1

Role of Candesartan

Antagonist: AT1 receptor interaction

Losartan Candesartan

Rapiddissociation

Slowdissociation

Lower affinity

High affinity

Re-association and prolonged antagonism

Insurmountableantagonism

Surmountableantagonism

R R

Morsing P, Vauquelin G. Cell Biochem Biophys 2001; 35(1): 89–102.

Chemical Structures of Angiotensin II Receptor Blockers

Olmesartan

CO2H

N

N

COH

CH3H3C

N

N N

NH

N

O

CO2H

Valsartan EXP 3174

N

N CO2H

CI

N

N N

NH

Irbesartan

ON

N

Candesartan

N

OCH2CH3

N

CO2HN

N N

NH

N

N N

NH

N

N N

NH

Insurmountable and Surmountable Antagonism: Relation to Duration of Binding

telmisartan olmesartancandesartan

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

Candesartan: selected properties

•Specific blockade of the effects of angiotensin II through selective AT1 receptor blockade

• Induces dose-dependent reduction in DBP response to exogenous angiotensin II

•The antihypertensive effect persists for more than 24 hours; this long duration of action appears to be related to a slow dissociation rate from the AT1 receptor

•Has placebo-like tolerability in hypertension clinical trials

Easthope SE, Jarvis B. Drugs 2002; 62: 1253–1287.

Years 1 and 2 Years 3 and 4

QualificationPeriod

Placebo

Life style counseling

Life style counseling

Candesartan (16mg)

Placebo

Placebo

At Visit 1: < 159/85-99 mm Hg or 130-159/ < 99 mm Hg

Avg. of 3 Visits: < 139/85-89 mm Hg or 130-139/ < 89 mm Hg

The TROPHY Study

TROPHY Study: ARB in Prehypertension

100

80

60

40

20

0

Cum

ulati

ve In

cide

nce

(%)

0 1 2 3 4

Placebo

Candesartan

Study YearJulius NEJM 2006; 354 : 1685-97

Long-lasting AT1-receptor blockade in isolated rat vessels

Morsing P, et al. Hypertension 1999; 33(6): 1406–1413.

Time (min)

Resp

onse

to a

ngio

tens

in II

(%)

Vehicle (n=37)

Irbesartan 50 nM (n=9)

Candesartan 1 nM (n=12)

EXP-3174 1 nM (n=9)

Losartan 30 nM (n=11)

0

20

40

60

80

100

120

-30 0 30 60 90 120 150 180

Antagonist

Meta-analysis based on USA New Drug Application evaluation reports

* x-axis is extended to the highest recommended dose in the EU at the time of meta-analysis

Elmfeldt D, et al. Blood Press 2002; 11: 293–301.

LosartanIrbesartanValsartanCandesartan

0000

2575804

50150160

8

7522524012

10030032016

0–1–2–3–4–5–6–7–8–9

–10

Redu

ction

in D

BP(m

mHg

)LosartanIrbesartanValsartanCandesartan

Dose (mg)*

Mean change from baseline to week 8 in SBP

Lacourciere Y, Asmar R. Am J Hyper 1999; 12: 1181–1187.

Candesartan(16 mg)

0

–2

–4

–6

–8

–10

–12

–14

–16

–18

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Losartan(100 mg)

Chan

ge in

SBP

(mm

Hg)

p=0.004

Hours after dose

Mean change from baseline to week 8 in DBP

Lacourciere Y, Asmar R. Am J Hyper 1999; 12: 1181–1187.

Chan

ge in

DBP

(mm

Hg)

0

–2

–4

–6

–8

–10

–12

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Hours after dose

p=0.022

Candesartan(16 mg)

Losartan(100 mg)

The CLAIM study:candesartan vs. losartan

Bakris G, et al. J Clin Hypertens (Greenwich) 2001; 3(1): 16-21.

TROUGH

Candesartan Losartan

0

–4

–8

–12

–16Mea

n ch

ange

from

bas

elin

e (m

m H

g)

*

*

0

–4

–8

–12

–16

48 hours POST-DOSE

**p<0.0001 compared with losartan *p<0.001 compared with losartan

****

Mea

n ch

ange

from

bas

elin

e (m

m H

g)

DBP DBPSBP SBP

Belcher G, et al. J Hum Hyper 1997; 11: S85–S89.

