Comparison of Candesartan vs Amlodipine Comparison of ...

Comparison of Candesartan vs Amlodipine
and vs. ACEI in High-Risk Hypertension
CASE CASE-J J Study and
HIJ-CREATE Studies
고려 고려대 구로병원 심혈관 센터
박창규

Key clinical trials of ARBs per clinical condition
High-risk Coronary artery Ds/ DM &/or Congestive
Hypertension Myocardial infarction Renal Ds Heart failure
LIFE VALIANT RENAL ELITE I and II
SCOPE OPTIMAAL IDNT Val-HeFT
VALUE IRMA 2 CHARM

30
20
10
0
‐10
‐20
‐30
‐40 40
High-risk Hypertension trials
; Cardiovascular and Outcome Results
4
‐5
%
‐13 ‐11 ‐11
*
1
‐25
‐28
**
**
15
*
7 11
19
* *p

%
‐10 0
10
‐20
‐30
‐40
10
Reduction of Endpoints in NIDDM with ARB
Losartan (RENAAL) & Irbesartan (IDNT)
‐20 ‐16
‐23 *
* **
‐25 ‐23 ‐23
‐33
‐28
‐37 ** **
** ***
‐8
4 2
37 Irbe vs Plac
IDNT
RENAAL
*p

LIFE
Incidence of Diabetes Mellitus – All Trials
CHARM overall
SCOPE
ALPINE
VALUE
37%
20%
24%
Losartan vs atenolol
Candesartan vs placebo
Candesartan vs s HCZ
Valsartan vs amlodipine
DM developed in 8.2% with ARBs, compared with 10.5% with placebo or other
agents (OR 0.73, 95% CI 0.64 to 0.84, p< 0.001)

LVH
Angiotensin II & LVH
Pathophysiology
Ang II Hypertension
Ang II
LV Remodelling
- increased LV mass
- increased LV stiffness
Ang II
Myocardial fibrosis
Ischemia Arrhythmia (AF)
Diastolic dysfunction
- LA enlargement
Systolic dysfunction

m2 Change
in LVVMI
(g/m )
LIFE Echo Substudy—Losartan vs. Atenolol: Losartan
Had a Greater Reduction in LVMI
0
-5
-10
-15
-20
-25
*
21.1
1 2 3 4 5 Last
Years
Adapted from Devereux et al Circulation 2004;110:1456–1462.
17 17.5 5
Losartan
Atenolol
* p= 0.011 0 011

ECHO-LVH and afPWV after Irbesartan Treatment
Park CG. et al. J Hypertension 2003. Korean J Intern Med. 2006;21:103-8

ARBs for
New-onset Atrial Fibrillation

Relative Risk of developing AF
• HHypertension pertension 1.4–2.1 1 4 21
• Heart failure 6.1–17.5
• Valvular disease 2.2–8.3
H However, because b of f th the hi high h prevalence l of f
hypertension, it accounts for more cases of atrial
fibrillation than the other risk factors
HHealey l JS JS, CConnolly ll SJ SJ. AAm J CCardiol di l 2003 2003; 91 91:9G–14G.
9G 14G

%
New-onset AF with ARB
Preventive effects of AF
*p

Clinical Trials with AT 1 Receptor Blockers
Post MI (Stage B)
OPTIMAL (losartan)
VALIANT (valsartan)
Ang II
CHF
(Stage C,D)
ELITE 2 (losartan)
Val Val-HeFT HeFT
(valsartan)
CHARM
(candesartan)

Beyond BP effect of ARBs
• Hi High-risk h i k HHypertension i
• Diabetes & Renal disease
• New onset AF
• Post-MI
• CHF
• LVH regression

Recent Update
on Candesartan Outcome Study
CASE CASE-J CASE CASE-J
J and CREATE

CASE CASE-J CASE J
CCandesartan d t AAntihypertensive tih t i
Survival Evaluation in Japan Trial
Ogihara T et al. Hypertension. 2008;51:1-6

Rationale of the Study
ARB ARBs and d CCB CCBs are th the most t widely id l used d
antihypertensive drugs in the world.
The incidences of stroke and coronary artery diseases,
however, are significantly different in Japan
compared to Europe and the USA.
The CASE-J Study was designed as a large-scale
clinical trial to evaluate the efficacy of Candesartan and
Amlodipine for reducing the incidences of cardiovascular
morbidity and mortality in Japanese patients.

