Nama : Prof. Dr. dr H. Djanggan Sargowo SpPD,SpJP(K), FIHA, FACC, FCAPC, FESC, FASCC
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:
0 5 10 15 20
Percentage of Mortality Attributable to Risk Factors
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)
JNC VI 1997
WHO / ISH 1999
BHS 1999
9
STRATIFICATION OF RISK
TO EQUALITY PROGNOSIS
Blood Pressure ( mmHg)
II. 1-2 Risk factors MED RISK MED RISK HIGH RISK
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)
60
40
20
0
England Sweden Germany Spain Italy
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
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
28
RESULTS OF HYPERTENSION TREATMENT
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
CCB or thiazide-
Step 1 ACEI (or ARB*)
type diuretic
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
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
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
- 1.1 - 1.9
67
- 9.0
- 9.8 - 9.9
- 11.8
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
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
0 1 2 3 4
Number of Agents
Fixed-dose combination
(amlodipine/benazepril) 87,9*
(n=2,839)
0 20 40 60 80 100
Hypertension =
Peripheral vasoconstriction in peripheral vascular resistance =
effective BP lowering with combination
therapy
CCBs
ARBs
Aldosterone Ang II
levels levels
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
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
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
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
10%
4.0
Atenolol thiazide
(No. of events 444)
3.0
Amlodipine perindopril
(No. of events 390)
2.0
3.0
Amlodipine perindopril
(No. of events 327)
2.0
12.0
Amlodipine perindopril
10.0
(No. of events 1362)
8.0
6.0
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
6.0
Amlodipine perindopril
4.0 (No. of events 738)
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
Whats the main reason for fatal
motorbike accidents in Jamaika?
77
78
Did you see it?
79
80
Did you see it?
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
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)
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.
Not at Goal
Blood Pressure
92
TOD = target organ damage
ESHESC Guidelines. J Hypertens 2003;21:177986
Definitions & classification of BP levels (mmHg)
(2007 ESC/ESH guidelines)