Role of Candesartan
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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.
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