Outline of the study
Objectives : A comparison of the efficacies of ARB
and CCB for reducing cardiovascular
mortality t lit and d morbidity bidit
Subjects : High-risk hypertensive patients
Test drugs : Candesartan and Amlodipine
Follow-up period: 3.0 years or more
Study period : September 2001 to December 2005
Study y design g : Open p Label Randomized Controlled Trial
Evaluation : The PROBE method

Inclusion Criteria
High-risk hypertensive patients
Age 20 – 85 years old
BP 140 and/or 90mmHg (

Dosage Schedule
Schedule
1 month
BP recording
add diuretics, diuretics ββ-blockers blockers etc etc.
titrate Candesartan
Candesartan 4 ~8 mg/day
Amlodipine 2.5 ~ 5 mg/day
titrate Amlodipine
add diuretics, , β-blockers β etc.
Informed consent
BP recording
Enrollment 3 years or more
Candesartan cilexeti : 4 to 8 mg/day. If necessary, the dose was increased up to 12 mg/day.
Amlodipine Amlodipine besilate besilate : 2.5 to 5 mg/day. If necessary, the dose was increased up to 10 mg/day.
If the response was insufficient, diuretics or β-blockers etc were added to the regimen in both groups.

Therapeutic Targets Targets of
of
Blood Pressure
Age of patient
(years)
BP
(mmHg)

Endpoints
Primary imary Endpoints
A composite of cardiovascular mortality and morbidity
Sudden death, death Cerebrovascular Cerebrovascular events events,
Cardiac events, Renal events,Vascular events
• Secondary Endpoints
Endpoints
All All-cause cause deaths, LVMI values, Withdrawal ratio
• Pre Pre-specified specified Analysis
New New-onset onset Diabetes
[Evaluation]
the PROBE method performed by the Event Evaluation Committee

Study Study Flow Flow Chart
Chart
Total patients patients enrolled enrolled :
:
4728 patients
Candesartan group :
Amlodipine group :
2364 patients p 2364 patients p
Excluded for GCP
deficiencies :
10 patients
Excluded for GCP
deficiencies :
15 patients
CCases ffor evaluation l ti :
CCases ffor evaluation l ti :
2354 patients
2349 patients
・Mean follow follow-up up period : 32years 3.2 years
・Follow-up rate : 97.1%

Patient Characteristics
Ttl Total number b
Males(%)
Age(years)
BMI(kg/㎡) ㎡
Candesartan
2354
1262(53.
6%)
63.8 ± 10.5
24.6 ± 3.7
Amlodipine
2349
1335(56.8%)
63.9 ± 10.6
24.5 ± 3.6
SBP(mmHg) 162 ± 14
163 ± 14
DBP(mmHg)
92 ± 11
92 ± 11
mean±SD

Patient Characteristics (2)
Cardiovascular risk factors (including duplications)
Severe HBP 180 and/or 110 mmHg
Type 2 diabetes
Cerebrovascular
disease
Cardiac disease
Renal
Cerebral hemorrhage
Cerebral infarction
TIA
LVH
Angina pectoris
MI
dysfunction s-Cr 1.3mg/dL g
Vascular disease ASO
Proteinuria
CCandesartan d t
(n=2354 n=2354)
454(19.3%)
1011(42.9%)
42(1.8%)
165(7.0%)
48(2.0%)
799(33 799(33.9%) 9%)
192(8.2%)
127(54%) 127(5.4%)
460(19.5%)
193(8.2%)
29(1.2%)
Amlodipine
(n=2349 n=2349)
493(21.0%)
1007(42.9%)
44(1.9%)
159(6.8%)
26(1.1%)
813(34 813(34.6%) 6%)
177(7.5%)
140(60%) 140(6.0%)
445(18.9%)
174(7.4%)
24(1.0%)

