PENGOBATAN HIPERTENSI DENGAN ARB

Prof. Dr. WH Sibuea, Sp.PD

DEFINITION AND CLASIFICATION OF BLOOD PRESSURE LEVEL

THE 7th REPORT OF THE JOINT NATIONAL COMMITTEE ON PREVENTION, DETECTION, EVALUATION, AND TREATMENT OF HIGH BLOOD PRESSURE (2003)

CATEGORY

BLOOD PRESSURE (mmHg) Diastolic Systolic

Normal
Pre hypertension Hypertension, stage 1 Hypertension, stage 2

<120
120-139 140-159 >160

and
or or or

<80
80-89 90-99 >100

Classification of hypertension according to aetiology

Primary (essential) hypertension Secondary hypertension
Renal hypertension Renoparenchymal hypertension; renovascular hypertension; post-kidney transplant hypertension Pheochromocytoma; primary hyperaldosteronism (Conns syndrome); deoxycorticosterone-producing tumours; adrenogenital syndrome; Cushing's syndrome; primary hyperrenism; acromegaly; hyperparathyroidism; endothelinproducing tumours; hypo- and hyperthyroidism (Pre-) eclampsia; transient hypertension Coarctation of the aorta; hyperkinetic heart syndrome; aortic valve insufficiency; sclerosis of the aorta; severe bradycardia; arteriovenous fistulae Oral contraceptives; high-dose mineralcorticoids or glucocorticoids; erythropoietin; cyclosporine; alcohol licorice Sleep apnoea syndrome; neurological disorders Stimpel. Arterial Hypertension, 1996; Walter de Gruyter Berlin, New York.

Endocrine hypertension

Pregnancy-specific hypertension Cardiovascular hypertension

Drug-/alimentation-induced hypertension Neurogenic hypertension

AUTOREGULATION
BLOOD PRESURE = CARDIAC OUTPUT HYPERTENSION = INCREASED CO X AND / OR PERIPHERAL RESISTANCE INCREASED PR

Preload

Contractility

Function constriction

Structural hypertrophy

Fluid Volume

Venous Contractility Sympathetic Renin nervous system angiotensin over activity excess Cell Hyper membrane Insullinemia alteration Endothelium derrived factors Stress Genetic alteration Genetic alteration Obesity

Renal sodium retention Excess sodium intake

Decreased fibration suface

Risk factors for the development of hypertension

Genetic predisposition Black race Diabetes mellitus

Hyperlipidaemia

Lack of exercise

Obesity
Distress (?)

Alcohol

 Pada pasien normotensif terdapat variasi tekanan darah di urnal. Pada malam hari tekanan darah turun 10 -20% Tekanan darah dipengaruhi oleh saraf simpatis dan sistim renin-angiotensin -aldosteron.

J Clin Endocrinol Metab 1985;60:1210-1215

Horm Metab Res 1990;22:636-639

Blood Pressure & Risk of Stroke

Relative Risk of Stroke

10 8 6 4 2 0

Systolic BP Diastoic BP

Systolic BP Diastolic BP

<112 <71

11271-

11876-

12179-

12581-

12984-

13286-

13789-

14292-

151 98

mm Hg

Hypertension
He J, Whelton PK, J Hypertens, MRFIT Study1999;17(suppl 2):S7-13.

Effect of SBP and DBP on Age-Adjusted CAD Mortality: MRFIT

CAD Death Rate per 10,000 Person-Years
80.6

48.3 37.4 34.7 24.6 13.9 11.8

43.8

38.1 25.2

31.0
23.8 20.6

25.8 16.9

25.3 12.8 8.8

24.9 11.8

12.6

10.3

160+ 140-159

8.5

9.2

100+

90-99

80-89

75-79

70-74

<70

120-139 <120

Systolic BP (mm Hg)

Diastolic BP (mm Hg)

Adapted with permission from Neaton et al. Arch Intern Med. 1992;152:56-64.

