of Candesartan Antagonist AT 1 receptor interaction Losartan Candesartan Rapid dissociation Slow dissociation Lower affinity High affinity Reassociation and prolonged antagonism Insurmountable ID: 562347
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Slide1
1
Role
of
CandesartanSlide2
Antagonist: AT
1
receptor interaction
Losartan
Candesartan
Rapid
dissociation
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. Slide3
Chemical Structures of
Angiotensin
II Receptor Blockers
Olmesartan
CO
2
H
N
N
C
OH
CH
3
H
3
C
N
N
N
NH
N
O
CO
2
H
Valsartan
EXP 3174
N
N
CO
2
H
CI
N
N
N
NH
Irbesartan
O
N
N
Candesartan
N
OCH
2
CH
3
N
CO
2
H
N
N
N
NH
N
N
N
NH
N
N
N
NHSlide4
Insurmountable and Surmountable Antagonism: Relation to Duration of Binding
telmisartan
olmesartan
candesartan
EXP 3174
valsartan
irbesartan
losartan
0
120
Dissociation t
1/2
0
100
Insurmountability
(%)
80
100
80
60
40
60
40
20
20
Van Liefde et al 2009Slide5
Candesartan
: selected properties
Specific blockade of the effects of
angiotensin II through selective AT
1 receptor blockadeInduces 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 AT
1 receptorHas placebo-like tolerability in hypertension clinical trials
Easthope SE, Jarvis B. Drugs 2002; 62
: 1253–1287.Slide6
Years 1 and 2
Years 3 and 4
Qualification
Period
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 StudySlide7
TROPHY Study: ARB in
Prehypertension
100
80
60
40
20
0
Cumulative Incidence (%)
0
1
2
3
4
Placebo
Candesartan
Study
Year
Julius NEJM 2006; 354 : 1685-97Slide8
Long-lasting AT
1
-receptor blockade in isolated rat vessels
Morsing P,
et al. Hypertension 1999; 33(6): 1406–1413.
Time (min)
Response to angiotensin 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
AntagonistSlide9
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.
Losartan
Irbesartan
Valsartan
Candesartan
0
0
0
0
25
75
80
4
50
150
160
8
75
225
24012
100
300
320
16
0
–
1
–
2
–
3
–
4
–
5
–
6
–
7
–
8
–
9
–
10
Reduction in DBP
(mmHg)
Losartan
Irbesartan
Valsartan
Candesartan
Dose (mg)
*Slide10
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)
Change in SBP (mm Hg)
p=0.004
Hours after doseSlide11
Mean change from baseline to
week 8 in DBP
Lacourciere Y, Asmar R.
Am J Hyper
1999; 12: 1181–1187.
Change 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)Slide12
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
–
16
Mean change from baseline (mm Hg)
*
*
0
–
4
–
8
–
12
–
16
48 hours POST-DOSE
**
p<0.0001 compared with losartan
*
p<0.001 compared with losartan
**
**
Mean change from baseline (mm Hg)
DBP
DBP
SBP
SBPSlide13
Belcher G,
et al
.
J Hum Hyper 1997; 11: S85–S89.
Candesartan: adverse events
in hypertension trials
Candesartan(n=1388)
Placebo(n=573)
HeadacheRespiratory infection
Back pain
Dizziness
NauseaCough
% of patients reporting adverse events
11
4
3
2
1
5
6
7
10
9
8
0Slide14
Candesartan
:
tolerability
in hypertension trials
Belcher G, et al. J Hum Hyper 1997;
11: S85–S89.
Withdrawals due to
adverse events (%)
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
CandesartanSlide15
Real Life study: CVD Risk
0
5
10
15
20
25
30
35
Candesartan
Losartan
0
6
12
18
24
30
36
42
48
54
60
66
72
78
84
90
96
Cumulative incidence (%)
Time (months)
Primary composite endpoint
6771
5812
4548
3913
3188
2591
2090
1738
1458
1169
923
715
526
385
259
183
95
7329
6291
4860
4091
3385
2742
2242
1875
1580
1302
1021
794
592
436
257
152
78
Number at risk
Los.
Can.
Adjusted risk reduction 14.4% p=0.0062
Unadjusted risk reduction 20.6% p<0.0001Slide16
Real Lifestudy: Risk of Separate Endpoints
B Arrhythmias
A 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
Candesartan
Losartan
Cumulative incidence (%)
Time (months)
6771
5902
4666
4057
3347
2761
2252
1887
1602
1317
1044
820
611
456
314
221
126
7329
6385
4975
4230
3529
2875
2372
1998
1693
1409
1113
878
664
496
301
175
89
Number at risk
Los.
Can.
Adjusted risk reduction 35.9% p=0.0004
Unadjusted 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
Cumulative incidence (%)
Time (months)
6771
5909
4666
4053
3337
2745
2235
1874
1591
1300
1041
814
598
439
301
212
115
7329
6380
4968
4216
3515
2855
2351
1977
1677
1390
1097
867
654
488
294
169
90
Number at risk
Los.
Can.
Adjusted risk reduction 20.0% p=0.0330
Unadjusted risk reduction 26.7% p=0.0029
Candesartan
Losartan
0
2
4
6
8
10
12
0
6
12
18
24
30
36
42
48
54
60
66
72
78
84
90
96
Cumulative incidence (%)
Time (months)
6771
5932
4696
4087
3376
2788
2273
1907
1619
1331
1063
834
624
460
320
225
126
7329
6400
4983
4244
3541
2883
2382
2009
1706
1424
1128
892
677
507
307
179
91
Number at risk
Los.
Can.