Antihypertensive Antihypertensive Drugs at Entry
AAntihypertensive ih i drugs d at entry
CCB
ARB
ACE-Inhibitor
β-blocker
α-blocker
Diuretics
Others
Candesartan
(n=2354 n=2354)
1610(68 1610(68.4%) 4%)
941(40.0%)
480(20.4%)
345(14.7%)
315(13.4%)
159(68%) 159(6.8%)
74(3.1%)
14(0.6%) ( )
Amlodipine
(n=2349 n=2349)
1552(66 1552(66.1%) 1%)
946(40.3%)
421(17.9%)
339(14.4%)
262(11.2%)
131(56%) 131(5.6%)
78(3.3%)
15(0.6%) ( )

Primary Composite Endpoints
Comparison of Cardiovascular Events
event
Prroportion
of o patientss
with first
%
9.0
80 8.0
7.0
6.0
5.0
4.0
30 3.0
2.0
1.0
Amlodipine
Candesartan
P=0.969
HR=1.01 HR 1.01 ; 95% CI 0.79-1.28 0.79 1.28
Baseline 6 12 18 24 30 36 42 48 months
Candesartan 17.7 / 1000 patient years
Amlodipine 17.6 / 1000 patient years

Comparison of Cardiovascular Cardiovascular Events
Event
Candesartan Amlodipine p Hazard Ratio P Value
(n=2354) (n=2349) Cardesartan/Amlodipine
Cardiovascular
events
134 (5.7%) 134 (5.7%)
0.969
Sudden deaths 11 (0.5%) 15 (0.6%)
0.434
Cerebrovascular
events
Cardiac events
61
43
(2.6%)
(1.8%)
50
47
(2.1%)
(2.0%)
0.282
0.680
Renal events 19 (0.8%) 27 (1.1%)
0.230
Vascular events 11 (0.5%) 7 (0.3%)
405 4.05
0.348
0.25
0.5 1 2
Favors Candesartan Favors Amlodipine
4

CASE CASE-J: CASE CASE-J:
J: Candesartan Antihypertensive Survival
Evaluation in Japan
BP
(mmHg)
180
160
140
120
100
80
60
162.5
163.2
91.6
91.8
143.5
141.4
82.0
80.7
141.6
139.7
80.7
79.7
Candesartan
Amlodipine
139.7 138.2
137.7 136.7
79.8
78.5
78.8
78.2
Baseline 6 Months 12 Months 18 Months 24 Months
2364 2246 2157 2071 1970
2364 2250 2155 2076 1967

Time Time-specific Time Time-specific specific Events Rates
Cardiovascular Events
Cardesaartan
Ammlodipine
(%)
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
0.6
0.4
0.2
0
-0.2
-0.4
(△%)
Candesartan
Amlodipine
0~6M 6~12M 12~18M 18~24M 24~30M 30~36M
Diff Differences i in th the outcomes t d due t to ti time-specific ifi cardiovascular di l events t

Risk Reduction of Renal Events with
C Candesartan d t by b Baseline B li Risk Ri k Factors F t
0
25
50
75
70y.o.
CCardiac di
Disease
(+)
LVH
68% 70% 68%
0
25
50
75
Creatinine Clearance (ml/min)

Renal Renal Events
Events
per 1000
patiennts
years
70
60
50
40
30
20
10
0
C Candesartan d t
Amlodipine
n.s
253.5 2.5 3.5
ALL
-57% -57% -81% 81%
P = 0.022
3.7
8.7
Calculation : Cockcroft-Gault formula
P = 0.040
5.6
13.4
P = 0.003
4.9
26.3

Secondary Secondary Endpoint
All-Cause Mortailty
Cumuulative
eveent
rate
5 %
4
3
2
1
0
P=0.303
Amlodipine
Candesartan
HR=0.85
95% CI 0.62-1.16
0 6 12 18 24 30 36 42 48
(months)
0
20
40
BMI

