pengobatan hipertensi dgn arb
TRANSCRIPT
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PENGOBATAN HIPERTENSIDENGAN ARB
Prof. Dr. WH Sibuea, Sp.PD
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BLOOD PRESSURE (mmHg)
DiastolicSystolicCATEGORY
DEFINITION AND CLASIFICATION OF BLOOD PRESSURE LEVELTHE 7th REPORT OF THE JOINT NATIONAL COMMITTEE
ON PREVENTION, DETECTION, EVALUATION, AND TREATMENT OF HIGH BLOOD PRESSURE
(2003)
Normal 100
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Classification of hypertension
according to aetiologyPrimary (essential) hypertension
Secondary hypertensionRenal hypertension Renoparenchymal hypertension; renovascular hypertension;
post-kidney transplant hypertension
Endocrine hypertension Pheochromocytoma; primary hyperaldosteronism (Conns
syndrome); deoxycorticosterone-producing tumours;
adrenogenital syndrome; Cushing's syndrome; primary
hyperrenism; acromegaly; hyperparathyroidism; endothelin-
producing tumours; hypo- and hyperthyroidism
Pregnancy-specific (Pre-) eclampsia; transient hypertension
hypertension
Cardiovascular hypertension Coarctation of the aorta; hyperkinetic heart syndrome;
aortic valve insufficiency; sclerosis of the aorta; severe
bradycardia; arteriovenous fistulae
Drug-/alimentation-induced Oral contraceptives; high-dose mineralcorticoids or
hypertension glucocorticoids; erythropoietin; cyclosporine; alcohol
licorice
Neurogenic hypertension Sleep apnoea syndrome; neurological disorders
Stimpel. Arterial Hypertension, 1996; Walter de Gruyter Berlin, New York.
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AUTOREGULATION
BLOOD PRESURE = CARDIAC OUTPUT
HYPERTENSION = INCREASED CO
PERIPHERAL RESISTANCE
INCREASED PR
Preload ContractilityFunction
constrictionStructural
hypertrophy
Fluid Volume Venous
Contractility
Renal
sodium
retention
Decreasedfibration
suface
Sympathetic
nervous system
over activity
Renin
angiotensin
excess
Cell
membrane
alteration
Hyper
Insullinemia
Excess
sodium
intakeGenetic
alteration
Stress Obesity
Endothelium
derrived
factors
X
AND / OR
Genetic
alteration
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Risk factors for the development
of hypertension
Hyperlipidaemia
Black race
Geneticpredisposition
Diabetes
mellitus
Lack of
exercise
Alcohol
Distress (?)
Obesity
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Pada pasien normotensif terdapat variasitekanan darah di urnal.
Pada malam hari tekanan darah turun 10 -20%
Tekanan darah dipengaruhi oleh saraf simpatis
dan sistim renin-angiotensin -aldosteron.
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J Clin Endocrinol Metab 1985;60:1210-1215
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Horm Metab Res 1990;22:636-639
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0
2
4
6
8
10
Blood Pressure & Risk of Stroke
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Effect of SBP and DBP on
Age-Adjusted CAD Mortality: MRFIT
CAD Death Rate per 10,000 Person-Years
100+ 90-99 80-89 75-79 70-74
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Target Organ Damage caused by
Hypertension
Jantung
LVH PJK
Angina pektoris Gagal Jantung
Otak
Stroke, TIA
Demensia
Penyakit Ginjal Kronik (CKD)
Penyakit Arteri perifer
Retinopati
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Hypertension & Risk for ESRD
Compared with BP < 120/80 mmHg,
the adjusted relative risksfordeveloping ESRDin subject without baseline renal disease:
Hsu CY, et al. Arch Intern Med. 2005; 165:923-928.
