성균관의대 강북삼성병원 순환기내과 이종영 · · 2017-05-11p
TRANSCRIPT
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성균관의대 강북삼성병원 순환기내과
이종영
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Contents
Importance of Intensive BP Lowering 1
Efficacy of Combination Therapy 2
Combination of Fimasartan and Amlodipine 3
Dukarb for Efficacy, Safety, Cost-effectiveness, Adherence
4
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Importance of Intensive BP Lowering
BP, Risk Factor for CVD
02 Effects of Intensive BP Lowering
03 Management of Hypertension in Korea
− SPRINT − Meta-analysis Study
01
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Dukarb®
N Engl J Med 2001;345:1291-1297
Women
Normal: SBP of 120-129 mmHg DBP of 80-84 mmHg
Optimal: SBP <120 mmHg DBP < 80 mmHg
High-normal: SBP of 130-139 mmHg DBP of 85-89 mmHg
Cu
mu
lati
ve In
cid
ence
(%
)
10
8
6
4
2
0
0 2 4 6 8 10 12 14
Time (yr)
BP, Risk Factor for CVD (1)
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Dukarb®
N Engl J Med 2001;345:1291-1297
Men
Normal: SBP of 120-129 mmHg DBP of 80-84 mmHg
Optimal: SBP <120 mmHg DBP <80 mmHg
High-normal: SBP of 130-139 mmHg DBP of 85-89 mmHg
Cu
mu
lati
ve In
cid
ence
(%
)
10
8
6
4
2
0
0 2 4 6 8 10 12 14
Time (yr)
BP, Risk Factor for CVD (2)
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Time in BP control and Clinical Outcomes
Mancia G, et al. Circulation 2011
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Time to treatment Intensification of BP treatment and risk of CV events or death
Xu W, et al. BMJ 2015
The longer you wait before you intensify treatment – the greater
the risk to the patient
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BP, Risk Factor for CVD
02 Effects of Intensive BP Lowering
03 Management of Hypertension in Korea
− SPRINT − Meta-analysis Study
01
Importance of Intensive BP Lowering
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Dukarb®
N Engl J Med 2015;373:2103-2116
Primary outcome
− First occurrence of MI, non-MI ACS, Stroke, Acute decompensated HF, CVD death
The SBP Intervention Trial (1)
Screened n=14,692
Eligible n=10,601
Randomized n=9,361
Intensive BP (120 mmHg)
n=4,678
Standard BP (140 mmHg)
n=4,683 Total Ineligible: n=4,091 Age <50: n=34 Low standing BP: n=352 BP/meds: n=2,284 Not high risk: n=718 Miscellaneous: n=703
The overall enrollment experience
- CONSORT(consolidated standards of reporting trials) diagram
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Dukarb®
Results – Primary outcome
N Engl J Med 2015;373:2103-2116
During Trial (median follow-up=3.26 years) Number Needed to Treat (NTT) to prevent a primary outcome=61
25%
Cu
mu
lati
ve H
azar
d
0.10
0.08
0.06
0.04
0.02
0.00
0 1 2 3 4 5
Year
Hazard Ratio = 0.75 (95% CI: 0.64 to 0.89) P <0.001
Standard (319 events)
Intensive (243 events)
The SBP Intervention Trial (2)
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Dukarb®
27%
During Trial (median follo-up)=3.26 years Number Needed to Treat (NTT) to prevent a death=90
Cu
mu
lati
ve H
azar
d
0.10
0.08
0.06
0.04
0.02
0.00
0 1 2 3 4 5
Year
Hazard Ratio = 0.73 (95% CI: 0.60 to 0.90)
Standard (210 events)
Intensive (155 events)
Results – Death from any cause
N Engl J Med 2015;373:2103-2116
The SBP Intervention Trial (3)
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Dukarb®
-20
Results – Major CVD M
ajo
r C
ard
iova
scu
lar
Dis
ease
Eve
nts
P
rop
ort
ion
al R
isk
Red
uct
ion
(%
) 60
40
20
0
0 5 10 15 20
Reduction in SBP (mmHg)
