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Pathophysiology of Hypertension!

!
Wasan Udayachalerm, MA, FAPSIC!
Overview!

Section 1: !Definition and Classification of !


! !Hypertension!
Section 2: !Prevalence of Hypertension!
Section 3: !Unmet Needs!
Section 4: !Impact of Hypertension!
Section 5: !Treatment Guidelines!
Section 1: Definition and Classification
of Hypertension!
Definition and classification of
hypertension: ESH/ESC 2007!
Hypertension is defined as blood pressure ≥140/90 mmHg!
Category! Systolic! Diastolic!
(mmHg)! (mmHg)!
Optimal! <120 and <80

Normal! 120-129 and/or 80-84

High normal! 130-139 and/or 85-89

Grade 1 hypertension! 140-159 and/or 90-99

Grade 2 hypertension! 160-179 and/or 100-109

Grade 3 hypertension! ≥180 and/or ≥110

Isolated systolic hypertension! ≥140 and <90

When a patient’s systolic and diastolic blood pressures fall into different categories,
the higher category should apply for quantification of CV risk, decisions about drug ESH/ESC Guidelines 2007. !
2008 update treatment and estimation of treatment efficacy!
Eur Heart J 2007;28:1462-1536!
Definition and classification of
hypertension: ESH/ESC 2007!

§  For patients at high risk of a CV event, such as


those with organ damage, metabolic syndrome
or diabetes, ESH/ESC guidelines recommend
early and aggressive intervention with drug
therapy in addition to lifestyle changes !
§  The ‘high-risk’ patient category now includes
patients with evidence of subclinical organ
damage!

ESH/ESC Guidelines 2007. Eur Heart J 2007;28:1462-1536!


2008 update
Definition and classification of
hypertension: JNC VII!

Hypertension is defined as blood pressure ≥140/90 mmHg!

Category! Systolic! Diastolic!


(mmHg)! (mmHg)!
Normal! <120 and <80!

Prehypertension! 120-139 or 80-89!

Stage 1 hypertension! 140-159 or 90-99!

Stage 2 hypertension! ≥160 Or ≥100!

JNC VII. JAMA 2003;289:2560-2572!


Definition and classification of
hypertension: WHO/ISH 1999/2003!
Hypertension is defined as blood pressure ≥140/90 mmHg!
Category! Systolic! Diastolic!
(mmHg)! (mmHg)!
Optimal! <120 <80!
Normal! <130 <85!
High-normal! 130-139 85-89!
Grade 1 hypertension (mild)! 140-159 or 90-99!
Subgroup: borderline! 140-149 90-94!
Grade 2 hypertension (moderate)! 160-179 or 100-109!
Grade 3 hypertension (severe)! ≥180 Or ≥110
Isolated systolic hypertension! ≥140 <90
Subgroup: borderline! 140-149 <90

2003 WHO/ISH Statement on Hypertension. !


When a patient’s systolic and diastolic blood pressures fall ! J Hypertens 2003;21:1983-1992; 1999 WHO/ISH Guidelines for the
into different categories, the higher category should apply! Management of Hypertension. J Hypertens 1999;17:151-183!
Section 2: Prevalence of Hypertension!
Global Burden of Hypertension
2025 Projection

Year 2000 Year 2025

•  29.2% of world’s adults will have


•  26.4% of world’s adults had hypertension! hypertension
•  A total of 972 million adults!
•  A total of 1.56 billion adults
•  Highest prevalence in 

established market economies 
 –  60% increase overall
(eg, North America, Europe)!
•  developed nations—24%
increase
•  developing nations—80%
increase
•  Highest prevalence will be in
economically developing continents
(eg, Asia, Africa)
–  will account for 75%
of hypertensive patients
Kearney PM et al. Lancet. 2005;365:217-223.
Prevalence of hypertension*: 

North America and Europe!
* BP ≥140/90 mmHg or treatment with antihypertensive medication !
60
Men
Prevalence (%)

Women
40
Total

20

Ong LK, et al. Hypertension 2007;49:69-75; Tu K, et al. CMAJ 2008;178:1429-1435; World Health Organization Global
2008 update Infobase; Macedo ME, et al. J Hypertens 2005;23:1661-1666; CÍfková R, et al. J Hypertens 2004;22:1479-1485 !
Prevalence of hypertension*: Asia!
* BP ≥140/90 mmHg or treatment with antihypertensive medication !
60
Prevalence (%)

