Do we Still need High Doses?

Professor : Mohamed Gamal Abdel Aziz

Aswan

8/2/2012

Hypertension goes uncontrolled in more than half of adults with the disease

33%

67%

NHANES 1999 - 2002

Controlled BloodPressure

UncontrolledBlood Pressure

46% 54%

NHANES 2005-2008

Controlled BloodPressure

UncontrolledBlood Pressure

Ref.: Centers for Disease Control and Prevention. Vital signs: Prevalence, treatment, and control of hypertension—United States, 1999-2002 and 2005-2008. MMWR Morb Mortal Wkly Rep 2011; 60:1-6.

Despite the significant improvement in Blood pressure control, still the problem of

Uncontrolled patients remains

Trials in diabetic patients 40

30

20

10

0

Major CV events (% of patients over 5 years)

Zanchetti A, 2009

Antihypertensive treatments fail to reduce incidence of major CV events below high-risk threshold of 10% in 5-year period

Trials in high-risk patients 50

40

30

20

10

0

Major CV events (% of patients over 5 years)

Reduction of risk

Residual risk

Trials in elderly patients 40

30

20

10

0

Major CV events (% of patients over 5 years)

Dashed horizontal line indicates conventional threshold of high risk; x axes show randomized controlled trials of anti-HTN treatments.

Current Guidelines Recommend Initiating Combination Therapy Early in Patients with Stage 2 Hypertension or High Cardiovascular Risk

• JNC 7 guidelines state1:

―When BP is more than 20 mmHg above systolic goal or 10 mmHg above diastolic goal, consideration should be given to initiate therapy with 2 drugs...‖

• ESH/ESC guidelines state2:

―A combination of two drugs at low doses should be preferred as first step treatment when initial BP is in the grade 2 or 3 range or total cardiovascular risk is high or very high.‖

1Chobanian et al. Hypertension 2003;42:1206–52 2Mancia et al. J Hypertens 2007:25:110587

ESH = European Society of Hypertension ESC = European Society of Cardiology JNC = Joint National Committee

Low-dose 2-drug combination Low-dose single agent

Not at BP goal

Full dose of single agent

Switch to different agent

at low dose

Full dose of 2-drug

combination

Add a third drug

at low dose

Not at BP goal

2–3 drug combination at full dose

Full doses of 2–3-drug combination

ESH–ESC: Algorithm for Treatment of Hypertension

Full-dose single agent

TOD = target organ damage

Marked BP elevation

High/very high CV risk

Lower BP target

Mild BP elevation

Low/moderate CV risk

Conventional BP target

Task Force for ESH–ESC. J Hypertens 2007;25:1105–87 4

CCB Alpha

blockers

Beta

blockers Diuretics Other

RAS blockade

The Foundation

RAAS Blockade With ARBs Can Be Considered a Foundation of Antihypertensive and CV Preventive Therapy

Pre-diabetes

Diabetes – Renal

RAAS Blockers Have Been Studied Extensively in Outcomes Trials

High Risk Myocardial

infarction

• LIFE

• SCOPE

• STOP 2

• VALUE

• KYOTO HEART

• CAPPP

• ALLHAT

• ANBP2

• HOPE

• ONTARGET

• TRANSCEND

• JIKEI HEART

• KYOTO HEART

• OPTIMAAL

• VALIANT

• CONSENSUS II

• ISIS-4

• GISSI-3

• SMILE

• SAVE

• AIRE

• TRACE Heart failure

• NAVIGATOR

• DREAM

• RENAAL

• IDNT

• ABCD

Hypertension

Coronary Artery

Disease

• EUROPA

• PEACE

• IMAGINE

• ELITE II

• Val-HeFT

• CHARM

• CONSENSUS I

• SOLVD

• V-HeFT II

• PEP-CHF

GFR

Proteinuria

Aldosterone release

Glomerular sclerosis

AII AT1

Receptor

Atherosclerosis*

Vasoconstriction

Vascular hypertrophy

Endothelial dysfunction

LV hypertrophy Fibrosis

Remodeling

Apoptosis

Stroke

Death

*Preclinical data. LV=left ventricular; MI=myocardial infarction; GFR=glomerular filtration rate.