RR CI BP
1,62 95% CI (1,27 - 2,07) 120-129 / 80- 84
1,98 95% CI (1,55 2,52) 130-139 / 85-89
2,59 95% CI (2,07-3,25) 140-159 / 90-99
3,86 95% CI (3,00 4,96) 160-179 / 100-109
3,88 95% CI (2,82- 5,34) 180-209 / 110-119
4,25 95% CI (2,63-6,86) 210 / 120
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Diastolic BP (mm Hg)
76 84 91 98 105
4.0
3.0
2.0
1.0
Stroke
Risk ratio
Diastolic BP (mm Hg)
76 84 91 98 105
4.0
3.0
2.0
1.0
Myocardial Infarction
Risk Ratio
MacMahon S. J Hypertens. 1990;8(suppl):239-244.
Blood Pressure, Stroke, & CAD
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Hypertension and the risk of
further disease
Disease Relative risk(hypertensives versus normotensives)
Coronary artery disease 2- to 3-fold
Stroke 7-fold
Heart failure 2- to 3-fold
Peripheral vascular disease 2- to 3-fold
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Achieved SBPmm Hg
Risk of a major cardiovascular event reduced
by 22% in the HOT Study
0
5
10
15
20
25
30
170 160 150 140 130
% risk reduction
Optimal SBPreduction in theHOT Study
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Achieved DBPmm Hg
Risk of a major cardiovascular event reduced
by 30% in the HOT Study
0
5
10
15
20
25
30
105 100 95 90 85 80
% risk reduction
Optimal DBPreduction in theHOT Study
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Management of Hypertension
Assess the risk
Treat to target
Lifestyle
Combination therapy
Compliance
Important messages
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Reduce CVD and renal morbidity andmortality.
Treat to BP
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History of antihypertensive drugs
Direct
vasodilators
Alpha-
blockers
Peripheral
sympatholytics
Ganglion
blockers
Veratrum
alkaloids
Central 2agonists
Calcium
antagonists-
non-DHPs
Beta-
blockers
Thiazide
diuretics
Calcium
antagonists-
DHPs
ARBs
1940s 1950 1957 1960s 1970s 1980s 1990s 2000
ACE
inhibitors
DHP, dihydropyridine;ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker
Effectiveness and general tolerability
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Treatment Algorithm for Adults with Systolic-Diastolic
Hypertension withoutanother compelling indication
TARGET
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Hypertension
Without
Compelling indication
Stage 1 Hypertension
Syst. 140 159 OR
Diast. 80 90 mmHg
Thiazide type diuretics
for mostMay consider ACE inh,
ARB, CCB, Betablocker
Or Combination
Stage 2 Hypertension
Syst. > 160 mmHg OR
Diast > 100 mmHg
2 Drug Combination
for mostUsualy thiazide type with
ACE inh. orARB or Beta
Blocker or CCB
JNC VII2003
JAMA. 2003;289
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Possible Combination of Difference Classes of Antihypertensive Agents2003 European Society of Hypertension-European Society of Cardiology
Guidelines for management of arterial hypertension
Calcium
antagonists
AT1-receptors
blockers-blockers
-blockers
Diuretics
ACE inhibitorsThe most rational combinations
Classes of antihypertensive
agents proven to be beneficial
in controlled interventional trial
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Anti-hypertensive effects of
ARBs RAA cascade, ACEIs & ARBs
Various ARBs
Valsartan Antihypertensive Long-
Term Use Evaluation (VALUE)
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Classical "circulating" system (RAAS):
Renin-Angiotensin Systems (I)
Angiotensin II
Angiotensin I
Angiotensinogen
Aldosterone
Na+-retentionK+-loss
glomerular zone
ACE
Renin
Blood pressure
Na+
Sympathetic system
Renin
maculadensa
adrenalglands
adapt. from Dominiak & Unger (eds.) in Ang II-AT1-Receptor Antagonists, Steinkopff (1997)
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t-PA = tissue plasminogen activatoCAGE = chymostatin-sensitiveangiotensin generating enzyme
Local "tissue-bound" system (RAS):
Renin-Angiotensin Systems (II)
AT1 AT2
Bradykinin
inactive fragments
B2B1
Angiotensin II
Angiotensin I
Angiotensinogen
ACE
Renin
specific cellular response
ChymasesCathepsin G
CAGE
t-PACathepsin GTonin
specific cellular response
adapt. from Dominiak & Unger (eds.) in Ang II-AT1-Receptor Antagonists, Steinkopff (1997)
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Distribution ofACE:
Renin-Angiotensin Systems (III)
mod. from Dzau V, Arch Intern Med 153 (1993)
R A S
circulating (plasma) local (tissue)
10 % 90 %
Acute and short-term effectscardiovascular/
renal homeostasis
Long-term effectslocal "organ adaptation"
renal-independent activation
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Angiotensin II generating systems/organs:
Local Renin-Angiotensin-Systems
Tissue/Compartment
HeartBrain
KidneyBlood vessels
atherosclerotic plaquesTestisUterus
Nebenniere
Cell systems (e.g.)
