INITIATING THERAPY OF HYPERTENSION.

WHEN AND HOW

Department of Medicine School of

Medicine Central
Sanglah Central Public Hospital
Udayana University Bali

Contact address: email

rakawidiana@yahoo.com and
postal address: I Gde Raka Widiana Jalan
Badak Agung XV no 4 Renon Denpasar
(80114)
 Scope to be discussed
• Burden of illness high blood pressure
• Impact of reducing BP in hypertension
• Classification of high BP
• When to start antihypertensive treatment
• How to treat
• What the BP target acheived
 CV Mortality Risk Doubles With
Each 20/10 mm Hg BP Increment*
8
7
6

CV 5
mortality 4
risk
3
2
1
0
115/75 135/85 155/95 175/105
SBP/DBP (mm Hg)

*Individuals aged 40-69 years, starting at BP 115/75 mm Hg.

CV, cardiovascular; DBP, diastolic blood pressure; SBP, systolic blood pressure.
Lewington S et al. Lancet. 2002;360:1903-1913.
Chobanian AV et al. JAMA. 2003;289:2560-2572.
 Scope to be discussed
• Burden of illness high blood pressure
• Impact of reducing BP in hypertension
• Classification of high BP
• When to start antihypertensive treatment
• How to treat
• What the BP target acheived
 Current Antihypertensive Therapy Reduces CV
Events
Major CV
Stroke Events CV Death
0
Average Reduction in Events, %

–20
20%–30%
–40 30%–40% 30%–40%

–60
Can we do better?
–80

–100

CV=cardiovascular.
Neal B et al. Lancet. 2000;356:1955–1964.
BP Differences of 10 mmHg Are Associated With Up to a
40% Effect on CV Risk

• Meta-analysis of 61 prospective, observational studies

• 1 million adults
• 12.7 million person-years
30% reduction in
risk of IHD
10 mmHg mortality
decrease in
mean SBP 40% reduction in
risk of stroke
mortality
Lewington S et al. Lancet. 2002;360:1903–1913.
 Importance of Lowering BP
(Data from Multiple Clinical Trials Measuring the Impact of Hypertensive Therapy
on Cardiovascular Mortality)
Cardiovascular Mortality
actively controlled trials.
1.50 MIDAS/NICS/VHAS
placebo-controlled studies or
UKPDS C vs A P=0.002
Odds Ratio (experimental/reference)

trials with an untreated control

1.25 group.
NORDIL INSIGHT
HOT L vs H
STOP2/ACEIs
Negative values indicate tighter
HOT M vs H MRC1 BP control on reference
1.00
MRC2
STOP2/CCBs treatment.
SHEP HEP
0.75 CAPPP STONE Syst-Eur EWPHE
HOPE
UKPDS L vs H
Syst-China RCT70-80
0.50
PART2/SCAT STOP1
ATMH
0.25

–5 0 5 10 15 20 25
Difference (reference treatment minus experimental treatment) in Systolic BP (mmHg)

Greater differences in BP reduction mean greater reductions in the risk of cardiovascular mortality.
BP, blood pressure
Staessen JA et al. Hypertension Research. 2005;28:385-407.
 Scope to be discussed
• Burden of illness high blood pressure
• Impact of reducing BP in hypertension
• Classification of high BP
• When to start antihypertensive treatment
• How to treat
• What the BP target acheived
Definition and Classification of Hypertension
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
Classification of HT ACC/AHA 2017
 Scope to be discussed
• Burden of illness high blood pressure
• Impact of reducing BP in hypertension
• Classification of high BP
• When to start antihypertensive treatment
• How to treat
• What the BP target acheived
Treatment guidelines

– Initiating antihypertensive treatment

• ESH/ESC 2003
• JNC VII
• WHO/ISH 1999
– Goals of antihypertensive treatment
• ESH/ESC 2003
• JNC VII
• WHO/ISH 2003
– Treatment strategy
• ESH/ESC 2003
• JNC VII
• WHO/ISH 2003
• British Hypertension Society (BHS)
 Treatment initiation: ESH/ESC 2003
Blood pressure
Other risk factors Normal High normal Grade 1 Grade 2 Grade 3
and disease
history
No other risk No BP No BP Lifestyle changes Lifestyle changes Immediate drug
factors intervention intervention for several for several treatment and
months, then months, then lifestyle changes
drug treatment if drug treatment
preferred by the
patient and
resources
available
1-2 risk factors Lifestyle Lifestyle Lifestyle changes Lifestyle changes Immediate drug
changes changes for several for several treatment and
months, then months, then lifestyle changes
drug treatment drug treatment