Hypertension

Heart Failure

MI

Renal Failure

Angiotensin II Plays a Central Role in Organ Damage

. Willenheimer R, Dahlof B, Rydberg E, Erhardt L. AT1-receptor blockers in hypertension and heart failure: clinical experience and future directions. Eur Heart J. 1999;20:997–1008.

2. Dahlof B. Effect of angiotensin II blockade on cardiac hypertrophy and remodelling: a review. J Hum Hypertens.1995;9(suppl 5):S37–44.

3. Daugherty A, Manning MW, Cassis LA. Angiotensin II promotes atherosclerotic lesions and aneurysms in

apolipoprotein E-deficient mice. J Clin Invest. 2000;105:1605–12.

Effects of RAS blockade on stroke: meta-analysis of ARBs and ACE inhibitors

MI

Cardiovascular mortality

All-cause mortality

Stroke

Favours ARB Favours

ACE inhibitor

Reboldi et al. J Hypertension 2008;26:1282–1289

Studies (N=63,409 ): ELITE; ELITE-II; OPTIMAAL; DETAIL; VALIANT; ONTARGET

Elliott and Meyer. Lancet 2007;369:201–7

0.57 (0.46–0.72) p<0.0001

0.67 (0.56–0.80) p<0.0001

0.75 (0.62–0.90) p=0.002

0.77 (0.63–0.94) p=0.009

0.90 (0.75–1.09) p=0.30

Referent

ARB

ACE inhibitor

CCB

Placebo

β-blocker

Diuretic

Odds ratio of incident diabetes Incoherence=0.000017

0.50 0.70 0.90 1.26

Effects of Different Antihypertensive Agents on Incidence of Diabetes

Network meta-analysis assessing the effects of different

antihypertensive agents on incidence of diabetes in 48 randomised groups

from 22 clinical trials* (n=143,153)

*17 trials enrolled patients with hypertension, three enrolled high-risk

patients and one enrolled patients with heart failure (HF)

ARB=angiotensin receptor blocker; ACE=angiotensin-converting

enzyme; CCB=calcium channel blocker

Conditions favoring use of some antihypertensive drugs versus others:

Are all ARBs

the same?

There is no such thing as a simple Class Effect that cover all aspect of

different molecules

Go with the evidence,do not assume

1. VALUE

2. VALIANT

3. NAVIGATOR

4. Val-HeFT

5. JIKEI HEART

6. KYOTO HEART*

7. VART*

8. VALISH*

27. IDNT

28. ACTIVE-I*

29. NID-2

30. SUPPORT*

31. COLM*

32. OSCAR*

33. ORIENT*

34. MOSES

1. Julius et al. 2004; 2. Pfeffer et al. 2003; 3. Califf et al 2008; 4. Cohn et al. 2001; 5. Mochizuki et al. 2007;

6. http://clinicaltrials.gov (NCT00149227); 7. Nakayama et al. 2008; 8. NCT00151229; 9. ONTARGET Investigators 2008;

10. Yusuf et al 2008; 11. TRANSCEND Investigators 2008; 12. http://clinicaltrials.gov (NCT00283686); 13. Dahlöf et al.

2002; 14. Dickstein et al. 2002; 15. Pitt et al. 2000; 16. Brenner et al. 2001; 17. http://clinicaltrials.gov (NCT00090259); 18.

http://clinicaltrials.gov (NCT00555217); 19. Pfeffer et al 2003; 20. Papademetriou et al. 2004; 21. http://clinicaltrials.gov

(NCT00120003); 22. Ogihara et al. 2008; 23. http://clinicaltrials.gov (NCT00108706); 24. Laufs et al. 2008; 25. Suzuki et al.

2005; 26. Massie et al 2008; 27. Lewis et al. 2001; 28. http://clinicaltrials.gov (NCT00249795); 29. http://clinicaltrials.gov

(NCT00535925); 30. http://clinicaltrials.gov (NCT00417222); 31. http://clinicaltrials.gov (NCT00454662); 32.

http://clinicaltrials.gov (NCT00134160); 33. http://clinicaltrials.gov (NCT00141453); 34. Schrader et al. 2005

