Nebil

HYPERTENSIONT H E D A J A L O F 2 1 S T C E N T U R Y

P r e s e n t e d b y

DR. ABDUL RAB SHAIKH M D C A R D I O L O G Y ( U K )D I P L O M A I N C A R D I O L O G Y ( U K )C O N S U LTA N T I N T E R V E N T I O N A L C A R D I O L O G I S TR E D C R E S C E N T I N S T I T U T E O F C A R D I O L O G Y.

CARDIOVASCULAR MORTALITY RISK WITH 20/10 MMHG INCREMENTS IN SBP/DBP*

2X risk

4X risk

8X risk

1X risk

8

6

4

2

0

Car

dio

vasc

ula

r m

ort

alit

y ri

sk

115/75 135/85 155/95 175/105

SBP/DBP (mmHg)

Lewington et al. Lancet 2002;360:1903–13

*Individuals aged 40–69 yearsSBP = systolic blood pressureDBP = diastolic blood pressure

Risk is multiplied…Not added

2 MM HG BP REDUCTIONS CAN SIGNIFICANTLY REDUCE THE RISK OF CV EVENTS

Lewington S et al. Lancet 2002;360:1903-1913.

2 mm Hg decrease in mean SBP

10%

7%

• Meta-analysis of 61 prospective, observational studies• 1 million adults

Every digit counts in BP reduction

Aprovel Vs. Other Antihypertensive

How to get rid of this Dajjal.

• Phase 1 – dietary protocols.• Phase 2 - medical therapy.

JNC 7: Treatment Algorithm for Hypertension

SBP=systolic blood pressure; DBP=diastolic blood pressure; ACEI=angiotensin- converting enzyme inhibitor; ARB=angiotensin receptor blocker; BB=b-blocker; CCB=calcium channel blocker

JNC 7. May 2003. NIH publication 03-5233.

Optimize dosages or add additional drugs until goal blood pressure is achieved.Consider consultation with hypertension specialist.

Not at goal blood pressure

Without compelling indications

Stage 1 hypertension(SBP 140–159 or DBP 90–99 mm Hg)Thiazide-type diuretic for most.May consider ACEI, ARB, BB, CCB, or combination.

Stage 2 hypertension(SBP ³160 or DBP ³100 mm Hg)Two-drug combination for most (usually thiazide-type diuretic and ACEI or ARB or BB or CCB).

Lifestyle modifications

Not at goal blood pressure (<140/90 mm Hg)(<130/80 mm Hg for those with diabetes or chronic kidney disease)

Initial drug choices

With compelling indications

Drugs for compelling indicationsOther antihypertensive drugs (diuretic, ACEI, ARB, BB, CCB) as needed.

®

© 2003 Thomson Professional Postgraduate Services®

www.lipidhealth.org

• Phase 2 – Medical therapy.

Management of Endothelial Dysfunction

Role of Beta Blockers

Click to edit Master title styleBeta Blockers and Endothelial Dysfunction

• Beta blockers classically do not affect

endothelial dysfunction.

• Only Nebivolol, a beta blocker with

NO donor properties, has been shown

to improve endothelial function.

Journal of Human Hypertension (2005) 19, S21-S25

Click to edit Master title styleComparison of Beta Blockers

Properties Atenolol Metoprolol Bisoprolol Carvedilol Nebivolol

Generation 2nd 2nd 2nd 3rd 3rd

Cost per day 6 6.2 4.5 11 11.5

Initial recommended

dose50mg OD

100 mg OD but

preferably in divided doses

5 mg OD 6.25 mg BD 5 mg OD

Vasodilatory action N N N Y (alpha-1

antagonism)Y (NO

mediated)

Half life Up to 7 hrs Up to 7 hrs Up to 12 hrs Up to 10 hrs Up to 30 hrs

Bioavailability 50% 80% Up to 35% Up to 96%

Sleep disturbance Y Y Y N N

Vascular Health and Risk Management 2007:3 (5) 647-654

Nebivolol

Highly selective β1 antagonist

&

NO mediated vasodilator

Click to edit Master title styleChemical Structure of Nebivolol

Mangrella et al, Pharmacol Res 1998, 38(6); 419-31

RSSS(levo-nebivolol)

(R 67 145)

SRRR(dextro-nebivolol)

(R 67 138)

