocardial infarction.

Figure Legend:

Changing patterns of betablocker use

BISOPROLOL…. THE MOST CARDIOSELECTIVE BETA BLOCKER

Bisoprolol experience in Indian patients

Mar 2012

Objectives: This study was aimed to evaluate the efficacy and

tolerability of bisoprolol, in Indian patients diagnosed with stage I essential hypertension as first line drug.

Primary and secondary outcomes measures:• The primary outcome measure was percentage

of patients achieving blood pressure (BP) <140/90 mm Hg at the end of 12 weeks, while multiple secondary outcome measures were assessed.

Bisoprolol in hypertension

Channaraya V, Marya RK, Somasundaram M, et al. BMJ Open 2012;2:e000683

• Results: – 2131 (96.44%) patients

achieved BP control. – There was significant reduction

in systolic blood pressure (25.29; SD: 13.22 mm Hg), diastolic blood pressure (14.14; SD: 7.67 mm Hg) and heart rate (12/min; SD: 6.15) compared with baseline (all p values <0.05).

– The median dose of bisoprolol and average period required for the response were 5 mg/day and 33 days,

Baseline 2 4 8 120

20

40

60

80

100

120

140

160

180

SBPDBP

65

70

75

80

85

90

HR

HR

Channaraya V, Marya RK, Somasundaram M, et al. BMJ Open 2012;2:e000683

Bisoprolol: Pharmacology• Pharmacology

–Bisoprolol is a highly potent ß1 adrenoceptor blocking agent

–No ISA–No pronounced negative inotropic effects–Low affinity for ß2-receptors involved with

metabolic regulation• does not influence airways resistance• no adverse changes in lipid profile• no adverse changes in blood glucose levels

–Maximal antihypertensive effect reached in 2 weeks

Modified from: 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

Highly β1-selective

1:35

1:75

Increasing β1-selectivity

Increasing β2-selectivity 1.8:1 Propranolol

Atenolol

Bisoprolol

No selectivity

Ratio of constants of inhibition

1:20Metoprolol

ß1-selectivity of bisoprolol compared with other ß-blockers

Selectivity at clinical dose

β1-adrenoceptor occupancy, as achieved in a dosage interval of 24 h equivalent to a single dose

ß1- and ß2-receptor occupancy in relation to plasma concentrations

Wellstein A et al. J Cardiovasc Pharmacol 1986;8(Suppl. 11):41–54Wellstein A et al. Eur Heart J 1987;8(Suppl. M):3–8

AtenololOccupancy Ration = 80% : 20%

BisoprololOccupancy Ration = 100% : 0%

Bisoprolol in HTN with COPD 2013

•Cardioselective beta-1 blockers such as metoprolol, bisoprolol, or nebivolol may be beneficial in COPD.

•Atenolol does not reduce cardiovascular events in patients with hypertension.

•Nonselective beta blockers such as propranolol may induce bronchospasm and should not be used in patients with COPD

Dipak Chandy1, Wilbert S Aronow2, Maciej Banach3, 1Division of Pulmonary, Critical Care and Sleep, 2Division of Cardiology, Department of Medicine, New York Medical College, Valhalla, NY, USA; 3Department of Hypertension, Medical University of Lodz,Lodz, Poland) - Current perspectives on treatment of hypertensive patients with chronicobstructive pulmonary disease

Comparison of PK properties of BB

True OD

administrat

ion

Metabolic DisturbanceChange in plasma triglyceride and high-density lipoprotein (HDL) levels in normocholesterolemic hypertensive patients after long-term therapy with propranolol (nonselective), atenolol (moderately β1-selective), mepindolol (nonselective with ISA), and bisoprolol (highly β1-selective).

Fogari R, Zoppi A. Rev Contemp Pharmacother 1997;8:45–54.

