Anti-hypertension

Medications
- Beyond Blood
Pressure Control
台中縣 大里市 仁愛綜合 醫
院
心臟血 管中心 副主任
楊文義

Wenyi Yang MD
Da-Li Jen-Ai Hospital, Taichung County, Taiwan
Essential hypertension
 Effect of Antihypertensive Drug Treatment on CV Events
in Events ** PLACEBO CONTROLLED TRIALS
% Reduction

CHF Strokes LVH CVD CHD events

Fatal/Non-fatal Deaths Fatal/Non-fatal

*Combined results from 17 randomized placebo controlled

treatment trials (48.000 subjects) Diuretic or Beta-blocker based
**All differences are statistically significant

Moser,J Am Coll Cardiol. 1996;27:1214-1218; Arch Intern Med 1993;S76-S71

• The risk of cardiovascular disease increases
progressively and continuously with increases in
systolic or diastolic blood pressure, approximately
doubling for every 20/10 mm Hg incremental
increase in blood pressure that occurs within the
range of 115/75 to 185/115 mm Hg.

Age-specific relevance of usual blood pressure to vascular mortality: a

meta-analysis of individual data for one million adults in 61 prospective
studies
The Lancet, Volume 360, Issue 9349, Pages 1903 - 1913, 14 December 2002
 JNC-7 for initial drug therapy for hypertension

Initial Drug
Therapy

Lifestyle Without Compelling With Compelling

BP Classification SBP, mm Hg DBP, mm Hg
Modifications Indications Indications

Normal <120 And <80 Encourage

Prehypertension 120-139 Or 80-89 Yes No antihypertensive Drug(s) for

drug indicated compelling
indications †
Stage 1 140-159 Or 90-99 Yes Thiazide-type diuretics for Drug(s) for the
Hypertension most. May consider ACEI, compelling
ARB, BB, CCB, or indications. ‡ Other
combination antihypertensive
drugs (diuretics,
ACEI, ARB, BB,
CCB) as needed

Stage 2 >160 Or >100 Yes Two-drug combination for

Hypertension most † (usually thiazide-
type diuretic and ACEI or
ARB or BB or CCB)
 JNC-7 for initial drug therapy for hypertension

Initial Drug
Therapy

Lifestyle Without Compelling With Compelling

BP Classification SBP, mm Hg DBP, mm Hg
Modifications Indications Indications

Normal <120 And <80 Encourage

Prehypertension 120-139 Or 80-89 Yes No antihypertensive Drug(s) for

drug indicated compelling
indications †
Stage 1 140-159 Or 90-99 Yes Thiazide-type diuretics for Drug(s) for the
Hypertension most. May consider ACEI, compelling
ARB, BB, CCB, or indications. ‡ Other
combination antihypertensive
drugs (diuretics,
ACEI, ARB, BB,
CCB) as needed

Stage 2 >160 Or >100 Yes Two-drug combination for

Hypertension most † (usually thiazide-
type diuretic and ACEI or
ARB or BB or CCB)
 JNC-7 for initial drug therapy for hypertension

Initial Drug
Therapy

Lifestyle Without Compelling With Compelling

BP Classification SBP, mm Hg DBP, mm Hg
Modifications Indications Indications

Normal <120 And <80 Encourage

Prehypertension 120-139 Or 80-89 Yes No antihypertensive Drug(s) for

drug indicated compelling
indications †
Stage 1 140-159 Or 90-99 Yes Thiazide-type diuretics for Drug(s) for the
Hypertension most. May consider ACEI, compelling
ARB, BB, CCB, or indications. ‡ Other
combination antihypertensive
drugs (diuretics,
ACEI, ARB, BB,
CCB) as needed

Stage 2 >160 Or >100 Yes Two-drug combination for

Hypertension most † (usually thiazide-
type diuretic and ACEI or
ARB or BB or CCB)
 JNC-7 for initial drug therapy for hypertension