F

F

N

OOO

O

N

O OO

F

F

O

Click to edit Master title styleUnique Dual Mode of Action of Nebivolol

Cardiovasc 2008; 26:115

Am J Cardio 2003; 92: 344-348

Cardiovasc Ther 2008; 26 (3): 189-202

Nebivolol

d-Nebivolol l-Nebivolol

Highly selectiveβ1 antagonist

Endothelial NOmediated vasodilator

↑ stroke volume

Sustained vasodilation

↓ PVR

↓ heart rate

Click to edit Master title styleThe Cardioselectivity of Nebivolol

Carvedilol Metoprolol Bisoprolol Nebivolol0

5

10

15

20

25

30

35

40

45

0.74.2

15.6

40.7

Brixius K, et al. Br J Pharmacol 2001; 133:1330-8

1-s

elec

tivity

Click to edit Master title styleReduction in Systemic Vascular Resistance:Comparison with Bisoprolol

Clin Drug Invest 2002; 22: 355-9

Bisoprolol Nebivolol2500

2550

2600

2650

2700

2750

2800

2850

29002848 2854

2787

2646

Syst

emic

Vas

cula

r Res

ista

nce

Inde

x(d

yn.s

ec.c

m-5

.m2 )

Click to edit Master title styleBlood Pressure Lowering Efficacy: Comparison with Atenolol

Gracie et al. Blood pressure suppl 2003; 2:35

Series1

-25

-20

-15

-10

-5

0

-18.2

-14.6

-19.2

-14.8

Atenolol 100mg OD

Systolic Diastolic Blood Pressure Blood Pressure

n = 205 hypertensivesDuration = 12 weeks

Click to edit Master title styleBlood Pressure Lowering Efficacy:Nebivolol, Bisoprolol Multicenter Study (NEBIS)

Cardiovasc Drugs Ther 2003; 17:257-63

n = 273Duration = 16 weeks

Response Rate

Bisoprolol Nebivolol88%

89%

90%

91%

92%

93%

90%

92%

Bisoprolol Nebivolol0%

1%

2%

3%

4%

5%

6%

7%

8%

9%

10%8.9%

5.8%

DBP Lowering

AE Rate

Series1

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

-16 -16

Bisoprolol Nebivolol

mm

Hg

Click to edit Master title styleBlood Pressure Lowering Efficacy: Comparison with Metoprolol

Drug Invest 1991; 3:107-10

Metoprolol Nebivolol55%

60%

65%

70%

75%

80%

85%

66%

79%

Complete Normalization of BP

n = 155Duration = 12 weeks

Click to edit Master title styleSustained Blood Pressure Control: Comparison with Bisoprolol & Carvedilol

Cardiology 2006; 106:199-206

Effect on HR During Exercise and Trough to Peak Ratios

Series1

-30%

-25%

-20%

-15%

-10%

-5%

0%

-24%

-17%-15%

Bisoprolol Carvedilol Nebivolol First Morn 10mg 50mg 10mg 1 week 5mg OD 25mg BD 5mg OD

58%

85% 91%% c

hang

e in

Hea

rt R

ate

Column 1: 3 hrs following first doseColumn 2: 24 hrs following first doseColumn 3: 24 hrs following last dose of 7 days treatment

Click to edit Master title styleHaemodynamic Effects of Nebivolol

De Crée J et al. Drug Invest 1991; 3:40-50.

Series1

-30

-20

-10

0

10

20

30 Nebivolol 5mg OD for 14 days Atenolol 100mg OD for 14 daysVa

riatio

n (%

)

EDV ESV SV HR CO LVEF PVR

Metabolic Profile

Nebivolol

Click to edit Master title styleNebivolol and Exercise Tolerance

Van Bortel LMAB. Cardiovasc Drugs Ther 1992;6:239-47.

Placebo Nebivolol 5mg OD Atenolol 100mg OD0

10

20

30

40

50

60

7064

59

50

Endu

ranc

e tim

e (m

in)

8% 22%

Click to edit Master title styleNebivolol and Lipid Metabolism

Pesant Y et al. Am J Ther 1999; 8:283-8.

Series1

-15

-10

-5

0

5

10

15

20

-4.6

-10.1-11.5

-2-2.4 -2.7

8.7

16.3Nebivolol 5mg OD

Atenolol 50mg OD

TC LDL-C LDL-C/HDL-C TG

Chan

ges

in th

e lip

id p

rofil

en = 27Duration = 12 weeks

Click to edit Master title styleNebivolol and Carbohydrate Metabolism

Celik T, et al. J Hypertens 2006;24:591-6

Insulin resistance

Nebivolol 5mg OD Metoprolol 100mg OD0

0.5

1

1.5

2

2.5

3 2.792.67

2.29

2.83

Base

line

Insu

lin re

sist

ance

(HO

MA

inde

x)

Base

line

6 m

onth

s

6 m

onth

s

n = 72Duration = 12 weeks

18% 6%

Click to edit Master title styleNebivolol and New Onset of Diabetes

Agabiti-Rosei E, et al. Drugs 2007; 67:1097-107.