MyocytesNeurons
Mesangium,TubuleEndothelium
Macrophages?Smooth muscle?Glomerulosa cells
mod. from Dzau V, Arch Intern Med 153 (1993)
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GFR
Proteinuria
Aldosterone releaseGlomerular sclerosis
Angiotensin II plays a central role
in organ damage
A II AT1
receptor
Atherosclerosis*
Vasoconstriction
Vascular hypertrophy
Endothelial
LV hypertrophy
Fibrosis
Remodeling
Apoptosis
Stroke
DEATH
*preclinical dataLV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate
Hypertension
Heart failure
MI
Renal failure
dysfunction
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Effects of Angiotensin II at AT1 and AT2Receptors
Blocked by ARBs
AT2AT1
- Vasoconstriction
- Aldosterone release
- Oxidative stress
- Vasopressin release
- SNS activation- Inhibits renin release
- Renal Na+ and H2O reabsorption
- Cell growth and proliferation
- Vasodilation
- Antiproliferation
- Apoptosis
- Antidiuresis/antinatriuresis
- Bradykinin production- NO release
Siragy H.Am J Cardiol. 1999;84:3S8S.
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AngiotensinII
Abnormalvasoconstriction
Activate SNS
AldosteroneVasopressin
Collagen
ContractilityPAI-1/
thrombosis
Plateletaggregation
Superoxideproduction
EndothelinVascular smooth
muscle growth
Myocyte growth
Burnier M, Brunner HR. Lancet. 2000;355:637645.
Pathophysiologic Effects of Angiotensin II
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Actions of Angiotensin II via AT1
Receptor Stimulation
Sistemic (endocrine) effects of circulating angiotensin II-vasoconstictive (preferentially coronary, renal, cerebral)
- Steroidogenic (aldosterone)
- Dipsogenic (CNS effect)
- Renin-supressing (negative feedback)
Tissue-specific effects of angiotensin II as local hormone-Tropic/mitogenic (cardiac and vascular myocytes)
-Inotropic/contractile (cardiomyocytes)
-Chronotropic/arrhythmogenic (cardiomyocytes)
-Thrombogenic (plasminogen actifator inhibitor)
-Oxidative (generation of reactive oxygen species)
-Ion transport channels (myocytes, renal cells)
-Neuroexciation (sympathetic nerve terminals)
-Endothelin stimulation (endothelial cells)
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Various ARBs
Losartan = Cozaar (MSD)
Valsartan = Diovan (Novartis)
Candesartan = Blopress (Takeda)
Irbesartan = Aprovel (Sanofi)
Telmisartan = Micardis (Boehringer Ingelheim)
Eprosartan not available in Indonesia
Olmesartan = Olmetec (Pfizer)
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Comparisons of ARB-Based
Regimens With Control Regimens
BP Lowering Treatment Trialists Collaboration. Lancet. 2003;362:1527-1535.
