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Curriculum Vitae

Nama : Prof. Dr. dr H. Djanggan Sargowo SpPD,SpJP(K), FIHA, FACC, FCAPC, FESC, FASCC

Tempat/Tgl lahir : Sragen, 21 September 1947


Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395
Pendidikan :
1. Lulus Dokter dari UGM, tahun 1974
2. Lulus Cardiologist dari Univ. Indonesia, tahun 1983
3. Lulus Internist dari Univ. Airlangga, tahun 1986
4. Lulus Doktor, Univ. Airlangga, tahun 1996
5. Advanced Cardiology Course, Univ. Hongkong, tahun 1984
6. Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996
7. Fellow American College of Cardiology (FACC), September 2006.
8. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007
9. Fellow European Sociaty of Cardiology (FESC), 2008
10. Fellow Asean Collage of Cardiology (FASCC), 2008

Jabatan :
1. Dosen Pengajar Program Pascasarjana Universitas Brawijaya
2. Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya
3. Ketua PERKI Cabang Malang Raya
4. Anggota Kolegium Kardiovaskuler Indonesia 1
MANAGEMENT OF HYPERTENSION

Djanggan Sargowo

2
Clinical history:

Hypertension is, very largely, an


asymptomatic condition until and
unless it is very severe
Contribution of CV Risk Factors to Burden of
Disease Mortality*
Blood pressure
Tobacco Developing
Underweight countries
Alcohol
Developed
Cholesterol
countries
Unsafe sex
Overweight
Unsafe water, sanitation,
hygiene
Low fruit and vegetable
intake
Indoor smoke from solid
fuels
Physical inactivity

0 5 10 15 20
Percentage of Mortality Attributable to Risk Factors

*Based on The World Health Report 2003.


Yach et al. JAMA. 2004;291:2616-2622.
Hypertension With Other CV Risk
Factors Increases Risk of MI
2.9 2.4 1.9 3.3 13.0 42.3 68.5 182.9 333.7
(2.6-3.2) (2.1-2.7) (1.7-2.1) (2.8-3.8) (10.7-15.9) (33.2-54.0) (53.0-88.6) (132.6-252.2) (230.2-483.9)

512
256
Odds Ratio (95% CI)

128
64
32
16
8
4
2
1
Smk DM HTN ApoB/A1 1+2+3 All 4 +Obes +PS All RFs
(1) (2) (3) (4)

Smk=smoking; DM=diabetes mellitus; HTN=Hypertension; Obes=abdominal obesity; PS=psychosocial;


RF=risk factor; MI=myocardial infarction.
Yusuf S et al. Lancet. 2004; 364:937-952.
Effect of Long-Term Modest
Reductions in CV Risk Factors

10% 10% 45%


Reduction
in BP + Reduction
in TC = Reduction
in CVD

Emberson et al. Eur Heart J. 2004;25:484-491.


Management of Hypertension

The main objective in lowering BP is


to reduce the patients absolute risk
of premature death and disease,
primarily by reducing their risk of
cardiovascular diseases.

Ogden LG,et al. Hypertension. 2000


HYPERTENSION PREVENTION & MANAGEMENT

Goals : To reduce morbidity and mortality by


the least instrusive means possible

This is accomplished by achieving and


maintaining :
SBP < 140 mm Hg
DBP < 90 mm Hg
Controlling other CV risk factors

Arch Intern Med 1997;157:2413-2446


8
STRATEGI TERAPI HIPERTENSI

JNC VI 1997
WHO / ISH 1999
BHS 1999
9
STRATIFICATION OF RISK
TO EQUALITY PROGNOSIS
Blood Pressure ( mmHg)

Other risk factor & Grade1 Grade 2 Grade 3


Disease history SBP 140-159 or SBP 160-179 or SBP=/> 180 or
DBP 90-99 DBP 100-109 DBP =/> 110

I no other risk factor LOW RISK MED RISK HIGH RISK

II. 1-2 Risk factors MED RISK MED RISK HIGH RISK

III. 3 or more risk HIGH RISK HIGH RISK V HIGH RISK


factors or TOD or DM

IV. ACC V HIGH RISK V HIGH RISK V HIGH RISK

CV risk in 10 years : <15%(lr), 15-20%(mr), 20-30%(hr), >30%(vhr)


10
RISK STRATIFICATION AND TREATMENT

Blood Pressure High-normal Stage 1 Stages 2+3


Stages (mm Hg) 130-139/85-89 140-159/90-99 160/100

Risk Group A Lifestyle Lifestyle Drug therapy


(No risk factors; modification modification
No TOD/CCD*)

Risk Group B Lifestyle Lifestyle


(At least 1 risk factor; modification modification Drug therapy
Not including (up to 12 months) (up to 6 months)
Diabetes; No TOD/CCD)

Risk Group C Drug therapy Drug therapy Drug therapy


(TOD/CCD and/or
Diabetes; with or
without other risk
factor)