** **** **

**

**

** ****

*

6 12 18 24 30 36 months

Bisoprolol 10 mg/day (n=17)

Propranolol 160 mg/day (n=15)Atenolol 100 mg/day (n=22)

vs baseline

*p<0.05**p<0.01

%

HD

L-ch

ole

stero

l

+10

0

-10

-20

-30

-40

Difference in effect on lipid profile

– Beta-1 selectivity is the key.

Different beta blockers and sexual dysfunction versus placebo

Elimination routes of various beta blockers from body

Product Information for Bisoprolol

Product Information for Bisoprolol

Use in Pregnancy: not labeled; though used by many

COMPARISONS

Atenolol BisoprololModerately β1-selective Highly β1-selective

No first-pass effect Little first-pass effect (10%)

Bioavailability: 40-50% Bioavailability: 90%

Unchanged renal elimination=> dose reduction in renal impairment

Balanced clearance: no dose adjustment in mild-to-moderate renal impairment. Do not exceed 10 mg in severe cases

Once-daily administration (SPC!) BUT: twice daily necessary

Once-daily administration sufficient and clinically proven

24 h Peak-trough BP control ratio 31% 24 h Peak-trough BP control ratio 78%

No CHF indication CHF indication

Competitor ß-blocker Pharmacology: atenolol

Bisoprolol Vs Atenolol: ABPM study results

• Multi-centric, double-blind, randomized ABPM study.

• Bisoprolol (10 – 20 mg/OD) Vs Atenolol (50 – 100mg/OD) for 8 weeks.

• N = 659. • Efficacy Variables –

–Average 24 hour fall in BP–Night time 4 hour fall in BP–Fall in BP from BaselineNeutal J et al. Am J Med,1993;94(2):181-187

Bisoprolol Vs Atenolol: Change in night time BP

|------------------------------------P value > 0.05------------------------|

|-----P<0.05----|Night Time Fall in BP

Neutal J et al. Am J Med,1993;94(2):181-187

Bisoprolol Vs Atenolol: Conclusion

• Conventional BP measurement fails to detect difference between bisoprolol and atenolol.

• Bisoprolol – –Greater fall in DBP from baseline than atenolol.

–Greater fall in SBP and DBP in night time BP than atenolol.

Neutal J et al. Am J Med,1993;94(2):181-187

Competitor ß-blocker Pharmacology: metoprolol succinate

Metoprolol (succinate) Bisoprololβ1-selective (due to ZOK formulation) Highly β1-selective

50% bioavailability due to first-pass elimination (CYP2D6)

High bioavailability, small first-pass-effect

Dose-reduction in hepatic impairment required

Balanced clearance: no dose adjustment in mild-to-moderate hepatic impairment. Do not exceed 10 mg in severe cases

Once-daily administration (due to ZOK formulation)

Once-daily administration

CHF indication proven (MERIT-HF) CHF indication proven (CIBIS II)

Competitor ß-blocker Pharmacology: metoprolol tartrate

Metoprolol (tartrate) BisoprololModerately β1-selective, reliable selectivity only in lower dose range

Highly β1-selective

Bioavailability: 50% High bioavailability, small first-pass-effect

Predominantly hepatic clearance:Dose-reduction in hepatic impairment required (CYP2D6)

Balanced clearance: no dose adjustment in mild-to-moderate hepatic impairment. 10 mg in severe cases not to be exceeded

Short half-life of 3–4 h, no once daily administration

Once-daily administration

No CHF indication proven CHF indication proven

180

160

140

120

100

80

9080706050

mm Hg SBPn.s.

DBP

2-4 weeks0 + 2 + 4weeks

placebo ß-blocker

p < 0.01p < 0.05

HRbeats/min

Bisoprolol (n = 44)Metoprolol (n = 43)

B vs. M

n.s.= not significant

*

** **

* **

***

Haasis R et al. Eur Heart J 1987; 8 (Suppl M): 103–113

± SDx_

Bisoprolol Vs Metoprolol : Change in

BP & HR (at rest)