Initial Drug
Therapy

Lifestyle Without Compelling With Compelling

BP Classification SBP, mm Hg DBP, mm Hg
Modifications Indications Indications

Normal <120 And <80 Encourage

Prehypertension 120-139 Or 80-89 Yes No antihypertensive Drug(s) for

drug indicated compelling
indications †
Stage 1 140-159 Or 90-99 Yes Thiazide-type diuretics for Drug(s) for the
Hypertension most. May consider ACEI, compelling
ARB, BB, CCB, or indications. ‡ Other
combination antihypertensive
drugs (diuretics,
ACEI, ARB, BB,
CCB) as needed

Stage 2 >160 Or >100 Yes Two-drug combination for

Hypertension most † (usually thiazide-
type diuretic and ACEI or
ARB or BB or CCB)
 JNC 7 & 2007 ESC/ESH : Compelling
Indications for Antihypertensive Drug Classes
Recommended Drugs
Aldo
Compelling Indication Diuretic BB ACEI ARB CCB ANT
Heart failure •• •• •• •• ••
Post MI •• •• • •
High coronary
disease risk • • • •
Angina pectoris • •
Diabetes • • • • •
Chronic kidney disease •• ••
Macroalbuminuria • •
Recurrent stroke
prevention •• • •• • • •
LVH • • •
Asymptomatic atherosclerosis • •
JAMA 2003; 289:2560-72 Ref. J Hypertens 2007; 25:1105-1187
 Role of Angiotensin II in Vascular Disease
Blocking the RAAS with ACE inhibitors and ARBs

adapted from: Chung, Unger., Am J Hypertens 1999;12:150S–156S

Mean Blood Pressure According to Age and Race
or Ethnic Group in U.S. Adults.

Prevalence of hypertension in the US adult population: results from the Third

National Health and Nutrition Examination Survey, 1988-1991.
Hypertension 1995;25:305-313
Frequency of Untreated Hypertension
According to Subtype and Age.

Circulation 1997;96:308-315.
Hemodynamic patterns of age-related changes in blood pressure:
the Framingham Heart Study.
Systolic Hypertension
In The Elderly

Age-related aortic stiffening

Cartoon of Young and Old Human Aorta

young old

fraying and fracture of the elastic lamellae (yellow)

loss of muscle attachments (red)
increase in collagen fibers (black)
foci of "medionecrosis. J Am Coll Cardiol, 2007; 50:1-13
 Ann Intern Med. 2000;132:233-237.
The Diastolic Blood Pressure in Systolic Hypertension
Development of malignant hypertension during a 12-month period.
Systolic and diastolic arterial pressures of Franklin D. Roosevelt
1935-1941 and in the year before his death due to cerebral
hemorrhage on April 12, 1945.
MICHAEL F. O’ROURKE et al. Mayo Clin Proc. 2006;81(8):1057-1068
 已上市 的 ARB 的比
商品名
較
Blopress Cozaar Diovan Aprovel Micardis Olmetec
Candesartan Olmesartan
學名 Losartan Valsartan Irbesartan Telmisartan
cilexetil medoxomil
百靈佳殷
公司 台灣武田 默沙東 諾華 賽諾菲 輝瑞 / 三共
格翰
本態性高血 本態性高
本態性高 本態性高 本態性高
適應症 壓 / 心臟衰 血壓 / 心 本態性高血壓
血壓 血壓 血壓
竭 臟衰竭
FDA / EU CHF
Indication FDA / EU 　 FDA 　 　 　
80mg
50mg Capsule/ 150mg 40mg
劑型劑量 8mg Tablet 20mg Tablet
Tablet film- Tablet Tablet
coated tab
健保價 (NT$ /
tablet) 20.1 23.9 22.6 21.6 23.8 27.6
 ARB 藥理性 的比 較 (1)
商品 名 Blopress Cozaar Diovan Aprovel Micardis Olmetec
AT1Receptor
Blopress®>Irbesartan>Telmisartan/Valsartan> Losartan
結合 力
混合型 混合 型 混合型 混合 型
Antagonistic
非競爭性 ( 競爭性 / ( 競爭 性 / ( 競爭性 / ( 競爭 性 / ?
properties
非競爭性 ) 非競 爭性 ) 非競爭性 ) 非競 爭性 )
Trough/
Peak ratio > 80% 70% 60-70%3 60-70% 60-70% 60-80%

食物交互 反 ↓ 40%AUC &

不影 響 ↓Cmax 不影響 ↓20% AUC 不影響
應 ↓50%Cmax

臨床效 應 1.5 1 1 1.2 ≒ Losartan ?