Target Organ Damage caused by Hypertension

Jantung LVH Angina pektoris Otak PJK Gagal Jantung

Stroke, TIA Demensia

Penyakit Ginjal Kronik (CKD) Penyakit Arteri perifer Retinopati

Hypertension & Risk for ESRD

Compared with BP < 120/80 mmHg, the adjusted relative risks for developing ESRD in subject without baseline renal disease:

RR
1,62 1,98 2,59

CI
95% CI (1,27 - 2,07) 95% CI (1,55 2,52) 95% CI (2,07-3,25) 95% CI (3,00 4,96) 95% CI (2,82- 5,34) 95% CI (2,63-6,86)

BP
120-129 / 80- 84 130-139 / 85-89 140-159 / 90-99 160-179 / 100-109 180-209 / 110-119 210 / 120
Hsu CY, et al. Arch Intern Med. 2005; 165:923-928.

3,86 3,88
4,25

Blood Pressure, Stroke, & CAD

Risk Ratio 4.0 Risk ratio 4.0

Myocardial Infarction
3.0 3.0

Stroke

2.0 1.0

2.0 1.0

76 84 91 98 105 Diastolic BP (mm Hg)

76 84 91 98 105 Diastolic BP (mm Hg)

MacMahon S. J Hypertens. 1990;8(suppl):239-244.

Hypertension and the risk of further disease

Disease Coronary artery disease Relative risk
(hypertensives versus normotensives)

2- to 3-fold

Stroke
Heart failure

7-fold
2- to 3-fold

Peripheral vascular disease

2- to 3-fold

Risk of a major cardiovascular event reduced by 22% in the HOT Study

170 0 5 10 15 20 25 Optimal SBP reduction in the HOT Study 160 150 140 Achieved SBP mm Hg 130

30 % risk reduction

Risk of a major cardiovascular event reduced by 30% in the HOT Study

105 0 5 10 Optimal DBP reduction in the HOT Study 100 95 90 85 Achieved DBP 80 mm Hg

15
20 25 30 % risk reduction

Management of Hypertension Important messages

Assess the risk Treat to target Lifestyle Combination therapy Compliance

Goals of Therapy
Reduce CVD and renal morbidity and mortality.
Treat to BP <140/90 mmHg or BP <130/80 mmHg in patients with diabetes or chronic kidney disease.

Achieve SBP goal especially in persons >50 years of age.

JNC VII 2003

History of antihypertensive drugs

Effectiveness and general tolerability

1940s 1950 Direct vasodilators Peripheral sympatholytics Ganglion blockers Veratrum alkaloids 1957 1960s 1970s Alphablockers 1980s 1990s 2000

ARBs ACE inhibitors

Thiazide diuretics

Central 2 agonists

Calcium antagonistsnon-DHPs

Calcium antagonistsDHPs

Betablockers
DHP, dihydropyridine; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker

Treatment Algorithm for Adults with Systolic-Diastolic Hypertension without another compelling indication
TARGET <140/90 mmHg INITIAL TREATMENT AND MONOTHERAPY

Lifestyle modification therapy

Thiazide

ACE-I ARB

Long-acting DHP-CCB

Betablocker
Alpha-blocker as initial monotherapy

JNC VII
2003

Hypertension Without Compelling indication

Stage 1 Hypertension Syst. 140 159 OR Diast. 80 90 mmHg

Stage 2 Hypertension Syst. > 160 mmHg OR Diast > 100 mmHg

Thiazide type diuretics for most

May consider ACE inh, ARB, CCB, Betablocker Or Combination

2 Drug Combination for most

Usualy thiazide type with ACE inh. or ARB or Beta Blocker or CCB
JAMA. 2003;289

Possible Combination of Difference Classes of Antihypertensive Agents

2003 European Society of Hypertension-European Society of Cardiology Guidelines for management of arterial hypertension Diuretics AT1-receptors blockers

-blockers

-blockers
The most rational combinations Classes of antihypertensive agents proven to be beneficial in controlled interventional trial

Calcium antagonists ACE inhibitors

Anti-hypertensive effects of ARBs

RAA cascade, ACEIs & ARBs
Various ARBs

Valsartan Antihypertensive LongTerm Use Evaluation (VALUE)

Renin-Angiotensin Systems (I)

Classical "circulating" system (RAAS):
Angiotensin II
glomerular zone
adrenal glands

ACE Angiotensin I Renin Angiotensinogen

macula densa

Aldosterone Na+-retention K+-loss Renin

Blood pressure

Na+
Sympathetic system

adapt. from Dominiak & Unger (eds.) in Ang II-AT1-Receptor Antagonists, Steinkopff (1997)

Renin-Angiotensin Systems (II)