9. ONTARGET

10. PRoFESS

11. TRANSCEND

12. HALT-PKD*

13. LIFE

14. OPTIMAAL

15. ELITE II

16. RENAAL

17. NCT00090259*

*Expected

enrolment

‡Ongoing and completed

randomized controlled trials

with death or hard CV events

as or part of the primary

endpoint ¶Valid as of January 2009

Mortality & Morbidity Endpoint Trials with ARBs

18. VA NEPHRON-D*

19. CHARM

20. SCOPE

21. SCAST*

22. CASE-J

23. ACCOST

24. HIJ-CREATE

25. E-COST

26. I-PRESERVE

0

10,000

20,000

30,000

40,000

50,000

60,000

Num

ber

of

patients

Valsartan Telmisartan Losartan Candesartan Irbesartan Olmesartan Eprosartan

57,781 52,896

24,841 23,940

6,577

1,405

15,693

1

2

5

4

3

7

8

6

9

10

16

11

17

18

15

13

14

22

25

21

19

20

34 31

30

32

33

28

27

26

24

Selectivity on AT1 Receptor

Valsartan Candesartan Losartan Irbesartan Telmisartan

10000

20000

30000 30,000

1000

8500 10,000

3,000

Valsartan is 3 times more selective for AT1 receptors than other ARB agents

Siragy H. Am J Cardiol. 1999;84:3S-8S.

Valsartan: Extensively Studied Across the Cardiovascular Continuum

1. Julius et al. Lancet 2004; 363:2022–31; 2. Pfeffer et al. N Engl J Med 2003;349:1893–906; 3. Cohn et al. N Engl J Med 2001; 345:1667–75

4. Califf et al. Am Heart J 2008;156:623–32; 5. Mochizuki et al. Lancet 2007;369:1431–9; 6. Viberti et al. Circulation 2002;106:6728

7. Karalliedde et al. Hypertension 2008;51:161723; 8. SMART Group. Diabetes Care 2007;30:1581–3; 9. Hollenberg et al. J Hypertens 2007;25:19216

MARVAL6

MARVAL II7

SMART8

DROP9

Endothelial

dysfunction Microalbuminuria Proteinuria

End-stage

renal disease

Risk factors

Diabetes

Hypertension

Atherosclerosis

and LVH

Myocardial

infarction

Ventricular

Remodelling

Ventricular

Dilation

Heart

Failure

End-stage

Heart Disease

Death

Includes

over 50,000

patients*19

JIKEI HEART 1

2

3

4 ‡5

*Not all patients in these

studies received valsartan ‡Independent, investigator-initiated study

19

Titrating Valsartan to full dose optimizes CV/Renal Protection in outcome trial Tareg based therapy 40 - 320 mg out come trials

Trial Drug used Dose titration NO. of patient outcome

VAL-HEFT Valsartan 40 - 320 mg About 5000 pts Composite

Mortality &

Morbidity end point

reduced by 13.2%,

Patients not on

ACEi Group

reduced By 44%

VALLIANT valsartan 40-320 mg

About 15,000 25% Mortality risk

reduction in Post

MI patients

DROP valsartan 160 – 320 - 640mg 390 pts 51% reduction in

UAER

•Maggioni et al. J Am Coll Cardiol 2002;40:1414–21,,

•McMurray et al. J Am Coll Cardiol 2006; 47:726–33,,

•Hollenberg et al J Hypertens 2007,25:1921-1926

Valsartan* Provides Powerful Systolic

BP Reductions Across Hypertension Severities

-15.9

-23.5

-27

-32.2

-38.9

-46.4

-12.1 -14.3

-17.4

-23.1

-31.5

-25.9

-50

-45

-40

-35

-30

-25

-20

-15

-10

-5

0 140–149 150–159

Post-hoc analysis C-DITT study Category of baseline MSSBP (mmHg)

160–169 170–179 180–189

Ch

an

ge

in

MS

SB

P (

mm

Hg

)

at

We

ek

4 (

LO

CF

)

6-week, double-blind, multicentre, forced-titration study in patients with DBP ≥110 mmHg and

<120 mmHg and SBP ≥140 mmHg and <200 mmHg.

Valsartan 160 mg force-titrated to 320 mg at Week 2.

Valsartan/HCTZ 160/12.5 mg force-titrated to 160/25 mg and 320/25 mg at Weeks 2 and 4.

BP = blood pressure; DBP = diastolic BP; SBP = systolic BP; MSSBP = mean sitting SBP;

LOCF = last observation carried forward; C-DITT = Co-Tareg Initial Therapy Trial

190-199

Calhoun et al.

