SALLY AMAN NASUTION, MD, PhD, FINASIM, FACP

- Born in Medan, August 8th 1967

- Internist – Cardiologist
- Faculty Member Division of Cardiology, Department of
Internal Medicine at Faculty of Medicine University of
Indonesia, Jakarta
- Head of Intensive Coronary Care Unit (ICCU), Cipto
Mangunkusumo National General Hospital Jakarta
- President of Indonesian Society of Internal Medicine
ROLE OFTHE NEW 3RD GENERATION OF
BETABLOCKER IN THE MANAGEMENT OF
HYPERTENSION TO HEART FAILURE

Dr dr SALLY AMAN NASUTION, SpPD-KKV, FINASIM, FACP

Division of Cardiology Department of Internal Medicine
Faculty of Medicine Universitas Indonesia
Cipto Mangunkusumo National General Hospital
Jakarta
OVERVIEW

• Scope of the Problem

• Beta Blockers in guidelines
• Older Beta-Blocker vs Nebivolol
• Clinical Efficacy and Tolerability of Nebivolol
• Updated Management in Heart Failure
• Conclusions
2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA, Guideline for the Prevention, Detection, Evaluation, and
Management of High Blood Pressure in Adults
A meta-analysis demonstrated a fairly linear positive relationship for cardiovascular
disease as the systolic BP increased past 115 mm Hg and the diastolic BP
increased past 75 mm Hg.
Goals of Hypertension Treatment
• In hypertensive patients, the primary goal of treatment
is to achieve maximum reduction in the long-term total
risk of cardiovascular disease.
• This requires treatment of the raised BP per se as well as
of all associated reversible risk factors.
• BP should be reduces to at least below 140 / 90
mmHg (systolic/diastolic) and to lower values, if
tolerated, in all hypertensive patients.

Mancia G, et al. 2007 ESH/ESC Guidelines for the Management of Arterial Hypertension. J Hypertens 2007;25:1105-1187
 BLOOD PRESSURE REDUCTION AND
CARDIOVASCULAR PROTECTION

Meta-analysis of 61 prospective, observational studies

1 million adults
12.7 million person-years
7% reduction
in risk of
ischemic heart
disease
2–mm Hg mortality
decrease in
mean SBP
10% reduction in
risk of stroke
mortality

*Epidemiologic studies, not clinical trials of hypertension agents.

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

• Scope of the Problem

• Beta Blockers in guidelines
• Older Beta-Blocker vs Nebivolol
• Clinical Efficacy and Tolerability of Nebivolol
• Conclusions
 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/
APhA/ASH/ASPC/NMA/PCNA Guideline

ORAL ANTIHYPERTENSIVE DRUGS

Primary Agents Secondary Agents

1. Thiazide 1. Diuretic Loop
2. ACE-I 2. Diuretic – Potassium Sparing
3. ARB 3. Diuretic Aldosterone Antagonist
4. CCB-DHP 4. BB-Cardio Selective
5. CCB-NDHP 5. BB-Cardio Selectve + Vasodilator
6. BB-Intrinsic Sympathomimetic Act
7. BB-Combined Alpha + Beta
NEBIVOLOL 8. Direct Renin
9. Alpha Blocker
10. Central Alpha Agonist
11. Direct Vasodilator

Whelton PK, et al. 2017 High Blood Pressure Clinical Practice Guideline
OVERVIEW

• Scope of the Problem

• Beta Blockers in guidelines
• Older Beta-Blocker vs Nebivolol
• Clinical Efficacy and Tolerability of Nebivolol
• Updated Management in Heart Failure
• Conclusions
bisoprolol
Saudi Med J 2014; Vol. 35 (11): 1307-1317
 Nebivolol :
Ultraselective, Vasodilating 1-Blocker
A Nitric-oxide-donating, vasodilating, lipophilic 3rd generation
highly selective beta-1 adrenoceptor blocker

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 antagonist
• responsible for the vasodilatory,
and a β3-receptor agonist.
antioxidant, antiproliferative and anti-
platelet actions of the drug.
Gori T. J Am Coll Cardiol 2009;54:1491–9
 Nebivolol : ß1 Receptor Selectivity
Human Myocardium
50
40.7
40
ß1 selectivity

30

20 15.6

10
4.23
0.49 0.73
0
Bucindolol Carvedilol Metoprolol Bisoprolol Nebivolol

ß1 Selectivity = K1 (ß2)/K1(ß1).; In extensive metabolizers and at doses less than or equal to 10

mg, nebivolol is preferentially ß1 selective.; Brixius K et al. Br J Pharmacol. 2001;133:1330-1338
NEBIVOLOL : VASODILATION
OVERVIEW

• Scope of the Problem

• Beta Blockers in guidelines
• Older Beta-Blocker vs Nebivolol
• Clinical Efficacy and Tolerability of Nebivolol
• Updated Management in Heart Failure
• Conclusions
 Efficacy of Nebivolol in Black Patients:
Diastolic and Systolic BP
N 47 46 51 49
Baseline DBP (mm Hg) 100.6 99.9 100.3 101.4
Baseline SBP (mm Hg) 151.4 151.7 154.2 156.4
Dose Placebo 5 mg 10 mg 20 mg
Mean Δ in BP vs baseline (mm Hg)

