Strategic Choice of ARB’S To Provide
Optimal Blood Pressure Management and
Reduction of Cardiovascular Events
Focus On Candesartan
Masrul Syafri
Bagian Kardiologi & Kedokteran Vaskular
FK Unand-RSUP DR.M.Djamil Padang
‘Controlling blood pressure with
medication is unquestionably one of the
most cost-effective methods of reducing
premature CV morbidity and mortality’
Elliott. J Clin Hypertens 2003;5(Suppl. 2):3–13
WHAT GUIDELINE SAY’S
- JNC 8 GUIDELINES
The Earlier, The Better:
Early Intervention Reduces Events
CV disease deaths over 10 years (%)
Female smoker
BP 180  140 mmHg
20
No diabetes or dyslipidaemia
19
No intervention
15
11
12
10
6
5
Intervention
7
7
3
4
4
0
1
1
0
40
2
1
50
SCORE High Risk Region
2
55
Age at start
60
65
OPTIMAL BLOOD PRESSURE
MANAGEMENT
UPDATED GUIDELINES
Publication on JAMA ( The Journal of the American Medical Association )
JAMA February 5, 2014 Volume 311, Number 5
JAMA February 5, 2014 Volume 311, Number 5
JAMA February 5, 2014 Volume 311, Number 5
JAMA February 5, 2014 Volume 311, Number 5
JAMA February 5, 2014 Volume 311, Number 5
BP LOWERING AGENT
WHY ARB’S?
Persistence with Antihypertensive Therapy
after 1 & 4 Years of Treatment
On treatment
%
70
AT1-blocker p<0.02 compared to all other classes
1 year
60
4 years
50
40
30
20
10
0
AT1-blocker
ACE-I
CCBs
Beta- blockers
Diuretics
Conlin et al 2001
Regression of Left Ventricular Hypertrophy with
Antihypertensive Therapy by Drug Class
Mean % change in LV Mass from baseline (with 95% CI’s) adjusted for
change in diastolic BP & duration of treatment
* p<0.05; **
p<0.001 vs beta blocker
-5
-10
*
**
Calcium
Antagonists
ACE-Is
-15
-20
Diuretics
b-Blockers
*
change in LV Mass(%)
0
ARB’s
Klingbeil et al 2003
MECHANISM OF ACTION :
ACE I vs ARB
Angiotensinogen
Jalur Non-ACE
Cth: khimase
ARB
Renin
ACEI
Bradikinin
Angiotensin I
ACE
Angiotensin II
Fragmen
inaktif
Reseptor AT1
Reseptor AT2
Sekresi Aldosteron
Vasokonstriksi
Vasodilatasi
Antiproliferasi (kinin)
Tekanan darah naik
Tekanan darah turun
Batuk
AT1
• Vasoconstriction (via ↓ NO,
↑ intracellular Ca2+, and ↑
superoxide)
and ↑ BP
• Inflammation (via ↑ NFκB)
• Cell growth and proliferation (via c-fos,
c-myc, c-jun)
• Anti natriuresis
• Increased atherogenicity (via ↑ OxLDL)
• Modulation of sympathetic nervous
system activity
• ↓ renal blood flow
• ↑ myocardial contractility
• ↑ arrhythmias
• ↑ PAI-1
• ↑ endothelin release
• ↑ sympathetic activity
AT2
• Foetal tissue development
• Vasodilatation (via ↑ bradykinin and
NO) and ↓ BP
• Growth inhibition (VSMC, endothelial
cell, cardiomyocyte, cardiac fibroblast,
via ‚MAP kinases)
• Improvement in cardiac function
(LVEDV, LVESV and EF) and decrease in
chronotropic effect
• Vascular cell differentiation
• Extracellular matrix composition
• Apoptosis (via ↓MAP kinases)
STRATEGIC CHOICE OF ARB’S
The PARAMETER’s
1.
2.
3.
4.
5.
6.
7.
