240178444444444444444444444444444444.ppt

PROFESSOR Dr.ALAA ETMAN MD
NATIONAL HEART INSTITUTE
Get to Goal,
Achieve Control

WHO World Health Report 2004
CV diseases
Cancer
Infectious and
parasitic diseases
Other non-infectious
diseases
Injuries
Respiratory diseases
Respiratory infections
Maternal and perinatal conditions
Nutritional deficiencies
Cardiovascular diseases leading causes of global
mortality

Prevalence of Hypertension
12.08
13.6
26.3
6.07
20.4
22
0
5
10
15
20
25
30
India China Egypt Bangladesh USA Candada
%

Proportion of Patients Treated/Not Treated
for Hypertension in Europe*
Wolf-Maier et al. Hypertension 2004;43:10–17
Patients (%)
England Sweden Germany Spain Italy
*Age adjusted; patients aged 35–64 years
Hypertension = 140/90mmHg threshold

Prevalence of Hypertension
Increases with Age
Brown. BMJ 2006;332:8336
2039 4059 60
Prevalence of Hypertension (%)
Age (years)
Estimated non-institutionalized US adults, 19992002
Adapted from Centers for Disease Control and Prevention

Stroke & IHD* Mortality Rate in Each
Decade of Age, vs Usual Systolic BP at the
Start of that Decade
*IHD= Ischaemic Heart Disease
Mortality*
Usual SBP (mmHg)
50–59 y
60–69 y
70–79 y
80–89 y
Stroke
Age at risk
256
128
64
32
16
8
4
2
1
0
120 140 160 180
Ischaemic Heart Disease
Usual SBP (mmHg)
50–59 y
60–69 y
70–79 y
80–89 y
Age at risk
40–49 y
256
128
64
32
16
8
4
2
1
0
120 140 160 180
*Floating absolute risk and 95% CI
Reproduced from The Lancet, 360, Lewington et al. pp. 1903–13. Copyright © 2002, with permission from Elsevier

Cardiovascular Mortality Risk
Systolic BP/Diastolic BP (mmHg)
115/75 135/85 155/95 175/105
0
2
4
8
6
Lewington et al. Lancet 2002;360:1903–13
Cardiovascular Mortality Risk Doubles with
Each 20/10 mmHg Increment in
Systolic/Diastolic BP*
*Individuals aged 40–69 years
4X risk
8X risk
2X risk
1X risk

BP Reduction of 2 mmHg Decreases the Risk
of CV Events by 7–10%
• Meta-analysis of 61 prospective, observational studies
• 1 million adults
• 12.7 million person-years
2 mmHg
decrease in
mean SBP 10% reduction in risk
of stroke mortality
7% reduction in risk
of ischaemic heart
disease mortality
Lewington et al. Lancet 2002;360:1903–13

Hypertension in Egypt
 Hypertension is a major health problem in Egypt with
a prevalence rate of 26.3% among the adult
population (> 25 years)1.
Only 8% of hypertensive Egyptians have their
blood pressure controlled1.
1- Ibrahim MM, Rizk H, Apple LJ, et al. For the NHP investigation team. Hypertension, prevalence, awareness, treatment and control in Egypt.
Results from the Egyptian National hypertension Project (NHP). Hypertension 1995; 26:880.

More Than 80% Of hypertensive Patients have
additional Co-morbidities

Controlling SBP Is the Main Problem
Adapted from Lloyd-Jones DM, et al. Hypertension. 2000;36:594–599.
DBP, mmHg
SBP,
mmHg
20 60 100 120 140
80
40
67% did not reach
SBP goal
4%
13%
29%
54%
80
100
120
140
160
180
200
220
90
140
Not at SBP
or DBP goal
At SBP and
DBP goal

<140
140–159
160–179
≥180
Relative risk
Predictive Power of Systolic BP on Cardiovascular Mortality
Alli et al. Arch Intern Med 1999;159:1205–12
Relative risk
0.5 1 1.5 2 2.5 0.5 1 1.5 2 2.5
<90
90–99
100
Prognosis
better
Prognosis
worse
Prognosis
better
Prognosis
worse
Systolic BP (mmHg) Diastolic BP (mmHg)

