strategic choice of arb’s to provide optimal blood pressure management and reduction of...
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Strategic Choice of ARB’S To Provide Optimal Blood Pressure Management and Reduction of Cardiovascular EventsFocus On Candesartan
Masrul SyafriBagian 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
Female smoker
BP 180 140 mmHg
No diabetes or dyslipidaemia
1
2
4
7
12
1
3
6
11
19
1 2
4
7
0
Age at start
CV
dis
ease
dea
ths
ove
r 10
yea
rs (
%)
SCORE High Risk Region
20
15
10
5
0
40 50 55 60 65
No intervention
Intervention
OPTIMAL BLOOD PRESSUREMANAGEMENT
UPDATED GUIDELINES
Publication on JAMA ( The Journal of the American Medical Association )
JAMA February 5, 2014 Volume 311, Number 5
THE DIFFERENCES
JAMA February 5, 2014 Volume 311, Number 5
JAMA February 5, 2014 Volume 311, Number 5
Strategies to Dose Antihypertensive Drugs
JAMA February 5, 2014 Volume 311, Number 5
JAMA February 5, 2014 Volume 311, Number 5
BP LOWERING AGENT
WHY ARB’S?
Conlin et al 2001
0
10
20
30
40
50
60
70
On treatment%
AT1-blocker ACE-I CCBs Beta- blockers Diuretics
AT1-blocker p<0.02 compared to all other classes
1 year
4 years
Persistence with Antihypertensive Therapyafter 1 & 4 Years of Treatment
Diuretics b-Blockers Calcium ACE-Is ARB’s Antagonists
chan
ge in
LV M
ass(
%)
0
-5
-10
-15
-20
Regression of Left Ventricular Hypertrophy with Antihypertensive Therapy by Drug Class
Klingbeil et al 2003
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
ACE
Angiotensinogen
Angiotensin I
Angiotensin II
Reseptor AT1 Reseptor AT2
Renin
Sekresi AldosteronVasokonstriksi
VasodilatasiAntiproliferasi (kinin)
Tekanan darah naik Tekanan darah turun
Bradikinin
Fragmen inaktifARB
ACEIBatuk
Jalur Non-ACE Cth: khimase
MECHANISM OF ACTION :ACE I vs ARB
AT1 AT2
• 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
• 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)
The PARAMETER’s
1. GUIDELINES RECOMMENDATION2. AT1 Affinity → Efficacy to reduce BP3. Protection on Target Organ Damage (TOD)4. Pleiotropic effect5. Safety 6. Quality Assurance of Drugs7. Pharmacoeconomics
STRATEGIC CHOICE OF ARB’S
2014 – Evidence based guidelines for the management of High Blood Pressure in adultsReport Form Panel Member Appointed of JNC - 8
The PARAMETER’s
1. GUIDELINES RECOMMENDATION2. AT1 Affinity → Efficacy to reduce BP3. Protection on Target Organ Damage (TOD)4. Pleiotropic effect5. Safety 6. Quality Assurance of Drugs7. Pharmacoeconomics
STRATEGIC CHOICE OF ARB’S
4 sites - candesartan2 sites - losartan
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
3 sites - valsartan
Bhuiyan et al 2009
Number of AT1-Receptor Binding Sites for Different Angiotensin II Receptor Antagonists
Insurmountable and Surmountable Antagonism: Relation to Duration of Binding
telmisartan
olmesartan
Candesartan
EXP 3174
valsartan
irbesartan
losartan
0 120Dissociation t1/2
0
100
Insu
rmou
ntab
ility
(%
)80
10080
60
40
6040
20
20
Van Liefde et al 2009
p<0.0001 from baseline untuk semua kelompok
Peru
baha
n Ra
ta2
TD d
ari b
asel
ine
hing
ga 6
bul
an (m
mH
g)
Hellenic J Cardiol, 2006, Effects of Antihypertensive Treatment with Angiotensin II Receptor Blockers on Lipid Profile
Candesartan 16 mg od (n=470)
Valsartan 160 mg od
(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)
-45
-40
-35
-30
-25
-20
-15
-10
-5
0
-38.5 -37.4 -37-34.7 -34.3 -34.2
-19.5 -20.1 -19.6 -18.2 -18.6 -19.1
SBPDBP
Candesartan vs Other ARB
Efikasi penurunan tekanan darah Canderin superior dibandingkan dengan ARB lainnya, baik tekanan darah sistolik
dan diastolik.
−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.