Curr Med Opin Res 2008;24:230311

0

–5

–10

–15

–20

–25

–30

Blacks Hispanic Elderly# Obese‡ Diabetes

n=202 n=51 n=117 n=477 n=69

21.4 21.7

25.5 23.6

19.5

n=190 n=58 n=103 n=493 n=97

*p≤0.01 vs valsartan monotherapy: ¶Valsartan 160 mg or valsartan/HCTZ 160/12.5 mg force-titrated to valsartan

320 mg or valsartan/HCTZ 320/12.5 mg, respectively, at Week 2; §SBP ≥160 mmHg and/or DBP ≥100 mmHg;

#≥65 years of age; ‡body mass index ≥30 kg/m2; HCTZ = hydrochlorothiazide

Val-MARC = Valsartan-Managing blood pressure Aggressively and evaluating Reductions in hsCRP Everett et al.Clin Ther 2008;30:66172

Mean

ch

an

ge f

rom

baselin

e

in

SB

P a

t W

eek 6

(m

mH

g)

12.6

16.3 16.9 15.9 16.3

*

*

*

*

Valsartan and Valsartan-HCTZ Therapy Provides

Effective BP Reductions Across Diverse Patient

Populations

Valsartan/HCTZ¶ Valsartan¶

Co-Tareg® 320 achieves BP goal in up to 9 out of

10 patients with HTN

#BP=Blood pressure; DBP=Diastolic blood pressure; HTN=Hypertension;

Ref.: Weir et al. J Clin Hypertens 2007;9:103-112

Results from a pooled analysis of 9 randomized trials# in 4278 patients with

HTN§

Patients achieving BP goal <140/90

mmHg (%)

Co-Tareg 320/25 mg

(n=80)

Tareg 320 mg

(n=271)

Co-Tareg 320/12.5 mg

(n=87)

40 60 80 100

Tareg/Co-Tareg: Proportion of Patients Achieving

BP Goal <140/90 mmHg

Co-Tareg 320/25 mg

Co-Tareg 320/12.5 mg

Tareg 320 mg

Co-Tareg 160/25 mg

Co-Tareg 160/12.5 mg

Tareg 160 mg

Co-Tareg 80/12.5 mg

Tareg 80 mg

Placebo

n

167

168

646

94

261

907

96

782

1157

0 10 20 30 40 50 60 70 80 90 100

Patients achieving goal (%)

Weir et al. J Clin Hypertens 2007;9:103–112

Meta-analysis of nine randomised, double-blind, placebo-controlled trials; data for overall population shown

Pooled Analysis of Nine Trials Showed More Patients

Achieve JNC-7 Goals* in Less Time with Higher Doses or

with Combination Therapy

Cu

mu

lati

ve p

rop

ort

ion

of

pati

en

ts r

eac

hin

g

JN

C-7

go

als

* (%

)

Weir et al. Am J Hypertens 2007;20:811–15

Placebo

(n=1,156) Tareg

80 mg

(n=781)

Co-Tareg

80/12.5 mg

(n=96)

Tareg 160

mg

(n=907)

Co-Tareg

160‡ mg

(n=355)

Tareg

320 mg

(n=646)

Co-Tareg

320‡ mg

(n=335)

90

80

70

60

50

40

30

20

10

0

Pooled analysis of data from nine randomised, double-blind, placebo-controlled trials ‡Tareg at stated dose + HCTZ 12.5 or 25 mg *<140/90 mmHg

Cardiovascular Continuum

Proteinuria Is an Independent Risk Factor

for Mortality in Type 2 Diabetes

1.0

0.9

0.8

0.7

0.6

0.5

0 1 2 3 4 5 6

Years

Su

rviv

al

(all

-ca

use

mort

ali

ty)

Normoalbuminuria

(n=191) [8%]

Microalbuminuria

(n=86) [20%]

Macroalbuminuria

(n=51) [35%]

Gall, MA et al. Diabetes 1995;44:1303

P<0.01 normo vs. micro- and macroalbuminuria

P<0.05 micro vs. macroalbuminuria

Tareg Reduction of Proteinuria

(DROP) Study:

Albuminuria response to very

high-dose valsartan in type 2

diabetes mellitus

Hollenberg et al.,

Journal of Hypertension 2007, 25:1921-1926

The DROP study: Objectives

Purpose:

• To assess the ability of high-dose valsartan to reduce proteinuria in subjects with diabetic nephropathy

Primary Objective:

• To compare responses to valsartan at 160, 320, and 640 mg/day in patients with hypertension, type 2 diabetes mellitus, and albuminuria (30–1,000 mg/d)

Hollenberg NK et al, J Hypertens, 2007, 25:1921-1926

Study Design

• Design: multicentre, double-blind, randomized, parallel group study

• Patient population: subjects with hypertension, proteinuria and T2DM

Valsartan 160 mg

Valsartan 320 mg

Valsartan 640 mg

Placebo

run-in Screening Valsartan 160 mg

Week –6 (Visit 1)

Week –3 (Visit 3)

Week –2 (Visit 4)

Week 0 (Visit 6)

(Randomisation)

Week 4 (Visit 8)

Week 16 (Visit 11)

Week 30 (Visit 12)

Valsartan 160 mg

Valsartan 160 mg

Hollenberg NK et al, J Hypertens, 2007, 25:1921-1926

DROP Study: Change From Baseline in

UAER at Week 30 (ITT-1 Population)‡

–25†

–51* –49*

–60

–50

–40

–30

–20

–10

0

Med

ian

ch

an

ge i

n

UA

ER

at

Week 3

0 (

%)

Tareg 160 mg

(n=130) Tareg 320 mg

(n=130)

Tareg 640 mg

(n=131)

‡Overall population

*p<0.001 vs baseline Hollenberg NK. Suppl to Circulation abstracts from

scientific sessions 2006:114(18); II-61

DROP Study: Proportion of Patients Who

Returned to Normalisation of UAER (<20

μg/min) at Week 30‡

12.4

19.2

0

5

10

15

20

25

30

Pati

en

ts w

ith

UA

ER

<2

0

g/m

in a

t en

dp

oin

t (%

)

‡LOCF cases methodology

(ITT-1 population) was used

*p=0.02 vs Tareg 160 mg

Tareg 160 mg

(n=130)

Tareg 320 mg

(n=130)

Hollenberg NK. Suppl to Circulation abstracts from

scientific sessions 2006:114(18); II-61

Novartis data on file

24.3*

Tareg 640 mg

(n=131)

DROP Study: Summary

• Tareg produced a significant reduction in UAER of up to 48% in

hypertensive patients with diabetes and proteinuria

• Up-titration of Tareg to either 320 or 640 mg offered a

numerically greater reduction in proteinuria vs 160 mg

• Outstanding BP goal rates of up to 74% were achieved with a

Tareg-based regimen (64% with the approved doses)

• In patients that achieved target BP control of <130/80 mmHg,

UAER was reduced by up to 65%

• A rapid reduction in proteinuria (17–23%) was observed in all

groups during the first 4 weeks

• All three doses of Tareg were safe and well tolerated with

slightly more frequent dizziness and headache at the 640 mg

dose

Hollenberg NK. Suppl to Circulation abstracts from scientific sessions 2006:114(18); II-61

Time post-randomization (months)

100

95

90

85

80

75

70

65

0

Tareg (n=2,511)

Placebo (n=2,499)

0 3 6 9 12 15 18 21 24 27

13.2% risk

reduction‡

Even

t-fr

ee p

rob

ab

ilit

y (

%)

‡p=0.009 vs. placebo

*Combined primary endpoint: all-cause mortality, cardiac arrest with resuscitation, hospitalization for

worsening heart failure, or therapy with intravenous inotropes or vasodilators

RR = relative risk; CI = confidence interval; CHF = congestive heart failure;

Val-HeFT = Valsartan Heart Failure Trial.

Results from a 23-month mean follow-up study in 5,010 patients with

CHF on standard therapy (Val-HeFT study)

Cohn et al. N Engl J Med 2001;345:1667–75

Tareg Improves CV Outcomes* in Patients with

Congestive Heart Failure on Standard Therapy

RR=0.87; 97.5% CI=0.770.97

*p<0.001;‡Combined primary endpoint: all-cause mortality, cardiac arrest with resuscitation,

hospitalization for worsening heart failure, or therapy with intravenous inotropes or vasodilators

33% relative risk reduction (p=0.017) for all-cause mortality

ACEI = angiotensin-converting enzyme inhibitor; CHF = congestive heart failure

RR = relative risk; CI = confidence interval; Val-HeFT = Valsartan Heart Failure Trial

0

0.486

0.571

0.657

0.743

0.829

0.914

1.000

Time since randomization (months)

Even

t-fr

ee

pro

bab

ilit

y‡

Tareg (n=185)

Placebo (n=181)

44% risk

reduction*

0 3 6 9 12 15 18 21 24 27

Maggioni et al.

