FROM HYPERTENSION TO HEART FAILURE:

ROLE OF NOVEL BETA BLOCKER

Irsad Andi Arso, MD, FIHA

KSM Jantung RSUP Dr Sardjito/Departemen
Kardiologi dan Kedokteran Vaskular FK UGM,
Yogyakarta
Introduction
 -blockers:
Compelling Indications

Modified from Chobanian AV, et al. JAMA 2003;289:2560-2572.

 -blockers:
Targets and Receptor Selectivity
 ß-blockers:
Heterogenous Drug Class
 Overcome the challenges!!!

• Bradycardia or heart block

• If the bradycardia is accompanied by dizziness or lightheadedness or if 2nd
or 3rd degree heart block occurs, decrease the dose.

• Hypotension
• Administer the β-blocker and ACE inhibitor at different times.
• May also resolve after a decrease in the dose of diuretics in patients who
are volume depleted.
• If accompanied by other clinical evidence of hypoperfusion, should be
decreased or discontinued.

Yancy et al. 2013. JACC:e147–239.

 PROPERTIES OF -BLOCKERS

Name -1 a- Increases Other ancillary

Selective blockade Lipophilic ISA properties
Atenolol Yes No No No No
Acebutolol Disputed No No Disputed No
Bisoprolol Yes No Weak No No
Bucindolol No No Yes Disputed Vasodilator action
Antioxidant, effects
Carvedilol No Yes Yes No on endothelial
function
Celiprolol Yes No No -2 only No
Metoprolol Yes No Yes No No
Nebivolol Yes No Yes No Vasodilation
through nitric oxide
Propranolol No No Yes No Membrane
stabilizing Effect
Timolol No No Weak No Anti-platelet effects
Xamoterol Yes No No Marked No
 Nebivolol:
Ultraselective, Vasodilating 1-blocker

A Nitric-oxide-donating, vasodilating, lipophilic 3rd generation

highly selective Beta-1- adrenoceptor Blocker
Racemic mixture of 2 enantiomers d & l-Nebivolol

d- Nebivolol l- Nebivolol
• involved in the nitric oxide (NO)-mediated
• responsible for selective β-1-
endothelium-dependent dilatation,
antagonism
through L-arginine / NO pathway †
• highly selective β1-receptor
• responsible for the vasodilatory,
antagonist and a β3-receptor
antioxidant, antiproliferative and anti-
agonist.
platelet actions of the drug.
 1-Selectivity

50
45
40
35
30
25
20

15
10
5
0
Nebivolol Bisoprolol Carvedilol Metoprolol Bucindolol

Brixius K, et al. Br J Pharmacol 2002;133:1330-1338.

 Nebivolol: Potential Benefits
of Nitric Oxide Potentiation
►Endothelial dysfunction is:
nA key marker of atherosclerosis
nCharacterized by impaired nitric oxide
bioactivity
►Nebivolol has been shown to enhance nitric oxide
bioactivity and improve endothelial function
►This effect may explain the cardioprotective
benefits of the vasodilating β-blocker nebivolol

Mason RP, et al. J Clin Hypertens. 2006;8 (suppl 2):31-40

Nebivolol : Vasodilation
Nebivolol Hemodynamic Effect
►To evaluate the effects of nebivolol on
morbidity and mortality in elderly
patients (age ≥70) with chronic heart
failure, regardless of ejection fraction

Flather MD et al. Eur Heart J. 2005;26:215-225

►Age 70 years
►A clinical diagnosis of chronic HF and either
a) documented LVEF 35% within previous 6 months
or
b) hospital admission within previous year for HF
►Written consent prior to enrollment into
the study