P <0.0001
Lancet 2016;387:957-967
BP Lowering for Prevention of CVD and Death (1)
Meta-analysis
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Dukarb®
Results - Stroke St
roke
Pro
po
rtio
nal
Ris
k R
edu
ctio
n (
%)
60
40
20
0
-20
80
10 15 20
P <0.0001
Reduction in SBP (mmHg)
0 5
Lancet 2016;387:957-967
BP Lowering for Prevention of CVD and Death (2)
Meta-analysis
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Dukarb®
All-
cau
se M
ort
alit
y P
rop
ort
ion
al
Ris
k R
edu
ctio
n (
%)
40
20
0
-20
0 5 10 15 20
Reduction in SBP (mmHg)
Results – All-cause mortality
Lancet 2016;387:957-967
P <0.0001
BP Lowering for Prevention of CVD and Death (3)
Meta-analysis
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BP, Risk Factor for CVD
02 Effects of Intensive BP Lowering
03 Management of Hypertension in Korea
− SPRINT − Meta-analysis Study
01
Importance of Intensive BP Lowering
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Dukarb®
[Trends in awareness, treatment, control of high BP, over 30 years old, 1998-2012]
80
70
1998 2001 2005 2007-2009 2010-2012
60
50
40
30
20
10
0
(%)
23.5
34.1
57.1
66.3 65.9
60.7 60.3
49.6
32.7
20.4
12.3
27.2
42.1 42.5
4.9
2013 KNHANES, PUBLIC HEALTH WEEKLY REPORT, KCDC 2015;8:477-480
KNHANES, Korean National Health and Nutrition Examination Survey
HTN Awareness HTN Treatment HTN Control
Management of Hypertension in Korea
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Dukarb®
PRESSURE!! KNOCKDOWN ♪~♫
I have to keep it constantly!
• High-normal BP is associated with a more than twofold increase in relative risk from CVD as compared with those with optimal BP
• Incidence of primary outcome (composite of CVD events) and all-cause mortality were lowered in intensive BP lowering, than standard BP lowering
• In Korea, the hypertension control rate has been increasing since 1998, but the rate has not reached 50% yet
Summary
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Efficacy of Combination Therapy
01 Limitation of Monotherapy
02 Effect of Combination Therapy on BP Reduction
03 Hypertension Guidelines
04 The role of ARB & CCB Combination Therapy
Adherence of Single-Pill Combination 05
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Dukarb®
Am J Manag Care 2005;11:S220-7, Vasc Health Risk Manag 2010;6:321-325
40% of hypertension patients are initially treated with monotherapy
BUT, more than 60% of hypertension patients require
combination therapy
Limitation of Monotherapy
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Efficacy of Combination Therapy
01 Limitation of Monotherapy
02 Effect of Combination Therapy on BP Reduction
03 Hypertension Guidelines
04 The role of ARB & CCB Combination Therapy
Adherence of Single-Pill Combination 05
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Dukarb®
Adding an Antihypertensive Agent is More Effective Than Titrating
Wald et al. Am J Med 2009;122:290–300
Conclusions from a meta-analysis comparing combination antihypertensive therapy with monotherapy in over 11,000 patients from 42 trials
‘The extra blood pressure reduction from combining drugs from 2 different
classes is approximately 5 times greater than doubling the dose of 1 drug’
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Efficacy of Combination Therapy
01 Limitation of Monotherapy
02 Effect of Combination Therapy on BP Reduction
03 Hypertension Guidelines
04 The role of ARB & CCB Combination Therapy
Adherence of Single-Pill Combination 05