Local "tissue-bound" system (RAS):
Angiotensinogen
Renin

inactive fragments ACE Bradykinin

Angiotensin I

t-PA Cathepsin G Tonin Chymases Cathepsin G CAGE

Angiotensin II

B1

B2

AT1

AT2

t-PA = tissue plasminogen activator CAGE = chymostatin-sensitive angiotensin generating enzyme

specific cellular response

specific cellular response

adapt. from Dominiak & Unger (eds.) in Ang II-AT1-Receptor Antagonists, Steinkopff (1997)

Renin-Angiotensin Systems (III)

Distribution of ACE:

10 % circulating (plasma)

RAS

90 % local (tissue) Long-term effects

Acute and short-term effects

cardiovascular/ renal homeostasis

local "organ adaptation" renal-independent activation

mod. from Dzau V, Arch Intern Med 153 (1993)

Local Renin-Angiotensin-Systems
Angiotensin II generating systems/organs: Tissue/Compartment Cell systems (e.g.)

Heart Brain Kidney Blood vessels atherosclerotic plaques Testis Uterus Nebenniere
mod. from Dzau V, Arch Intern Med 153 (1993)

Myocytes Neurons Mesangium,Tubule Endothelium Macrophages ? Smooth muscle? Glomerulosa cells

Angiotensin II plays a central role in organ damage

Atherosclerosis* Vasoconstriction Vascular hypertrophy Endothelial dysfunction Stroke

Hypertension

A II

AT1 receptor

LV hypertrophy Fibrosis Remodeling Apoptosis GFR Proteinuria Aldosterone release Glomerular sclerosis

Heart failure MI

DEATH

Renal failure

*preclinical data LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate

Effects of Angiotensin II at AT1 and AT2 Receptors

AT1
Blocked by ARBs
Vasoconstriction Aldosterone release Oxidative stress Vasopressin release SNS activation Inhibits renin release Renal Na+ and H2O reabsorption Cell growth and proliferation -

AT2
Vasodilation Antiproliferation Apoptosis Antidiuresis/antinatriuresis Bradykinin production NO release

Siragy H. Am J Cardiol. 1999;84:3S8S.

Pathophysiologic Effects of Angiotensin II

Abnormal vasoconstriction Contractility Activate SNS Aldosterone Vasopressin Endothelin PAI-1/ thrombosis Platelet aggregation

Angiotensin II

Superoxide production

Vascular smooth muscle growth

Myocyte growth

Collagen
Burnier M, Brunner HR. Lancet. 2000;355:637645.

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)

Various ARBs
Losartan Valsartan = Cozaar (MSD) = Diovan (Novartis)

Candesartan = Blopress (Takeda) Irbesartan Telmisartan = Aprovel (Sanofi) = Micardis (Boehringer Ingelheim)

Eprosartan not available in Indonesia

Olmesartan

= Olmetec (Pfizer)

Comparisons of ARB-Based Regimens With Control Regimens

Trials Events/Participants
Stroke CHD Heart failure 4 4 3 396/8412 435/8412 302/5935 1135/8412 491/8412 887/8412 500/8379 450/8379 359/5919 2 / 1 1268/8379 511/8379 943/8379 2 / 1 2 / 1 0.94 (0.861.02) 2 / 1 0.5 1.0 2.0 Favours Relative Risk Favours Control ARB
BP Lowering Treatment Trialists Collaboration. Lancet. 2003;362:1527-1535.

Diff. in BP (mean, mmHg)

2 / 1 2 / 1

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)

P
0.46 0.43 0.26 0.78 0.34 0.59

Major CV 4 events CV death 4 Total mortality 4

VALUE Valsartan Antihypertensive Long-Term Use Evaluation

VALUE: Significance
First trial to compare ARB valsartan, the most to calcium channel blocker, amlodipine
Designed to evaluate effectiveness of a valsartan-based regimen vs an amlodipine-based regimen on overall cardiac outcomes
Mann J, Julius S. Blood Press. 1998;7:176183.

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 secondary endpoint

VALUE: Primary Hypothesis

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

Julius S et al. Lancet. June 2004;363:202231.

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: 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.