JNC VI, Arch Intern Med 1997; 157: 2413-46 11


WHO-ISH (1999)
Klasifikasi Derajat Tekanan Darah menurut WHO-
ISH 1999 yang diadaptasi dari JNC VI 1997
Kategori Sistolik Diastolik
(mmHg) (mmHg)
1 Optimal 120 80
2 Normal 130 85
3 Normal Tinggi 130 - 139 85 - 89
4 Hipertensi derajat 1 (ringan) 140 - 159 90 - 99
Subgrup : perbatasan 140 - 149 90 - 94
5 Hipertensi derajat 2 (sedang) 160 - 179 100 - 109
6 Hipertensi derajat 3 (berat) 180 110
7 Hipertensi Sistolik 140 90
(Isolated Systolic Hypertension)
12
CLASSIFICATION OF BLOOD PRESSURE IN US ADULTS:
JNC VII GUIDELINES

BP category Systolic Diastolic


(mmHg) (mmHg)
Normal <120 and <80
Pre-hypertension 120139 or 8089
Hypertension, 140159 or 9099
stage 1
Hypertension, 160 or 100
stage 2
13
Chobanian et al. JAMA 2003;289:256072
CLASSIFICATION OF BLOOD PRESSURE IN EUROPEAN ADULTS:
ESHESC GUIDELINES

BP category Systolic Diastolic


(mmHg) (mmHg)
Optimal <120 and <80
Normal 120129 and 8084
High normal 130139 or 8589
Hypertension
Grade 1 (mild) 140159 or 9099
Grade 2 (moderate) 160179 or 100109
Grade 3 (severe) 180 or 110 14
Guidelines Committee. J Hypertens 2003;21:101153
JNC VII AND ESHESC SUMMARY :
Target Blood Pressure Goals

Type of hypertension BP goal (mmHg)


Uncomplicated <140/90
Complicated
Diabetes mellitus <130/80
Kidney disease <130/80

Chobanian et al. JAMA 2003;289:256072


Guidelines Committee. J Hypertens 2003;21:101153 15
HYPERTENSION IS A PREVALENT DISEASE
AFFECTING 1 BILLION PEOPLE TODAY
60
55
49
50 47
Prevalence* of HTN (%)

42
40 38 38

30 27 28

20

10

0
Canada USA Italy Sweden England Spain Finland Germany

*Among persons aged 3564 years old; age and sex adjusted
HTN = BP 140/90 mmHg or on treatment Wolf-Maier et al. JAMA 2003;289:23639 16
PREVALENCE OF HYPERTENSION
INCREASES WITH AGE
Prevalence of HTN (%)
80
70 65,2

60
50
40
29,1
30
20
10 6,7

0
2039 4059 60
SBP/DBP (mmHg)
SBP = systolic BP; DBP = diastolic BP
Estimated non-institutionalised US adults, 19992002 17
Brown. BMJ 2006;332:8336
From Centers for Disease Control and Prevention
Which one ??
18
CARDIOVASCULAR MORTALITY RISK DOUBLES
WITH EACH 20/10 MMHG INCREMENT*
CV mortality risk
8
8x
6

4
4x
2
2x
1x
0
115/75 135/85 155/95 175/105
SBP/DBP (mmHg)

*Individuals aged 4069 years Lewington et al. Lancet 2002;360:190313 19


BLOOD PRESSURE REDUCTION OF 2 MMHG REDUCES
THE RISK OF CARDIOVASCULAR EVENTS BY 710%
Meta-analysis of 61 prospective,
observational studies
1 million adults
12.7 million person-years 7% reduction in
risk of ischaemic
heart disease
2 mmHg mortality
decrease in
mean SBP 10% reduction in
risk of stroke
mortality

Lewington et al. Lancet 2002;360:190313 20


THE BURDEN OF UNCONTROLLED
BLOOD PRESSURE
Not all patients with hypertension are
treated
The majority of patients do not achieve BP
goal
Health burden of uncontrolled BP
Economic burden of CV disease and
hypertension
21
APPROXIMATELY 73% OF EUROPEAN PATIENTS
WITH HYPERTENSION REMAIN UNTREATED
Patients (%) Treated Untreated
100
75 74 74 73 68
80

60

40

20

0
England Sweden Germany Spain Italy

Wolf-Maier et al. Hypertension 2004;43:1017 22


LIFESTYLE MODIFICATIONS TO
PREVENT AND MANAGE HYPERTENSION
Reduce weight Moderate consumption of:
alcohol
sodium
saturated fat
cholesterol

Maintain adequate intake of dietary:


Increase potassium
physical calcium
activity magnesium

Avoid tobacco
(JNC VI. Arch Intern Med. 1997)
23
FIRST LINE ANTIHYPERTENSIVE DRUGS