Men Women
40

20

# Data for Hong Kong are crude prevalence; all other data are age-adjusted prevalence!
Dates in square brackets are publication date, all others are survey date !
Martiniuk ALC, et al. J Hypertens 2007;25:73–79; National Health Survey 2004, Singapore. Epidemiology and Disease
Department, Ministry of Health, Singapore.; Rampal L, et al. Public Health 2008;122:11-18; Philippines Facts and
2008 update Figures 2003. Part I. Clinical Facts and Figures. National Nutrition and Health Survey (NNHes 2003-2004)!
Prevalence of hypertension: 

Other countries!
60
Men
Women
Prevalence (%)

40 Total

20

Ordunez P, et al. Pan Am J Public Health 2001;10:226-231; Cubillos-Garzon LA, et al. Am Heart J 2004;147:412-417;
Israel Centre for Disease Control. MABAT: First Israeli National Health and Nutrition Survey 1999-2001, 2003,
2008 update Personal communication: Dorit Nitzan Kaluski!
Projected increase in hypertension by 2025!

Established market economies!

Former socalist economies!

India!

Latin America and the Carribean!

Middle eastern crescent!

China!

Other Asia and islands!


2000! 2025!

Sub-Saharan Africa!

0! 50! 100! 150! 200! 250! 300!

Number of people with hypertension (millions)!

Kearney PM, et al. Lancet 2005;365:217-223!


Section 3: Unmet Needs!
Hypertension control rates around the world!
<140/90 mmHg (%)! <140/90 mmHg (%)
!
United States !37! Thailand 37
France ! !46! Malaysia ! !27!
Germany ! !40! India ! ! !27!
Spain ! ! !40! Korea 11
UK ! ! !36! China 6!
Italy ! ! !31! !
Czech Republic !17! !

Ong LK, et al. Hypertension 2007;49:69-75 ; Wang YR, et al. Arch Intern Med 2007;167:141-147; Choi KM, et al. J Hypertens
2006;24:1515-1521; Wang Z, et al. Hypertens Res 2004;27:703-709; CÍfková R, et al. J Hypertens 2004;22:1479-1485;
Aekplakorn W, et al. J Hypertens 2008 ;26:191-198; Rampal L, et al. Public Health 2008 ;122:11-18; !
2008 update Hathial M. J Indian Med Assoc 2007;105:401-402, 404, 410 !
National Health and Nutrition
Examination Survey (NHANES) !
Trends in awareness, treatment and control of 

high blood pressure in adults aged 18-74*!
II! III! III ! ! ! !
(1976-80)! (Phase 1 (Phase 2 1999-2000! 2001-2002! 2003-2004!
1988-91)! 1991-94)!

! ! ! ! ! ! !
Awareness! 51%! 73%! 68%! 63%! 63%! 67%!

! ! ! ! ! ! !
Treatment! 31%! 55%! 54%! 47%! 50%! 54%!

! ! ! ! ! ! !
Control†! 10%! 29%! 27%! 25%! 30%! 33%!

* High blood pressure defined as SBP ≥140 mmHg or 



DBP ≥90 mmHg or taking antihypertensive medication

† SBP <140 mmHg and DBP <90 mmHg among all with hypertension! Ong LK, et al. Hypertension 2007;49:69-75.!
Hypertension - We try hard but it does not get much better
80
73 70
68

59
60 55 54
51
%

40 34
31 29
27

20
10

0
1976-1980 1988-1991 1991-1994 1999-2000

known treated controlled

NHANES, JNC 7, 2003


Section 4: Impact of Hypertension!
Millimetres matter …!

“A 2-mmHg reduction in DBP would 



result in … a 6% reduction in the risk of 

CHD and a 15% reduction in the risk of 

stroke and TIAs”!

DBP, diastolic blood pressure; CHD, coronary heart disease; 



Cook NR, et al. Arch Intern Med 1995;155:701-709!
TIA, transient ischaemic attack!
Millimetres matter …!

“For individuals 40-70 years of age, each


increment of 20 mmHg in systolic BP or !
10 mmHg in diastolic BP doubles the risk !
of CVD across the entire BP range from 

115/75 to 185/115 mmHg”!

BP, blood pressure; CVD, cardiovascular disease! JNC VII. JAMA 2003;289:2560-2572!
Hypertension: A risk factor for
cardiovascular disease!
Coronary
 Stroke! Peripheral artery
 Cardiac

disease! disease! failure!