Flather MD et al. Eur Heart J. 2005;26:215-225

 Nebivolol Placebo
(n=1067) (n=1061)
Mean age (years) 76.1 76.1
Male, n (%) 657 (61.6) 686 (64.7)
LVEF 35%, n (%) 683 (64.3) 686 (64.8)
Mean LVEF (%) 36.0 (13) 36.0 (12)
NYHA Class, n (%)
I 32 (3.0) 29 (2.7)
II 603 (56.5) 597 (56.3)
III 413 (38.7) 411 (38.7)
IV 19 (1.8) 24 (2.3)
SiBP (mm Hg) 138.6/80.5 139.5/80.6
NYHA, New York Heart Association; SiBP, sitting blood pressure.
Flather MD et al. Eur Heart J. 2005;26:215-225
 Nebivolol Placebo
(n=1067) (n=1061)
Medical history, n (%)
Prior history of CAD 735 (68.9) 717 (67.6)
Prior MI 467 (43.8) 463 (43.7)
Hypertension 652 (61.1) 660 (62.3)
Diabetes 287 (26.9) 268 (25.3)
Medication for HF, n (%)
ACE inhibitor 872 (81.7) 876 (82.6)
Diuretic 915 (85.8) 907 (85.5)
Cardiac glycoside 415 (38.9) 422 (39.8)
Aldosterone antagonist 307 (28.8) 280 (26.4)
Antiarrhythmic 122 (11.4) 145 (13.7)
Lipid-lowering drug 217 (20.3) 238 (22.4)
Aspirin 456 (42.7) 441 (41.6)

Flather MD et al. Eur Heart J. 2005;26:215-225

 600

500

400
Number 300
of patients
200

100

0
9

9
29
34

9
24

4
0
19

9
14

-3

-4
-4

-5
-5

-6

-7
-8
-6
-
-
-
-
-

35

45
25
30

40

55
20

50

60

70
75
15

65
10

Left ventricular ejection fraction (%)

Flather MD et al. Eur Heart J. 2005;26:215-225

 Primary and Main
Secondary Endpoints in SENIORS

Nebivolol. Marit D. Moen and Antona J. Wagstaff. Drugs 2006;66(10):1389–1409

Effect of Nebivolol on Time to
Sudden Cardiac Death in SENIORS

Nebivolol. Marit D. Moen and Antona J. Wagstaff. Drugs 2006;66(10):1389–1409

 Tolerability Profile of Nebivolol
in Tolerability
SENIORS

Nebivolol. Marit D. Moen and Antona J. Wagstaff. Drugs 2006;66(10):1389–1409

 Favors Favors
Primary outcome treatment placebo

SENIORS – Overall population

Age <75 yrs and LVEF ≤35%

All-cause mortality
SENIORS – Overall population
Age <75 yrs and LVEF ≤35%
CIBIS II
MERIT-HF
COPERNICUS

0.40 0.50 0.60 0.70 0.80 0.90 1.00 1.10 1.20

Hazard ratio and 95% CI

CIBIS-II Investigators and Committees. Lancet. 1999;353:9-13. Flather MD et al. Eur Heart J.
2005;26:215-225. Packer M et al. N Engl J Med. 2001;344:1651-1658. Packer M et al.
Circulation. 2002;106:2194-2199. Hjalmarson A et al. JAMA. 2000;283:1295-1302. MERIT-
HF Study Group. Lancet. 1999;353:2001-2007
 SENIORS: Conclusions

►Nebivolol significantly reduced death or

hospitalization in elderly patients with heart
failure

►SENIORS further expands our understanding

of the use of cardioselective blockers
among elderly patients and patients with
diastolic dysfunction

Flather MD et al. Eur Heart J. 2005;26:215-225

NEBIVOLOL IN HYPERTENSION
NEBIVOLOL in Hypertension
 Nebivolol vs Ramipril
Parameter Yang Diukur Nebivolol Ramipril

Index Berat Ventrikel Kiri -31,9 g/m2 -14,8 g/m2

Berat Ventrikel Kiri -15,6 g/height -7,3 g/height

Tekanan Darah Tidak ada perbedaan dalam penurunan tekanan darah

Hasil :
Nebivolol lebih efektif untuk menurunkan hipertrofi ventr
ikel kiri dibandingkan dengan RamiprilP < 0,001
Nebivolol vs Valsartan