The PARAMETER’s
1. GUIDELINES RECOMMENDATION2. AT1 Affinity → Efficacy to reduce BP3. Protection on Target Organ Damage (TOD)4. Pleiotropic effect5. Safety 6. Quality Assurance of Drugs7. Pharmacoeconomics
STRATEGIC CHOICE OF ARB’S
• 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
Goals of Hypertension Treatment
Event Base Trials Comparing Active Hypertensive Treatment to Placebo
Fatal and nonfatal stroke :
30-40%
Coronary events :
20%
Mancia G, et al. 2007 ESH/ESC Guidelines for the Management of Arterial Hypertension. J Hypertens 2007;25:1105-1187
AT II Plays a Central Role in Organ Damage
GFRProteinuriaAldosterone releaseGlomerular sclerosis
Adapted from Willenheimer R et al Eur Heart J 1999; 20(14): 9971008, Dahlöf B J Hum Hypertens 1995; 9(suppl 5): S37S44, Daugherty A et al J Clin Invest 2000; 105(11): 16051612, Fyhrquist F et al J Hum Hypertens 1995; 9(suppl 5): S19S24, Booz GW, Baker KM Heart Fail Rev 1998; 3: 125130, Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories 1999: 16821704, Anderson S Exp Nephrol 1996; 4(suppl 1): 3440, Fogo AB Am J Kidney Dis 2000; 35(2):179188
Atherosclerosis*VasoconstrictionVascular hypertrophyEndothelial dysfunction
LV hypertrophyFibrosisRemodelingApoptosis
Stroke
DEATH
*preclinical dataLV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate
Hypertension
Heart failureMI
Renal failure
A II AT1
receptor
Angiotensinogen
Angiotensin I
Angiotensin II
ACE
Renin
Non-ACE enzymes
Non-renin enzymes
XACE inhibitors
X
Kininogens
Bradykinin
Metabolites
Kallikrein
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
AT2
X ARBs
The Renin-Angiotensin Aldosterone System (RAAS)
The Cardiovascular ContinuumCANDESARTAN Clinical Study
CLINICAL TRIALS OF CANDESARTAN CILEXETIL (1)
Target Study Patient population added
to standard therapy
Treatment added to standard therapy
Primary endpoint Benefit
Heart Failure
CHARM-Added CHF, EF<40% (41 moths)
Candesartan + ACEI vs ACEI
Reduction in mortality and morbidity
Confirmed
CHARM-Alternative
CHF, EF<40%, in tolerant to ACEI (33,7 months)
Candesartan vs placebo
Reduction in mortality and hospital admission
Confirmed
CHARM-Preserved
CHF, EF >40% (36,6 months)
Candesartan vs placebo
Reduction in mortality and hospital admission
Moderate confirmed
High blood pressure
TROPHY Prehypertension (4 years)
Candesartan vs placebo
Prevention HTN Confirmed
Five trials HTNDM (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 Meta-analysis
Candesartan vs losartan
Treatment HTN Better, Not cost-effective
Vascular Health and Risk Management 2011:7 749–759
Target Study Patient population added to standard therapy
Treatment added to standard therapy
Primary endpoint
Benefit
Renal Protection
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
Stroke 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
New-onset diabetes prevention
CASE- HTN-obesity Candesartan vs amlodipine
Reduction in new-onset DM and mortality
Confirmed
Vascular Health and Risk Management 2011:7 749–759
CLINICAL TRIALS OF CANDESARTAN CILEXETIL (2)
Kjeldsen et al. J Hum Hypertens 2009
Real-Life study – components of the primary composite outcome with candesartan vs. losartan
Supramaximal Dose of Candesartan in Proteinuric Renal Disease
J Am Soc Nephrol ●●: –, 2009SMART (Supra Maximal Atacand Renal Trial)
The PARAMETER’s
1. GUIDELINES RECOMMENDATION2. AT1 Affinity → Efficacy to reduce BP3. Protection on Target Organ Damage (TOD)4. Pleiotropic effect5. Safety 6. Quality Assurance of Drugs7. Pharmacoeconomics
STRATEGIC CHOICE OF ARB’S
Pemakaian Candesartan mampu menurunkan tingkat total kolesterol dan LDL lebih superior dibandingkan
dengan ARB lainnya.
Profil Lipid
Hellenic J Cardiol, 2006, Effects of Antihypertensive Treatment with Angiotensin II Receptor Blockers on Lipid Profile
New-onset Diabetes
-41%-47%
-62%
4%
-80%
-60%
-40%
-20%
0%
<22 ≥22 ≥25 ≥27.5
P=0.947 P=0.015 P=0.028 P=0.0034
BMI
Risk Reductionin Candesartan group
0.0%
1.0%
2.0%
3.0%
4.0%
5.0%
6.0%
0 6 12 18 24 30 36 42 48
months
P=0.301
HR=0.64; 95%
CI 0.43-0.97
Amlodipine
Candesartan
The PARAMETER’s
1. GUIDELINES RECOMMENDATION2. AT1 Affinity → Efficacy to reduce BP3. Protection on Target Organ Damage (TOD)4. Pleiotropic effect5. Safety 6. Quality Assurance of Drugs7. Pharmacoeconomics
STRATEGIC CHOICE OF ARB’S
The PARAMETER’s
1. GUIDELINES RECOMMENDATION2. AT1 Affinity → Efficacy to reduce BP3. Protection on Target Organ Damage (TOD)4. Pleiotropic effect5. Safety 6. Quality Assurance of Drugs7. Pharmacoeconomics
STRATEGIC CHOICE OF ARB’S
Bioequivalence study of CANDERIN®
CANDERIN® Bioekuivalen dengan originatornya
The PARAMETER’s
1. GUIDELINES RECOMMENDATION2. AT1 Affinity → Efficacy to reduce BP3. Protection on Target Organ Damage (TOD)4. Pleiotropic effect5. Safety 6. Quality Assurance of Drugs7. Pharmacoeconomics
STRATEGIC CHOICE OF ARB’S
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)
TERIMA KASIH
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 non-communicable 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