120 130 140
0
1
2
3
4
5
Office
Home
24h
11-Year Increase in Risk of CV Death for 10 mmHg Increase
in SBP at Different Baseline SBP Values
Sega et al., Circulation 2005
Increase
in
risk
of
CV
death
(%)
Baseline SBP (mmHg)
0.6
0.8
1.1
0.9
1.3
2.0
1.8
2.4
4.
5

Evolution of Cardiovascular Risk in Hypertension
Low Risk Higher Risk Highest Risk
Clinical Trial
Treatment Guidelines
Disease Evolution; 20 – 50 years
Hypertension:
• No TOD
• No CVD
• Younger
Target Organ Damage:
• LVH
• Vascular Structure
• Albuminuria
Cardiovascular Disease:
• CHD / CHF
• Stroke / TIA
• Renal Disease
Hard Endpoints
Surrogate Endpoints
Drug
Treatment
Atrial Fibrillation
Systolic Dysfunction
Diastolic Dysfunction
Metabolic Syndrome to Diabetes

Hypertension
Diabetes
Dislipidemia
Central Obesity
Arteriosclerosis
Vascular remodeling
LVH
> IM thickness
Lacunar infarcts
Microalbuminuria
MI, Angina
Stroke
Congestive Cardiac Failure
Renal Failure
Periferal Artery Disease
Non-fatal
recurrent
events
CRF
Dialysis
Dementia
Treatment of
Cardiovascular Risk
Factors
Genes
Life style
Death
Life Style Changes
Treatment of
Silent Lesions
To Interrupt Vascular
Disease Progression
Treatment of
Clinical Events
Natural History of Cardiovascular Disease

Angiotensin II Plays a Central Role in Organ
Damage
A II
Atherosclerosis*
Vasoconstriction
Vascular hypertrophy
LV hypertrophy
Fibrosis
Remodeling
Apoptosis
Stroke
DEATH
GFR
Proteinuria
Aldosterone release
Glomerular sclerosis
Renal failure
Hypertension
Heart failure
MI
AT1 Receptor
*preclinical data
LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate
Adapted from Willenheimer R et al Eur Heart J 1999;20(14):997-1008; Dahlöf B J Hum Hypertens 1995;9(suppl 5):S37-S44;
Daugherty A et al J Clin Invest 2000;105(11):1605-1612; Fyhrquist F et al J Hum Hypertens 1995;9(suppl 5):S19-S24;
Booz GW, Baker KM Heart Fail Rev 1998;3:125-130; Beers MH, Berkow R, eds. The Merck Manual. 17th ed.
Whitehouse Station, NJ: Merck Research Laboratories, 1999:1682-1704; Anderson S Exp Nephrol 1996;4(suppl 1):34-40;
Fogo AB Am J Kidney Dis 2000;35(2):179-188.

“Controlling blood pressure with
medication is unquestionably one of the
most cost-effective methods of reducing
premature CV morbidity and mortality”
Elliott. J Clin Hypertens 2003;5(Suppl. 2):313

Blood Pressure and Cardiovascular Risk: ESHESC
Guidelines
Other RF,
OD or
disease
BP (mmHg)
Normal
SBP 120–129
or DBP 80–84
High normal
SBP 130–139
or DBP 85–89
Grade 1
SBP 140–159
or DBP 90–99
Grade 2
SBP 160–179
or DBP 100–
109
Grade 3
SBP 180
or DBP 110
No other
RF
Average risk Average risk
Low added
risk
Moderate
added risk
High added
risk
1–2 RF
Low added
risk
Low added
risk
Moderate
added risk
Moderate
added risk
Very high
added risk
3 RF, MS,
OD or
diabetes
Moderate
added risk
High added
risk
High added
risk
High added
risk
Very high
added risk
Established
CV or renal
disease
Very high
added risk
Very high
added risk
Very high
added risk
Very high
added risk
Very high
added risk
MS = metabolic syndrome
OD = subclinical organ damage
RF = risk factors
Reproduced from the Task Force of ESH–ESC. J Hypertens 2007;25:1105–87;
Copyright © 2007, with permission from Lippincott Williams and Wilkins