50
45.5
45
Biennial age-adjusted rate !

40
per 1,000 subjects!

35 Normotensive

30 Hypertensive

25 22.7
21.3
20
13.9
15 12.4
9.5 9.9
10 7.3 6.3
6.2 5.0
5 3.3 2.4 3.5
2.0 2.1
0 Men Women Men Women Men Women Men Women

Risk
ratio:! 2.0! 2.2! 3.8! 2.6! 2.0! 3.7! 4.0! 3.0!

Kannel WB. JAMA 1996;275:1571-1576!


Untreated Hypertension Is Associated With
Macrovascular and Microvascular Complications

Cushman WC. J Clin Hypertens. 2003;5(suppl 2):14-22.


Relative importance of SBP and DBP as
predictors of CHD risk as a function of age!
1.0 Favours
SBP!
0.5

0.0
β(SBP)
- -0.5 p=0.008!
β(DBP)
* Favours
-1.0
DBP!

-1.5
25 35 45 55 65 75
Age (years)
* The difference between SBP and DBP proportional hazard regression 

coefficients, ie, β(SBP) - β(DBP), was estimated for each age group!
!
SBP, systolic blood pressure; DBP, diastolic blood pressure;

CHD, coronary heart disease! Franklin SS, et al. Circulation 2001;103:1245-1249!
Impact of high-normal BP on CV risk!
16!
14! Men! High-normal BP!
Cumulative 12!
10! Normal BP!
incidence of 8!
CV events
 6! Optimal BP!
(%)! 4!
2!
0!

12!
Women!
Cumulative 10! High-normal BP!
incidence of 8!
CV events
 6!
4! Normal BP!
(%)!
2!
Optimal BP!
0!
0! 2! 4! 6! 8! 10! 12!
Years!
Optimal BP: <120/80 mmHg; normal BP: 120-129/80-84 mmHg;
high-normal BP: 130-139/85-89 mmHg!
!
BP, blood pressure; CV, cardiovascular! Vasan RS, et al. N Engl J Med 2001;345:1291-1297!
Implications of small reductions in DBP

for primary prevention!
DBP reduction

7.5 mmHg 5-6 mmHg 2 mmHg


0

-10 -6
Risk reduction (%)

-16 -15
-20
-21
-30

-40 CHD
-38
Stroke

-50 -46

DBP, diastolic blood pressure; CHD, coronary heart disease Cook NR, et al. Arch Intern Med 1995;155:701-709!
Comparison of tight BP vs tight glucose
control in UKPDS!
Any diabetes-! Microvascular! Diabetes-related!
Stroke! related endpoint! endpoints! deaths!
0!

-10!
Risk reduction (%)!

†!

-20!

*! †!
-30!
*!
-40! *!
Tight glucose control!
*! Tight BP control!
-50!
* p<0.02, tight BP control (achieved BP 144/82 mmHg) vs less tight control (achieved BP 154/87 mmHg).!
† p<0.03, intensive glucose control (achieved HbA 7.0%) vs less intensive control (achieved HbA 7.9%).!
1c 1c

BP, blood pressure; UKPDS, United Kingdom Prospective Diabetes Study! UKPDS 38. BMJ 1998;317:703-713;!
UKPDS 33. Lancet 1998;352:837-853!
Steno-2: Patients who reached intensive-
treatment goals at a mean of 7.8 years!
80 Good BP control
Intensive reduces risk of
p=0.21!
p<0.001!
70 therapy cardiovascular events
Conventional p=0.19!
60
Patients (%)

therapy
50 p=0.001!

40

30

20 p=0.06!
10

0
HbA1c! Cholesterol! Triglycerides! Systolic BP! Diastolic BP!
<6.5%! <175 mg/dL! <150 mg/dL! <130 mmHg! <80 mmHg!
BP, blood pressure! Gaede P, et al. N Engl J Med 2003;348:383-393!
Steno-2: Composite CV endpoints!
60
p=0.007 Conventional therapy
50 BP 146/78 mmHg
Primary composite
endpoint* (%)

Hazard ratio=0.47
40 (95% CI, 0.24 to 0.73; p=0.008)

30

20
Intensive therapy
10 BP 132/73 mmHg

0
0 12 24 36 48 60 72 84 96
Months of follow-up
* Primary composite endpoint = composite of death from cardiovascular (CV) causes,
nonfatal myocardial infarction, nonfatal stroke, revascularization and amputation! Gaede P, et al. N Engl J Med 2003;348:383-393!
Section 5: Treatment Guidelines!
Treatment guidelines!

