Transcript Dia 1 - pace

Role of Candesartan
1
Antagonist: AT1 receptor interaction
Surmountable
antagonism
Losartan
Candesartan
R
R
Rapid
dissociation
Slow
dissociation
Lower
affinity
High affinity
Insurmountable
antagonism
Re-association and prolonged
antagonism
Morsing P, Vauquelin G. Cell Biochem Biophys 2001; 35(1): 89–102.
Chemical Structures of
Angiotensin II Receptor Blockers
O
CI
N
N
N
N
CO2H
N
N
N
CO2H
N
N
NH
NH
CH3
H3C
N
EXP 3174
C
OH
Valsartan
N
CO2H
N
N
N
NH
N
N
OCH2CH3
N
CO2H
N
N
N
N
NH
N
Olmesartan
Candesartan
N
O
Irbesartan
N
NH
Insurmountable and Surmountable
Antagonism: Relation to Duration of Binding
100
candesartan
Insurmountability (%)
80
telmisartan
olmesartan
EXP 3174
60
valsartan
40
irbesartan
20
losartan
0
0
20
40
60
80
100
120
Dissociation t1/2
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.
The TROPHY Study
Placebo
Qualification
Period
Placebo
Life style counseling
Life style counseling
Candesartan (16mg)
Years 1 and 2
Placebo
Years 3 and 4
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
Cumulative Incidence (%)
TROPHY Study: ARB in Prehypertension
100
80
Placebo
60
40
Candesartan
20
0
0
1
2
3
4
Study Year
Julius NEJM 2006; 354 : 1685-97
Long-lasting AT1-receptor
blockade in isolated rat vessels
Response to angiotensin II (%)
120
Losartan 30 nM (n=11)
Vehicle (n=37)
100
EXP-3174 1 nM (n=9)
80
Irbesartan 50 nM (n=9)
Candesartan 1 nM (n=12)
60
40
20
0
-30
0
30
60
Antagonist
90 120 150 180
Time (min)
Morsing P, et al. Hypertension 1999; 33(6): 1406–1413.
Reduction in DBP
(mmHg)
Meta-analysis based on USA New
Drug Application evaluation reports
Losartan
Irbesartan
Valsartan
Candesartan
Losartan
Irbesartan
Valsartan
Candesartan
0
–1
–2
–3
–4
–5
–6
–7
–8
–9
–10
0
0
0
0
25
75
80
4
50
150
160
8
75
225
240
12
100
300
320
16
Dose (mg)*
* 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.
Mean change from baseline to
week 8 in SBP
Hours after dose
12 14 16 18 20 22 24 26 28 30 32 34 36
0
Change in SBP (mm Hg)
–2
–4
–6
–8
p=0.004
Losartan
(100 mg)
–10
–12
–14
–16
Candesartan
(16 mg)
–18
Lacourciere Y, Asmar R. Am J Hyper 1999; 12: 1181–1187.
Mean change from baseline to
week 8 in DBP
Hours after dose
12 14 16 18 20 22 24 26 28 30 32 34 36
Change in DBP (mm Hg)
0
–2
Losartan
(100 mg)
–4
–6
p=0.022
–8
–10
–12
Candesartan
(16 mg)
Lacourciere Y, Asmar R. Am J Hyper 1999; 12: 1181–1187.
The CLAIM study:
candesartan vs. losartan
TROUGH
SBP
0
–4
–8
–12
*
–16
*
Candesartan
DBP
Mean change from baseline (mm Hg)
Mean change from baseline (mm Hg)
DBP
48 hours POST-DOSE
SBP
0
–4
–8
–12
**
**
–16
*p<0.001 compared with losartan
**p<0.0001 compared with losartan
Losartan
Bakris G, et al. J Clin Hypertens (Greenwich) 2001; 3(1): 16-21.
Candesartan: adverse events
in hypertension trials
Headache
Respiratory infection
Back pain
Placebo
(n=573)
Dizziness
Candesartan
(n=1388)
Nausea
Cough
0
1
2
3 4
5
6
7
8
9 10 11
% of patients reporting adverse events
Belcher G, et al. J Hum Hyper 1997; 11: S85–S89.
Candesartan: tolerability
in hypertension trials
Withdrawals due to
adverse events (%)
5
4
3
2
1
0
2.4
1.6
2.2
1.6
n=573
n=311
n=537
n=303
4 mg
Candesartan
8 mg
16 mg
Placebo
Belcher G, et al. J Hum Hyper 1997; 11: S85–S89.
Real Life study: CVD Risk
Primary composite endpoint
Cumulative incidence (%)
35
Losartan
Candesartan
30
25
20
15
10
5
Adjusted risk reduction 14.4% p=0.0062
Unadjusted risk reduction 20.6% p<0.0001
0
0
6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time (months)
Number at risk
Los.
Can.
Real Lifestudy: Risk of Separate Endpoints
A Heart failure
Cumulative incidence (%)
8
6
4
2
Adjusted risk reduction 35.9% p=0.0004
Unadjusted risk reduction 41.9% p<0.0001
0
0
6
10
8
6
4
2
Adjusted risk reduction 20.0% p=0.0330
Unadjusted risk reduction 26.7% p=0.0029
0
0
6
8
6
4
2
0
Los.
Los.
Can.