Candesartan: adverse events in hypertension trials

Candesartan(n=1388)

Placebo(n=573)

Headache

Respiratory infection

Back pain

Dizziness

Nausea

Cough

% of patients reporting adverse events

114321 5 6 7 10980

Candesartan: tolerabilityin hypertension trials

Belcher G, et al. J Hum Hyper 1997; 11: S85–S89.

With

draw

als d

ue to

ad

vers

e ev

ents

(%)

n=573

Placebo

n=311

4 mg

n=537

8 mg

n=303

16 mg

2.4 1.6 2.2 1.6

0

1

2

3

4

5

Candesartan

Real Life study: CVD Risk

0

5

10

15

20

25

30

35CandesartanLosartan

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Cum

ulati

ve in

cide

nce

(%)

Time (months)

Primary composite endpoint

67715812

45483913

31882591

20901738

14581169

923715

526385

259183 95

73296291

48604091

33852742

22421875

15801302

1021794

592436

257152 78

Number at risk

Los.

Can.

Adjusted risk reduction 14.4% p=0.0062Unadjusted risk reduction 20.6% p<0.0001

Real Lifestudy: Risk of Separate Endpoints

B ArrhythmiasA Heart failure C Peripheral artery disease

D Chronic ischemic heart disease F Stroke

0

2

4

6

8

10

12

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

CandesartanLosartan

Cum

ulati

ve in

cide

nce

(%)

Time (months)

67715902

46664057

33472761

22521887

16021317

1044820

611456

314

221126

73296385

49754230

35292875

23721998

16931409

1113878

664496

301

175 89

Number at risk

Los.

Can.

Adjusted risk reduction 35.9% p=0.0004Unadjusted risk reduction 41.9% p<0.0001 0

2

4

6

8

10

12

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Cum

ulati

ve in

cide

nce

(%)

Time (months)

67715909

46664053

33372745

22351874

15911300

1041814

598439

301212

115

73296380

49684216

35152855

23511977

16771390

1097867

654488

294169 90

Number at risk

Los.

Can.

Adjusted risk reduction 20.0% p=0.0330Unadjusted risk reduction 26.7% p=0.0029

CandesartanLosartan

0

2

4

6

8

10

12

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Cum

ulati

ve in

cide

nce

(%)

Time (months)

6771

59324696

40873376

27882273

19071619

13311063

83462

446

0320

225126

7329

64004983

42443541

28832382

20091706

14241128

89267

750

7307

179 91

Number at risk

Los.

Can.

Adjusted risk reduction 38.8% p=0.0140Unadjusted risk reduction 44.1% p=0.0035

CandesartanLosartan

0

2

4

6

8

10

12

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Cum

ulati

ve in

cide

nce

(%)

Time (months)

67715903

46594044

33352741

22341872

15771286

1021798

590431

297208

113

73296378

49504205

35022844

23451968

16701384

1091854

644480

290172 89

Number at risk

Los.

Can.

Adjusted risk reduction 14.3% p=0.1400Unadjusted risk reduction 19.6% p=0.0350

E Myocardial infarction

0

2

4

6

8

10

12

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Cum

ulati

ve in

cide

nce

(%)

Time (months)

67715921

46864079

33642782

22721904

16101318

104782

2612

452312

221123

73296387

49724231

35162858

23621992

16881406

111387

6661

494299

175 91

Number at risk

Los.

Can.

Adjusted risk reduction 7.0% p=0.5600Unadjusted risk reduction 15.5% p=0.1800 0

2

4

6

8

10

12

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96Cu

mul

ative

Inci

denc

e (%

)Time (months)

67715916

46814064

33612769

22511887

15981309

1047819

609448

307217

118

73296374

49634220

35152859

23621991

16911408

1113877

662489

295172 89

Number at risk

Los.

Can.