- Initiating antihypertensive treatment!


•  ESH/ESC 2007 !
•  JNC VII!
•  WHO/ISH 1999!
–  Goals of antihypertensive treatment!
•  ESH/ESC 2007 !
•  JNC VII!
•  WHO/ISH 2003!
–  Treatment strategy!
•  ESH/ESC 2007 !
•  JNC VII!
•  WHO/ISH 2003!
•  British Hypertension Society (BHS)!

2008 update
Treatment initiation: ESH/ESC 2007!
Blood pressure!

Other risk factors OD Normal! High normal! Grade 1! Grade 2! Grade 3!


or disease!

No other risk factors! Lifestyle changes Lifestyle changes Lifestyle


No BP No BP for several for several weeks, changes +!
intervention! intervention! months, then drug then drug Immediate drug
treatment! treatment! treatment !

1-2 risk factors! Lifestyle


Lifestyle changes Lifestyle changes changes +!
Lifestyle for several weeks, for several weeks,
Lifestyle changes! Immediate drug
changes! then drug then drug
treatment !
treatment! treatment!
!
3 or more risk factors, Lifestyle changes
MS or OD! Lifestyle
and consider drug
changes! Lifestyle
treatment ! Lifestyle changes Lifestyle changes
changes +!
+! +!
Diabetes! Lifestyle changes Immediate drug
Lifestyle Drug treatment ! Drug treatment !
+! treatment !
changes!
Drug treatment !

Established CV or Lifestyle Lifestyle changes Lifestyle changes Lifestyle changes Lifestyle


renal disease! changes +! +! +! +! changes +!
Immediate drug Immediate drug Immediate drug Immediate drug Immediate drug
treatment ! treatment ! treatment ! treatment ! treatment !

Average Low Moderate High Very high


risk! added risk! added risk! added risk! added risk!
MS, metabolic syndrome; OD, organ damage; CV, cardiovascular!
2008 update Mancia G, et al. Eur Heart J 2007;28:1462-1563!
Treatment initiation: JNC VII!
Normal! Pre- Stage 1 Stage 2
! hypertension! hypertension! hypertension!

Lifestyle Encourage! Yes! Yes! Yes!


modification

Initial drug therapy!


Without No antihypertensive drug Thiazide-type Two-drug
compelling indicated! diuretics for most; combination for
indication! ! may consider most (usually
! ACE-I, ARB, BB, thiazide-type
CCB, or diuretic and
combination! ACE-I or ARB
or BB or CCB)!
With Drug(s) for compelling Drug(s) for compelling indications;
compelling indications! other antihypertensive drugs
indications! (diuretics, ACE-I, ARB, BB, CCB)
as needed!
ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin II
receptor blocker; BB, beta-blocker; CCB, calcium-channel blocker! JNC VII. JAMA 2003;289:2560-2572!
Treatment initiation: WHO/ISH 1999!
SBP 140-180 mmHg or DBP 90-110 mmHg on several occasions!
(Grades 1 and 2 hypertension)!

Assess other risk factors, TOD and ACC!

Initiate lifestyle measures!

Stratify absolute risk!

Very high! High! Medium! Low!

Begin drug ! Begin drug ! Monitor BP ! Monitor BP !


treatment! treatment! and other risk ! and other risk !
factors for ! factors for !
3-6 months! 6-12 months!

SBP !140 or! SBP <140 or! SBP !150 or! SBP <150 or!
DBP !90 –! DBP <90 –! DBP !95 –! DBP <95!
Begin drug! Continue to ! Begin drug! (borderline) –!
treatment! monitor! treatment! Continue to !
monitor!
SBP, systolic blood pressure; DBP, diastolic blood pressure;
TOD, target organ damage; ACC, associated clinical conditions, 1999 WHO/ISH Guidelines for the Management of Hypertension.!
including cardiovascular disease and renal disease! J Hypertens 1999;17:151-183!
Treatment guidelines!

–  Initiating antihypertensive treatment!


