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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
PLACEBO CONTROLLED TRIALS

% Reduction in Events ** CHF

Fatal/Non-fatal

Strokes

LVH

Deaths Fatal/Non-fatal

CVD CHD events

*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

BP Classification

SBP, mm Hg

DBP, mm Hg

Lifestyle Modifications

Without Compelling Indications

With Compelling Indications

Normal
Prehypertension

<120
120-139

And <80
Or 80-89

Encourage
Yes No antihypertensive drug indicated
Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination

Drug(s) for compelling indications †
Drug(s) for the compelling indications. ‡ Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed

Stage 1 Hypertension

140-159

Or 90-99

Yes

Stage 2 Hypertension

>160

Or >100

Yes

Two-drug combination for most † (usually thiazidetype diuretic and ACEI or ARB or BB or CCB)

JNC-7 for initial drug therapy for hypertension
Initial Drug Therapy

BP Classification

SBP, mm Hg

DBP, mm Hg

Lifestyle Modifications

Without Compelling Indications

With Compelling Indications

Normal
Prehypertension

<120
120-139

And <80
Or 80-89

Encourage
Yes No antihypertensive drug indicated
Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination

Drug(s) for compelling indications †
Drug(s) for the compelling indications. ‡ Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed

Stage 1 Hypertension

140-159

Or 90-99

Yes

Stage 2 Hypertension

>160

Or >100

Yes

Two-drug combination for most † (usually thiazidetype diuretic and ACEI or ARB or BB or CCB)

JNC-7 for initial drug therapy for hypertension
Initial Drug Therapy

BP Classification

SBP, mm Hg

DBP, mm Hg

Lifestyle Modifications

Without Compelling Indications

With Compelling Indications

Normal
Prehypertension

<120
120-139

And <80
Or 80-89

Encourage
Yes No antihypertensive drug indicated
Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination

Drug(s) for compelling indications †
Drug(s) for the compelling indications. ‡ Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed

Stage 1 Hypertension

140-159

Or 90-99

Yes

Stage 2 Hypertension

>160

Or >100

Yes

Two-drug combination for most † (usually thiazidetype diuretic and ACEI or ARB or BB or CCB)

JNC-7 for initial drug therapy for hypertension
Initial Drug Therapy

BP Classification

SBP, mm Hg

DBP, mm Hg

Lifestyle Modifications

Without Compelling Indications

With Compelling Indications

Normal
Prehypertension

<120
120-139

And <80
Or 80-89

Encourage
Yes No antihypertensive drug indicated
Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination

Drug(s) for compelling indications †
Drug(s) for the compelling indications. ‡ Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed

Stage 1 Hypertension

140-159

Or 90-99

Yes

Stage 2 Hypertension

>160

Or >100

Yes

Two-drug combination for most † (usually thiazidetype diuretic and ACEI or ARB or BB or CCB)

JNC 7 & 2007 ESC/ESH : Compelling Indications for Antihypertensive Drug Classes
Recommended Drugs ACEI ARB Compelling Indication Heart failure Post MI High coronary disease risk Angina pectoris Diabetes Chronic kidney disease Macroalbuminuria Recurrent stroke prevention LVH Asymptomatic atherosclerosis Diuretic BB Aldo CCB ANT

••

•• •• • • •

•• •• • • •• •

•• • • • •• • • • • • • • •

•• •

• •

••

•• • •

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

商品名 學名 公司

已上市 的 ARB 的比 較 Blopress Cozaar Diovan Aprovel Micardis
Candesartan cilexetil Losartan Valsartan Irbesartan Telmisartan

Olmetec
Olmesartan medoxomil

台灣武田

默沙東

諾華

賽諾菲

百靈佳殷 輝瑞 / 三共 格翰

適應症 FDA / EU CHF Indication

本態性高血 本態性高 本態性高 本態性高 本態性高 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 8mg Tablet   50mg Tablet 23.9 FDA     40mg Tablet 23.8   20mg Tablet 80mg Capsule/ 150mg filmTablet coated tab 22.6 21.6

劑型劑量

健保價 (NT$ / tablet)

20.1

27.6

ARB 藥理性 的比 較 (1)
商品 名
AT1Receptor 結合 力 Antagonistic properties Trough/ Peak ratio 食物交互 反 應 臨床效 應 非競爭性 > 80% 不影 響

Blopress

Cozaar

Diovan

Aprovel

Micardis

Olmetec

Blopress®>Irbesartan>Telmisartan/Valsartan> Losartan
混合型 ( 競爭性 / 非競爭性 ) 70% ↓Cmax 混合 型 ( 競爭 性 / 非競 爭性 ) 60-70%3 ↓ 40%AUC & ↓50%Cmax 1 混合型 ( 競爭性 / 非競爭性 ) 60-70% 不影響 混合 型 ( 競爭 性 / 非競 爭性 ) 60-70% ↓20% AUC ? 60-80% 不影響