Saunders E et al. J Clin Hypertens. 2007;9:866-875

Placebo DBP Placebo SBP

 Efficacy of Nebivolol in Obese* Patients :
Diastolic and Systolic BP
N 92 189 188 196
Baseline DBP (mm Hg) 100.6 99.9 100.3 101.4
Baseline SBP (mm Hg) 151.4 151.7 154.2 156.4
Dose Placebo 5 mg 10 mg 20 mg
Mean Δ in BP vs baseline (mm Hg)

•Obesity defined as body mass index >30 kg/m2.

•Data on file, Forest Laboratories, Inc. New York, NY Placebo DBP Placebo SBP
NEBIVOLOL IN HYPERTENSION
 NEBIVOLOL IN HYPERTENSION

Parameter Yang
Nebivolol Ramipril
Diukur

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

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

Tidak ada perbedaan dalam penurunan
Tekanan Darah
tekanan darah
HASIL :
Nebivolol lebih efektif untuk menurunkan hipertrofi ventrikel kiri dibandingkan dengan Ramip
ril P < 0,001
 NEBIVOLOL IN HYPERTENSION

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 dibandingkan
dengan Valsartan
META-ANALYSIS OF EFFICACY OF ANTI
HYPERTENSIVE AGENTS
 PULMONARY EFFECTS OF NEBIVOLOL
N,
Reference Patient type Study design Parameters P
subject
Cazzola et al (2004) 20 COPD stage 1 and 2 Double-blinded, crossover FEV1 NS

Double-blinded, crossover
Nuttali et al (2003) 24 Healthy volunteers Serum K, glycaemia NS
versus placebo
Mild-to-moderate Double-blinded, crossover VC, FVC, FEV1, PEFR,
Dal Negro et al (2002) 12 NS
asthma versus placebo MMEF, sRaw, e-NO

Iakushin et al (2002) 30 COPD stage 1 Open FEV1, clinical signs NS

Double-blinded, crossover
Matthys et al (2001) 24 Mild asthma* FEV1, Raw NS
versus placebo
* β-blockers are contraindicated in asthmatic patients but nebivolol is not. COPD, chronic obstructive pulmonary disease; e -
NO, endothelial-nitric oxide; FEV1, forced expiratory volume; FVC, forced vital capacity; NS, not significant; MMEF, maximum
midexpiratory flow rate; PEFR, peak expiratory flow rate; Raw, airway resistance; sRaw, specific airway resistance; VC, vital
capacity.
In contrast to older compounds, nebivolol, which modulates the endogenous production of
nitric oxide and affects oxidative cascade, proved clinically well tolerated in terms of
respiratory outcomes in this type of subject. Moreover, due to the substantial dissociation
between its cardiac and pulmonary activity, nebivolol confirmed a very good safety profile
when regularly administered to hypertensive subjects with obstructive respiratory
comorbidities. Dal Negro R, et al. Ther Adv Cardiovasc Dis 2009;329–34
Vasodilating b–blockers do not
adversely affect insulin
sensitivity, glycemic control, or lipid
profiles. Moreover, use of vasodilating
b-blockers may reduce the risk of
new-onset diabetes compared with
traditional b-blockers.

J Clin Hypertens (Greenwich). 2011;13:52–59

Nebivolol
OVERVIEW

• Scope of the Problem

• Beta Blockers in guidelines
• Older Beta-Blocker vs Nebivolol
• Clinical Efficacy and Tolerability of Nebivolol
• Updated Management in Heart Failure
• Conclusions
Chain of Events Leading to End stage
Cardio--Vascular Disease
Cardio
Myocardial
Infraction

Coronary Sudden
Thrombosis Arrhythmias
Death

Silent
Myocardial Angina
Ischemia Remodeling
Hibernation

Ventricular
Stroke CAD PAD Dilatation

Atherosclerosis
LVH Heart Failure

Risk Factors
Hypertension & Metabolic
Death
Syndrome
DEFINITION OF HEART FAILURE
 CLASSIFICATION OF HEART FAILURE
ACCF/AHA Stages of HF NYHA Functional Classification
At high risk for HF but without
A structural heart disease or symptoms None
of HF.
No limitation of physical activity.
Structural heart disease but without
B I Ordinary physical activity does not cause
signs or symptoms of HF.
symptoms of HF.
No limitation of physical activity.
I Ordinary physical activity does not cause
symptoms of HF.
Slight limitation of physical activity.
Comfortable at rest, but ordinary
Structural heart disease with prior or II
C physical activity results in symptoms of
current symptoms of HF.
HF.
Marked limitation of physical activity.
Comfortable at rest, but less than
III
ordinary activity causes symptoms of
HF.
Unable to carry on any physical activity
Refractory HF requiring specialized
D IV without symptoms of HF, or symptoms
interventions.
of HF at rest.
 38