DIURETIC
BETA-BLOCKER
ACEI
CALCIUM ANTAGONIST
ALFA BLOCKER
ACE INHIBITOR
ANGIOTENSIN RECEPTOR
BLOCKER
LOW DOSE COMBINATION 24
GUIDELINES FOR SELECTING DRUG TREATMENT OF HYPERTENSION
Class of drug Compelling indications Possible Compelling Possible
indications contraindications contraindications
Diuretics Heart failure Diabetes Gout Dyswlipidemia
Elderly patients Sexually
Systolic hypertension activemales
Beta-blockers Angina Heart failure Asthma and COPD Dyslipidemia
After myocardial infarct Pregnancy Heart block Athletes &
Tachyarrhytmia Diabetes physically active
patients
PVD
ACEI Heart failure Pregnancy
LV dysfunction Hyperkalemia
After MI Bilateral RAS
DM nephropathy
Calcium Angina PVD Heart block CHF
antagonists Elderlypatients
Sysstolic hypertension
Alfa-blockers Prostatic hypertrophy IGT Orthostatic
Dyslipidemia hypotension

AII ACEI cough Heart failure Pregnancy


antagonists Bilateral RAS
Hyperkalemia
25
TRENDS IN AWARENESS, TREATMENT, AND CONTROL OF HIGH BLOOD
PRESSURE IN ADULTS AGES 18 - 74

NATIONAL HEALTH AND NUTRITION


EXAMINATION SURVEY, Weighted %
II III (Phase III (Phase
(1976-1980) 1 1988- 2 1991- 1999-2000
1991) 1994)

Awareness 51 73 68 70

Treatment 31 55 54 59

Control 10 29 27 34

High blood pressure is systolic blood pressure (SBP) 140 mmHg or diastolic blood pressure (DBP) 90 mmHg
or taking antihypertensive medication. SBP < 140 mmHg and DBP < 90 mmHg
26
EFFECT OF ANTIHYPERTENSIVE DRUG TREATMENT ON
CORONARY HEART DISEASE, STROKE AND VASCULAR MORTALITY
IN SEVENTEEN 3 TO 5 YEAR CLINICAL TRIALS
40%* 16%* 21%*
(#s) Percent Percent Percent
1200
Reduction Reduction Reduction
1000

800

600

400

200

0
Stroke CHD Vascular
Mortality
Control Active Drug Treatment

* Highly statistically significant


From : Hebert P, et al. Arch Intern Med. 1993;153:578-581 27
UNEXPECTED RESULTS OF
HYPERTENSION TREATMENT
Due to :
Inadequate education of doctors
and publics, and inadequate
evidence on desirable goals of
treatment, due to overreliance
on high dose of monotherapy
and newer drugs

28
RESULTS OF HYPERTENSION TREATMENT

Half (probably 2/3) need combination


of AHD for effective controlled BP to
level below 140/90 mmHg
Survey of BP controlled :
in USA only 25% contolled or lowered
to below 140/90 mmHg
in UK even only 6%

29
BARRIERS TO ACHIEVE BP GOALS
Poor compliance
Under aggressiveness of physician in
HT treatment
Wrong medication; not proper
combination; medication interfering
risk with BP control
White Coat HT
Pseudo HT
Secondary HT 30
ESTIMATED EFFICACY OF MONO THERAPY
WITH OLD CRITERIA
DRUG RESPONDERS (%)

Thiazides 50-55
Beta blockers 45-50
ACE - inhibitors 50-60
Calcium channel blockers 40-60
Alpha blockers (prazosin) 35-40
Central agonists 30-35
Data derived from Am J cardiol, 1987;59(13):48F-52F10
31
Algorithm for Treatment of Hypertension from
JNC-7
Lifestyle Modifications

Not at Goal Blood Pressure (<140/90 mmHg)


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

Initial Drug Choices

Without Compelling With Compelling


Indications Indications

Stage 1 Hypertension Stage 2 Hypertension Drug(s) for the compelling


(SBP 140159 or DBP 9099 mmHg) (SBP >160 or DBP >100 mmHg) indications
Thiazide-type diuretics for most. 2-drug combination for most (usually Other antihypertensive drugs
May consider ACEI, ARB, BB, CCB, thiazide-type diuretic and (diuretics, ACEI, ARB, BB, CCB)
or combination. ACEI, or ARB, or BB, or CCB) as needed.

Not at Goal
Blood Pressure

Optimize dosages or add additional drugs


until goal blood pressure is achieved.
Consider consultation with hypertension specialist.
THERAPEUTIC STRATEGIES OF HYPERTENSION
ESH-ESC GUIDELINES 2003
Choose between

Single agent 2 drug combination


at low dose at low dose

If goal BP not achieved

Previous agent Switch to different Previous Add a


at full dose Agent at low dose combination third drug
at full dose at low dose

If goal BP not achieved

2-3 drug combination 2-3 drug combination


33
J.hypertension 2003 ,21, 1011 - 1053
UPDATED UK NICE GUIDELINES FOR THE
TREATMENT OF NEWLY DIAGNOSED HYPERTENSION
55 years or
<55 years
black at any age

CCB or thiazide-
Step 1 ACEI (or ARB*)
type diuretic

ACEI (or ARB*) + CCB or


Step 2
ACEI (or ARB*) + thiazide diuretic

Step 3 ACEI (or ARB*) + CCB + diuretic

Add further diuretic therapy, -blocker, or -blocker.