Adjusted risk reduction 38.8% p=0.0140
Unadjusted risk reduction 44.1% p=0.0035
Candesartan
Losartan
0
2
4
6
8
10
12
0
6
12
18
24
30
36
42
48
54
60
66
72
78
84
90
96
Cumulative incidence (%)
Time (months)
6771
5903
4659
4044
3335
2741
2234
1872
1577
1286
1021
798
590
431
297
208
113
7329
6378
4950
4205
3502
2844
2345
1968
1670
1384
1091
854
644
480
290
172
89
Number at risk
Los.
Can.
Adjusted risk reduction 14.3% p=0.1400
Unadjusted 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
Cumulative incidence (%)
Time (months)
6771
5921
4686
4079
3364
2782
2272
1904
1610
1318
1047
822
612
452
312
221
123
7329
6387
4972
4231
3516
2858
2362
1992
1688
1406
1113
876
661
494
299
175
91
Number at risk
Los.
Can.
Adjusted risk reduction 7.0% p=0.5600
Unadjusted 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
96
Cumulative Incidence (%)
Time (months)
6771
5916
4681
4064
3361
2769
2251
1887
1598
1309
1047
819
609
448
307
217
118
7329
6374
4963
4220
3515
2859
2362
1991
1691
1408
1113
877
662
489
295
172
89
Number at risk
Los.
Can.
Adjusted risk reduction 5.2% p=0.6400
Unadjusted risk reduction 12.0% p=0.2600Slide17
CHARM-
added
CHARM-
preserved
CHARM study programme
Three component trials comparing
candesartan
with placebo in patients with symptomatic heart failureCHARM-
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=2548
LVEF
£40%ACE inhibitor treated
n=3025
LVEF >40%
ACE inhibitor
treated/not treatedSlide18
CV death and CHF hospitalisation in the CHARM studies
Proportion with cardiovascular
death
or hospital
admission for CHF (%)
0
10
20
30
40
50
yrs
3.5
0
1
2
3
yrs
Placebo
Candesartan
Proportion with cardiovascular
death
or hospital
admission for CHF (%)
HR 0.77 (95% CI 0.67
–
0.89), p=0.0004
Adjusted HR 0.70, p<0.0001
CHARM-Alternative
0
10
20
30
40
50
yrs
3.5
0
1
2
3
10
Placebo
Candesartan
HR 0.85 (95% CI 0.75
–
0.96), p=0.011
Adjusted HR 0.85, p=0.010
CHARM-Added
Placebo
Candesartan
HR 0.84 (95% CI 0.77
–
0.91), p<0.0001
Adjusted HR 0.82, p<0.0001
CHARM-Overall
Proportion with cardiovascular
death
or hospital
admission for CHF (%)
0
10
20
30
40
50
yrs
3.5
0
1
2
3
0
10
20
30
40
50
yrs
3.5
0
1
2
3
Placebo
Candesartan
CHARM-Preserved
Proportion with cardiovascular
death
or hospital
admission for CHF (%)
HR 0.89 (95% CI 0.77
–
1.03), p=0.118
Adjusted HR 0.86, p=0.051
McMurray JJ
et al, Lancet
2003;
362
(9386): 767–771
Pfeffer MA
et al
;
Lancet
2003;
362
(9386): 759–766.
Yusuf S, Pfeffer MA, Swedberg K,
et al
.
Lancet
2003;
362
(9386): 777–781.
Granger CB, McMurray JJ, Yusuf S,
et al. Lancet
2003;
362
(9386): 772–776. Slide19
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
01.0
2.0
3.03.5
Time (years)
0
2
4
6
8
p=0.020
12
10
202 (7.4%)
163 (6.0%)
Candesartan 2715 2565 2395 1662
Placebo 2721 2501 2304 1622
Proportion of patients (%)
Candesartan
ControlSlide20
Comparing
C
andesartan
with other antihypertensive agents
Reference
Treatments
Response rate (%)
Comparative efficacy
Himmelmann
et al
. 2001
1
Candesartan 8–16 mg od
Enalapril 10–20 mg od
58
50
Candesartan > enalapril
Malmqvist
et al
. 2000
1
Candesartan 8–16 mg od
Enalapril 10–20 mg od
HCTZ 12.5–25
60
51
43
Candesartan > enalapril
Candesartan > HCTZ
Andersson
et al
. 1998
2
Candesartan 8–16 mg od
Losartan 50 mg od
Placebo
–
Candesartan 16 mg > losartan
Candesartan 8 mg = losartan
Bakris
et al
. 2001
1
Candesartan 16–32 mg od
Losartan 50–100 mg od
62
54
Candesartan 32 mg > losartan 100 mg
Vidt
et al.
2001
1
Candesartan 16–32 mg od
Losartan 50–100 mg od
59
52
Candesartan 32 mg > losartan 100 mg
Gradman
et al
. 1999
1
Candesartan 16–32 mg od
Losartan 50–100 mg od
64
54
Candesartan 16–32 mg > losartan 50–100 mg
Lacourciere & Asmar 1999
1
Candesartan 8–16 mg od
Losartan 50–100 mg od
–
Candesartan 16 mg > losartan 100 mg
Farsang
et al
. 2001
1
Candesartan 8 mg od
Amlodipine 5 mg od
44
44
Candesartan = amlodipine
Kloner
et al
. 2001
1
Candesartan 16–32 mg od
Amlodipine 5–10 mg od
79
87
Candesartan
=
amlodipine
Adapted from Easthope SE, Jarvis B.
Drugs
2002; 62: 1253
–
1287.
Adapted from McClellan KJ, Goa KL.
Drugs
1998;
56
: 847–869.