Elliott. J Clin Hypertens 2003;5(Suppl. 2):3 – 13

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 smokerBP 180 140 mmHgNo diabetes or dyslipidaemia

12

4

7

12

1

3

6

11

19

1 2

4

7

0

Age at start

CV

dise

ase

deat

hs o

ver 1

0 ye

ars

(%)

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

mHg

)

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 48months

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