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Which ARB is Suitable For Your Patients?

Tirta Kristina / Scientific Communication / Medical Affairs

Panduan Terapi Hipertensi

ARB’s: Compelling Indications

New studies

CHF

Post-MI

CAD risk

Diabetes mellitus

Renal disease

Recurrent stroke prevention

BB

ACEI

ARB

CCB

AA Diuretic

Mechanism Of Action

AT1R

Inflammation Endhotelial dysfuntion

Sympathetic activation

Cardiac (myocrdial) cells Smooth

muscle

Vascular Edothelium

CNS

Angiotensinogen

Angiotensin I

Angiotensin II

Individual cell growth

Renin

ACE

Adrenal cortex

Kidney

AT2R ARB

Inactive Prorenin

Kidney

Active Prorenin

Prorenin receptor

Fibrosis

Sodium retention

Kidney

Aldosterone

Bradykinin

Inactive fragments

Alternative pathway

(Chymase)

Kaplan’s 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

4 sites - candesartan 2 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

0 120 Dissociation t1/2

0

100

Insu

rmo

un

tab

ility

(%

)

80

100 80

60

40

60 40

20

20

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 8-16 mg

Losartan 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

0

-2

-4

-6

-8

-10

-12

-14

-16

-18

12 14 16 18 20 22 24 26 28 30 32 34 36

Hours after dose

Change in SBP (mm Hg)

Lacourcière & Asmar 1999

Losartan 100mg

Candesartan cilexetil 16mg

p=0.004

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

0 25 50 100 mg Losartan 0 80 160 320 mg Valsartan 0 75 150 300 mg Irbesartan

Reduction in diastolic BP (mmHg)

Elmfeldt et al 2002

Meta-Analysis Based on US New Drug Application Evaluation Reports

Candesartan

0 4 8 16 mg Candesartan

Losartan

Valsartan Irbesartan -6

-4

-2

-0

Clinical and Experimental Hypertension, 2012; 34(2): 86–91

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 130–139/89 mm Hg; or 139/85–89 mm Hg Julius S et al. N Engl J Med. 2006;354:1685-97.

TROPHY – study design

Two Years Two Years

Qualifying period*

Placebo

Non-pharmacological treatment

Non-pharmacological treatment

Candesartan cilexetil

16 mg daily

n 400

n 400

Placebo

Placebo

*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

66.3%*

15.6%*

Candesartan vs Placebo Placebo only

*Relative risk reduction †P < 0.001; ‡P = 0.007 Julius S et al. N Engl J Med. 2006;354:1685-97.

†

‡

N = 772

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

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%

J Am Soc Nephrol ●●: –, 2009

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

Penurunan Proteinuria Candesartan (SMART Study)

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

Proteinuria can be reduced by increasing the dosage of candesartan

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

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

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 ;

Résumé / 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)]

Pemakaian Candesartan

mampu menurunkan

level kolesterol

total 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

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

Pharmacodinamics Efikasi:

Penurunan tekanan darah lebih baik Efek proteksi terhadap ginjal, otak, jantung Pleiotropic effect: menurunkan kekakuan arteri, memperbaiki profil lipid

Tolerability Aman untuk pasien asma

Quality of Assurance Drug Bioekivalen dengan originator

Cost Lebih cost effective

Tirta Kristina/ Scientific Communication / Medical Affairs

Terima kasih atas dukungan dan kepercayaan dokter terhadap produk-produk PT Dexa Medica

PRODUK 2013

Akses juga melalui:

http://cme.medicinus.co/

Untuk berlangganan hubungi: Email: manenda.rossi@dexa-medica.com (u.p. Ninda)/ medical@dexa-medica.com