Can.
Can.
12
10
10
10
4
2
Adjusted risk reduction 14.3% p=0.1400
Unadjusted risk reduction 19.6% p=0.0350
0
0
Number at risk
6
4
2
Adjusted risk reduction 7.0% p=0.5600
Unadjusted risk reduction 15.5% p=0.1800
0
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time (months)
6
0
Number at risk
6
Cumulative Incidence (%)
12
6
Time (months)
8
6
4
2
Adjusted risk reduction 5.2% p=0.6400
Unadjusted risk reduction 12.0% p=0.2600
0
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time (months)
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
F Stroke
12
Cumulative incidence (%)
Cumulative incidence (%)
E Myocardial infarction
8
6
Number at risk
Los.
8
Adjusted risk reduction 38.8% p=0.0140
Unadjusted risk reduction 44.1% p=0.0035
0
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time (months)
Number at risk
D Chronic ischemic heart disease
Losartan
Candesartan
12
10
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time (months)
Number at risk
Losartan
Candesartan
12
10
C Peripheral artery disease
Cumulative incidence (%)
Losartan
Candesartan
12
Cumulative incidence (%)
B Arrhythmias
0
Number at risk
Los.
Los.
Los.
Can.
Can.
Can.
6
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time (months)
CHARM study programme
Three component trials comparing candesartan
with placebo in patients with symptomatic heart failure
CHARMalternative
CHARMadded
CHARMpreserved
n=2028
n=2548
n=3025
LVEF 40%
ACE inhibitor
intolerant
LVEF 40%
ACE inhibitor
treated
LVEF >40%
ACE inhibitor
treated/not treated
Primary outcome for each trial: CV death or CHF hospitalisation
Primary outcome for overall programme: all-cause death
Pfeffer MA, et al. Lancet 2003; 362(9386): 759–766.
40
Placebo
30
Candesartan
20
10
0
Proportion with cardiovascular death
or hospital admission for CHF (%)
CHARM-Alternative
HR 0.77 (95% CI 0.67–0.89), p=0.0004
Adjusted HR 0.70, p<0.0001
0
50
1
2
3
3.5 yrs
CHARM-Preserved
40
30
Placebo
20
Candesartan
10
0
HR 0.89 (95% CI 0.77–1.03), p=0.118
Adjusted HR 0.86, p=0.051
0
1
2
3
Proportion with cardiovascular death or
hospital admission for CHF (%)
50
Proportion with cardiovascular death
or hospital admission for CHF (%)
Proportion with cardiovascular death
or hospital admission for CHF (%)
CV death and CHF hospitalisation
in the CHARM studies
3.5 yrs
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.
50
CHARM-Added
40
Placebo
30
Candesartan
20
10
0
HR 0.85 (95% CI 0.75–0.96), p=0.011
Adjusted HR 0.85, p=0.010
0
50
1
2
3
3.5 yrs
CHARM-Overall
40
Placebo
30
Candesartan
20
10
0
HR 0.84 (95% CI 0.77–0.91), p<0.0001
Adjusted HR 0.82, p<0.0001
0
1
2
3
3.5 yrs
3. McMurray JJ et al, Lancet 2003; 362(9386): 767–771
4. Pfeffer MA et al; Lancet 2003; 362(9386): 759–766.
CHARM-Overall: new diagnosis
of diabetes
Proportion of patients (%)
12
10
202 (7.4%)
Control
Candesartan
8
p=0.020
163 (6.0%)
6
4
2
Hazard ratio=0.78; 95% CI: 0.64–0.96
0
0
1.0
2.0
3.0
3.5
Time (years)
Candesartan
Placebo
2715
2721
2565
2501
2395
2304
1662
1622
Yusuf S, et al. Circulation 2005; 112(1): 48–53.
Comparing Candesartan with
other antihypertensive agents
Reference
Treatments
Response rate (%)
Comparative efficacy
Himmelmann et al. 20011
Candesartan 8–16 mg od
Enalapril 10–20 mg od
58
50
Candesartan > enalapril
Malmqvist et al.
20001
Candesartan 8–16 mg od
Enalapril 10–20 mg od
HCTZ 12.5–25
60
51
43
Candesartan > enalapril
Candesartan > HCTZ
Andersson et al.
19982
Candesartan 8–16 mg od
Losartan 50 mg od
Placebo
–
Candesartan 16 mg > losartan
Candesartan 8 mg = losartan
Bakris et al. 20011
Candesartan 16–32 mg od
Losartan 50–100 mg od
62
54
Candesartan 32 mg > losartan 100 mg
Vidt et al. 20011
Candesartan 16–32 mg od
Losartan 50–100 mg od
59
52
Candesartan 32 mg > losartan 100 mg
Gradman et al. 19991
Candesartan 16–32 mg od
Losartan 50–100 mg od
64
54
Candesartan 16–32 mg > losartan 50–
100 mg
Lacourciere & Asmar
19991
Candesartan 8–16 mg od
Losartan 50–100 mg od
–
Candesartan 16 mg > losartan 100 mg
Farsang et al. 20011
Candesartan 8 mg od
Amlodipine 5 mg od
44
44
Candesartan = amlodipine
Kloner et al. 20011
Candesartan 16–32 mg od
Amlodipine 5–10 mg od
79
87
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.