生體可用 率 42% 33% 23% 60-80% -57% 26%

 ARB 藥理性 的比 較 (2)
商品名 Blopress Cozaar Diovan Aprovel Micardis Olmetec

蛋白質結合率 > 90%

1.5-2
半衰期 ( 小時 ) 9-13 (EXP- 6 11-15 23 13
3174: 6-9)

代謝途徑 經肝臟 P450 在肝臟以

幾乎以原型排 經肝臟 P450 經肝臟 P450
(Cytochrome 3A4 & P450 glucuronidati 幾乎以原型排出
出 酵素代謝 2C9 酵素代謝
P450) 2C9 酵素代謝 on 途徑代謝

Phenobarbital
Cimetidine
無明顯臨床上 Phenobarbital Fluconazole 無明顯臨床上之交互
藥物交互反應 Fluconazole Fluconazole
之交互作用 Cimetidine Digoxin 作用
Rifampin
Phenytoin

排除途徑尿液：
33:67 45:55 13:87 20:80 3:9710 ~ 1:1
糞便 (%)
 CANDESARTAN

STRONGEST AT1 RECEPTOR BINDING LONG ACTING

AMONG ARBs
ARB “equivalent” doses for the reduction of
sitting BP by 8 to 10 mm Hg

Candesartan 16mg

Valsartan 160 mg

Irbesartan 150 mg

Telmisartan 40 mg

Olmesartan 20 mg
Losartan, 100 mg

Eprosartan 800 mg

Dominiak and Häuser

Dtsch Med Wochenschr 2003;128:2313–2318.
ACC2008 LBCT analysis

Blopress ---We CanTARGET !!!

 Candesartan Cilexetil v Losartan :
Mean Change From Baseline To Week 8 In Systolic ABP

Hours after dose

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
0
-2
-4
-6
Losartan 100mg
-8
p=0.004
-10
-12
-14
-16 Candesartan cilexetil 16mg

-18
Change in SBP (mm Hg)
Blood Pressure 2001 , 10 33-39
Ref : Blood pressure 2001; 10 : 33-39
 HT -
initial :8mg;
Max:32mg
Q.D.

HF -
initial:4mg;
Max :32mg
Q.D.
 CHARM Programme
New-onset diabetes
Proportion of patients (%)
12

10 202 (7.4%)

8 Placebo p=0.020
163 (6.0%)
6
Candesartan
4

2
HR 0.78 (0.64–0.96)
0
0 1.0 2.0 3.0 3.5 years
Number at risk
Candesartan 2715 2565 2395 1662
Placebo 2721 2501 2304 1622

Yusuf et al. Circulation 2005

30
 First Diagnosis of Diabetes mellitus During
AT1- Receptor Antagonist Therapy

• LIFE Losartan vs. Atenolol -25%

• VALUE Valsartan vs. Amlodipin -23%

• CHARM-Preserved Candesartan vs. Placebo -39%

Lancet (2002) 359:995 Lancet (2004) 363:2049 Circulation (2005) 112:48

 Blopress 有統計意義的降低 36% 新生糖尿病
風險
BMI
（％
<22 ≧22 ≧25 ≧27.5
）
6.0 P=0.031
HR=0.64 ; 95% 0
5.0 4%
CI 0.43-0.97
Amlodipine
4.0 36 20
3.0 %
40
2.0 41%
47%
1.0 Blopress 60
62%
0 (%)
P=0.947 P=0.01 P=0.02 P=0.03
6 12 18 24 30 36 42 48 5 8 4
Baseline
（ month Risk Reduction in Blopress group
s）
Candesartan Antihypertensive Survival Evaluation
in JAPAN
CASE-J
CASE-J
 CASE-J
ALL CAUSE MORTALITY
 CASE-J
NEW ONSET OF DIABETES
 CASE-J
LV HYPERTROPHY REGRESSION
Treating Pre-hypertension in the
young with ARB - Candesartan