0.5 1.0 2.0FavoursControl
FavoursARB
Relative Risk
Stroke
CHD
Heartfailure
Major CVevents
CV death
Totalmortality
4
4
3
4
4
4
Relative Risk(95% CI)
0.79 (0.690.90)
0.96 (0.851.09)
0.84 (0.720.97)
0.90 (0.830.96)
0.96 (0.851.08)
0.94 (0.861.02)
396/8412
435/8412
302/5935
1135/8412
491/8412
887/8412
500/8379
450/8379
359/5919
1268/8379
511/8379
943/8379
Diff. in BP(mean,mmHg)
2 / 1
2 / 1
2 / 1
2 / 1
2 / 1
2 / 1
P
0.46
0.43
0.26
0.78
0.34
0.59
Events/ParticipantsTrials
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VALUE
Valsartan Antihypertensive
Long-Term Use Evaluation
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VALUE: Significance
First trial to compare ARB valsartan, themost to calcium channel blocker,
amlodipine
Designed to evaluate effectiveness of a
valsartan-based regimen vs an
amlodipine-based regimen on overallcardiac outcomes
Mann J, Julius S. Blood Press. 1998;7:176183.
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VALUE: Rationale for Endpoints
Strokes seem to be mostly BP dependent,
whereas coronary and other cardiac events
might be related, to excess of angiotensin II
Consequently, composite cardiac events
were designated as primary endpoints and
stroke was classified as a secondaryendpoint
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In hypertensive patients at high cardiovascular
risk, for the same level of blood pressure
control, valsartan will be more effective than
amlodipine in reducing cardiac morbidity and
mortality
VALUE: Primary Hypothesis
Julius S et al. Lancet. June 2004;363:202231.
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VALUE: Primary Endpoint
Composite cardiac morbidity and mortality sudden cardiac death
fatal/nonfatal MI
evidence of recent MI on autopsy
emergency thrombolytic/fibrinolytic treatment and/or
emergency PTCA/CABG to avoid MI
death during/after PTCA/CABG
new or chronic CHF requiring hospital management
heart failure death
Mann J, Julius S. Blood Press. 1998;7:176183.
VALUE S d E d i t d
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VALUE: Secondary Endpoints and
Pre-specified Analyses
Secondary Endpoints:
fatal/non-fatal myocardial infarction
fatal/non-fatal stroke fatal/non-fatal heart failure
Pre-specified Analyses:
all-cause mortality
new-onset diabetes
Julius S et al. Lancet. June 2004;363:202231.
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VALUE: DesignElective titration to target BP (
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VALUE: Number of Antihypertensive Medications
Taken Before Randomisation
Data on file. Novartis Pharmaceuticals.
Valsartan (n = 7649)Amlodipine (n = 7596)
%ofPatients
3 or MoreMedications
2Medications
1Medication
None0
10
20
30
40
50
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VALUE: Blood Pressure Changes FromBaseline to the End of the Study
Valsartan-Based Therapy
Amlodipine-Based Therapy
SBPDBP
20
15
10
5
0
mmHg
Julius S et al. Lancet. June 2004;363:202231.
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BeforeRandomisation Study End
Valsartan-BasedRegimen
Amlodipine-BasedRegimen
VALUE: Trends in SBP Control(
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VALUE: Systolic Blood Pressure in Study
Julius S et al. Lancet 2004;363:202231.
Valsartan(N= 7649)
Amlodipine(N = 7596)
135
140
145
150
155
mmHg
Months (or final visit)
Sitting SBP by Time and Treatment Group
Baseline 1 24 482 3 4 6 12 18 30 36 42 54 60 66
0
1.02.0
3.0
4.0
1 24 48
mmH
g
2 3 4 6 12 18 30 36 42 54 60 66
Months (or final visit)
5.0Difference in SBP Between Valsartan and Amlodipine
1.0
4.0(p
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VALUE: Diastolic Blood Pressure in Study
Valsartan
(N= 7649)
Amlodipine
(N = 7596)
mmHg
Months (or final visit)
Sitting DBP by Time and Treatment Group
mm
Hg
Baseline 1 24 482 3 4 6 12 18 30 36 42 54 60 66
75
85
80
90
0
1.02.0
1 24 482 3 4 6 12 18 30 36 42 54 60 66
Months(or final visit)
3.0
Difference in DBP Between Valsartan and Amlodipine
1.0
4.0
5.0
Julius S et al. Lancet 2004;363:202231.