1.5

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
蛋白質結合率 1.5-2 半衰期 ( 小時 ) 代謝途徑 (Cytochrome P450) 9-13 (EXP3174: 6-9) 6 11-15 23 13

Blopress

Cozaar

Diovan

Aprovel
> 90%

Micardis

Olmetec

幾乎以原型排 出

經肝臟 P450 在肝臟以 經肝臟 P450 經肝臟 P450 3A4 & P450 glucuronidati 酵素代謝 2C9 酵素代謝 2C9 酵素代謝 on 途徑代謝

幾乎以原型排出

藥物交互反應

Phenobarbital Cimetidine 無明顯臨床上 Phenobarbital Fluconazole Fluconazole 之交互作用 Cimetidine Rifampin Phenytoin 33:67 45:55 13:87 20:80

Fluconazole 無明顯臨床上之交互 Digoxin 作用

排除途徑尿液: 糞便 (%)

3:9710

~ 1:1

CANDESARTAN

STRONGEST AT1 RECEPTOR BINDING AMONG ARBs

LONG ACTING

ARB “equivalent” doses for the reduction of sitting BP by 8 to 10 mm Hg
Candesartan Valsartan Irbesartan Telmisartan Olmesartan Losartan, Eprosartan 16mg 160 mg 150 mg 40 mg 20 mg 100 mg 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 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

0 -2 -4 -6 -8 -10 -12 -14 -16 -18

2

4

6

Losartan 100mg

p=0.004

Candesartan cilexetil 16mg

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 8 6 4 2 0
Number at risk Candesartan 2715 Placebo 2721

202 (7.4%) Placebo p=0.020 163 (6.0%) Candesartan HR 0.78 (0.64–0.96) 0 1.0
2565 2501

2.0
2395 2304

3.0
1662 1622

3.5 years

30 Yusuf et al. Circulation 2005

First Diagnosis of Diabetes mellitus During AT1- Receptor Antagonist Therapy

• LIFE • VALUE • CHARM-Preserved

Losartan vs. Atenolol Valsartan vs. Amlodipin Candesartan vs. Placebo

-25% -23% -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
(% ) 6.0 5.0 4.0 3.0 2.0 1.0

BMI

P=0.031
HR=0.64 ; 95% CI 0.43-0.97

<22
0

≧22

≧25

≧27.5

4%

Amlodipine

36 20
%
40

41%

Blopress

47% 62%

60
P=0.947

0 6 12 18 24 30 36 42 48 Baseline ( month Candesartan Antihypertensive Survival ) s Evaluation
in JAPAN

(%)

P=0.01 P=0.02 P=0.03 5 8 4

Risk Reduction in Blopress group

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 Cumulative incidence (%) and 95% CI 6 4 2 0 0 2 4 6 Time (years) 8 10 12
130–139/85–89 mm Hg

Normal BP
120–129/80–84 mm Hg

Optimal BP
<120/<80 mm Hg

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 80

Candesartan vs placebo

Placebo only
RRR 16% HR = 0.84 (0.75–0.95) P = 0.007

Cumulative 60 incidence (%) 40
20 0 0 1 2 3 4
RRR 66% HR = 0.34 (0.25–0.44) P < 0.001

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 3 2.5 2 1.5 1 0.5 0 Candesartan Placebo
Julius et al. N Engl J Med 2006

3.3

2.2

(3.0-3.8)

(2.0-2.5)

CHARM-Alternative: Primary outcome CV death or CHF hospitalisation
50 40 30 20 10 0 0
HR 0.77 (95% CI 0.67-0.89), p=0.0004 Adjusted HR 0.70, p<0.0001

%

Placebo

406 (40.0%) 334 (33.0%)

Candesartan

Number at risk Candesartan 1013 Placebo 1015

1
929 887

2
831 798

3

3.5 years

434 122 427 126
46

All Cause Mortality Comparison
NYHA ELITE-II ValHeFT CHARMOverall II-IV II-IV LVEF ≤40%
≤ 40% ≤ 40%: 60.2% >40%: 39.8%

P’t no. 3,152 5,010

All cause Study drug mortality (HR) p-Value losartan vs captopril valsartan vs placebo candesartan vs background therapy
candesartan vs background therapy

1.13 1.02 0.91

0.16 0.8

II-IV

7,599

0.055

CHARM-Alt II-IV + CHARM Add

≤ 40%

4,576

0.88

0.018*

47

CONCLUSIONS

BLOPRESS(CANDESARTAN) IS PHARMACOLOGICALLY UNIQUE AMONG ARBs

• INDICATED BOTH FOR HYPERTENSION AND
HEART FAILURE TREATMENT

• HAS EFFECTS BEYOND BLOOD
PRESSURE REDUCTION