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Which ARB is Suitable For Your Patients?

Tirta Kristina / Scientific Communication / Medical Affairs

Panduan Terapi Hipertensi

ARBs: Compelling Indications

Diuretic BB ACEI ARB CCB AA

CHF Post-MI CAD risk Diabetes mellitus

Renal disease
Recurrent stroke prevention

New studies

Mechanism Of Action
Angiotensinogen
Renin
Kidney

Angiotensin I
Alternative pathway (Chymase)

Inactive Prorenin
Bradykinin

ACE

Angiotensin II

Inactive fragments

Active Prorenin

ARB
AT1R
CNS Vascular Edothelium Cardiac Smooth (myocrdial) cells muscle

AT2R
Adrenal cortex

Prorenin receptor

Aldosterone Fibrosis Kidney Kidney Endhotelial dysfuntion Inflammation

Sympathetic activation

Individual cell growth

Sodium retention
Kaplans Clinical Hypertension, 2010

Angiotensin-II Receptor Antagonist

Angiotensin Reseptor Blocker (ARB) :
Losartan Valsartan Irbesartan Candesartan Telmisartan

Which ARB is Suitable For Your Patients?

Tirta Kristina/ Scientific Communication / Medical Affairs

Pharmacokinetic

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 80
Insurmountability (%) telmisartan

olmesartan

candesartan

60
40
irbesartan

EXP 3174
valsartan

20
losartan

0 0 20 40
Dissociation t1/2

60

80

100

120
Van Liefde et al 2009

EFIKASI
PENURUNAN TEKANAN DARAH

Ideal Antihypertensive Agents

Duration of action which is appropriate for once-daily administration High trough:peak ratio which is consistent over the recommended dosage range

Maintenance of control of blood pressure fully and consistently throughout 24 h

Maintenance of control of blood pressure beyond 24 h despite poor compliance with treatment No increases in blood pressure variability
Meredith et al, 1995

Range of T/P Ratio

Candesartan Losartan
8-16 mg 50-100 mg

Irbesartan
150-300 mg

Valsartan
80 mg

Range of trough-to-peak ratio at once daily dosinhg (pacebo adjusted) as measured in various studies (DBP)1 Gordon McInnes. Pocket Reference to Angiotensin II Antagonists. Science Press

Candesartan Cilexetil vs Losartan : Mean Change From Baseline to Week 8 in Systolic ABP
Hours after dose 12 14 16 18 20 22 24 26 28 30 32 34 36

-2
-4 -6 -8 -10 -12 -14

Losartan 100mg

p=0.004

Candesartan cilexetil 16mg -16 Maintenance of control of blood pressure fully and consistently throughout 24 h -18 Maintenance of control of blood pressure beyond 24 h despite poor compliance with Change in SBP (mm Hg) treatment
Lacourcire & Asmar 1999

Meta-Analysis Based on US New Drug Application Evaluation Reports

-0 Reduction in diastolic BP (mmHg)

-2
Losartan Valsartan Irbesartan

-4

-6

Candesartan
0 0 0 0 25 80 75 4 50 160 150 8 100 mg 320 mg 300 mg 16 mg Losartan Valsartan Irbesartan Candesartan
Elmfeldt et al 2002

Clinical and Experimental Hypertension, 2012; 34(2): 8691

Effect of Switching from Telmisartan, Valsartan, Olmesartan, or Losartan to Candesartan on Morning Hypertension
Hiroshi Hasegawa,1 Hiroyuki Takano,1 Yoshihito Kameda,1 Akihiko Kubota,1 Yoshio Kobayashi,1 Issei Komuro2 1Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, Japan, 2Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

Method:
Seventy-eight mild to moderate hypertensive patients, who were treated with the standard doses of ARBs except candesartan (losartan, 50 mg; valsartan, 80 mg;

telmisartan, 40 mg; or olmesartan, 20 mg), were entered into 12-week treatment

period with candesartan 8 mg according to a multicenter, open-label design.

To control morning BPs, well-tolerated antihypertensive agents with long durations of action are required.

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.