2.1(p
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VALUE:
Primary Endpoint Results
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VALUE: Primary CompositeCardiac Endpoint
14
12
10
8
64
2
0
Time (months)
0 6 12 18 24 30 36 42 48 54 60 66
ProportionofPatients
WithFir
stEvent(%) Valsartan-based regimenAmlodipine-based regimen
HR = 1.03; 95% CI = 0.941.14; P= 0.49
Julius S et al. Lancet. June 2004;363:202231.
Number at risk
Valsartan
Amlodipine 7596
7649
7469
7459
7424
7407
7267
7250
7117
7085
6772
6732
6955
6906
6576
6536
5959
5911
3725
3765
1474
1474
6391
6349
O d S iff
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VALUE: Outcome and SBP Differences atSpecific Time Periods: Primary Endpoint
Time Interval(months)
Overall study
3648
2436
1224612
03
48end
Favours amlodipine
1.0 2.00.5
PRIMARY ENDPOINTOdds Ratios and 95% CIs
DSBPmmHg
1.4
1.6
1.82.0
3.8
1.7
2.2
36 2.3
Favours valsartan
4.0
Julius S et al. Lancet. June 2004;363:202231.
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VALUE:
Total Mortality Result
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VALUE: All-cause Death
Number at risk
Valsartan
Amlodipine 7596
7649
7520
7527
7484
7496
7385
7383
7276
7267
7025
6994
7155
7136
6874
6843
6312
6273
3961
3981
1582
1563
6729
6682
Time (months)0 6 12 18 24 30 36 42 48 54 60 66
ProportionofPatients
WithFirstEvent(%)
16
14
12
10
8
6
4
2
0
Valsartan-based regimen
Amlodipine-based regimen
HR = 1.04; 95% CI = 0.94-1.14; P= 0.45
Julius S et al. Lancet. June 2004;363:202231.
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VALUE:
Secondary Endpoint Results
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VALUE: Fatal and Non-fatal Stroke
Julius S et al. Lancet. June 2004;363:202231.
Number at risk
Valsartan
Amlodipine 7596
7649
7499
7494
7455
7448
7334
7312
7195
7170
6918
6877
7055
7022
6744
6692
6163
6093
3846
3859
1532
1516
6587
6515
6
5
4
3
2
1
0
Time (months)0 6 12 18 24 30 36 42 48 54 60 66
Proportio
nofPatients
WithFirstEvent(%)
Valsartan-based regimen
Amlodipine-based regimen
HR = 1.15; 95% CI = 0.981.35; P= 0.08
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VALUE: Outcome and SBP Differencesat Specific Time Periods: Stroke
Julius S et al. Lancet. June 2004;363:202231.
Odds Ratios and 95% CIs
Favours valsartan Favours amlodipine
1.0 2.00.5
Time Interval(months)
Overall study
3648
2436
1224
612
03
48end
D SBP(mmHg)
1.4
1.6
1.8
2.0
3.8
1.7
2.2
36 2.3
0.25 4.0
STROKE
VALUE: Fatal and Non Fatal
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Time (months)Number at risk
Valsartan
Amlodipine 7596
7649
7497
7499
7458
7458
7332
7319
7205
7177
6905
6853
7065
7016
6727
6680
6141
6078
3840
3864
1532
1520
6562
6504
ProportionofPatients
WithFirstEvent(%)
7
6
5
4
3
2
1
0
VALUE: Fatal and Non-FatalMyocardial Infarction
0 6 12 18 24 30 36 42 48 54 60 66
Valsartan-based regimenAmlodipine-based regimen
HR = 1.19; 95% CI = 1.02-1.38; P= 0.02
Julius S et al. Lancet. June 2004;363:202231.
VALUE O t d SBP Diff
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VALUE: Outcome and SBP Differencesat Specific Time Periods: Myocardial Infarction
Julius S et al. Lancet. June 2004;363:202231.