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Dukarb®
Comparison of Target BP in Several Guidelines
2013 대한고혈압학회 진료지침 , 2011 NICE
Eur Heart J 2013;34:2159-2219, JAMA 2014;311:507-520
KSH, The Korean society of hypertension
NICE (2011)
ESH/ESC (2013)
KSH (2013)
JNC 8 (2014)
Target BP (mmHg)
General population
140/90 (Ages <80)
140/90 140/90 140/90
(Ages <60)
For elderly 150/90
(Ages ≥80)
150/90 (Ages ± 80)
140-150 (DBP ≥60)
150/90 (Ages ≥60)
140/90 (Ages <80)
Adult with diabetes
140/85 140/85 140/90
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Hypertension Pathobiology
Oparil S et al. Annals of Internal Medicine 2003;139(9):761–76
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Evidence-based combination therapy
RAAS
blockade
CCB Diuretic
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Efficacy of Combination Therapy
01 Limitation of Monotherapy
02 Effect of Combination Therapy on BP Reduction
03 Hypertension Guidelines
04 The role of ARB & CCB Combination Therapy
Adherence of Single-Pill Combination 05
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Dukarb®
Am J Cardiovasc Drugs 2013;13:301-313
Post myocardial infarction
Atrial fibrillation
Heart failure
Isolated systolic hypertension (elderly)
Hypertension
Angina pectoris
Left ventricular hypertrophy
Coronary atherosclerosis
Diabetic nephropathy
Proteinuria / microalbuminuria
- Metabolic syndrome
- ACEi-induced cough
- Pregnancy
The Role of ARB & CCB Combination Therapy
ARB CCB
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Dukarb®
Vasc Health Risk Manag 2010;6:253-260
Eur Heart J 2011;32:2499-2506
RAS, Renin-angiotensin system; SNS, Sympathetic nervous system
The Role of ARB & CCB Combination Therapy
Synergistic effect
Vasodilation
Attenuated peripheral edema
Effective in high-renin patients
No effect cardiac ischemia
RAS ↓
SNS ↓
ARB & CCB Combination
therapy
Arteriodilation
Peripheral edema
Effective in low-renin patients
Reduces cardiac ischemia
RAS ↑
SNS ↑
ARB CCB
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Efficacy of Combination Therapy
01 Limitation of Monotherapy
02 Effect of Combination Therapy on BP Reduction
03 Hypertension Guidelines
04 The role of ARB & CCB Combination Therapy
Adherence of Single-Pill Combination 05
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Dukarb®
Un
adju
sted
od
ds
rati
o f
or
com
plia
nce
(>8
0%
) to
bo
th a
nti
hyp
erte
nsi
ve t
her
apy
and
LLT
Number of pre-existing prescription medications
0.5
1.0
2.0
1.5
0 1 2 3-5 ≥ 6
Vasc Health Risk Manag 2010;6:321-325 Arch intern med 2005;165:1147-1152
LLT, lipid-lowering therapy; OR, odd ratio
Number of drugs Unadjusted OR (95% CI)
P value
0 1.73 (1.56-1.90) P <0.001
1 1.25 (1.13-1.39) P <0.001
2 0.96 (0.86-1.06) P = 0.41
3-5 0.87 (0.79-0.94) P <0.001
≥6 0.65 (0.59-0.71) P <0.001
Medication Adherence
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Dukarb®
Hypertension 2010;55:399-407.
Study OR (95% CI)
Trial
Schweizer et al. 2007 1.08 (0.75, 1.54)
Asplund et al. 1984 1.74 (0.96, 3.15)
Subtotal (I-squared=45.6%, P=0.175) 1.22 (0.90, 1.66)
Cohort
Taylor et al. 2003 1.09 (0.80, 1.51)
Gerbino et al. 2004 1.28 (0.93, 1.75)
Dickson et al. 2008 1.29 (0.89, 1.89)
Subtotal (I-squared=0.0%, P=0.740) 1.21 (1.00, 1.47)
Heterogeneity between groups: P=0.960
Overall (I-squared=0.0%, P=0.655) 1.21 (1.03, 1.43)
0.5 1.0 1.5 2.0
Adherence of single-Pill Combination