TROPHY
TRial Of Preventing HYpertension
TROPHY : Study objectives
TROPHY evaluated 2 years of treatment with candesartan in individuals with prehypertension* Primary objective: Determine if the incidence of HTN can be reduced for up to 2 years after discontinuation of active treatment Secondary objective:

Evaluate the incidence of HTN during 2 years of treatment with candesartan of

placebo
Average BP 130139/89 mm Hg; or 139/8589 mm Hg Julius S et al. N Engl J Med. 2006;354:1685-97.

TROPHY study design

Placebo Placebo n 400

Non-pharmacological treatment

Qualifying period*
Non-pharmacological treatment
Candesartan cilexetil 16 mg daily Placebo

n 400

Two Years

Two Years

*Clinic BP reading of 130-139/ 89 mm Hg

or 139/85-89 mm Hg

Julius et al, Hypertension 2006

TROPHY: Reduction in new-onset hypertension

N = 772
Candesartan vs Placebo Placebo only 15.6%* 66.3%*

the effect of active treatment on delaying the onset of hypertension can

*Relative risk reduction P < 0.001; P = 0.007 Julius S et al. N Engl J Med. 2006;354:1685-97. extend to up to two years after the discontinuation of treatment.

MENCEGAH KERUSAKAN ORGAN TARGET

Scientific Communication / Medical Affairs

OBJECTIVE: The aim of this study was to test the hypothesis that the angiotensin II type 1 receptor blocker (ARB) candesartan (8 mg OD in the morning) can reduce the risk of stroke in elderly patients with isolated systolic

hypertension (ISH).

SCOPE

Candesartan mampu menurunkan risiko stroke (fatal dan non fatal) sebesar 42%

Metode: 269 patients who had persistent proteinuria (1 g/d) despite 7 wk of treatment with the highest approved dosage of candesartan (16 mg/d) to 16, 64, or 128 mg/d candesartan for 30 wk

Objective:
To evaluated whether supramaximal dosages of candesartan would

reduce proteinuria to a greater extent than the maximum approved

antihypertensive dosage
J Am Soc Nephrol : , 2009

Penurunan Proteinuria Candesartan (SMART Study)

Proteinuria can be reduced by increasing the dosage of candesartan

Ellen Burgess, SMART investigators, et all, J Am Soc Nephrol, 2009, Supramaximal Dose of Candesartan in Proteinuric Renal Disease.

Relative Effects of Telmisartan, Candesartan and Losartan on Alleviating Arterial Stiffness in Patients with Hypertension Complicated by Diabetes Mellitus: An Evaluation Using the Cardio Ankle Vascular Index
Method
95 pasien hipertensi-DM tipe II ditreatment selama 12 bulan dengan telmisartan 40mg/hari (n=31), candesartan 8mg/hari (n=40) atau losartan 50mg/hari (n=24) Evaluation

CAVI measurement and changes in blood pressure, blood glucose, HbA1c,

triglyceride, HDL

The Journal of International Medical Research 2008; 36: 1094-1102

Candesartan is a potentially useful therapy against arterial stifness in hypertensive patients with type 2 diabetes mellitus

Comparison of Anti-arteriosclerotic Effects of Candesartan and Valsartan in Type 2 Diabetic Patients with Hypertension Evaluation by Flow-mediated Dilatation (FMD)
Auteur(s) / Author(s) UEHARA Goro ; MORI Kanako ; SAKAI Takako ; MORITA Yasuko ; TAKEDA Hiroshi ;

Rsum / Abstract Objective To compare the effects of candesartan and valsartan on endothelial function assessed by measurement of flow-mediated vasodilation (FMD) in type 2 diabetes patients with hypertension. Methods Subjects who were receiving treatment with valsartan prior to registration were switched to candesartan 8 mg/day (VC group, n=21) whereas those who were receiving candesartan were switched to valsartan 80 mg/day (CV group, n=19) for an observation period lasting 3 months. Percent FMD, blood pressure, and HbA1c were examined at baseline and 3 months after starting treatment. Results The two groups did not differ in terms of patients' baseline clinical characteristics and laboratory data. At 3 months, there were no significant changes in blood pressure and HbA1c in both groups. In the VC group percent FMD significantly increased at 3 months (from 4.7% to 5.8% ; p<0.001), while in the CV group it significantly decreased (from 4.7% to 4.3% ; p<0.001). Moreover, percent FMD at 3 months in the VC group was significantly higher than that in the CV group (p< 0.05). Conclusions This study indicates that suppression of progression of endothelial dysfunction by

different ARBs is not a class effect ; candesartan

is more effective against progression of arterial sclerosis than valsartan.