Step 4
Consider seeking specialist advice

*If ACE inhibitor (ACEI) not tolerated http://www.nice.org.uk/download.aspx?o=CG034fullguideline. 34


Accessed June 2006
Initiation of Antihypertensive Treatment

Blood Pressure mmHg


Other risk factors, Normal High Normal Grade 1 HT Grade 2 HT Grade 3 HT

OD SBP 120-129 SBP 130-139 SBP 140-159 SBP 160-179 SBP 180
or DBP 80-84 or DBP 85-89 or DBP 90-99 or DBP 100-199 or DBP 110
Or disease
Lifestyle changes for Lifestyle changes for Lifestyle changes
No other risk No BP No BP several months then drug several months then drug +
treatment if BP treatment if BP Immediate drug
factors intervention intervention uncontrolled uncontrolled treatment

Lifestyle changes for Lifestyle changes for Lifestyle changes


1-2 risk factors Low added Low added several months then drug several months then drug +
treatment if BP treatment if BP Immediate drug
risk risk uncontrolled uncontrolled treatment

3 risk factors, MS, Lifestyle changes Lifestyle changes &


Lifestyle changes Lifestyle changes Lifestyle changes
consider drug
or OD treatment + + +
Lifestyle changes Lifestyle changes drug treatment drug treatment Immediate drug
Diabetes + drug treatment treatment
Lifestyle changes Lifestyle changes Lifestyle changes Lifestyle changes Lifestyle changes
Established CV + + + + +
Immediate drug Immediate drug Immediate drug Immediate drug Immediate drug
or renal disease treatment treatment treatment treatment treatment

ESH/ESC Guidelines 2007


Eur Heart Journal 2007
COMPLIANCE WITH ANTIHYPERTENSIVE
MEDICATIONS: CLINICAL AND ECONOMIC IMPACT

Non-compliance and persistence: extent of


the problem
Reasons for non-compliance
Improved compliance with antihypertensive
therapy improves clinical and economic
outcomes
36
HYDROCHLOROTHIAZIDE

Diuretik golongan tiazid


Bioavailabilitas 70%
T 1/2 = 6 - 15 jam
Ekskresi melalui ginjal
Dosis terapi 12,5 - 200 mg

37
BISOPROLOL
1-blocker dengan selektifitas tertinggi
Tanpa efek ISA & MSA
Bioavailabilitas tinggi 88%
Tidak dipengaruhi makanan
Balance clearance melalui ginjal & hati
T max = 1-3 Jam
T 1/2 = 9 - 11 jam
Dosis sekali sehari
Dosis terapi 5 - 20 mg / hari
38
NOT ALL -BLOCKERS ARE THE SAME !

Non-selective with
NON SELECTIVE SELECTIVE alfa-blocking activity
Labetolol
ISA - ISA + ISA - ISA + Bucindolol
Carvedilol
Nadolol Pindolol Atenolol Acebutolol
Propanolol Penbutolol Esmolol Celiporlol
Timolol Alprenolol Metoprolol
Sotalol Oxprenolol Bisoprolol
Bisoprolol
Betaxolol 39
40
RECOMMENDATION OF JNC VI:

Beta blocker
Diuretic

FIRST LINE THERAPY OF HYPERTENSION

41
COMBINATION THERAPY
Theoretical Requirements :
1. Combination is superior to monotherapy
2. Each component contributes to
therapeutic effect
3. Dosage forms must be satisfactory
regarding
Bioavailability
Absense of unwanted interctions
Selection of doses for each component

Oster JR, Epstein M. J Clin Hypertens 1987;3:28-293


42
ADVANTAGES OF
COMBINATION PRODUCTS
Simplicity of regiment
Simple titration process
Improve compliance
Cost advantage
Potentiation of hypotensive effects
Reduction in side effects
Offsetting of undesirable side effects

Oster JR,Opstein M. J Clin Hyperten 1987 3:278-293


43
COMBINATION THERAPY VS MONOTHERAPY
Randomized, Doble-Blind, Placebo Controlled Parallel Group
Dose-Escalation Study)
Systolic Blood Pressure Diastolic Blood Pressure

- 1.1 - 1.9

67

- 9.0
- 9.8 - 9.9

- 11.8

p< 0.001 vs placebo - 12.7 p< 0.001 vs placebo


- 14.9 p< 0.029 vs enalapril p< 0.020 vs emlodipine
p< 0.001 vs enalapril

Bisoprolol Amlodipine Enalapril Placebo Bisoprolol Amlodipine Enalapril Placebo


/HCTZ /HCTZ

44
Netrel JM. Et al. Cardiovas Rev. & Ren. 1996:33-44
POTENTIAL DRUG COMBINATIONS
Angiotensin Receptor
ACE Inhibitors ?
Blockers

+ + ?
X
+ ?

Diuretics Beta-
Blockers

+ +
+ !