•  ESH/ESC 2007 !
•  JNC VII!
•  WHO/ISH 1999!
–  Goals of antihypertensive treatment!
•  ESH/ESC 2007 !
•  JNC VII!
•  WHO/ISH 2003!
–  Treatment strategy!
•  ESH/ESC 2007 !
•  JNC VII!
•  WHO/ISH 2003!
•  British Hypertension Society (BHS)!

2008 update
Goals of treatment: ESH/ESC 2007!
•  Achieve maximum reduction in total
cardiovascular risk !
•  Treat all reversible risk factors and associated
clinical conditions in addition to treating raised
blood pressure!
•  Target blood pressure <140/90 mmHg and to
lower values, if tolerated!
•  For those with diabetes or a history of
cerebrovascular disease, target blood pressure
is <130/80 mmHg!
–  this target should also be considered in
patients with coronary disease!
Mancia G, et al. Eur Heart J 2007;28:1462-1563!
2008 update
Goals of treatment: JNC VII!

•  The SBP and DBP targets are <140/90 mmHg !


•  The primary focus should be on achieving the
SBP goal!
•  In patients with hypertension and diabetes or
renal disease, the BP goal is <130/80 mmHg!

SBP, systolic blood pressure; DBP, diastolic blood pressure; 



BP, blood pressure! JNC VII. JAMA 2003;289:2560-2572!
Goals of treatment: WHO/ISH 2003!

•  Decisions about the management of


hypertensive patients should be based on
blood pressure levels and the presence of
other cardiovascular risk factors, target organ
damage and associated clinical conditions!
•  In hypertensive patients at low to medium
risk*, the SBP goal is <140 mmHg!
•  In hypertensive patients at high risk*, a target
of <130/80 mmHg is appropriate!
* Risk of developing a major cardiovascular event (fatal and nonfatal stroke, and
myocardial infarction) !
!
SBP, systolic blood pressure! 2003 WHO/ISH statement on hypertension. J Hypertens 2003;21:1983-1992!
Treatment guidelines!

–  Initiating antihypertensive treatment!


•  ESH/ESC 2007 !
•  JNC VII!
•  WHO/ISH 1999!
–  Goals of antihypertensive treatment!
•  ESH/ESC 2007 !
•  JNC VII!
•  WHO/ISH 2003!
–  Treatment strategy!
•  ESH/ESC 2007 !
•  JNC VII!
•  WHO/ISH 2003!
•  British Hypertension Society (BHS)!

2008 update
Hypertension treatment strategy: ESH/
ESC 2007!
Consider:!
Untreated BP level!
Presence or absence of TOD and risk factors!
Mild BP elevation Marked BP elevation
Low/moderate CV risk High/very high CV risk
Conventional BP target Choose between:! Lower BP target

Single agent! Two-drug combination!


at low dose! at low dose!

If goal BP not achieved!

Previous agent ! Switch to different! Previous combination ! Add a third drug !


at full dose! agent at low dose! at full dose! at low dose!

If goal BP not achieved!

Two- to three-drug ! Full-dose! Three-drug combination !


combination! monotherapy! at effective doses!

BP, blood pressure; CV, cardiovascular; TOD, target organ damage!


Mancia G, et al. Eur Heart J 2007;28:1462-1563!
2008 update
Choice of antihypertensive therapy:

ESH/ESC 2007!

•  Main benefits are due to BP lowering!


•  Specific drug classes may differ in their effects!
•  Drugs are not equal in adverse-event profiles!
•  Major drug classes are suitable for initiation and
maintenance of therapy!
•  Choice of drug will be influenced by patient
experience and preference, concomitant
conditions, cost and risk profile!
•  Long-acting drugs that provide once-daily,
24-hour efficacy are preferable!
BP, blood pressure!
Mancia G, et al. Eur Heart J 2007;28:1462-1563!
2008 update
Hypertension treatment strategy: JNC VII!
Lifestyle modifications!

Not at goal blood pressure (<140/90 mmHg)!


(<130/80 mmHg for patients with diabetes or chronic kidney disease)!

Initial drug choices!


Without compelling ! With compelling !
indications! indications!

Stage 1 hypertension! Stage 2 hypertension!


(SBP 140-159 or DBP! (SBP !160 or DBP !100 Drug(s) for the !
90-99 mmHg)! mmHg)! compelling indications!
Thiazide-type diuretics ! Two-drug combination for! !
for most. May consider ! most (usually thiazide-type! Other antihypertensive!
ACE-I, ARB, BB, CCB! diuretic and ACE-I or ! Drugs (diuretics, ACE-I, !
or combination ! ARB, or BB, or CCB)! ARB, BB, CCB) as needed!