CASE-J vs. VALUE

Dose titration
VALUE (Valsartan) CASE-J (Candesartan)
valsartan amlodipine Atacand ®
CASE-J (Candesartan)
amlodipine
Titrationstep
1 80 5 4-8 25-5 2.5-5
2 160 10 12 10
3 160+12.5 10+12.5 diuretic/β-block diuretic/β-block
4 160+25 10+25
5 160+25+ 10+25+
”free add-on” ”free add-on”

Primary endpoint
VALUE (Valsartan) CASE CASE-J J (C (Candesartan) d t )
Time to first cardiac event Composite p of CV mortality y and mo
rbidity
– Cardiac death
– heart failure requiring
hospitalisation
– NNon-fatal ftl AMI
– any other interventional
procedure performed to
prevent full blown MI
– Sudden death
– Cerebrovascular events
– Cardiac events
– Renal events
– Vascular events

Baseline characteristics
VALUE (Valsartan) CASE-J (Candesartan)
val amlo Atacand ®
amlo
n= 7649 n= 7596 n=2354 n=2349
Mean age (years) ( ears) 67 67 64 64
Men (%) 58 57 54 57
SBP mmHg 155 155 162 163
DBP mmHg 87 88 92 92
BMI Kg/m2 Medical history (%)
29 29 25 25
coronary disease 46 46
myocardial infarction 5 6
diabetes 43 43
stroke/TIA 20 20 11 10
proteinuria 20 19

BP reduction during studies
mmHg
SBP
DBP D mmHHg
VALUE
170 Valsartan
165
(N= 7649)
Amlodipine
(N = 7596)
155
150
145
140
135
130
90
85
80
75
Baseline 1 2 3 4 6 12 18 24 30 36 42 48 54 60 66
Months
CASE-J
(or final visit)
Atacand ®
(N = 2354)
Amlodipine
(N= 2349)

Cardiac event
(VALUE Primary endpoint)
Proportion of patients
with first event (%)
14
12
10
8
6
4
2
0
VALUE (Valsartan) CASE-J (Candesartan)
HR = 1.03 (95% CI = 0.94–1.14)
p= 0.49
0 6 12 18 24 30 36 42 48 54 60 66
Proportion of patients
with first event (%)
10
8
6
4
2
0
Time (months)
HR=1.01 (95% CI 0.79-1.28)
p=0.969
Baseline 6 12 18 24 30 36 42 48
Valsartan-based Valsartan based regimen
Amlodipine-based regimen
Atacand ®
-based regimen

All-cause mortality
(CASE-J Primary endpoint)
Proportion of patients
with event (%)
16
14
12
10
8
6
4
2
0
VALUE (Valsartan) CASE-J (Candesartan)
4%
HR = 1.04 (95% ( % CI = 0.94–1.14) )
p= 0.45
0 12 24 36 48 60 66
5
4
3
2
1
0
CASE-J (Candesartan)
Proportion of patients
with event (%)
15%
HR=0.85 (95% CI 0.62-1.16)
p=0.303 p
0 12 24 36 48
Time (months) Vl Valsartan-based t b d regimen i
Amlodipine-based regimen
Atacand ®
-based regimen

Changes Changes in in LVMI LVMI in in Patients Patients with with LVH
LVH
0.0
-5.0
-10.0
-15.0 15 0
-20.0
-25.0
(g/m2 (g/m )
Candesartan
(n=205)
-22.9 22.9
P=0.023
Amlodipine
(n=199)
-13.4 13.4

New New-onset New New-onset onset Diabetes
Diabetes
(%)
6.0 P=0.031
HR=0.64 ; 95%
5.0 CI 0.43-0.97
4.0
3.0
20 2.0
1.0
Amlodipine
Candesartan
0
6 12 18 24 30 36 42 48
Baseline
(months)
0
20
4%
BMI

Summary
Candesartan and Amlodipine equally reduced the
number of CV events in high-risk hypertensive patients
under strict BP control (< 140/80 mmHg) mmHg).
Candesartan suppressed the progression of renal
dysfunction in patients with renal impairments
impairments.
Candesartan decreased total mortality in obese patients.
A significantly larger decrease in the left ventricular mass
index values was observed in the Candesartan group
than in the Amlodipine group group.
Candesartan prevented new-onset diabetes.