GUIDELINES RECOMMENDATION
AT1 Affinity → Efficacy to reduce BP
Protection on Target Organ Damage (TOD)
Pleiotropic effect
Safety
Quality Assurance of Drugs
Pharmacoeconomics
2014 – Evidence based guidelines for the management of High Blood Pressure in adults
Report Form Panel Member Appointed of JNC - 8
STRATEGIC CHOICE OF ARB’S
The PARAMETER’s
1.
2.
3.
4.
5.
6.
7.
GUIDELINES RECOMMENDATION
AT1 Affinity → Efficacy to reduce BP
Protection on Target Organ Damage (TOD)
Pleiotropic effect
Safety
Quality Assurance of Drugs
Pharmacoeconomics
Number of AT1-Receptor Binding Sites
for Different Angiotensin II Receptor Antagonists
2 sites - losartan
3 sites - valsartan
4 sites - candesartan
Hydrogen bonds between ligand and receptor are shown as red dotted
lines with hydrogen bond lengths. Carbon atoms of the ligands are
coloured light blue and those of the receptors are green
Bhuiyan et al 2009
Insurmountable and Surmountable Antagonism:
Relation to Duration of Binding
100
Candesartan
Insurmountability (%)
80
olmesartan
EXP 3174
telmisartan
60
valsartan
40
irbesartan
20
losartan
0
0
20
40
60
Dissociation t1/2
80
100
120
Van Liefde et al 2009
Candesartan Valsartan
16 mg od
160 mg od
(n=470)
(n=401)
Irbesartan
300 mg od
(n=508)
Eprosartan
600 mg od
(n=208)
Telmisartan
80 mg od
(n=274)
Losartan
50 mg od
(n=577)
Perubahan Rata2 TD dari baseline
hingga 6 bulan (mmHg)
0
-5
-10
-15
-20
-19.5
-19.6
-20.1
-18.2
-18.6
-19.1
-25
-30
-35
-40
-45
-38.5
-37.4
-37
-34.7
-34.3
-34.2
SBP
DBP
p<0.0001 from baseline untuk semua kelompok
Efikasi penurunan tekanan darah Canderin superior dibandingkan dengan
ARB lainnya, baik tekanan darah sistolik dan diastolik.
Hellenic J Cardiol, 2006, Effects of Antihypertensive Treatment with Angiotensin II Receptor Blockers on Lipid Profile
−10.1 ± 10.5/−4.5 ± 8.4 mmHg
−13.1 ± 17.3/−6.2± 11.3 mm Hg
Candesartan treatment significantly reduced the morning
and office BPs compared with other ARBs in Japanese
patients with morning hypertension.
STRATEGIC CHOICE OF ARB’S
The PARAMETER’s
1.
2.
3.
4.
5.
6.
7.
GUIDELINES RECOMMENDATION
AT1 Affinity → Efficacy to reduce BP
Protection on Target Organ Damage (TOD)
Pleiotropic effect
Safety
Quality Assurance of Drugs
Pharmacoeconomics
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
Event Base Trials Comparing Active
Hypertensive Treatment to Placebo
Fatal and nonfatal stroke :
Coronary events
:
30-40%
20%
Mancia G, et al. 2007 ESH/ESC Guidelines for the Management of Arterial Hypertension.
J Hypertens 2007;25:1105-1187
Atherosclerosis*
Vasoconstriction
Vascular hypertrophy
Endothelial dysfunction
A II  AT1
receptor
LV hypertrophy
Fibrosis
Remodeling
Apoptosis
GFR
Proteinuria
Aldosterone release
Glomerular sclerosis
Stroke
Hypertension
Heart failure
MI
Renal failure
*preclinical data
LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate
Adapted from Willenheimer R et al Eur Heart J 1999; 20(14): 9971008, Dahlöf B J Hum Hypertens 1995; 9(suppl 5): S37S44,
Daugherty A et al J Clin Invest 2000; 105(11): 16051612, Fyhrquist F et al J Hum Hypertens 1995; 9(suppl 5): S19S24, Booz GW,
Baker KM Heart Fail Rev 1998; 3: 125130, Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed.