VALUE: Design
Elective titration to target BP (<140/90 mmHg)
Valsartanbased regimen
V 160 mg V 160 mg + HCTZ 12.5 mg V 160 mg + HCTZ 25 mg V 160 mg + HCTZ 25 mg + "Free" add-on

Rollover from previous therapy (92%)

V 80 mg

A 5 mg A 10 mg A 10 mg + HCTZ 12.5 mg A 10 mg + HCTZ 25 mg

Amlodipinebased regimen
Month 0.5 0 1

A 10 mg + HCTZ 25 mg + "Free" add-on

72

Screening Randomisation
Julius S et al. Lancet. June 2004;363:202231.

End of treatment adjustment period

*Patient visits every 6 months for months 672.

VALUE: Number of Antihypertensive Medications Taken Before Randomisation

50 40 % of Patients 30 20 10 0 None 1 Medication 2 Medications 3 or More Medications Valsartan (n = 7649) Amlodipine (n = 7596)

Data on file. Novartis Pharmaceuticals.

VALUE: Blood Pressure Changes From Baseline to the End of the Study
0 5 mmHg 10 15 20

SBP DBP

ValsartanBased Therapy

AmlodipineBased Therapy

Julius S et al. Lancet. June 2004;363:202231.

Before Randomisation 22%

VALUE: Trends in SBP Control (<140 mmHg)

Study End Valsartan-Based Regimen
Noncontrolled Controlled

57%

22% Amlodipine-Based Regimen

63%

Noncontrolled Controlled

92% of patients were previously treated with antihypertensive medication(s) at time of entry. Julius S et al. Lancet. June 2004;363:202231.

VALUE: Systolic Blood Pressure in Study

155 mmHg 150 145 140 135 Baseline 1 2 3 4 6 12 18 24 30 36 42 48 54 60 66

Sitting SBP by Time and Treatment Group

Valsartan (N= 7649) Amlodipine (N = 7596) 139.3 mmHg 137.5 mmHg

Months
5.0 4.0 3.0 2.0 1.0 0 1.0
2.1 (p<.0001) 4.0 (p<.0001)

(or final visit)

Difference in SBP Between Valsartan and Amlodipine

mmHg

12 18 24 30 36 42 48 54 60 66

Months

(or final visit)

Julius S et al. Lancet 2004;363:202231.

VALUE: Diastolic Blood Pressure in Study

Sitting DBP by Time and Treatment Group
mmHg 90 85 80 75 Baseline 1 2 3 4 6 12 18 24 30 36 42 48 54 60 66 Valsartan (N= 7649) Amlodipine (N = 7596) 79.2 mmHg 77.7 mmHg

Months
5.0 2.1 4.0 (p<.0001) 3.0 2.0 1.0 0 1 2 1.0

(or final visit)

Difference in DBP Between Valsartan and Amlodipine

1.6 (p<.0001)

mmHg

12 18 24 30 36 42 48 54 60 66

Months

(or final visit)

Julius S et al. Lancet 2004;363:202231.

VALUE: Primary Endpoint Results

14 Proportion of Patients With First Event (%) 12 10 8 6 4

VALUE: Primary Composite Cardiac Endpoint

Valsartan-based regimen

Amlodipine-based regimen

2
0

HR = 1.03; 95% CI = 0.941.14; P = 0.49

12 18 24 30 36 42 48 54 60 66
Time (months)

Number at risk Valsartan Amlodipine

7649 7459 7407 7250 7085 6906 6732 6536 6349 5911 3765 1474 7596 7469 7424 7267 7117 6955 6772 6576 6391 5959 3725 1474

Julius S et al. Lancet. June 2004;363:202231.

VALUE: Outcome and SBP Differences at Specific Time Periods: Primary Endpoint
Time Interval (months) Overall study 03 36 612 1224 2436 3648 48end D SBP mmHg 2.2 3.8 2.3 2.0 1.8 1.6 1.4 1.7
4.0 0.5 1.0 2.0 Favours amlodipine Favours valsartan

PRIMARY ENDPOINT Odds Ratios and 95% CIs

Julius S et al. Lancet. June 2004;363:202231.

VALUE: Total Mortality Result

VALUE: All-cause Death

16 Proportion of Patients With First Event (%) 14 12 10 8 6 4 2 0 0
Number at risk Valsartan Amlodipine

Valsartan-based regimen Amlodipine-based regimen

HR = 1.04; 95% CI = 0.94-1.14; P = 0.45

12 18 24 30 36 42 48 54 60 66 Time (months)

7649 7527 7496 7383 7267 7136 6994 6843 6682 6273 3981 1563 7596 7520 7484 7385 7276 7155 7025 6874 6729 6312 3961 1582

Julius S et al. Lancet. June 2004;363:202231.