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Combination of Fimasartan and Amlodipine : Phase II study
A randomized, double-blind, placebo-controlled, 3ⅹ3 factorial design, phase II study to
evaluate the antihypertensive efficacy and safety of combination of fimasartan and
amlodipine in patients with essential hypertension
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Dukarb®
Overall Study Design
screening Baseline Week 2 Week 4 Week 8
7 days 14 days
Rnadomization
Treatment period 8 weeks (n=419)
Washout
Placebo run-in
Placebo (n=51) fimasartan 30 mg (n=45) fimasartan 60 mg (n=45) amlodipine 5 mg (n=46) amlodipine 10 mg (n=45) fimasartan 30 mg / amlodipine 5 mg (n=45) fimasartan 30 mg / amlodipine 10 mg (n=48) fimasartan 60 mg / amlodipine 5 mg (n=47) fimasartan 60 mg / amlodipine 10 mg (n=47)
9 groups
(Telephone Visit)
Clin Ther 2015;37:2581-2596
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Dukarb®
0
-5
-10
-15
-20
-25
Overall: Monotherapy vs. Combination therapy P <0.05
Clin Ther 2015;37:2581-2596
F, fimasartan; A, amlodipine
Mea
n C
han
ge in
DB
P (
mm
Hg)
, P <0.05; , P <0.01; , P < 0.0001 *** ** *
-10.6 -10.1 -10.6
-13.0
-15.9
-10.1
-15.9
-13.0
**
*** ***
* *
*** **
**
-16.2 -16.6
-19.5
-21.5
Change in mean DBP at week 8 Primary Endpoint
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Dukarb® M
ean
Ch
ange
in S
BP
(m
mH
g)
0
-5
-10
-15
-20
-25
Overall: Monotherapy vs. Combination therapy P <0.05
-16.8 -17.7 -16.8
-21.3
-25.0
-17.7
-25.0
-21.3
-24.8
-28.6
-32.9 -34.5 **
*
***
* **
*** ***
***
Clin Ther 2015;37:2581-2596
F, fimasartan; A, amlodipine
Change in mean SBP at week 8 Secondary Endpoint
, P <0.05; , P <0.01; , P < 0.0001 *** ** *
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Dukarb®
Results [Response rate] R
esp
on
se R
ate
at w
eek
8 (
%)
100
80
60
40
20
0
Clin Ther 2015;37:2581-2596
F, fimasartan; A, amlodipine
72.7
87.5 89.4
78.7
**
* ***
** ***
45.5
54.6
45.5
61.4
72.7
54.6
72.7
61.4
, P <0.05; , P <0.01; , P < 0.0001 *** ** *
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Dukarb®
Results [Safety]
Placebo (n=51)
F-mono (n=90)
A-mono (n=91)
F/A (n=187)
Total (n=419)
TEAEs
P-value [1]
6(11.8) [10]
20(22.2) [32]
14(15.4) [16]
35(18.7) [48]
75(17.9) [106]
0.0884
SAEs
P-value [2]
0(0.00) [0]
2(2.2) [2]
2(2.2) [2]
0(0.00) [0]
4(0.95) [4]
0.0799
ADRs
P-value [2]
2(3.9) [3]
3(3.3) [4]
3(3.3) [4]
8(4.3) [9]
16(3.82) [20]
0.9921
[1] Difference between treatment group(chi-square test) [2] Difference between treatment group(Fisher’s exact test) SAEs include erythema nodosum, ligament rupture, contusion, intervertebral disc protrusion
Clin Ther 2015;37:2581-2596
F-mono, fimasartan monotheraphy; A-mono, amlodipine monotherapy; F/A, fimasartan/amlodipine combination therapy;
TEAEs, Treatment Emergent Adverse Events; SAEs, Serious Adverse Events; ADRs, Adverse Drug Reactions
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A randomized, double-blind, multicenter, phase III study to evaluate the efficacy and
safety of combination of fimasartan/amlodipine versus fimasartan monotherapy in
patients with essential hypertension who fail to respond adequately to fimasartan
monotherapy
Combination of Fimasartan and Amlodipine : Phase III study
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Dukarb®
Overall Study Design
Screening Baseline 4W 8W
fimasartan 60 mg (n=355)
Randomization
Treatment Period (8 weeks)
Run-in Period
fimasartan 60 mg
(Visit 3) (Visit 1)
-4W 0W
(Visit 2) (Visit 4)