Not at blood pressure goal!

Optimize dosages or add additional drugs until goal blood pressure is achieved.!
Consider consultation with hypertension specialist.!
SBP, systolic blood pressure; DBP, diastolic blood pressure; ACE-I,
angiotensin-converting enzyme inhibitor; ARB, angiotensin II JNC VII. JAMA 2003;289:2560-2572!
receptor blocker; BB, beta-blocker; CCB, calcium-channel blocker!
Hypertension treatment strategy:
WHO/ISH 2003!
!

•  Regardless of the blood pressure level, 



all patients should adopt appropriate lifestyle
modifications!
•  A low dose of a diuretic should be considered
as the first choice of therapy for the majority
of patients without a compelling indication for
another class of drug!

2003 WHO/ISH Statement on Hypertension. J Hypertens 2003;21:1983-1992!


Treatment strategy: WHO/ISH 2003 (cont.)!
Compelling indication! Preferred drug!
Elderly with isolated systolic Diuretic, DHPCCB!
hypertension!
Renal disease!
Diabetic nephropathy type 1! ACE-I!
Diabetic nephropathy type 2! ARB!
Non-diabetic nephropathy! ACE-I!
Cardiac disease!
Post-myocardial infarction! ACE-I, beta-blocker!
Left ventricular dysfunction! ACE-I!
Congestive heart failure (diuretics Beta-blocker,
almost always included)! spironolactone!
Left ventricular hypertrophy! ARB!
Cerebrovascular disease! ACE-I + diuretic, diuretic!
DHPCCB, dihydropyridine calcium-channel blocker; 

ACE-I, angiotensin-converting enzyme inhibitor; 

2003 WHO/ISH Statement on Hypertension.!
ARB, angiotensin II receptor blocker; CCB, calcium-channel blocker!
J Hypertens 2003;21:1983-1992!
The BHS recommendations for combining
blood pressure-lowering drugs!
<55 years ≥55 years or black
patients at any age

Step 1 A
C or D

Step 2 A + C or A + D

Step 3 A + C + D

Step 4 Add: further diuretic therapy or alpha-blocker or beta-blocker


Consider seeking specialist advice

A: ACE inhibitor or ARB, if ACE inhibitor intolerant


C: Calcium-channel blocker D: Diuretic (thiazide)
BHS, British Hypertension Society; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker!

National Collaborating Centre for Chronic Conditions. Hypertension: management in


adults in primary care: partial update. London: Royal College of Physicians, 2006!
History of antihypertensive drugs!

Effectiveness and general tolerability!

! 1940’s !1950 !1957 !1960’s !1970’s !1980’s !1990’s !2000!

Direct
 Alpha-
 ACE
 ARBs!


vasodilators! blockers! inhibitors!
Peripheral
 Thiazide

sympatholytics! diuretics!
Central α2
Ganglion agonists! Calcium

blockers! antagonists-DHPs!
Calcium

Veratrum
 antagonists- The primary goal of treatment is to
alkaloids! non-DHPs!
achieve maximum reduction in total
Beta- CV risk, through treatment of
blockers! elevated BP and all associated
CV, cardiovascular; BP, blood pressure; DHP, dihydropyridine; 
 reversible risk factors
ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker! ESH/ESC 2007
2008 update
Main classes of antihypertensive drugs!
•  Diuretics!
–  Inhibit the reabsorption of salts and water from kidney
tubules into the bloodstream!
•  Calcium-channel antagonists!
–  Inhibit influx of calcium into cardiac and smooth muscle!
•  Beta-blockers!
–  Inhibit stimulation of beta-adrenergic receptors!
•  Angiotensin-converting enzyme (ACE) inhibitors!
–  Inhibit formation of angiotensin II!
•  Angiotensin II receptor blockers (ARBs)!
–  Inhibit binding of angiotensin II to type 1 angiotensin II
receptors!
Renin-angiotensin-aldosterone system!
Angiotensinogen!
(-)!
Renin!
Angiotensin I! Bradykinin!
Angiotensin-!
converting !
enzyme!
Angiotensin II! Inactive kinins!