VALUE: Secondary Endpoint Results

VALUE: Fatal and Non-fatal Stroke

6 Proportion of Patients With First Event (%) 5 4
Valsartan-based regimen

Amlodipine-based regimen

3
2 1 0
HR = 1.15; 95% CI = 0.981.35; P = 0.08

Number at risk Valsartan Amlodipine

12 18 24 30 36 42 48 54 60 66 Time (months)

7649 7494 7448 7312 7170 7022 6877 6692 6515 6093 3859 1516 7596 7499 7455 7334 7195 7055 6918 6744 6587 6163 3846 1532

Julius S et al. Lancet. June 2004;363:202231.

VALUE: Outcome and SBP Differences at Specific Time Periods: Stroke

Time Interval (months)
Overall study 03 36 612 1224 2436 3648 48end

D SBP (mmHg)
2.2 3.8 2.3 2.0 1.8 1.6 1.4 1.7

STROKE Odds Ratios and 95% CIs

0.25 0.5 1.0 2.0 4.0 Favours valsartan Favours amlodipine

Julius S et al. Lancet. June 2004;363:202231.

7 Proportion of Patients With First Event (%) 6 5 4 3 2 1 0

VALUE: Fatal and Non-Fatal Myocardial Infarction

Valsartan-based regimen Amlodipine-based regimen

HR = 1.19; 95% CI = 1.02-1.38; P = 0.02

0
Number at risk Valsartan Amlodipine

12 18 24 30 36 42 48 54 60 66 Time (months)

7649 7499 7458 7319 7177 7016 6853 6680 6504 6078 3864 1520 7596 7497 7458 7332 7205 7065 6905 6727 6562 6141 3840 1532

Julius S et al. Lancet. June 2004;363:202231.

VALUE: Outcome and SBP Differences at Specific Time Periods: Myocardial Infarction
Time Interval (months) Overall study 03 36 612 1224 2436 3648 48end D SBP (mmHg) 2.2 3.8 2.3 2.0 1.8 1.6 1.4 1.7
4.0 0.5 1.0 2.0 0.25 Favours valsartan Favours amlodipine
Julius S et al. Lancet. June 2004;363:202231.

Myocardial Infarction Odds Ratios and 95% CIs

VALUE: Hazard Ratios for Fatal and Non-fatal Myocardial Infarction

Myocardial Infarction Fatal and non-fatal Fatal Non-fatal Hazard Ratio Valsartan/Amlodipine

0.5 1 2 Favours valsartan Favours amlodipine

Julius S et al. Lancet. June 2004;363:202231.

VALUE: Heart Failure

9
8 Proportion of Patients With First Event (%) 7 6 5 4 3

Hospitalisation for HF or death from HF

Valsartan-based regimen Amlodipine-based regimen

2
1 0 0 6
HR = 0.89; 95% CI = 0.77-1.03; P = 0.12

Number at risk Valsartan Amlodipine

12 18 24 30 36 42 48 54 60 66 Time (months)

7649 7485 7444 7312 7169 7012 6852 6671 6498 6072 3860 1513 7596 7486 7444 7312 7176 7033 6874 6702 6534 6100 3823 1511

Julius S et al. Lancet. June 2004;363:202231.

VALUE: Outcome and SBP Differences at Specific Time Periods: Heart Failure
Time interval (months) Overall study 03 36 612 1224 2436 3648 48end D SBP (mmHg) 2.2 3.8 2.3 2.0 1.8 1.6 1.4 1.7
0.25 0.5 1.0 2.0 4.0 Favours valsartan Favours amlodipine
Heart Failure: Hospitalisation for HF or death from HF.
Julius S et al. Lancet. June 2004;363:202231.

Heart Failure Odds Ratios and 95% CIs

VALUE: Incidence of New-onset Diabetes

18
16 New-Onset Diabetes (% of patients in treatment group) 23% Risk Reduction With Valsartan P < 0.0001

14
12 10 8 6 4 2 0 13.1% 16.4%

Valsartan-based Regimen (n = 5254)

Amlodipine-based Regimen (n = 5168)

Julius S et al. Lancet. June 2004;363:202231.