Whitehouse Station, NJ: Merck Research Laboratories 1999: 16821704, Anderson S Exp Nephrol 1996; 4(suppl 1): 3440, Fogo AB
Am J Kidney Dis 2000; 35(2):179188
DEATH
The Renin-Angiotensin Aldosterone System
(RAAS)
Angiotensinogen
Kininogens
Kallikrein
Renin
Non-renin
enzymes
Angiotensin I
Non-ACE
enzymes
X
Bradykinin
ACE inhibitors
ACE
Angiotensin II
X
Metabolites
X ARBs
AT2
AT1
•
•
•
•
•
•
Vasoconstriction
• Aldosterone release
Oxidative stress
• Vasopressin release
SNS activation
• Inhibits renin release
Renal Na+ & H2O reabsorption
Increased myocardial contractility
Cell growth & proliferation
•
•
•
•
•
•
Vasodilation
Antiproliferation
Apoptosis
Antidiuresis/antinatriuresis
Bradykinin production
NO release
The Cardiovascular Continuum
CANDESARTAN Clinical Study
CLINICAL TRIALS OF CANDESARTAN CILEXETIL (1)
Target
Heart
Failure
High
blood
pressure
Study
Patient population
added to standard
therapy
Treatment added
to standard
therapy
Primary endpoint
Benefit
CHARM-Added
CHF, EF<40% (41
moths)
Candesartan + ACEI
vs ACEI
Reduction in mortality
and morbidity
Confirmed
CHARMAlternative
CHF, EF<40%, in
tolerant to ACEI (33,7
months)
Candesartan vs
placebo
Reduction in mortality
and hospital
admission
Confirmed
CHARMPreserved
CHF, EF >40% (36,6
months)
Candesartan vs
placebo
Reduction in mortality
and hospital
admission
Moderate
confirmed
TROPHY
Prehypertension (4
years)
Candesartan vs
placebo
Prevention HTN
Confirmed
Five trials
HTNDM (12-14
weeks)
Candesartan vs
placebo
Treatment HTN
Confirmed
Candesartan
comperative trial
HTN+DM (3 months)
Candesartan vs
telmisartan and
valsartan
Treatment HTN
As good as the
other two
Candesartan
comperative trial
HTN and CHF Metaanalysis
Candesartan vs
losartan
Treatment HTN
Better, Not costeffective
Vascular Health and Risk Management 2011:7 749–759
CLINICAL TRIALS OF CANDESARTAN CILEXETIL (2)
Target
Renal
Protection
Stroke
New-onset
diabetes
prevention
Study
Patient population
added to standard
therapy
Treatment added
to standard
therapy
Primary endpoint
Benefit
SECRET
Renal graft + HTN (3
years)
Candesartan vs
placebo
Reduction in mortality
and graft failure
Confirmed
CKD stage 4-5
CKD stage 4-5 and BP
< 140/90 mmHg (3
years)
Candesartan vs
placebo
Reduction in mortality
and hemodialysis
Confirmed
CKD stage 1-3
CKD stage 1-3, DM,
ALB
Candesartan vs
placebo
Reduction in ALB
Confirmed
SCOPE
Aged 70-89 years,
HTN (3,7 years)
Candesartan vs
placebo
Reduction in stroke
and cognitive decline
Confirmed for
stroke only
ACCESS
Early stroke, HTN (1
year)
Candesartan vs
placebo
Reduction in mortality
and morbidity
Confirmed
CASE-
HTN-obesity
Candesartan vs
amlodipine
Reduction in newonset DM and
mortality
Confirmed
Vascular Health and Risk Management 2011:7 749–759
Real-Life study – components of the primary composite outcome
with candesartan vs. losartan
Kjeldsen et al. J Hum Hypertens 2009
Supramaximal Dose of Candesartan in
Proteinuric Renal Disease
SMART (Supra Maximal Atacand Renal Trial)
J Am Soc Nephrol ●●: –, 2009
STRATEGIC CHOICE OF ARB’S
The PARAMETER’s
1.
2.
3.
4.
5.
6.
7.