Conclusions
Candesartan and Amlodipine equally reduce the number
of CV events in high-risk hypertensive patients under
strict BP control.
Candesartan is more beneficial than Amlodipine p for
hypertensive patients with chronic kidney disease or
obesity, and may be preferable for patients with
metabolic syndrome.

Randomized Trial of ARB based
versus NonARB Standard Therapy in
Patients with CAD and and Hypertension
The Heart Institute of Japan Candesartan
RRandomized d i d ttrial i l ffor EEvaluation l ti iin
Coronary Artery Disease (HIJCREATE)
Presented at 2007 AHA

Background
ACE ACE-inhibitors i hibit iimprove clinical li i l outcome t iin patients ti t
with coronary artery disease (CAD).
HHowever, it still till remains i uncertain t i whether h th
Angiotensin II receptor blockers (ARB) reduce the risk
of cardiovascular events.

Hypothesis
Candesartan-based pharmacotherapy reduces the
cardiovascular events compared to non non-ARB-based
ARB based
standard pharmacotherapy
in angiographically documented CAD patients with
hypertension.

Eligibility
Inclusion criteria :
Angiographically documented
coronary y artery y disease ppatients with hypertension,
yp ,
aged 20-80 yrs
Coronary Artery Disease :
ACS ACS, Stable Coronary Artery Disease
Hypertension :
SBP>140mmHg, DBP>90mmHg or current use of
antihypertensive tih t i medication. di ti
Major exclusion criteria :
Major exclusion criteria :
AMI within week
Cerebrovascular disease within months sCr >2.0mg/dL

Design and Treatment
Study Design :
Prospective randomized open-label blinded-endpoint
(PROBE) design. design
Conducted at 14 medical centers in Japan.
TTreatment t t :
R
Candesartan-based therapy without other RAS inhibitors
Target blood pressure of less than 130/85 mmHg
non-ARB-based Standard therapy
Randomized 6M 1Y 2Y 3Y 4Y 5Y

Endpoint
Primary Endpoint
Major Adverse Cardiovascular Events (MACE)
1. Death from cardiovascular cause
2. Non fatal myocardial infarction
3. Unstable angina g ppectoris
4. Heart failure
requiring
5. Stroke
hospitalization
6. Other cardiovascular events
Secondary Endpoints
- Revascularization
- New-onset diabetes mellitus

Flow Flow Diagram Diagram for the Trial
Trial
June 2001
|
April 2004
median
Follow-upp
4.2 years
June 30
2007
Randomized
(n=2049)
Candesartan
-based therapy
Standard therapy
(n=1024) (n=1025)
lost to follow-up
3 (0.3%)
lost to follow-up
5 (0.5%)
Statistical consideration
・Sample size of 2,049 with an 80% power to detect a 20% risk reduction
at two-tailed 5%.
・Stratified, St tifi d permuted-block t d bl k randomization.
d i ti
・The intention-to-treat approach.

Patient Characteristics (1)
Candesartan Standard
Sta da d
(n=1024 n=1024)
(n=1025 n=1025)
Age
65 ± 9 65 ± 9
Women
BMI (Kg/m2) 186 (18%)
219 (21%)
25 ± 3
25 ± 3
SBP (mmHg) ( g)
135 ± 19
136 ± 18
DBP (mmHg)
76 ± 12
76 ± 12
treated Hypertension
933 (91%)
960 (94%)
Heart Rate (beats/min)
69 ± 11
69 ± 10
Diabetes
379 (37%)
401 (39%)
Hypercholesterolemia
604 (59%)
612 (60%)
Smoking
401 (39%)
377 (37%)
Cerebrovascular disease
111 (11%)
94 (9%)
Atrial fibrillation 58 (6%) 77 (8%)