CV Events in Treated Hypertensive Diabetic Patients

100 Probability of Event-Free Survival (%) 90 80 70

No diabetes
New-onset diabetes Previously known diabetes

60
50 40 30 0 3 6 9 12 Time to Event (years) 15

Patients with new or prior diabetes were 3-times more likely to have a CV event than those without diabetes. Verdecchia P et al. Hypertension. 2004;43:963969.

VALUE: Incidence of Endpoints

30

Valsartan (n = 7649) Amlodipine (n = 7596)

% of Patients

20
P < 0.0001 P = 0.49 P = 0.45 P = 0.71 P = 0.90 P = 0.02

10

P = 0.12

P = 0.08

0 Primary Composite Cardiac Mortality Cardiac Morbidity Myocardial Infarction* Heart Failure* Stroke* All-cause Death New-onset Diabetes

*Fatal and non-fatal. Julius S et al. Lancet. June 2004;363:202231.

VALUE: Hazard Ratios for Pre-specified Analyses

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 Favours valsartan Favours amlodipine
Julius S et al. Lancet. June 2004;363:202231.

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 Total mortality was not different Incidence of stroke was lower in the amlodipine group Incidence of non-fatal MI was significantly lower in the amlodipine group There was a positive trend in favour of valsartan for less heart failure There was a lower rate of new-onset diabetes in the valsartan group
Julius S et al. Lancet. June 2004;363:202231.

VALUE: Interpretations
The observed difference in stroke rates appears to be strongly related to differences in achieved BPs The benefits of valsartan in heart failure prevention emerged later in the study when BP differences were smaller, indicating that there is a potential beneficial effect of valsartan beyond BP control

Julius S et al. Lancet. June 2004;363:202231.

VALUE: Conclusions Prompt blood pressure control in hypertensive patients at high cardiovascular risk is very important The between-group differences in heart failure and diabetes suggest that valsartan may offer benefits beyond BP control
Julius S et al. Lancet. June 2004;363:202231.

VALUE: Analysis of Results Based on Serial Median Matching

Rationale: Differences in achieved BP levels in VALUE precluded valid comparisons of drug effects on outcomes. Therefore, a statistical technique that adjusts for BP differences was applied post hoc to create treatment cohorts with closely similar characteristics

Weber MA et al. Lancet. 2004;363:204749.

VALUE: Analysis of Results Based on Serial Median Matching

Description:
The novel computerised procedure of Serial Median Matching was applied at 6 months, following the treatment adjustments intended to achieve BP control.
The programme selected the most median patient (by achieved systolic BP) in the valsartan group; this patient was paired with one from the amlodipine group ( 2 mmHg) and was matched also for age, sex and the presence or absence of prior coronary disease, stroke and diabetes. The newly created patient pair was moved to a new database, and the procedure repeated serially until all possible patient pairs were matched.
Weber MA et al. Lancet. 2004;363:204749.

VALUE: Major Study Endpoints in 5006 Patient Pairs (N = 10,012) on Valsartan- or AmlodipineBased Therapies Using Serial Median Matching
Hazard Ratio (95% CI) Composite cardiac events Stroke Death Myocardial infarction Heart failure
0.90 (0.791.03) 1.02 (0.811.28) 0.96 (0.841.10) 0.97 (0.801.19)

P
0.111 0.899 0.566 0.791

0.81 (0.660.99)* 0.040

0.6
*P < 0.05.

0.8

1.0

1.2

1.4

Favours valsartan

Favours amlodipine

Weber MA et al. Lancet. 2004;363:204749.

VALUE: Analysis of Results Based on Serial Median Matching

Conclusions:
Serial median matching created valsartanamlodipine patient pairs matched exactly for systolic BP and demographic and clinical characteristics excluding the high and low extremes of achieved BPs. It allowed us to address the original study hypothesis, and demonstrated that for the same achieved BPs, valsartan in an intermediate dose had effects similar to amlodipine on most CV endpoints, and was more effective in reducing heart failure hospitalisations.
Weber MA et al. Lancet. 2004;363:204749.

VALUE: Analyses of Results Based on BP Control

Overall Conclusions:
Blood pressure control, and rapidity of response, are critical for reducing events in high-risk hypertension The significant between-group differences in heart failure and diabetes suggest that valsartan may offer benefits beyond BP control

Weber MA et al. Lancet. 2004;363:204749.

terimakasih