Time Interval(months)
Overall study
48end
1.0 2.00.5
Myocardial InfarctionOdds Ratios and 95% CIs
DSBP(mmHg)
1.4
1.6
1.8
2.0
3.8
1.7
2.2
2.3
4.00.25
3648
2436
1224
612
03
36
Favours amlodipineFavours valsartan
VALUE: Hazard Ratios for Fatal and
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VALUE: Hazard Ratios for Fatal and
Non-fatal Myocardial Infarction
Julius S et al. Lancet. June 2004;363:202231.
Favours valsartan Favours amlodipine
Hazard RatioValsartan/Amlodipine
Fatal and non-fatal
Fatal
Non-fatal
0.5 1 2
Myocardial Infarction
VALUE: Heart Failure
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Number at risk
Valsartan
Amlodipine 7596
7649
7486
7485
7444
7444
7312
7312
7176
7169
6874
6852
7033
7012
6702
6671
6100
6072
3823
3860
1511
1513
6534
6498
VALUE: Heart Failure
Time (months)0 6 12 18 24 30 36 42 48 54 60 66
9
87
6
5
4
3
2
1
0
Valsartan-based regimen
Amlodipine-based regimen
HR = 0.89; 95% CI = 0.77-1.03; P= 0.12Proportion
ofPatients
WithFirstEvent(%)
Julius S et al. Lancet. June 2004;363:202231.
Hospitalisation for HF or death from HF
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VALUE: Outcome and SBP Differencesat Specific Time Periods: Heart Failure
Time interval(months)
Overall study
48end
1.0 2.00.5
Heart FailureOdds Ratios and 95% CIs
D SBP(mmHg)
1.4
1.6
1.8
2.0
3.8
1.7
2.2
2.3
0.25 4.0
3648
2436
1224
612
03
36
Favours amlodipineFavours valsartan
Julius S et al. Lancet. June 2004;363:202231.
Heart Failure: Hospitalisation for HF or death from HF.
VALUE I id f N t Di b t
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62/75
VALUE: Incidence of New-onset Diabetes
New-OnsetDiabetes
(%ofpa
tientsin
treatmen
tgroup)
Julius S et al. Lancet. June 2004;363:202231.
0
2
4
6
8
10
12
14
Valsartan-basedRegimen
(n = 5254)
Amlodipine-basedRegimen
(n = 5168)
13.1%
16.4%
23% Risk ReductionWith Valsartan
16
18
P< 0.0001
CV Events in Treated
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63/75
100
90
80
70
60
50
40
30
Probab
ilityof
Event-FreeS
urvival(%)
Time to Event (years)
0 3 6 9 12 15
Hypertensive Diabetic Patients
Verdecchia P et al. Hypertension. 2004;43:963969.
No diabetes
New-onsetdiabetes
Previouslyknowndiabetes
Patients with new or prior diabetes were 3-times more likely to have a CVevent than those without diabetes.
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64/75
VALUE: Incidence of Endpoints
*Fatal and non-fatal.
Julius S et al. Lancet. June 2004;363:202231.
Valsartan (n = 7649)Amlodipine (n = 7596)
%ofPa
tients
MyocardialInfarction*
CardiacMorbidity
CardiacMortality
PrimaryComposite
0
10
20
30
HeartFailure*
Stroke* All-causeDeath
New-onsetDiabetes
P= 0.49
P= 0.90
P= 0.71
P= 0.02 P= 0.12 P= 0.08
P= 0.45
P< 0.0001
VALUE: Hazard Ratios
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65/75
Favours valsartan Favours amlodipine
Hazard Ratio
Valsartan/Amlodipine
Primary cardiac composite endpoint
cardiac mortality
cardiac morbidity
All myocardial infarction
All congestive heart failure
All stroke
All-cause death
New-onset diabetes
0.5 1 2
VALUE: Hazard Ratiosfor Pre-specified Analyses
Julius S et al. Lancet. June 2004;363:202231.
i l
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66/75
VALUE: Main Results
BP decrease in the amlodipine group
was more pronounced, particularly
early in the trial
Despite BP differences, the primary
composite cardiac endpoint in both
groups was not different
Julius S et al. Lancet. June 2004;363:202231.