Patient Characteristics (2)
ACS
Stable CAD
Previous MI
previous PCI
previous CABG
No. of diseased vessels 2
Candesartan Standard
Sta da d
(n=1024 n=1024)
(n=1025 n=1025)
346 (34%) 378 (37%)
678 (66%)
647 (63%)
406 (40%)
852 (83%)
124 (12%)
585 (57%)
439 (43%)
373 (36%)
844 (82%)
112 (11%)
583 (57%) (5 %)
442 (43%)
NYHA I/II/III/IV(%)
78 / 18 / 2 / 2 81 / 15 / 2 / 2
Ejection Fraction (%)
54 ± 11
55 ± 11
CRP (median : mg/L)
2 [1-4]
2 [1-4]
Ccr (mL/min) 63 ± 20 62 ± 19

Medications at at Randomization
Randomization
Candesartan < 8mg/day
ACEis
> 8mg/day
CCalcium l i channel h l blockers bl k
Beta blockers
Di Diuretics ti
Statins
Nit Nitrates t
Aspirin
Candesartan Standard
(n=1024 n=1024) (n=1025 n=1025)
771 (75%)
253 (25%)
not allowed
not allowed 723 (71%)
457 (45%) 574 (56%)
464 (45%)
103 (10%)
459 (45%)
503 (49%)
948 (93%)
506 (49%)
82 (8%)
447 (44%)
526 (51%)
935 (91%)

Blood Pressure Pressure Changes
(mmHg)
180
Candesartan
Standard
160
SBP
Mean±SD
140
120
100
80
60
DBP
P=0.379
P=0.194
40
Baseline 6 12 24 36 48 60(months)
PP-value: l ttrend d profile fil ttest t bby mixed-model
i d d l

Primary Primary Endpoint
Cumulative rate of MACE
35% P=0.194
30
25
20
15
10
Standard
C Candesartan d t
5 HR=0.89
(0 (0.76-1.06) 76 1 06)
0
baseline 1 2 3 4 5 years
MACE
Hazard Ratio (95%CI)
CV death+MI
UAP
HF
Stroke
Other
CVevents
P
Value
00.194 194
0.527
0.204
0.667
0.672
0.801
0 0.5 1 2
Standard 1025 891 828 717 443 93
Favors
Favors
CAN 1024 897 837 746 471 104 Candesartan Standard

Secondary Secondary Endpoint
40%
30
20
10
Incidence of
Revascularization
P=0.414
RRR=7%
25.0
26.4
4%
3
2
1
Incidence of
New-onset Diabetes
P=0.027
RRR=63%
1.1
2.9
0
Candesartan
Candesartan Standard
0
Candesartan
Candesartan Standard
(256/1024) (271/1025) (7/645) (18/624)

Candesartan vs vs Standard Standard with ACEi
Primary endpoint
MACE
CV death + MI
UAP
HF
Stroke
other CV events
Secondary endpoints
Candesartan ACEi HR
P
(n=1024) (n=723) [95%CI] value
264 (25.8%)
57 (5.6%)
151 (14.7%) ( %)
40 (3.9%)
45 (4.4%)
35 (3.4%)
203 (28.1%)
40 (5.5%)
117 (16.2%)
35 (4.8%)
38 (5.3%)
27 (3.7%)
0.90 [0.75-1.08]
1.01 [0.67-1.51]
0.90 [0.70-1.14] [ ]
0.80 [0.51-1.26]
0.83 [0.54-1.27]
0.91 [0.55-1.50]
0.24
0.96
0.38
0.34
0.39
0.70
revascularization 256 (25.0%) 192 (26.6%) 0.92 [0.77-1.12] 0.41
NNew-onset tDM DM 7/645 (1.1%) (1 1%) 12/418 (2.9%) 037[0150 0.37 [0.15-0.94] 94] 0.04

Secondary Secondary Endpoint
30%
20
10
0
30%
20
10
0
Drug-related AE
P=0.027
CAN STN
Hyperkalemia
P=0.410
CAN STN
30%
20
10
0
30%
20
10
0
Cough
P