Adjusted risk reduction 5.2% p=0.6400Unadjusted risk reduction 12.0% p=0.2600

CHARM- added

CHARM-preserved

CHARM study programmeThree component trials comparing candesartan

with placebo in patients with symptomatic heart failure

CHARM-alternative

Primary outcome for overall programme: all-cause death

Primary outcome for each trial: CV death or CHF hospitalisation

Pfeffer MA, et al. Lancet 2003; 362(9386): 759–766.

n=2028 LVEF £40%

ACE inhibitor intolerant

n=2548LVEF £40%

ACE inhibitor treated

n=3025LVEF >40%

ACE inhibitor treated/not treated

CV death and CHF hospitalisation in the CHARM studies

Prop

ortio

n w

ith ca

rdio

vasc

ular

dea

th o

r ho

spita

l adm

issio

n fo

r CHF

(%)

0

10

20

30

40

50

yrs3.50 1 2 3 yrs

Placebo

Candesartan

Prop

ortio

n w

ith ca

rdio

vasc

ular

dea

thor

hos

pita

l adm

issio

n fo

r CHF

(%)

HR 0.77 (95% CI 0.67–0.89), p=0.0004Adjusted HR 0.70, p<0.0001

CHARM-Alternative

0

10

20

30

40

50

yrs3.50 1 2 3

10

Placebo

Candesartan

HR 0.85 (95% CI 0.75–0.96), p=0.011Adjusted HR 0.85, p=0.010

CHARM-Added

Placebo

Candesartan

HR 0.84 (95% CI 0.77–0.91), p<0.0001Adjusted HR 0.82, p<0.0001

CHARM-Overall

Prop

ortio

n w

ith ca

rdio

vasc

ular

dea

thor

hos

pita

l adm

issio

n fo

r CHF

(%)

0

10

20

30

40

50

yrs3.50 1 2 30

10

20

30

40

50

yrs3.50 1 2 3

Placebo

Candesartan

CHARM-Preserved

Prop

ortio

n w

ith ca

rdio

vasc

ular

dea

thor

hos

pita

l adm

issio

n fo

r CHF

(%)

HR 0.89 (95% CI 0.77–1.03), p=0.118Adjusted HR 0.86, p=0.051

3. McMurray JJ et al, Lancet 2003; 362(9386): 767–7714. Pfeffer MA et al; Lancet 2003; 362(9386): 759–766.

1. Yusuf S, Pfeffer MA, Swedberg K, et al. Lancet 2003; 362(9386): 777–781.2. Granger CB, McMurray JJ, Yusuf S, et al. Lancet 2003; 362(9386): 772–776.

CHARM-Overall: new diagnosis of diabetes

Yusuf S, et al. Circulation 2005; 112(1): 48–53.

Hazard ratio=0.78; 95% CI: 0.64–0.96

0 1.0 2.0 3.0 3.5

Time (years)

0

2

4

6

8 p=0.020

12

10 202 (7.4%)

163 (6.0%)

Candesartan 2715 2565 2395 1662Placebo 2721 2501 2304 1622

Prop

ortio

n of

pati

ents

(%)

CandesartanControl

Comparing Candesartan with other antihypertensive agents

Reference Treatments Response rate (%) Comparative efficacy

Himmelmann et al. 20011 Candesartan 8–16 mg odEnalapril 10–20 mg od

5850 Candesartan > enalapril

Malmqvist et al. 20001Candesartan 8–16 mg odEnalapril 10–20 mg odHCTZ 12.5–25

605143

Candesartan > enalapril Candesartan > HCTZ

Andersson et al. 19982Candesartan 8–16 mg odLosartan 50 mg odPlacebo

– Candesartan 16 mg > losartanCandesartan 8 mg = losartan

Bakris et al. 20011 Candesartan 16–32 mg odLosartan 50–100 mg od

6254 Candesartan 32 mg > losartan 100 mg

Vidt et al. 20011 Candesartan 16–32 mg odLosartan 50–100 mg od

5952 Candesartan 32 mg > losartan 100 mg

Gradman et al. 19991 Candesartan 16–32 mg odLosartan 50–100 mg od

6454

Candesartan 16–32 mg > losartan 50–100 mg

Lacourciere & Asmar 19991

Candesartan 8–16 mg odLosartan 50–100 mg od – Candesartan 16 mg > losartan 100 mg

Farsang et al. 20011 Candesartan 8 mg odAmlodipine 5 mg od

4444 Candesartan = amlodipine

Kloner et al. 20011 Candesartan 16–32 mg odAmlodipine 5–10 mg od

7987 Candesartan = amlodipine

1. Adapted from Easthope SE, Jarvis B. Drugs 2002; 62: 1253–1287.2. Adapted from McClellan KJ, Goa KL. Drugs 1998; 56: 847–869.