GUIDELINES RECOMMENDATION
AT1 Affinity → Efficacy to reduce BP
Protection on Target Organ Damage (TOD)
Pleiotropic effect
Safety
Quality Assurance of Drugs
Pharmacoeconomics
Profil Lipid
Pemakaian Candesartan mampu
menurunkan tingkat total kolesterol dan
LDL lebih superior dibandingkan dengan
ARB lainnya.
Hellenic J Cardiol, 2006, Effects of Antihypertensive Treatment with Angiotensin II Receptor Blockers on Lipid Profile
New-onset Diabetes
BMI
6.0%
<22
P=0.301
5.0%
≥25
≥27.5
Amlodipine
HR=0.64; 95%
0%
4%
CI 0.43-0.97
4.0%
≥22
-20%
3.0%
Candesartan
2.0%
-40%
-41%
-47%
1.0%
-60%
-62%
0.0%
0
6
12
18
24
30
36
42
48
months
-80%
P=0.947
P=0.015
P=0.028
Risk Reduction
in Candesartan group
P=0.0034
STRATEGIC CHOICE OF ARB’S
The PARAMETER’s
1.
2.
3.
4.
5.
6.
7.
GUIDELINES RECOMMENDATION
AT1 Affinity → Efficacy to reduce BP
Protection on Target Organ Damage (TOD)
Pleiotropic effect
Safety
Quality Assurance of Drugs
Pharmacoeconomics
STRATEGIC CHOICE OF ARB’S
The PARAMETER’s
1.
2.
3.
4.
5.
6.
7.
GUIDELINES RECOMMENDATION
AT1 Affinity → Efficacy to reduce BP
Protection on Target Organ Damage (TOD)
Pleiotropic effect
Safety
Quality Assurance of Drugs
Pharmacoeconomics
Bioequivalence study of CANDERIN®
STRATEGIC CHOICE OF ARB’S
The PARAMETER’s
1.
2.
3.
4.
5.
6.
7.
GUIDELINES RECOMMENDATION
AT1 Affinity → Efficacy to reduce BP
Protection on Target Organ Damage (TOD)
Pleiotropic effect
Safety
Quality Assurance of Drugs
Pharmacoeconomics
WHY COPY PRODUCTS EXIST?
• Original products loose it’s patent protection
• Copy Products have more opportunities
– Definition: Branded copy products & OGB
– Health Care Cost is continue to increase, needs medicines
with lower price, especially for chronic disease.
– Stringent GMP and BIOEQUIVALENCY requirements ensure
the Quality of the products, compare to its originator
Conclusions
• Despite the idea that all ARBs are the same and show a ‘class’
effect, significant pharmacological differences with respect to
efficacy and duration of action are apparent within the ARB class.
• Such differences may translate into differences in BP reduction,
and thus a reduction in CV risk. These differences should be taken
into account by the prescribing physician
• Long-acting ARB Candesartan have better CV outcomes.
• Copy product may reduces health care cost, but must be
bioequivalent compare to originator (Quality Assurance of Drugs)
New WHO Report, April 2011, highlights NCD
and CVD Deaths worldwide !
 New WHO report reveals an ‘impending disaster’ caused by a rise
in deaths from heart disease and other non-communicable
diseases
 Geneva, April 27, 2011 – The World Health Organization has today published a
report on non-communicable diseases (NCDs), including cardiovascular disease
(CVD) which is the number one killer worldwide, and has described them as an
‘impending disaster’ for health, society and national economies.
 The World Heart Federation welcomed report recommendations
for a ‘forceful response’ to the potential tragedy posed by noncommunicable diseases, particularly in the developing world
7.6 Million deaths each year attributable to
suboptimal blood pressure
 7.6 million deaths each year (13.5% of total) are
attributable to high blood pressure.
 54% of Stroke and 47% of coronary heart disease
worldwide attributed to high blood pressure.
 Data obtained from Global Burden of Disease
study, updated in 2008.
Lawes, Hoorn, Rodgers, for ISH: Lancet 2008; 371: 1513-18