VALUE: Other Results
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67/75
VALUE: Other Results
Total mortality was not different
Incidence of stroke was lower in theamlodipine group
Incidence of non-fatal MI was significantly
lower in the amlodipine group
There was a positive trend in favour ofvalsartan for less heart failure
There was a lower rate of new-onset diabetesin the valsartan group
Julius S et al. Lancet. June 2004;363:202231.
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68/75
The observed difference in stroke ratesappears to be strongly related todifferences in achieved BPs
The benefits of valsartan in heart failureprevention emerged later in the study whenBP differences were smaller, indicating thatthere is a potential beneficial effect of
valsartan beyond BP control
VALUE: Interpretations
Julius S et al. Lancet. June 2004;363:202231.
VALUE: Conclusions
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69/75
Prompt blood pressure control inhypertensive patients at highcardiovascular risk is very important
The between-group differences in heartfailure and diabetes suggest that
valsartan may offer benefits beyond BPcontrol
VALUE: Conclusions
Julius S et al. Lancet. June 2004;363:202231.
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70/75
VALUE: Analysis of ResultsBased on Serial Median Matching
Rationale:
Differences in achieved BP levels in VALUE
precluded valid comparisons of drug effects onoutcomes. Therefore, a statistical technique thatadjusts for BP differences was applied post hoc tocreate treatment cohorts with closely similarcharacteristics
Weber MA et al. Lancet. 2004;363:2047
49.
VALUE: Analysis of Results
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71/75
VALUE: Analysis of ResultsBased on Serial Median Matching
Description:
The novel computerised procedure of Serial Median Matchingwas applied at 6 months, following the treatment adjustmentsintended to achieve BP control.
The programme selected the most median patient (by achievedsystolic BP) in the valsartan group; this patient was paired withone from the amlodipine group ( 2 mmHg) and was matchedalso for age, sex and the presence or absence of prior coronarydisease, stroke and diabetes.
The newly created patient pair was moved to a new database,and the procedure repeated serially until all possible patientpairs were matched.
Weber MA et al. Lancet. 2004;363:2047
49.
VALUE: Major Study Endpoints in 5006 Patient
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72/75
Composite cardiac events
Stroke
Death
Myocardial infarction
Heart failure
0.6 0.8 1.0 1.2 1.4
Favours valsartan Favours amlodipine
Pairs (N = 10,012) on Valsartan- or Amlodipine-
Based Therapies Using Serial Median Matching
Hazard Ratio(95% CI)
P
0.90 (0.791.03) 0.111
1.02 (0.811.28) 0.899
0.96 (0.841.10) 0.566
0.97 (0.801.19) 0.791
0.81 (0.660.99)* 0.040
*P< 0.05.
Weber MA et al. Lancet. 2004;363:204749.
VALUE A l i f R lt
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73/75
VALUE: Analysis of ResultsBased on Serial Median Matching
Serial median matching created valsartan-amlodipine patient pairs matched exactly forsystolic BP and demographic and clinical
characteristics excluding the high and lowextremes of achieved BPs.
It allowed us to address the original studyhypothesis, and demonstrated that for the same
achieved BPs, valsartan in an intermediate dosehad effects similar to amlodipine on most CVendpoints, and was more effective in reducingheart failure hospitalisations.
Conclusions:
Weber MA et al. Lancet. 2004;363:2047
49.
l f l
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74/75
VALUE: Analyses of ResultsBased on BP Control
Blood pressure control, and rapidity of response,are critical for reducing events in high-risk
hypertension
The significant between-group differences in heartfailure and diabetes suggest that valsartan mayoffer benefits beyond BP control
Overall Conclusions:
Weber MA et al. Lancet. 2004;363:2047
49.
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75/75
terimakasih