Dihydropyridine Nondihydropyridine
+
Calcium Blockers Calcium Blockers

45
Are you hungry
or
sleepy ????
Sciences
REASONS FOR NON-COMPLIANCE
Financial constraints
Doubts over treatment benefits
Patient characteristics
Unwelcome side effects or drug tolerability issues
Need for more than one agent or complex treatment
regimens
A lack of understanding of instructions provided by
physicians

Poor compliance is estimated to cost the US $100 billion annually*

DiMatteo et al. Med Care 2002;794811; Greenberg. Clin Ther 1984;6:5929; Dezii. Man Care 2000;9(Suppl):26; Taylor &
Shoheiber. Congest Heart Fail 2003;9:324 32; Rudd. Am J Manag Care 1998;4:95766; Degli et al. J Clin Hypertens 2004;6:7684 47
*Task Force for Noncompliance. Baltimore, Md: Task Force for Noncompliance, 1994
Majority of Hypertensive Patients Need Multiple
Medications for Effective Management
More Than 1 Agent Is Usually Required to Get to BP Goal

IDNT (135/85 mm Hg) 3,80

UKPDS 83 (< 85 mm Hgdiastolic) 2,70

ABCD (<75 mm Hgdiastolic) 2,75

MDRD (<92 mm Hgmean arterial pressure) 3,70

HOT (<80 mm Hgdiastolic) 3,25

ALLHAT (<140/90 mm Hg) 2,00

0 1 2 3 4
Number of Agents

Multiple medications can increase the complexity of treatment


Bakris et al. Am J Kidney Dis. 2000;36:646-661; Brenner et al. N Engl J Med. 2001;345: 861-869; Lewis et al. N Engl J Med. 2001;345:851-860; Cushman et
al. J Clin Hypertens. 2002;4:393-404.
49
PATIENTS ON FIXED-DOSE COMBINATION THERAPY HAVE
GREATER COMPLIANCE THAN THOSE ON INDIVIDUAL
COMPONENT-BASED THERAPY

Fixed-dose combination
(amlodipine/benazepril) 87,9*
(n=2,839)

Free combination 69,2


(ACEI + DHP-CCB)
(n=3,367)

0 20 40 60 80 100

*p<0.0001 Medication possession ratio (%)


MPR is an indicator of compliance measured by the proportion of days in the year when the patient is
supplied with the medication
DHP = dihydropyridine
Wanovich et al. Am J Hypertens 2004;17:223A 50
RATIONALE FOR A CCBARB COMBINATION

The calcium channel blocker (CCB)angiotensin


receptor blocker (ARB) reduces BP by targeting
two key BP effector pathways
Rationale for a CCBARB: tolerability and
efficacy
Rationale for CCBARB therapy with
Amlodipine/Valsartan
51
THE CCBARB TARGETS TWO KEY BP
EFFECTOR PATHWAYS (1)
Sympathetic nervous system (SNS)
SNS activity noradrenaline binds to 1-adrenergic
receptors on vascular smooth muscle vasoconstriction1
SNS also stimulates renin secretion from the kidney,
thereby activating the RAS2
CCBs inhibit SNS-induced vasoconstriction by blocking
influx of calcium ions (needed for contraction) through
voltage-gated calcium channels vasodilation3,4
Other effects of CCBs: natriuresis; inhibition of aldosterone
release; interference with angiotensin II-mediated
vasoconstriction4
1Grassi. J Hypertens 2001;19:171316; 2Mancia and Grassi. http://www.sns-web.org/pages/advances/11/article.asp; 3Robertson and Robertson. In: Hardman
JG, Limbard JG, editors-in chief. Goodman & Gilmans The Pharmacological Basis of Therapeutics. 9th ed. 1996. p. 75979
4Prisant. In: Oparil S, Weber MA, editors. Hypertension: Companion to Brenner & Rectors The Kidney. 2nd ed. 2005. p. 683704 52
THE CCBARB TARGETS TWO KEY BP
EFFECTOR PATHWAYS (2)
Renin angiotensin system (RAS)
Release of renin catalyses conversion of
angiotensinogen into angiotensin I, which is
converted by ACE to angiotensin II
Vasoconstriction; increased aldosterone and sodium/water
retention; SNS activation
ARBs block the effects of angiotensin II by binding to
AT1 receptors
Arterial and venous dilation
Reduced SNS activity
Reduced secretion of aldosterone and increased secretion of
sodium and water

Mistry et al. Expert Opin Pharmacother 2006:7:57581 53


RATIONALE FOR A CCBARB COMBINATION

Hypertension =
Peripheral vasoconstriction in peripheral vascular resistance =
effective BP lowering with combination
therapy
CCBs
ARBs

in BP triggers ARBs block the


the stimulation of the SNS action of Ang II
Peripheral vasodilation level at the AT1
resulting in lower BP and RAS
receptor

Aldosterone Ang II
levels levels

Quan et al. Am J Cardiovasc Drugs 2006;6:10313


54
Mistry et al. Expert Opin Pharmacother 2006;7:57581
PERIPHERAL OEDEMA ASSOCIATED WITH CCBS

Fluid leakage

Arterial No venous
dilation dilation

Fluid leakage
Capillary bed

Opie et al. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273
White et al. Clin Pharmacol Ther 1986;39:438
Gustaffson. J Cardiovasc Pharmacol 1987;10(Suppl 1):S12131 55
COMPLEMENTARY EFFECTS OF A CCB/ARB:
REDUCTION OF CCB-ASSOCIATED OEDEMA