Subgroup Subgroup analysis analysis for MACE
P-value
HHazard d RRatio ti PP-Value V l F Favors Candesartan C d t Favors F FFavors Standard St d d
for Interaction
Women
1.05 0.80
Men
0.88 0.11
Age 65 0.88 0.22
BMI 25 30 0.45 0.07
ACS Yes 0.91 0.48
No 0.90 0.31
EF 35 0.90 0.24
Ccr 60 1.04 0.76
CRP 2 0.90 0.36
* : median 0
0.5 1 2
0.361
0.749
00.143 143
0.962
0.584
0113 0.113
0.768

Subgroup analysis analysis by by renal renal function
function
(MACE)
50%
40
Ccr < 60mL/min Ccr > 60mL/min
P=0.039
HR:0.79 (0.63-0.99)
30 Standard
20
50%
40
30
20
P=0.764
HR:1.04 (0.81-1.34)
Standard
10
Candesartan
10
C Candesartan d t
0
0 1 2 3
years y
4 5
0
0 1 2 3
years y
4 5

Summary
IIn comparison i with i h standard d d therapy, h
Candesartan-based therapy
• reduced the incidence of MACE by 11%, while not
statistically significant.
• reduced the incidence of new-onset DM by 63%.
• caused a lower incidence of drug-related g AE.
• significantly reduced the incidence of MACE by 21%
in patients with impaired renal function.

Conclusion
• Candesartan-based therapy produced comparable
effects to Non-ARB-based standard therapy and was
well tolerated in CAD patients with hypertension.
hypertension
• Furthermore Furthermore, candesartan significantly reduced the
incidence of new-onset DM.
• The present study provides evidence to support the
rationale for candesartan candesartan-based based therapy in CAD
patients,particularly in those with chronic kidney
di disease.

Conclusions
Candesartan and Amlodipine equally reduce the
number of CV events in high-risk hypertensive
patients under strict BP control.
Candesartan-based therapy py pproduced comparable p
effects to Non-ARB-based standard therapy and was
well tolerated in CAD patients p with hypertension.
yp
Candesartan is more beneficial than Amlodipine and
ACEI for hypertensive patients with chronic kidney
disease or obesity, and may be preferable for
patients with metabolic syndrome syndrome.

The mechanism of prevention of DM
by inhibition of the RAS
• Hemodynamic benefits
- antagonizing the Ang II–mediated hypoperfusion of skeletal muscle
or pancreatic islet cells.
Circulation 2004;110:1507–1512
• Di Direct t iinhibitory hibit effects ff t of f angiotensin i t i II on iinsulin li signaling i li
and glucose g transport p
Am J Cardiol 2003;91(suppl):30H–37H
; ( pp)
• Reduction in islet fibrosis and increased B-cell mass, by
decreasing oxidative stress, apoptosis, and profibrotic
pathways J Hypertens 2005;23:463– 473.

%
Isolated systolic hypertension
0
‐10 Cardiac
‐20 mortality
‐30
‐40
‐50 ‐46
‐60 60
Stroke
‐40 ‐42
LIFE
SCOPE

Irbesartan vs. atenolol in hypertension & LVH: L
VMI reduction
LVMI
(%)
0
-5
-10
-15
-20
12 Week
24 48 12 Week Week
24 48
-5% 5%
-8%
Malmqvist K, K Kahan Kahan T T et et al. al J Hypertens
2001:19(6);1167-76.
-16%
-
1%
-4% 4%
Irb vs. Ate p = 0.024
Irbesartan p < 0.001
Atenolol p < 0.001
Irbesartan Atenolol
-9%

Predictors of new-onset atrial fibrillation
• Hypertension
• Left ventricular mass and hypertrophy
• LLeft ft atrial t i l enlargement l t
• Congestive heart failure and valvular and coronary heart
disease
• Heart rate below 72 beats/min (PIUMA study, Val-HeFT trial)
• Aging (>70세 1.5배), Male (1.5배)
• Diabetes
• BNP level