Cch An Presentation 2009-7-7

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

% Reduction in Events **

PLACEBO CONTROLLED TRIALS

CHF

Strokes

Fatal/Non-fatal

LVH

CVD CHD events

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

BP Classification

SBP, mm Hg

DBP, mm Hg

Lifestyle Modifications

Without Compelling Indications

With Compelling Indications

Normal

<120

And <80

Encourage

Prehypertension

120-139

Or 80-89

Yes

No antihypertensive drug indicated

Drug(s) for compelling indications †

Stage 1 Hypertension

140-159

Or 90-99

Yes

Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination

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

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

<120

And <80

Encourage

Prehypertension

120-139

Or 80-89

Yes

No antihypertensive drug indicated

Drug(s) for compelling indications †

Stage 1 Hypertension

140-159

Or 90-99

Yes

Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination

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

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

<120

And <80

Encourage

Prehypertension

120-139

Or 80-89

Yes

No antihypertensive drug indicated

Drug(s) for compelling indications †

Stage 1 Hypertension

140-159

Or 90-99

Yes

Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination

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

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

<120

And <80

Encourage

Prehypertension

120-139

Or 80-89

Yes

No antihypertensive drug indicated

Drug(s) for compelling indications †

Stage 1 Hypertension

140-159

Or 90-99

Yes

Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination

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

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

Compelling Indication

Diuretic

BB

ACEI

ARB

••

•• ••

•• ••

•• •

•

•

•

Heart failure Post MI High coronary disease risk Angina pectoris

•

Chronic kidney disease Macroalbuminuria Recurrent stroke prevention LVH Asymptomatic atherosclerosis

••

•

•• • •

• •

Diabetes

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

已上市 的 ARB 的比 較 Blopress Cozaar Diovan Aprovel Micardis

學名

Candesartan cilexetil

Losartan

Valsartan

公司

台灣武田

默沙東

諾華

適應症 FDA / EU CHF Indication

Irbesartan Telmisartan

賽諾菲

Olmetec Olmesartan medoxomil

百靈佳殷 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 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

　

劑型劑量

8mg Tablet

50mg Tablet

健保價 (NT$ / tablet)

20.1

23.9

FDA

　

80mg Capsule/ 150mg filmTablet coated tab 22.6

21.6

　

　

40mg Tablet

20mg Tablet

23.8

27.6

ARB 藥理性 的比 較 (1) 商品 名

Blopress

AT1Receptor 結合 力

Cozaar

Diovan

Aprovel

Micardis

Olmetec

Blopress®>Irbesartan>Telmisartan/Valsartan> Losartan 非競爭性

混合型 ( 競爭性 / 非競爭性 )

混合 型 ( 競爭 性 / 非競 爭性 )

混合型 ( 競爭性 / 非競爭性 )

混合 型 ( 競爭 性 / 非競 爭性 )

?

> 80%

70%

60-70%3

60-70%

60-70%

60-80%

食物交互 反 應

不影 響

↓Cmax

↓ 40%AUC & ↓50%Cmax

不影響

↓20% AUC

不影響

臨床效 應

1.5

1

1

1.2

≒ Losartan

?

生體可用 率

42%

33%

23%

60-80%

-57%

26%

Antagonistic properties Trough/ Peak ratio

ARB 藥理性 的比 較 (2) 商品名

Blopress

Cozaar

Diovan

蛋白質結合率

Aprovel

Micardis

Olmetec

23

13

> 90% 1.5-2

半衰期 ( 小時 )

9-13

代謝途徑 (Cytochrome P450)

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

排除途徑尿液： 糞便 (%)

33:67

(EXP3174: 6-9)

6

11-15

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

45:55

13:87

20:80

幾乎以原型排出

Fluconazole 無明顯臨床上之交互 Digoxin 作用

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

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

0

2

4

6

Hours after dose 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

-2 -4 -6

Losartan 100mg

-8

p=0.004

-10 -12 -14

Candesartan cilexetil 16mg

-16 -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%) p=0.020

Placebo

8

163 (6.0%)

6

Candesartan

4 2

HR 0.78 (0.64–0.96)

0 0

Number at risk Candesartan 2715 Placebo 2721

1.0

2.0

3.0

2565 2501

2395 2304

1662 1622

3.5 years

30 Yusuf et al. Circulation 2005

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 （％ ） 6.0 5.0 4.0

BMI <22

P=0.031

0

HR=0.64 ; 95% CI 0.43-0.97

Amlodipine

≧25

≧27.5

4%

36 20 %

3.0

40

41%

2.0 1.0

≧22

Blopress

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

47%

60

62% (%)

P=0.947

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 130–139/85–89 mm Hg

8 Cumulative incidence (%) and 95% CI

6

Normal BP

4

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

80

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

Cumulative 60 incidence (%) 40 RRR 66% HR = 0.34 (0.25–0.44) P < 0.001

20 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 3 2.5 2 1.5 1

3.3

2.2

(3.0-3.8)

(2.0-2.5)

Candesartan

Placebo

0.5 0

Julius et al. N Engl J Med 2006

CHARM-Alternative: Primary outcome CV death or CHF hospitalisation 50

% 406 (40.0%)

Placebo

40 30

334 (33.0%)

Candesartan

20 10 0

HR 0.77 (95% CI 0.67-0.89), p=0.0004 Adjusted HR 0.70, p<0.0001

0

Number at risk Candesartan 1013 Placebo 1015

1

2

929 887

831 798

3

3.5 years

434 122 427 126 46

All Cause Mortality Comparison NYHA

LVEF

P’t no.

All cause Study drug mortality (HR) p-Value

ELITE-II

II-IV

≤40%

3,152

losartan vs captopril

1.13

0.16

ValHeFT

II-IV

≤ 40%

5,010

valsartan vs placebo

1.02

0.8

7,599

candesartan vs background therapy

0.91

0.055

4,576

candesartan vs background therapy

0.88

0.018*

CHARMOverall

II-IV

CHARM-Alt II-IV + CHARM Add

≤ 40%: 60.2% >40%: 39.8%

≤ 40%

47

CONCLUSIONS •

BLOPRESS(CANDESARTAN) IS PHARMACOLOGICALLY UNIQUE AMONG ARBs

• INDICATED BOTH FOR HYPERTENSION AND HEART FAILURE TREATMENT

• HAS EFFECTS BEYOND BLOOD PRESSURE REDUCTION