AT1! AT2!
êBP!
•  Vasoconstriction! •  Vasodilation!
•  Aldosterone secretion! •  Inhibition of cell growth!
•  Catecholamine release! •  Cell differentiation!
•  Proliferation! •  Injury response!
•  Hypertrophy! •  Apoptosis!
Ellis ML, et al. Pharmacotherapy 1996;16:849-860;!
BP, blood pressure Carey RM, et al. Hypertension 2000;35:155-163!
Inhibition of the RAAS by ACE inhibitors!
ACE

Angiotensinogen!
(-)! inhibitor!
Renin!
Angiotensin I! Bradykinin!
Non- Angiotensin-!
Non-
renin! converting !
ACE! enzyme!
Angiotensin II! Inactive kinins!

AT1! AT2!
!B
•  Vasoconstriction! •  Vasodilation!
P! •  Aldosterone secretion! •  Inhibition of cell growth!
•  Catecholamine release! •  Cell differentiation!
•  Proliferation! •  Injury response!
•  Hypertrophy! •  Apoptosis!
RAAS, renin-angiotensin-aldosterone system; Ellis ML, et al. Pharmacotherapy 1996;16:849-860;!
ACE, angiotensin-converting enzyme; BP, blood pressure Carey RM, et al. Hypertension 2000;35:155-163!
Inhibition of the RAAS by ARBs!

Angiotensinogen
Renin

Angiotensin I Bradykinin
Angiotensin-!
converting !
enzyme!

Angiotensin II Inactive kinins

ARB!

BP AT1 AT2

Ellis ML et al. Pharmacotherapy 1996;16:849-860;!


RAAS, renin-angiotensin-aldosterone system; Carey RM et al. Hypertension 2000;35:155-163;!
ARB, angiotensin II receptor blocker; BP, blood pressure Mizuno M et al. Eur J Pharmacol 1995;285:181-188!
Tolerability!

•  Treatment with olmesartan is well tolerated,


with an incidence of AEs similar to placebo!
•  Events are generally mild, transient and are
not related to the dose of olmesartan!
•  Addition of HCTZ to olmesartan does not
appreciably increase the incidence of AEs or
cause significant metabolic disturbances !

AEs, adverse events; HCTZ, hydrochlorothiazide !


Factors influencing BP control!

Efficacy!

+!
Adverse effects!

+!
Convenience!
Dose-related efficacy and

side-effect profile!
•  Antihypertensive efficacy generally improves with
an increase in dose!
•  Common side effects associated with:!
! ACE inhibitors – cough!
! CCBs – ankle oedema, flushing!
! Beta-blockers – tiredness, impotence!
•  ARBs have demonstrated placebo-like tolerability
even at higher doses!
ACE, angiotensin-converting enzyme; 

CCB, calcium-channel blocker; ARB, angiotensin II receptor blocker!
Compliance at 1 year with

antihypertensive treatment!

70!
64!
*
* p<0.007 vs ACE inhibitors
58!
Compliance at 1 year (%)!

60!

50!
50!
43!
40! 38!

30!

20!

10!

0!
Diuretics! Beta-blockers! CCBs! ACE inhibitors! ARBs!

ACE, angiotensin-converting enzyme; 



CCB, calcium-channel blocker; ARB, angiotensin II receptor blocker! Bloom BS, et al. Clin Ther 1998;20:671-681!
Treatment persistence at 1 year with

initial antihypertensive treatment!

60! *
* p<0.007 vs ACE inhibitors 51.9!
Treatment persistence (%)!

50! 48.0!

40.3!
40! 38.3!

29.9!
30!

20!

10!

0!
Diuretics (n=34,934)! CCBs (n=36,246)! Beta-blockers ACE inhibitors ARBs (n=10,245)!
(n=82,241)! (n=78,616)!

ACE, angiotensin-converting enzyme; 



CCB, calcium-channel blocker; ARB, angiotensin II receptor blocker!
Patel BV, et al. J Clin Hypertens 2007;9:692-700!
2008 update
Importance of blood pressure control!

“It is estimated that in patients with 



stage 1 hypertension and additional
cardiovascular risk factors, 

achieving a sustained 12-mmHg reduction in
SBP over 10 years will prevent 1 death 

for every 11 patients treated.”!
!
!
JNC VII 2003!
The cardio-renal continuum!
REGRESS

Target organ damage


Asymptomatic

CKD
New risk factors

Atherosclerosis Target organ


damage
Symptomatic

Risk factors ESRD Death

2008 update Ruilope L. ESH Annual Meeting 2007; June 15-19, 2007; Milan, Italy