TROPHY study
NEJM March 14, 2006
High-normal BP increases CV risk
Incidence of CV events in women; N = 3892

10

High-normal BP
8 130–139/85–89 mm Hg

Cumulative
incidence (%) 6
and 95% CI

4 Normal BP
120–129/80–84 mm Hg

2
Optimal BP
<120/<80 mm Hg
0
0 2 4 6 8 10 12
Time (years)

Framingham Heart Study Vasan RS et al. N Engl J Med. 2001;345:1291-7.

 TROPHY study
• PATIENT CHARACTERISTICS
– Age ~ 48 y/o,
– Sex : ~ 60% white,
– Pre-hypertensive: ~ 134/84 mmHg
• Number of patients: Cande(391),
Placebo(381)

PREHYPERTENSION DEFININTION in this study

1. SBP 130 ~ 139 mm Hg and DBP <= 89 mm Hg

2. SBP <= 139 mm Hg and DBP 85 ~ 89 mm Hg
NEJM March 14, 2006
 TROPHY study

ALL RECEIVED LIFE-STYLE MODIFICATIONS

NEJM March 14, 2006

 TROPHY study
• Over a period of 4 years, 2/3 of placebo
group developed stage 1 hypertension 

• Treatment of prehypertension with

candesartan reduced the risk of
incident hypertension during the study
period.
TROPHY: Reduction in new-onset
hypertension over time
N = 772
100
Candesartan vs Placebo only
80 placebo RRR 16%
HR = 0.84 (0.75–0.95)
P = 0.007

Cumulative 60
incidence
(%) 40

RRR 66%
20 HR = 0.34 (0.25–0.44)
P < 0.001

0
0 1 2 3 4
Study year

Placebo Candesartan 16 mg qd
Julius S et al. N Engl J Med. 2006;354:1685-97.
Median time (95% confidence interval)
to development of clinical hypertension

Years
3.5

2.5

1.5 3.3 2.2

1 (3.0-3.8) (2.0-2.5)

0.5

0
Candesartan Placebo
Julius et al. N Engl J Med 2006
 CHARM-Alternative: Primary outcome
CV death or CHF hospitalisation
%
50
406 (40.0%)
Placebo
40 334 (33.0%)
30
Candesartan
20

10 HR 0.77 (95% CI 0.67-0.89), p=0.0004

Adjusted HR 0.70, p<0.0001
0
0 1 2 3 3.5 years
Number at risk
Candesartan 1013 929 831 434 122
Placebo 1015 887 798 427 126
46
 All Cause Mortality Comparison
All cause
NYHA LVEF P’t no. Study drug mortality (HR) p-Value

ELITE-II ≤40% 3,152 losartan 1.13 0.16

II-IV vs
captopril

ValHeFT II-IV ≤ 40% 5,010 valsartan 1.02 0.8

vs
placebo

CHARM- ≤ 40%: 60.2%

II-IV 7,599 candesartan 0.91 0.055
Overall >40%: 39.8% vs
background
therapy

CHARM-Alt candesartan
+ II-IV ≤ 40% 4,576 vs 0.88 0.018*
background
CHARM Add therapy

47
 CONCLUSIONS
• BLOPRESS(CANDESARTAN) IS
PHARMACOLOGICALLY UNIQUE AMONG ARBs

• INDICATED BOTH FOR HYPERTENSION AND

HEART FAILURE TREATMENT

• HAS EFFECTS BEYOND BLOOD

PRESSURE REDUCTION