2009, vol. 37, no9, pp. 757-762 [6 page(s) (article)]

Profil Lipid

Pemakaian Candesartan

menurunkan level kolesterol total dan LDL lebih superior dibandingkan

mampu
dengan ARB lainnya.

Hellenic J Cardiol, 2006, Effects of Antihypertensive Treatment with Angiotensin II Receptor Blockers on Lipid Profile

Safety and Tolerability (Mortality & Morbidity)

Scientific Communication / Medical Affairs

CHARM Program: Reduction in mortality and morbidity

CHARM-Overall: Reduction in new-onset diabetes

CHARM is the only study to provide clear evidence of the effects of an ARB in preventing DM in heart failure patients, most of whom were receiving a diuretic

Treatment with candesartan reduced the incidence of new- onset diabetes in patients with heart failure by 22%

Candesartan aman untuk penderita ASMA

Bioequivalence Study of Candesartan Cilexetil

(manufactured by PT Dexa Medica)

Quality of Assurance Drug

Mean plasma concentration-time profiles of candesartan in human subjects (n=24) after oral administration of 16 mg candesartan cilexetil tablet produced by PT Dexa Medica (Test Drug = Candesartan Cilexetil 16 mg) and the Reference (Reference Drug = Blopress 16 mg)

16 mg Candesartan cilexetil tablets produced by PT Dexa Medica and the Reference (BLOPRESS 16mg, PT Takeda Indonesia - Indonesia) are BIOEQUIVALENT

PROFILE PRODUCT

INDIKASI
HIPERTENSI Pengobatan pada pasien dengan gagal jantung dan gangguan fungsi sistolik ventrikel kiri (LVEF < 40%) ketika obat penghambat ACE tidak ditolelir

DOSIS dan CARA PEMBERIAN

DOSIS PADA HIPERTENSI Dosis awal Canderin adalah 4 mg per hari. Dosis dinaikkan sesuai dengan respons pengobatan sampai maksimum 16 mg sehari (Efek Maksimal dicapai dalam 4 minggu-6 minggu). Pasien dengan gagal ginjal sedang sampai berat, tidak memerlukan penyesuaian dosis, tapi disarankan diberikan dosis awal 2 mg. Pasien dengan gangguan hati ringan sampai sedang, direkomendasikan dosis awal 2 mg per hari.

DOSIS dan CARA PEMBERIAN

DOSIS PADA GAGAL JANTUNG Dosis awal 4 mg/hari. Peningkatan dosis sampai 32 mg/hari atau dosis tertinggi yang dpt ditoleransi dalam interval waktu minimal 2 minggu. Pasien lanjut usia dan pasien dengan pengurangan volume intravaskular, gangguan ginjal, dan gangguan hati ringan sampai sedang tidak perlu penyesuaian dosis. CARA PEMBERIAN Sekali sehari sebelum makan atau setelah makan

KONTRAINDIKASI
Penderita yang sensitif terhadap komponen CANDERIN. Wanita hamil dan menyusui Kerusakan hati yang berat dan/atau kolestasis

Kesimpulan
Pharmacokinetics
Afinitas lebih tinggi, durasi ikatan lebih panjang Efikasi: Penurunan tekanan darah lebih baik Efek proteksi terhadap ginjal, otak, jantung Pleiotropic effect: menurunkan kekakuan arteri, memperbaiki profil lipid Aman untuk pasien asma Bioekivalen dengan originator Lebih cost effective

Pharmacodinamics

Tolerability

Quality of Assurance Drug Cost

Tirta Kristina/ Scientific Communication / Medical Affairs

PRODUK

2013

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