fimasartan 60 mg / amlodipine 10 mg
(n=70)
(n=73)
Data on file
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Dukarb®
Results [Change in SBP]
F, fimasartan; A, amlodipine
*** ***
0
-5
-10
-15
-20
-25
week 4
Mea
n C
han
ge in
SB
P (
mm
Hg)
week 8
-7.8
-20.4
-7.5
-20.8 F60 (n=70)
F60/A10 (n=67)
Data on file
*** , P <0.001
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Dukarb®
Results [Change in DBP]
*** ***
0
-2
-4
-6
-8
-10
-3.7
-11.3
-3.8
-11.7
-12
-14
week 4 week 8
Mea
n C
han
ge in
DB
P (
mm
Hg)
*** , P <0.001
F, fimasartan; A, amlodipine
Data on file
F60 (n=70)
F60/A10 (n=67)
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Dukarb®
40
20
0
100
80
60
Res
po
nse
Rat
e at
wee
k8 (
%)
Results [Response rate]
*** , P <0.001
F, fimasartan; A, amlodipine
Data on file
F60 (n=70)
F60/A10 (n=67)
32.86
82.09
***
49.2%
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Dukarb®
Results [Safety]
F60 (n=73)
F60/A10 (n=70)
TOTAL (n=143)
P-value 1)
TEAEs 14 (19.18)
[19] 18 (25.71)
[28] 32 (22.38)
[47] 0.3485 (c)
SAEs 0 0 0
ADRs 6 (8.22)
[9] 3 (4.29)
[4] 9 (6.29)
[13] 0.4944 (f)
TEAEs, Treatment-Emergent Adverse Events; SAEs, Serious Adverse Events; ADRs, Adverse Drug Reaction
Data on file
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01 Comparison of Efficacy
02 Comparison of Safety
03 Comparison of Cost
04 Comparison of Pill Size
Dukarb for Efficacy, Safety, Cost-effectiveness, Adherence
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Dukarb®
Clin Ther 2007;29:563-580, J Clin Hypertens (Greenwich) 2009;11:207-213, Clin Ther 2008;30:587-604, Am J Cardiovasc Drugs 2012;12:35-47, Clin Ther 2015;37:2581-2596
Study I Study Ⅱ Study Ⅲ Study Ⅳ Study Ⅴ
Design
Multicenter, double-blind,
randomized placebo controlled,
parallel-group trials (Multinational)
Multicenter, randomized, double-blind,
double-dummy, placebo-controlled,
4ⅹ4 factorial design trial
(Multinational)
Multicenter, double-blind, randomized,
placebo-controlled, factorial study
(US)
Multicenter, double-blind,
randomized, phase Ⅱ study (Korea)
Multicenter, double-blind, randomized,
placebo-controlled, 3x3 factorial study
(Korea)
Treatment V80/A5 (n=127)
T40/A5 (n=141)
O20/A5 (n=161)
L50/A4 (n=38)
F60/A5 (n=47)
Duration 8 weeks 8 weeks 8 weeks 8 weeks 8 weeks
Baseline (mmHg)
SBP 153.2 DBP 99.1
SBP 153.2 DBP 101.7
SBP 163.8 DBP 101.7
SBP 158.4 DBP 101.5
SBP 159 DBP 99.2
Inclusion Criteria
BP (mmHg)
DBP >95 and <110 DBP ≥95 and ≤119 DBP: 95 to 120 DBP ≥95 and <115 90 ≤ DBP < 114
Patients Essential
hypertension Stage I or II
hypertension Stage II
hypertension Essential
hypertension mild to moderate
hypertension
Primary endpoint
Change from baseline
in DBP at the end of the study
Change in DBP At week 8
Change from baseline in mean
DBP at week 8
Mean change from baseline in DBP
after 8 weeks of treatment
Change in DBP from baseline and at
week 8
L, losartan; A, amlodipine; V, valsartan; O, olmesartan; F, fimasartan
Comparison of Efficacy (1)
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Dukarb®
V80/A5
Study I
T40/A5
Study II
O20/A5
Study III Study V
L50/A5
Study IV
F60/A5
Ch
ange
of
BP
(m
mH
g)
-25
-30
-10
-15
-20
L, losartan; A, amlodipine; V, valsartan; O, olmesartan; F, fimasartan
Clin Ther 2007;29:563-580, J Clin Hypertens (Greenwich) 2009;11:207-213, Clin Ther 2008;30:587-604, Am J Cardiovasc Drugs 2012;12:35-47, Clin Ther 2015;37:2581-2596
DBP SBP
Comparison of Efficacy (2)
-20.8 -21.0
-22.6
-25.7
-28.6
-14.5 -16.0