Arterial Venous
dilation dilation
(CCB and (ARB)
ARB)

Capillary bed

Opie. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273
White et al. Clin Pharmacol Ther 1986;39:438; Gustaffson. J Cardiovasc Pharmacol
1987;10(Suppl. 1):S12131; Messerli et al. Am J Cardiol 2000;86:11827 56
Anti Hypertension Combination
(2007 ESC/ESH guidelines)

Diuretic

-blockers ARBs

-blockers
CCBs=CA
Antagonist

ACE inhibitors
MECHANISM OF ACTION OF AMLODIPINE
Amlodipine inhibits the transmembrane influx of
calcium ions into vascular smooth muscle and
cardiac muscle
Inhibition is selective, with a greater effect on vascular
smooth muscle cells
It binds to both dihydropyridine and non-
dihydropyridine binding sites
Amlodipine is also a peripheral arterial vasodilator
Acts directly on vascular smooth muscle to cause a
reduction in peripheral vascular resistance and a
reduction in BP

http://www.pfizer.com/pfizer/download/uspi_norvasc.pdf 58
PHYSIOLOGIC EFFECTS OF RAAS: AT1
RECEPTOR INHIBITION
Angiotensinogen
Renin Bradykinin/Kinins
Angiotensin I
ACE
Degradation
AT1-Antag Angiotensin II

B1/B2-Receptor
AT2 Receptor
AT1 Receptor

Nitric Oxide
Vasoconstriction
Reactive oxygen species
Cellular growth Vasodilation
Apoptosis Growth inhibition
Neurohumoral activation Apoptosis 59
MECHANISM OF ACTION Of IBERSARTAN
Non-ACE Vasoconstriction
pathways Cell growth
(e.g. chymase)
Sodium/water retention
Angiotensinogen
Sympathetic activation

Angiotensin I
Ibersartan AT1 receptor
Angiotensin-converting enzyme
Angiotensin II

AT2 receptor

Aldosterone

Vasodilation
Sodium/water Antiproliferation
retention

60
BP REGULATION: THE TWO KEY
VASOCONSTRICTOR SYSTEMS

Sympathetic Nervous Renin Angiotensin


System (SNS) System (RAS)

Mutually reinforcing actions combine to regulate BP

Grassi. J Hypertens 2001;19:171316 61


INTERACTION OF CCBS AND ARBS ON VASCULAR
AND RENAL FUNCTION, SNS AND RAS ACTIVITY

Natriuresis

Vasodilation
Arterial Arterial +
Venous

CCB ARB

RAS RAS
SNS SNS

62
CCBARB: SYNERGY OF COUNTER-REGULATION

CCB
Arteriodilation ARB
Peripheral edema RAS blockade
Effective in low-renin patients CHF and renal
Reduces cardiac ischemia benefits

ARB CCB
Venodilation RAS activation
Attenuates peripheral edema No renal or CHF
Effective in high-renin patients benefits
No effect on cardiac ischemia

63
Trends in awareness,treatment, and control of
High BP in adults ages 18-74
National Health Ans Nutrition Examination Survey, Percent

II III(Phase 1 III(Phase 2
(1976-1980) 1988-91) 1991-94) 1999-2000

Awareness 51 73 68 70

Treatment 31 55 54 59

Control 10 29 27 34

Sources: Unpublished data for 1999-2000 computed by M.Wolz,NHLBI


Whats the Importance in
Hypertension management:

REACH THE TARGET


IMMEDIATELY
Large Hypertension Trials
on
Amlodipine
Norvask (amlodipine besylate) Extensively Studied in
Large Trials
CAMELOT/
ALLHAT ASCOT-BPLA VALUE NORMALISE
Patients High-risk Moderate-risk High-risk CHD
hypertensive hypertensive hypertensive patients
studied
(N=33,357) (N=19,342) (N=15,245) (n=1991)
Amlodipine
Amlodipine Amlodipine
besylate Amlodipine
besylate, besylate,
Comparators perindopril, besylate,
lisinopril, enalapril,
atenolol valsartan
chlorthalidone placebo
thiazide
Trial duration 6 years Trial 6 years 2 years
stopped
early

CV mortality 24 % Adverse CV Events 31%


Establishment Stroke 23 % Stroke 15% Hospitalization for Angina 42%
on renal & GI safety Total Coronary Endpoint 13% MI 19% Coronary Revascularization
Total CV Event & Procedures 16%

ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997; Julius et al, for the VALUE trial group. Lancet. 2004;363:2022-2031; Sever et al, for the ASCOT
Investigators.
J Hypertens. 2001;19:1139-1147; Nissen et al, for the CAMELOT Investigators. JAMA. 2004;292:2217-2226.
A randomised controlled trial of the prevention
of CHD and other vascular events by BP and
cholesterol lowering in a factorial study design

B.Dahlof (Co-chair), P.Sever (Co-chair), N. Poulter (Secretary)