3 or more risk Lifestyle Drug treatment Drug treatment Drug treatment Immediate drug
factors, target changes and lifestyle and lifestyle and lifestyle treatment and
changes changes changes lifestyle changes
organ damage, or
diabetes
Associated clinical Drug treatment Immediate drug Immediate drug Immediate drug Immediate drug
conditions and lifestyle treatment and treatment and treatment and treatment and
changes lifestyle lifestyle changes lifestyle changes lifestyle changes
changes

ESH/ESC Guidelines 2003. J Hypertens 2003;21:1011-1053

 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
 JNC-8 Recommendations
• In patients >60 years of age, start medications at
blood pressure of >150/90mm Hg and treat to
goal of <150/90mm Hg

• In patients >60 years of age, treatment does not

need to be adjusted if achieved blood pressure is
lower than goal and well-tolerated

James PA et al. JAMA 2014;311:507-20.

 JNC-8 Recommendations
• In patients <60 years of age, start medications at
blood pressure of >140/90mm Hg and treat to
goal of <140/90mm Hg

• In all adult patients with diabetes or chronic

kidney disease, start medications at blood
pressure of >140/90mm Hg and treat to goal of
<140/90mm Hg

James PA et al. JAMA 2014;311:507-20.

 Ambang Batas TD untuk Inisiasi Obat

Konsensus InaSH 219

 Alur Panduan Inisiasi Terapi Obat Sesuai dengan
Klasifikasi Hipertensi

Konsensus InaSH 219

 Scope to be discussed
• Burden of illness high blood pressure
• Impact of reducing BP in hypertension
• Classification of high BP
• When to start antihypertensive treatment
• What the BP target acheived
• How to treat
Treatment guidelines

– Initiating antihypertensive treatment

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

• 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 diabetics, target blood pressure is
<130/80 mmHg

ESH/ESC Guidelines 2003. J Hypertens 2003;21:1011-1053

 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
 Scope to be discussed
• Burden of illness high blood pressure
• Impact of reducing BP in hypertension
• Classification of high BP
• When to start antihypertensive treatment
• What the BP target acheived
• How to treat
Treatment guidelines

– Initiating antihypertensive treatment

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

Consider:
Untreated BP level
Presence or absence of TOD and risk factors
Choose between:

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; TOD, target organ damage ESH/ESC Guidelines 2003. J Hypertens 2003;21:1011-1053
 Choice of antihypertensive therapy:
ESH/ESC 2003

• 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, and cost and risk
profile
• Long-acting drugs that provide once-daily, 24-hour
efficacy are preferable

BP, blood pressure ESH/ESC Guidelines 2003. J Hypertens 2003;21:1011-1053

 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 mmHg) Drug(s) for the
90-99 mmHg) Two-drug combination for compelling indications
Thiazide-type diuretics most (usually thiazide-type
for most. May consider diuretic and ACE-I or Other antihypertensive
ACE-I, ARB, BB, CCB ARB, or BB, or CCB) Drugs (diuretics, ACE-I,
or combination 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
Algorithm of HT Treatment (ACC/AHA)
 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
Younger (eg <55 years) Older (eg 55 years)
and non-black or black

Step 1 A or B C or D

Step 2 A (or B) + C or D

Step 3
A + C + D

Step 4
Resistant Add: either alpha-blocker or spironolactone or other diuretic
hypertension

A: ACE inhibitor or ARB B: Beta-blocker

C: Calcium-channel blocker D: Diuretic (thiazide)

BHS, British Hypertension Society; ACE, angiotensin-converting enzyme;

ARB, angiotensin II receptor blocker Brown MJ, et al. J Hum Hypertens 2003;17:81-86
Section 6: Evolution of Antihypertensive Drugs
 Evolution of antihypertensive drugs

– History of antihypertensive drugs

– Mechanism of action of
antihypertensives
– The RAAS system
• Mechanism of action of ACE inhibitors
• Mechanism of action of ARBs
– Chemical structures of ARBs
• Chemical structure of Olmesartan
RAAS, renin-angiotensin-aldosterone system;
ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker
 Combination Therapy in Guidelines:
Where do we stand?