GLOBAL PANDEMIC OF HEART FAILURE

Heart failure: preventing disease and death worldwide

GLOBAL PANDEMIC
> 26 mio people and increasing

Indonesia : > 500.000 cases

Figure 3. Proportion of the population living with heart failure in individual countries across the
globe.4,8,9,11,42–46
Ambrosy PA et al. The Global
2014;63:1123–1133.
Health and Economic Burden of Hospitalizations for Heart Failure. Lessons Learned From Hospitalized Heart Failure Registries. J Am Coll Cardiol.

a
Data Riset Kesehatan Dasarfailure
2013, Badan Litbangkeslimbs.
Kementerian Kesehatan RI dan Data Penduduk Sasaran, Pusdatin Kementerian Kesehatan RI
Heart or swollen
Bui AL, Horwich TB, Fonarow GC. Epidemiology and 54. risk profile of heart failure. Nat Rev Cardiol 2011;8:30–41.
Estimates based on a single centre or hospital are indicated by an H.
No population-based studies have reportedly been conducted to estimate the proportion of the population
49 13
 HF patients in Indonesia has relatively
high rate of in-hospital mortality1,2

7.6% 8.2%
6.7% 6.5%
5.4% 5.4% 4.8%
3.0%
2.0%

Indonesia Phillipines Taiwan Australia US

1. Siswanto et al, 2010. Heart Failure in NCVC Jakarta and 5 hospitals in Indonesia. CVD Prevention and Control, 5, 35– 38
2. Ponikowski et al, 2014. Heart failure: preventing disease and death worldwide. ESC Heart Failure, 1: 4–25
Therapeutic algorithm for a patient with symptomatic heart
failure with reduced ejection fraction in 2016

(Ponikowski P. et al, EHJ 2016)

 GUIDELINES

HFrEF

HFmrEF
HFpEF

Ponikowski P, Voors AA, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and
chronic heart failure. European journal of heart failure 2016;18:891-975.
 ESC GUIDELINES FOR
THE DIAGNOSIS AND
THE TREATMENT OF
ACUTE AND CHRONIC
HEART FAILURE 2012

NEBIVOLOL RECOMMENDED AS ONE OF

EVIDENCE-BASED DRUGS IN HF WITH
REDUCED EJECTION FRACTION
ACC / AHA 2015 MARCH
HYPERTENSION, SCIENTIFIC STATEMENT
 47

Under-usage of guideline-recommended
HF pharmacological therapies
in Indonesian patients

Reyes et al, 2016. Heart failure across Asia, International Journal of Cardiology, 223, 163–167
 Nebivolol In Heart Failure

Randomized trial to determine the effect of nebivolol

on mortality and cardiovascular hospital
admission in elderly patients with heart failure
STUDY OBJECTIVE
►To evaluate the effects of nebivolol on morbidity and
mortality in elderly patients (age ≥70) with chronic
heart failure, regardless of ejection fraction

European Heart Journal (2005) 26, 215–225

PRIMARY AND MAIN SECONDARY ENDPOINTS
SENIORS STUDY

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

EFFECT OF NEBIVOLOL ON TIME TO ALL CAUSE MORTALITY
OR CV HOSPITALIZATION

P : 0.039

The SENIORS study shows that treating elderly patients with heart failure with
nebivolol reduces the composite risk of all cause mortality or cardiovascular
hospital admission compared with placebo

Flather MD, Shibata MC. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission
in elderly patients with heart failure (SENIORS). European Heart Journal (2005) 26, 215–225
 END POINT :
COMPOSITE ALL ISCHAEMIC EVENTS 15.9%

10.7%
J Am Heart Assoc. 2017;6:e007063. DOI: 10.1161/JAHA.117.007063.
 BIOEQUIVALENT 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.

BIOEQUIVALENCE = THERAPEUTIC EQUIVALENT

NEVODIO Bioekuivalen vs Originator artinya :
KUALITAS, KEAMANAN dan EFICACY NEVODIO SETARA dengan
ORIGINATORNYA
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
Summary
 Beta blockers are not all created equally.
 NEBIVOLOL is a Novel third generation β-Blocker with vasodilator
properties, mediated by a direct stimulatory effect on the endothelial
nitric oxide synthase ( eNOS).
 Beta Blocker can be used as a first line treatment in specific
condition hypertension ( CAD, Sympathetic Overdrive ).
 Guidelines publicized the importance of Beta Blocker on therapeutic
regiment of HF (Class 1A).
 NEBIVOLOL is a highly selective β1-receptor antagonist and a β3-
receptor agonist.
 NEBIVOLOL may produce clinical outcomes that differ from
traditional beta-blockers because of its efficacy, safety and tolerability
profile.
 NEVODIO BIOEQUIVALENT vs ORIGINATOR  EFFICACY and
QUALITY SIMILAR to its originator.
Pantai Kurunai, Gorontalo, 2019