Parameter Yang Diukur Nebivolol Valsartan

Tekanan Darah Sistolik -21 mmHg - 20 mmHg
Tekanan Darah Diastolik -12.3 mmHg -9.5 mmHg

Hasil :
Nebivolol lebih superior dalam menurunkan tekanan darah diastolik di
bandingkan dengan Valsartan
NEBIVOLOL in Hypertension
NEBIVOLOL in Hypertension
NEBIVOLOL in Hypertension
*P<0.05 vs. baseline
BP = sitting blood pressure; DBP=sitting diastolic blood pressure; SBP=sitting systolic blood pressure
Uhlir O et al. Drug Invest 1991;3(auppl 1):107-110
This study assessed blood pressure (BP) reductions and response rates following addition of
nebivolol to ongoing antihypertensive therapy in patients with uncontrolled stage I–II
hypertension despite antihypertensive treatment.

Study design: 12-week, randomized, double-blind, placebo-controlled, parallel-group study

conducted at 96 centres in the United States.
Effect of Nebivolol addition on blood pressure and heart rate

Addition of nebivolol to background antihypertensive therapy led to

significant additional BP and HR reductions compared with placebo
Effect of Nebivolol and Metoprolol
on Insulin Resistance
P=0.003

P=0.008 P=NS
Nebivolol: Effect on Glucose Levels
 BIOEQUIVALEN STUDY - NEVODIO

BIOEQUIVALENCE = THERAPEUTIC EQUIVALENT

NEVODIO Bioekuivalen vs Originator artinya : KUALITAS, KEAMANAN
dan EFICACY NEVODIO SETARA dengan ORIGINATORNYA

Aaroon S Kesselheim, JAMA 2008;300(21) 2514-2526

 BIOEKUIVALEN STUDY - NEVODIO
OBJECTIVE :
To find out whether the bioavailability of PT Dexa Medica’s
formulation 5 mg nebivolol tablets (NEVODIO ) is equivalent
to the reference product (Nebilet® 5 mg tablet, Berlin-
Chemie A.G for Menarini International Operations,
Luxembourg S.A).

This study was carried out in accordance with the Declaration of

Helsinki and its amendment and to the relevant Good Clinical Practice
(GCP) standards and in agreement with the local Ethics Committee
 BIOEKUIVALEN STUDY - NEVODIO
Mean plasma concentration-time profiles of nebivolol in human subjects (n = 17) after a
single dose oral administration of 5 mg nebivolol tablets produced by PT Dexa Medica (Test
drug) - NEVODIO and the reference (Reference drug = Originator) : COMPARABLE / SIMILAR
 NEVODIO BIOEKUIVALEN vs ORIGINATOR

Vertical bars indicate standard deviation

Conclusions 1.

NEBIVOLOL : Vasodilator Beta Blockers

F 1 - blocker with highest selectivity

F Vasodilatation properties through
L-arginine / NO pathway
F Without effect ISA & MSA
F Highly Lipophilic
F Safe & well tolerated
F Single dose
 Conclusion 2
• Beta blockers are not all created equally
• NEBIVOLOL (NEVODIO) is a Novel third generation
β-Blocker with vasodilator properties, mediated by a direct
stimulatory effect on the endothelial nitric oxide synthase
( eNOS)
• NEBIVOLOL (NEVODIO) is a highly selective β1-receptor
antagonist and a β3-receptor agonist
• NEBIVOLOL (NEVODIO) may produce clinical outcomes that
differ from traditional beta-blockers because of its efficacy,
safety and tolerability profile
• NEVODIO BIOEKUIVALEN vs ORIGINATOR  EFFICACY and
QUALITY SIMILAR to its Originator