H. Wedel (Statistician), G. Beevers, M. Caulfield, R. Collins
S. Kjeldsen, A. Kristinsson, J. Mehlsen, G. McInnes, M. Nieminen
E. OBrien, J. stergren, on behalf of the ASCOT Investigators
ASCOT- BPLA

Primary Objective
To compare the effect on non-fatal
myocardial infarction (MI) and fatal
CHD of the standard antihypertensive
regimen (-blocker diuretic) with a more
contemporary regimen
(CCB ACE inhibitor)
ASCOT patient population
risk factor profile
All patients in ASCOT have hypertension plus 3 risk factors for CHD

Hypertension 100
Age 55 years 84
Male 77
Microalbuminuria/proteinuria 61
Smoker 30
Family history of CHD 27
Plasma TC:HDL-C 6 24
Type 2 diabetes 24
Certain ECG abnormalities 14
LVH 13
Previous cerebrovascular events 11
Peripheral vascular disease 6

0 10 20 30 40 50 60 70 80 90 100
Patients with risk factor (%)
Systolic and diastolic
blood pressure
atenolol thiazide
180 amlodipine perindopril
164.1 SBP
160 163.9 Mean difference 2.7
140 137.7
mm Hg

136.1
120

100
DBP
94.8 Mean difference 1.9
94.5 79.2
80
77.4
60

Baseline 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 Last


visit
Time (years)
Endpoints: Non-fatal MI
(excl silent) + fatal CHD
% 5.0

10%
4.0
Atenolol thiazide
(No. of events 444)
3.0
Amlodipine perindopril
(No. of events 390)
2.0

1.0 HR = 0.87 (0.761.00)


p = 0.0458
0.0 Years
0.0 1.0 2.0 3.0 4.0 5.0
Number at risk
Amlodipine perindopril 9639 9485 9354 9193 8998 7895
Atenolol thiazide 9618 9475 9302 9099 8881 7768
Fatal and non-fatal stroke
% 5.0
Atenolol thiazide
(No. of events 422)
4.0

3.0
Amlodipine perindopril
(No. of events 327)
2.0

1.0 HR = 0.77 (0.660.89)


p = 0.0003
0.0
0.0 1.0 2.0 3.0 4.0 5.0 Years
Number at risk
Amlodipine perindopril 9639 9483 9331 9156 8972 7863
Atenolol thiazide 9618 9461 9274 9059 8843 7720
Total CV events and procedures
% 18.0
Atenolol thiazide
16.0 (No. of events 1602) 16%
14.0

12.0
Amlodipine perindopril
10.0
(No. of events 1362)
8.0

6.0

4.0 HR = 0.84 (0.780.90)


2.0 p < 0.0001
0.0
0.0 1.0 2.0 3.0 4.0 5.0 Years
Number at risk
Amlodipine perindopril 9639 9277 8957 8646 8353 7207
Atenolol thiazide 9618 9210 8848 8465 8121 6977
CV mortality
% 3.5
Atenolol thiazide 24%
3.0 (No. of events 342)

2.5

2.0
Amlodipine perindopril
1.5 (No. of events 263)

1.0
HR = 0.76 (0.650.90)
0.5 p = 0.0010
0.0
0.0 1.0 2.0 3.0 4.0 5.0 Years
Number at risk
Amlodipine perindopril 9639 9544 9441 9322 9167 8078
Atenolol thiazide 9618 9532 9415 9261 9085 7975
All-cause mortality
% 10.0

8.0 Atenolol thiazide


(No. of events 820) 11%

6.0

Amlodipine perindopril
4.0 (No. of events 738)

2.0 HR = 0.89 (0.810.99)


p = 0.0247
0.0

Number at risk
0.0 1.0 2.0 3.0 4.0 5.0 Years
Amlodipine perindopril 9639 9544 9441 9332 9167 8078
Atenolol thiazide 9618 9532 9415 9261 9085 7975
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77
78
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80
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81
Unstable angina

% 1.2
Atenolol thiazide
(No. of events 106)
1.0
32%
0.8

Amlodipine perindopril
0.6 (No. of events 73)

0.4

0.2 HR = 0.68 (0.510.92)


p = 0.0115
0.0
0.0 1.0 2.0 3.0 4.0 5.0 Years
Number at risk
Amlodipine perindopril 9639 9536 9416 9285 9123 8021
Atenolol thiazide 9618 9510 9374 9198 9007 7888
New-onset renal impairment
% 5.0
Atenolol thiazide 15%
(No. of events = 469)
4.0

3.0 Amlodipine perindopril


(No. of events = 403)

2.0

HR = 0.85 (0.750.97)
1.0
p = 0.0187

0.0
0.0 1.0 2.0 3.0 4.0 5.0 Years
Number at risk
Amlodipine perindopril 9639 9426 9277 9093 8877 7775
Atenolol thiazide 9618 9431 9247 9021 8782 7640
New-onset diabetes mellitus
% 10.0

Atenolol thiazide
8.0 (No. of events = 799) 30%

6.0

Amlodipine perindopril
4.0 (No. of events = 567)