New onset diabetes

Placebo Nebivolol1.6

1.7

1.8

1.9

2

2.1

2.2

2.1

1.8

Even

t rat

e %

per

yea

r 14%

Click to edit Master title styleNebivolol and Erectile Function

Doumas M, et al. Asaian J Androl 2006; 8:177-82.

Patients treated previously with beta-blockers switched to nebivolol

Before Nebivolol After Nebivolol

18%

30%18%

34%

Severe

Moderate

Mild

None

5% 27%

9%

59%

Severity of ED

Click to edit Master title styleNebivolol and Sexual Activity

Boydak B, et al. Clin Drug Invest 2005;25:409-16

Atenolol 50mg OD Nebivolol 5mg OD0

1

2

3

4

5

6

7

8

9

10

8.8

8

4.5

7.6

Sexu

al in

terc

ours

e/m

onth

Base

line

12 w

eeks

Base

line

12 w

eeks

n = 121

5%49%

Role of Nebivolol in HF

Landmark Trials

Click to edit Master title styleComparison with Carvedilol

Lombardo RMR, et al. Am J Cardiovasc Drugs 2006;6:259-63.

A multicentre, double-blind, head to head clinical trial

Study protocol

• CHF patients with left ventricular dysfunction

• Treatment duration: 6 months

• Dosage: Nebivolol 1.25 mg to 5mg OD

Carvedilol 3.125 mg to 25 mg BID

CHF patients with LV dysfunction

Click to edit Master title styleEffect on LV end-systolic volume (ml)

Lombardo RMR, et al. Am J Cardiovasc Drugs 2006;6:259-63.

Carvedilol Nebivolol55

60

65

70

75

80

85

79

7273

66

Base

line

6 m

onth

s

Base

line

6 m

onth

s

7.6% 9.1%

Click to edit Master title styleEffect on LVEF (%)

Lombardo RMR, et al. Am J Cardiovasc Drugs 2006;6:259-63.

Carvedilol Nebivolol30

31

32

33

34

35

36

37

38

39

33

34

37

38

Base

line

6 m

onth

s

Base

line

6 m

onth

s

12% 12%

Click to edit Master title styleThe ENECA Trial

Edes I, et al. Eur J Heart Fail 2005;7:631-9.

Efficacy of Nebivolol in the Treatment of Elderly Patients with Chronic cardiac

failure NYHA Class II-IV as an Add-on therapy to ACE-inhibitors or A-II

antagonists, diuretics and/or digitalis

A multicentre, double-blind, placebo-controlled clinical trial

ENECA trial: study protocol

• Main inclusion criteria: Hospitalised and out-patients aged more than 65 years, chronic heart failure stages (NYHA II – IV), left ventricular ejection fraction (LVEF) ≤ 35%, stable basic medication of heart failure with ACE-inhibitors or angiotensin II A1-receptor antagonists (A-II A), diuretics and/or digitalis for a minimum of 2 weeks prior to inclusion

• Number of subjects =260

• Dosage: Nebivolol 1.25 mg OD, increasing over 8 weeks to maximum target dose of 10 mg OD or placebo for 8 months

• Primary end point: Change on LVEF from baseline after 8 months of treatment

Click to edit Master title styleThe ENECA Trial: Results

Edes I, et al. Eur J Heart Fail 2005;7:631-9.

Relative improvement of LVEF

Placebo Nebivolol 5mg OD0%

5%

10%

15%

20%

25%

30%

35%

40%

20%

36%LV

EF %

impr

ovm

ent

(vis

it 1

vs v

isit

11)

80%

Click to edit Master title styleThe ENECA Trial: Results

Edes I, et al. Eur J Heart Fail 2005;7:631-9.

Survival Rate

Placebo Nebivolol 5mg OD76%

78%

80%

82%

78%

81%Su

rviv

al ra

te (%

)

Click to edit Master title styleThe ENECA Trial: Results

Edes I, et al. Eur J Heart Fail 2005;7:631-9.

Adverse EventsIn

cide

nce

of A

es (%

)

Adverse events Severe adverse events0%

10%

20%

30%

40%

50%

60%

70%

80%

90%78%

15%

81.0%

12.1%

Placebo

Click to edit Master title styleThe SENIORS Trial

Flather MD, et al. Eur Heart J 2005;26:215-25.

Study of Effects of Nebivolol Intervention on Outcomes and

Rehospitalisation in Seniors with Heart Failure

Double-blind, centrally randomized, placebo controlled, multicentre, international trial

SENIORS trial: study protocol

• Main inclusion criteria: Age ≥ 70 years (70-96 years), clinical diagnosis of chronic heart failure (CHF) and either of:

a) documented LVEF ≤ 35% within previous 6 months or

b) hospital admission within previous 1 year for CHF

• n = 2128 in from european countries

• Dosage: Nebivolol 1.25 mg OD, increasing over 16 weeks to maximum target dose of 10 mg OD or placebo

• Primary end point: To evaluate Nebivolol on top of standard therapy on total mortality and morbidity in elderly heart failure patients

Click to edit Master title styleEpidemiology of CHF

20-34 35-44 45-54 55-64 65-74 75+0

2

4

6

8

10

12

0.3 0.5

1.8

5.86.2

9.8

0.3 0.4

1.52.3

4.1

10.9

Men

Women

Ages

Perc

ent o

f pop

ulati

on

Source: CDC/NCHS and NHLBI.