 2009 European Guidelines

 New 2011 British Guidelines:

First draft released :
HCTZ not anymore endorsed
Chlorthalidone or Indapamide +++++

 American Guidelines : Awaited JNC VIII

“2007 Guidelines for the management of hypertension” J Hypertens. 2007;25:1105–1187.J Hypertens. 2009;27:2121-2158.
 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 2
Ganglion agonists Calcium
blockers antagonists-
Calcium
Veratrum antagonists- DHPs
alkaloids non-DHPs
Beta-
blockers
DHP, dihydropyridine;
ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker
 Multiple antihypertensive agents
are needed to achieve target BP
Number of antihypertensive agents
Trial Target BP (mmHg) 1 2 3 4

UKPDS DBP <85

ABCD DBP <75
MDRD MAP <92
HOT DBP <80
AASK MAP <92
IDNT SBP <135/DBP <85
ALLHAT SBP <140/DBP <90

Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;

DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, Lewis EJ, et al. N Engl J Med 2001;345:851-860;
systolic blood pressure Cushman WC, et al. J Clin Hypertens 2002;4:393-404
 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
 Comparisons to Other Guidelines
BP Goal JNC-7 JNC-8 ASH/ISH ESC/ESH CHEP

Age < 60 <140/90 <140/90 <140/90 <140/90 <140/90

Age 60-79 <140/90 <150/90 <140/90 <140/90 <140/90

Age 80+ <140/90 <150/90 <150/90 <150/90 <150/90

Diabetes <130/80 <140/90 <140/90 <140/85 <130/80

CKD <130/80 <140/90 <140/90 <130/90† <140/90

†Consider with overt proteinuria – otherwise consider goal BP<140/90

Adapted from Salvo M et al. Ann Pharmacother 2014;48:1242-8.
Target Tekanan Darah di Klinik
 JNC-8 Recommendations
• Initiate therapy according to recommendations
• If BP is not at goal in one month, increase dose or
add a second agent from recommended classes
• If patient is still not at goal, add a third drug from
recommended classes
– Do not use an ACEI and ARB together
• Drugs from other classes may be used if additional
BP lowering is needed or if contraindications exist
• Refer to HTN specialist whenever necessary

James PA et al. JAMA 2014;311:507-20.

 Comparisons to Other Guidelines
JNC-7 JNC-8 ASH/ISH ESC/ESH CHEP

Non-black Thiazide Thiazide, <60:ACEI,AR Thiazide, Thiazide,

(no DM or ACEI, ARB, B ACEI, ARB, ACEI, ARB
CKD) CCB >60:CCB, CCB, BB (BB if <60)
thiazide
Black (no Thiazide Thiazide, Thiazide, Thiazide, Thiazide,
DM or CKD) CCB CCB ACEI, ARB, ARB (BB if
CCB, BB <60)

Diabetes ACEI, ARB, CCB, ACEI, ARB, ACEI, ARB ACEI, ARB,
CCB, BB, thiazide CCB, CCB,
thiazide thiazide thiazide

CKD ACEI, ARB ACEI, ARB ACEI, ARB ACEI, ARB ACEI, ARB
Adapted from Salvo M et al. Ann Pharmacother 2014;48:1242-8.
 Strategi Penatalaksanaan Hipertensi Tanpa Komplikasi

Konsensus InaSH 219

 Strategi Pengobatan Hipertensi dan
Penyakit Arteri Koroner

Konsensus InaSH 219

 Strategi Pengobatan Hipertensi dan
Penyakit Arteri Koroner

Konsensus InaSH 219

 Strategi Pengobatan pada Hipertensi dan PGK

Konsensus InaSH 219