2.0 HR = 0.70 (0.630.78)


p < 0.0001
0.0
0.0 1.0 2.0 3.0 4.0 5.0 Years
Number at risk
Amlodipine perindopril 9639 9383 9165 8966 8726 7618
Atenolol thiazide 9618 9295 9014 8735 8455 7319
RESULTS OF HYPERTENSION TREATMENT

Glasgow Blood Pressure Clinic :


The higher the blood pressure
remain elevated, the higher the
morbidity and mortality

Guidelines : WHO/ISH and JNC VI 85


FACTOR INFLUENCING PROGNOSIS
RISK FACTORS FOR CV DISEASE
I Used for risk II Other factors adversely
stratification influencing prognosis
Level of systolic & diastolic BP Reduced HDL
Men > 55yrs, Women > 65yrs Raised LDL
Smoking
Microalbuminuria in DM
TCl >250 mg% (>6.5mmol/l)
IGT
Diabetes Mellitus
Obesity
Fam history of premature CVD
Sedentary lifestyle
Raised fibrinogen
High-risk socioeconomic group
High-risk ethnic group
High-risk geographic region

87
FACTOR INFLUENCING PROGNOSIS
TOD AND ASSOCIATED CLINICAL CONDITIONS
Target Organ Damage Associated Clinical Conditions
LVH (ekg, Cerebrovascular disease
echocardiog,or Ro) Ischaemic stroke, Cerebral
haemorrhage, TIA
Proteinuria / slight Heart disease
elevation of Cr (1.2 - 2.0 MI, Angina, CHF, Cor
mg%) revascularisation
Renal disease
USG / Ro evidence of
DN, CRF (Cr > 2 mg%)
atherosclerotic plaque Vascular disease
Generalised / focal Dissecting aorta, symptomatic
narrowing of the retinal arterial disease,
arteries Advanced hypertensive retionopathy
Haemorrhage/exudates,
Papilledema
88
BHS-NICE Guideline- Hypertension: Management of
Hypertension in Adults in Primary Care*

*BHS / NICE. Quick Reference Guide. June 2006. Available at. www.nice.org.uk/CG034.
Classification and Management
of BP from JNC-7
Lifestyle Initial drug therapy
BP SBP* DBP*
modificatio Without compelling With compelling
classification mmHg mmHg
n indication indications
Normal <120 and <80 Encourage
Prehypertensio 120139 or 8089 Yes No antihypertensive drug Drug(s) for
n indicated. compelling
indications.
Stage 1 140159 or 9099 Yes Thiazide-type diuretics for Drug(s) for the
Hypertension most. May consider ACEI, compelling
ARB, BB, CCB, or indications.
combination. Other
Stage 2 >160 or >100 Yes Two-drug combination for antihypertensive
Hypertension most (usually thiazide-type drugs (diuretics,
diuretic and ACEI or ARB or ACEI, ARB, BB,
BB or CCB). CCB) as needed.

*Treatment determined by highest BP category.


Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension.
Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg.
ALGORITHM FOR TREATMENT OF HYPERTENSION
Lifestyle Modifications

Not at Goal Blood Pressure (<140/90 mmHg)


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

Initial Drug Choices

Without Compelling With Compelling


Indications Indications

Stage 1 Hypertension Stage 2 Hypertension Drug(s) for the compelling


(SBP 140159 or DBP 9099 mmHg) (SBP >160 or DBP >100 mmHg) indications
Thiazide-type diuretics for most. 2-drug combination for most (usually Other antihypertensive drugs
May consider ACEI, ARB, BB, CCB, thiazide-type diuretic and (diuretics, ACEI, ARB, BB, CCB)
or combination. ACEI, or ARB, or BB, or CCB) as needed.

Not at Goal
Blood Pressure

Optimize dosages or add additional drugs


until goal blood pressure is achieved.
Consider consultation with hypertension specialist.
91
JNC 7 , Jama May 21,2003
ESHESC: ALGORITHM FOR TREATMENT
OF HYPERTENSION
Consider: BP level before treatment
Absence or presence of TOD and risk factors
Choose between:

Single agent at low dose 2-drug combination at low dose

If goal BP not achieved

Previous agent Switch to Previous Add a


at full dose different agent combination third drug
at low dose at full dose at low dose

If goal BP not achieved

23 drug Full-dose 3-drug combination


combination monotherapy at effective doses

92
TOD = target organ damage
ESHESC Guidelines. J Hypertens 2003;21:177986
Definitions & classification of BP levels (mmHg)
(2007 ESC/ESH guidelines)

Category Systolic Diastolic


Optimal <120 and < 80
Normal 120129 and/or 8084
High normal 130139 and/or 8589
Grade 1 140159 and/or 9099
Grade 2 160179 and/or 100109
Grade 3 180 and/or 110
Isolated systolic 140 and <90
hypertension
Isolated systolic hypertension should be graded (1, 2,3) according to systolic blood pressure
values in the ranges indicated, provided that diastolicvalues are ,90 mmHg. Grades 1, 2 and 3
correspond to classificationin mild, moderate and severe hypertension, respectively. These
termshave been now omitted to avoid confusion with quantification of total cardiovascular risk.