0

20

40

60

80

100

%

90%

SBP

Bisoprolol 10 mg

Metoprolol 100 mg

HR RPP

66%

93%

54%

92%

60%

n = 87

Haasis R et al. Eur Heart J 1987; 8 (Suppl M): 103–113

Bisoprolol Vs Metoprolol : 24 hr Efficacy

Competitor ß-blocker Pharmacology: nebivolol (1)

Nebivolol BisoprololHighly β1-selective Highly β1-selective

No adverse effects on lipid/glucose metabolism

No adverse effects on lipid/glucose metabolism

Vasodilatation via L-arginine/NO pathwayEnhanced NO release due to ISA at β2 or β3-receptors: stimulation β3=> negative inotropic effects

No ancillary properties

Bioavailability: 90% (poor metabolisers)Bioavailability: 12% (fast metabolisers)

Bioavailability: 90%

t½: 8 h (fast metabolisers) to 27 h (poor metabolisers)

t½: 10–12 h

Figure 12: Bisoprolol compared with nebivolol (part 1 of 2)

Competitor ß-blocker Pharmacology: nebivolol (2)

Nebivolol BisoprololIncrease in plasma concentration of nebivolol and active metabolites in patients with renal dysfunction

Balanced clearance: 2 independent and equally effective routes of clearance

High protein binding: ~98% Low plasma-protein binding: 30%

CHF indication (based on a composite endpoint of all-cause mortality & CV hospital admission)No significant mortality reductionIndication limited to elderly (70 years)

CHF indication with proven signifcant mortality reduction

No CAD indication CAD indication approved

Figure 12: Bisoprolol compared with nebivolol (part 2 of 2)

BISOPROLOL Vs

NEBIVOLOL

BISOPROLOL Vs

NEBIVOLOL

BISOPROLOL Vs

NEBIVOLOL

Indirect comparison 2013

STUDY BISOPROLOL NEBIOLOL

MAIN CHF II At half dose, LVEF increases ----

SENIORS ---- No significance on LVEF

Also,

NEBIVOLOL

Competitor ß-blocker Pharmacology: carvedilol

Carvedilol BisoprololNot β1-selective Highly β1-selective

Vasodilatation due to α1-blockade (but may cause orthostatic disorders)

No α1-blocking activity

Metabolic effects (in some studies):• No influence on carbohydrate

metabolism• Positive effect on lipids (HDL and

LDL)• Negative lipid effect (cholesterol, TG,

VLDL )

No relevant influence on carbohydrate metabolism

Lipid profile (almost) not affected

Antioxidative effect? No studies available

Antiproliferative effect? No studies available

Figure 13: Bisoprolol compared with carvedilol (part 1 of 2)

Competitor ß-blocker Pharmacology: carvedilol

Carvedilol BisoprololBioavailability: 25% Bioavailability: 90%

Protein binding: >98% Protein binding: 30%

Oral bioavailability of digoxin increased No interaction with other CV drugs known

Extensive metabolism in the liver (CYP2D6)Dose adjustment in patients with hepatic impairment

Balanced clearance: 2 independent and equally effective routes of clearanceNo dose adjustment required (10 mg not to be exceeded in terminal insufficiency)

Sensitive to liver enzyme induction Almost insensitive to liver enzyme induction

t½ 610 h => b.i.d. administration (extended release formulation available)

t½: 1012 h, once-daily administration

Figure 13: Bisoprolol compared with carvedilol (part 2 of 2)

6. CIBIS–ELD 2011

CIBIS–ELD 2011

CIBIS–ELD 2011

CIBIS–ELD 2011

CIBIS–ELD 2011

• More pulmonary adverse events occurred with Carvedilol.

7. Bisoprolol Vs

Carvedilolin

CHF and COPD2011

Bisoprolol Vs

Carvedilol

Bisoprolol Vs

Carvedilol

THANKYOU!

Cardiovascular contraindications

Classification of β-blockers

1st Generation Non-selective Propranolol

2nd Generation β1-selective

AtenololMetoprololBetaxololBisoprolol

3rd Generation

Additional properties, for

example vasodilation

CarvedilolNebivolol

Table 6: Classification of ß-blockers