-14.6 -15.6
-16.6
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Dukarb®
Data on file, Vascular Health and Risk Management 2011;7:183-192, International Journal of Hypertension 2013, Journal of Hypertension 2013;31:1245-1255, Internaional Journal of Cardiology 2013;167:2024-2030
T, telmisartan; A, amlodipine; V, valsartan; O, olmesartan; H, hydrochlorothiazide; F, fimasartan
Perc
enta
ge o
f H
yper
ten
sio
n P
atie
nts
A
chie
vin
g Ta
rget
BP
(%
)
40
20
100
80
60
0
58.8 61.3
49.5
86.7
Comparison of Efficacy (3)
78.7
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01 Comparison of Efficacy
02 Comparison of Safety
03 Comparison of Cost
04 Comparison of Pill Size
Dukarb for Efficacy, Safety, Cost-effectiveness, Adherence
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Dukarb®
Comparison of Safety (1)
Clin Ther 2011;33:1953–1963, Curr Med Res Opin 2010;26:1705-1713, Clin Drug Invest 2009;29:11-25, J Clin Hypertens 2011;13:459-466, Clin Ther 2015;37:2581-2596
Common ARB Adverse Events
Dizziness, headache, drowsiness, nausea, rash, vomiting, diarrhea, cough, elevated K+ levels, low BP, muscle or bone pain, etc.
Common CCB Adverse Events
Dizziness, headache, drowsiness, nausea, rash, constipation, edema(legs, feet), low BP, etc.
Fimasartan+amlodipine combination therapy showed similarity in terms of safety features compares to other combination agents
Drug-related Adverse events(%)
L50/A5 6.5%
O40/A5 7.5%
T80/A5 8.7%
F60/A5 6.4%
L, losartan; A, amlodipine; O, olmesartan; T, telmisartan; F, fimasartan
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Dukarb®
is non hygroscopic medication
Comparison of Safety (2)
telmisartan+amlodipine telmisartan+amlodipine telmisartan+amlodipine
취급상의 주의사항 1. 이 약은 습기에 약하므로, 원래의 포장 상태대로 보관하시고 복용 직전에 알루미늄 호일을 개봉하 십시오. 2. 이 약의 지정된 보관 온도는 1-30℃입니다. 30 ℃를 초과하는 고온에 노출되지 않도록 주의 하십시오
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01 Comparison of Efficacy
02 Comparison of Safety
03 Comparison of Cost
04 Comparison of Pill Size
Dukarb for Efficacy, Safety, Cost-effectiveness, Adherence
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Dukarb®
ARB + CCB Single-Pill
Combination
L100/A5 1,335 944
O40/A5 844 758
T80/A5 927 1,053
V160/A5 1,336 988
F60/A5 1,031 808 (원단위, 개당 단가)
약학정보원, http://www.health.kr/
L, losartan; A, amlodipine; O, olmesartan; T, telmisartan; V, valsartan; F, fimasartan
Comparison of Cost
is the most cost-effective ARB & CCB SPC Therapy
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01 Comparison of Efficacy
02 Comparison of Safety
03 Comparison of Cost
04 Comparison of Pill Size
Dukarb for Efficacy, Safety, Cost-effectiveness, Adherence
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Dukarb®
약학정보원, http://www.health.kr/
0 1 2 3 4 5 6 7 (cm)
Dukarb
olmesartan + amlodipine
valsartan + amlodipine
telmisartan + amlodipine
losartan + amlodipine
F30/A5 F30/A10 F60/A5 F60/A10
O20/A5 O40/A5 O20/A10 O40/A10
V80/A5 V160/A10 V160/A5
T40/A5 T40/A10 T80/A5
L50/A5 L50/A10 L100/A5
Comparison of Pill Size
Dukarb®
The smallest SPC
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Dukarb®
How to make a PERFECT
medicine?
PERFECT !! This is it!
• Fimasartan and amlodipine combination therapy superior reduction in BP compared with other ARB & CCB combination therapies
• Non-hygroscopic medication, Dukar b , is the smallest and most cost-effective available ARB & CCB SPCs
Summary
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Thank you