J Am Coll Cardiol 2002;40:1414–21

Results from a 23-month mean follow-up study in 366 patients with CHF not on ACEI

background therapy (Val-HeFT study post-hoc subgroup analysis)

Tareg Significantly Reduces Morbidity and Mortality

in Patients with Congestive Heart Failure not on an

ACEI

RR=0.56; 95% CI=0.390.81

Captopril

0

0.05

0.1

0.15

0.2

0.25

0.3

0 6 12 18 24 30 36

Pro

babili

ty o

f Event

Mortality by Treatment

Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

Valsartan 4909 4464 4272 4007 2648 1437 357

Months

Valsartan vs. Captopril: HR = 1.00; P = 0.982

Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726

Captopril 4909 4428 4241 4018 2635 1432 364

Valsartan + Cap 4885 4414 4265 3994 2648 1435 382

Valsartan

Valsartan + Captopril

Tareg is as effective as Captopril(ACE-I) in

reducing cardiovascular mortality & morbidity in

post MI patients by 25% Hazard Ratio for Mortality

Favors

Active Drug

Favors

Placebo

Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

0.5 1 2

Combined

TRACE

SAVE

AIRE

VALIANT

(Valsartan Vs Captopril)

25%

Mortality

Reduction

Tareg Reduce BP Beyond 24 Hours

Results from a 8-week study in 256 patients with mild-to-moderate hypertension#

#sitting DBP between 95 and 115 mm Hg at baseline, *intervals 2-24, n=21 (15 treated with valsartan 80 mg, 6 with 160 mg)

intervals 26-48, n=10 (9 treated with valsartan 80 mg, 1 with 160 mg), hour 25-48 without dose

Lasko et al. Blood Press Monit 2001;6(2):91-99

15

5 0

-5

-15

-25

-35

15

5 0

-5

-15

-25

-35

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48

Mean C

hange in

SB

P (

mm

Hg)

Mean C

hange in

DB

P (

mm

Hg)

Time after dose administration (hours)*

Mean BP and 95% CI

Tareg 320 as tolerable as placebo

Oparil et al. Lancet 2007;370:221–29

‡Increases in serum potassium over 5·5 mmol/L (but not ≥6·0 mmol/L) were more common with the combined drugs than with the monotherapies or

placebo, although the occurrence of such cases after correction for placebo was low. Most of these increases were transient and returned to normal by

Week 8. None were associated with AEs or patient discontinuation

Placebo

(n=458*)

Tareg 320

(n=455)

Adverse events

Any adverse event 168 (37%) 167 (37%)

Any serious adverse event 5 (1%) 6 (1%)

Discontinuations due to adverse events 10 (2%) 11 (2%)

Laboratory abnormalities

Serum potassium

<3.5 mmol/L 17 (4%) 20 (4%)

>5.5 mmol/L‡ 12 (3%) 7 (2%)

6.0 mmol/L 6 (1%) 5 (1%)

Creatinines

>176.8 µmol/L 0 2 (0.4%)

Blood urea nitrogens

>14.3 mmol/L 0 1 (0.2%)

High dose of Valsartan Tareg 320mg

for hypertensive high risk patients

Superior & complete blockade of the RAS system

Significant renal protection in hypertensive

patients with diabetes and proteinuria

So when to use the new high dose of Valsartan?

- High risk and very high risk hypertensive patients

- For Nephroprotection (Diabetics with proteinuria)

Conclusions

The recommended doses of AT1 receptor blockers are

adequate for blood pressure control.

However, they are probably too low to afford an optimal

protection of target organs.

Thus, there is today a rational for using higher doses

of ARBs such as Valsartan 320 mg in high risk patients (ISH

severe hypertension, metabolic syndrome,

diabetes with proteinuria…)

Thank You