Click to edit Master title styleAge and EF of patients in major placebo controlled trials of BBs in CHF

TrialBeta

Blocker nMean Age

Mean EF

US Carvedilol Carvedilol 1094 58 22

MERIT-HFMetoprolol

XL 3991 64 28

CIBIS-II Bisoprolol 2647 61 28

COPERNICUS Carvedilol 2289 63 20

Overall -- -- 6325(> 40

excluded)

CIBIS II Investigators & Committees. Lancet 1999; 353:9-13; MERIT HF Study group. Lancet 1999; 353:2001-7; Packer M, et al. N Eng J Med 2001; 344(22):1651-8;

Flather MD. EHJ 2005; 26:215-5.

SENIORS Nebivolol 2128 75 35

Click to edit Master title styleSENIORS: distribution of EF

Moen MD, et al. Drugs 2006; 66(10):1389-409.

Click to edit Master title styleThe SENIORS Trial: Results

Modified from Ghio S, et al. Eur Heart J 2006;27:562-8.

Left ventricular remodeling

Placebo Nebivolol

-1

0

1

2

3

4

5

-0.1

4.5

Placebo Nebivolol

-25

-20

-15

-10

-5

0

5

107

-19

Chan

ge in

LVEF

(%)

Chan

ge in

LVES

V (m

l)

Click to edit Master title styleThe SENIORS Trial: Results

Flather MD, et al. Eur Heart J 2005;26:215-25.

All-cause mortality or cardiovascular hospital admission

N. of events: nebivolol 332 (31.1%); placebo 375 (35.3%)

50

40

30

20

10

00 6 12 18 24 30

Months

RRR 14%

Patie

nts

havi

ng a

n ev

ent (

%)

Placebo

Nebivolol

Click to edit Master title styleThe SENIORS Trial: Results

Sudden cardiac death

Patie

nts

havi

ng a

n ev

ent (

%)

25

20

15

10

5

00 6 12 18 24 30

Months

RRR 38%

Moen MD, et al. Drugs 2006; 66(10):1389-409.

Placebo

Nebivolol

Click to edit Master title styleAchievement of Target Dose in BB Trials

CIBIS II Investigators & Committees. Lancet 1999; 353:9-13; MERIT HF Study group. Lancet 1999; 353:2001-7; Packer M, et al. N Eng J Med 2001; 344(22):1651-8;

Flather MD. EHJ 2005; 26:215-5.

Patients reaching target dose

SENIORS (nebivolol 10 mg o.d.)

68%

MERIT-HF (metoprolol 200 mg o.d.)

64%

CIBIS II (bisoprolol 10 mg o.d.) 42%

COPERNICUS (carvedilol 25 mg b.i.d.)

65%

Click to edit Master title styleConclusion

SENIORS provides the first large

scale data for a potentially beneficial

effect of beta blockade in HF patients:

–With preserved EF

– In elderly

Moen MD, et al. Drugs 2006; 66(10):1389-409.

Click to edit Master title styleResults of BB Trials in HF

Trial Beta Blocker % ↓

MERIT-HF Metoprolol XL 34

CIBIS-II Bisoprolol 34

COPERNICUS Carvedilol 35

SENIORS Nebivolol 38

Results for All Cause Mortality

CIBIS II Investigators & Committees. Lancet 1999; 353:9-13; MERIT HF Study group. Lancet 1999; 353:2001-7; Packer M, et al. N Eng J Med 2001; 344(22):1651-8;

Flather MD. EHJ 2005; 26:215-5.

Click to edit Master title styleThe SENIORS Trial: Sub Group Analysis

• Renal impairment is a common finding in

patients with HF and is independently

associated with an increased risk of death.

• No study has previously assessed the

interaction between beta blocker response

and renal function in elderly HF patients.

European Journal of Heart Failure (2009) 11, 872-880

Heart Failure and Renal Impairment

Click to edit Master title styleThe SENIORS Trial: Sub Group Analysis

• The efficacy of Nebivolol is not reduced in

elderly HF patients with mild or moderate

renal impairment.

• In addition, Nebivolol was safe for use in

those with renal dysfunction.

European Journal of Heart Failure (2009) 11, 872-880

Click to edit Master title style

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