Factors influencing prognosis in hypertension.
Subclinical organ damage
2007 Guidelines for the management of arterial
hypertension
• Electrocardiographic LVH
– Sokolow-Lyon >38 mm
– Cornell >2440 mm x ms
• Echocardiographic LVH (Left ventricular mass index):
– ≥125 g/m2 (males)
– ≥110 g/m2 (females)
• Carotid wall thickening (IMT >0.9 mm) or plaque
• Carotid-femoral pulse wave velocity >12 m/s
• Ankle / brachial blood pressure index >0.9
Mancia G, et al. J Hypertens. 2007;25:1105-87
LVH: Left ventricular hypertrophy
IMT: Intima media thickness

ESH/ESC & JNC 7 Summary:
Target BP Goals
Types of Hypertension BP Goal (mmHg)
Uncomplicated <140/90
Complicated
Diabetes mellitus <130/80
Kidney disease <130/80*
Other high risk (stroke, myocardial
infarction)
<130/80
Task Force of ESH–ESC. J Hypertens 2007;25:110587
Chobanian et al. JAMA 2003;289:256072
*Lower if proteinuria is >1 g/day

Blood Pressure Thresholds (mmHg)
for Definition of Hypertension with
Different Types of Measurement
SBP DBP
Office or Clinic 140 90
24-hour 125-130 80
Day 130-135 85
Night 120 70
Home 130-135 85

Causes of Inadequate Responsiveness to Therapy….cont.

Patient-Related Barriers to Effective
Antihypertensive Treatment
• Limited access to health care
– Lack of health insurance
– Lack of a regular provider
• Nonadherence to therapy
– Knowledge deficits
– Medication cost
– Complicated regimens
– Side effects
– Medication not taken by
patient
– Poor physician-patient
communication
– Lack of social support
• Increased susceptibility
– Advanced age
– Obesity
• Secondary causes (less common)
– Sleep apnea
– Drug side effects
– Chronic kidney disease
– Primary aldosteronism
– Renovascular disease
– Cushing syndrome
– Pheochromocytoma
– Coarctation of the aorta
– Thyroid/parathyroid disease
Wang TJ, Vasan RS. Circulation. 2005;112:1651-1662;
Chobanian AV, et al. JAMA. 2003;289:2560-2572.

Physician-Related Barriers to Effective
Antihypertensive Treatment
• Unfamiliarity with current treatment
guidelines
– Blood pressure thresholds
– Isolated systolic hypertension
– Threshold for diabetic patients
– Use of monotherapy to treat
patients with difficult-to-control
blood pressure
• Belief that in-office blood pressure
tends to be higher than at-home
blood pressure
• Lack of time at office visits
• Therapeutic inertia
• Overestimation of adherence to
guidelines
• Disagreement with guidelines
– Isolated systolic hypertension
– Concern about the relationship
between diastolic blood
pressure and myocardial
infarction (i.e., the J curve)
• Reluctance to treat a seemingly
“asymptomatic condition”
Wang TJ, Vasan RS. Circulation. 2005;112:1651-1662;
Chobanian AV, et al. JAMA. 2003;289:2560-2572;
Okonofua EC, et al. Hypertension. 2006;47:345-351.

Recommended Lifestyle Modifications
and Their Individual Effects on Blood
Pressure
Chobanian AV, et al. JAMA. 2003;289:2560-2572;
Blumenthal JA, et al. Arch Intern Med. 2000;160:1947-1958.
Modifications* Recommendation
Approximate
SBP Reduction
Reduce weight
Maintain normal body weight
(BMI of 18.524.9 kg/m2)
320 mm Hg
Adopt DASH diet
Rich in fruit, vegetables, and
low-fat dairy; reduced saturated
and total fat content
814 mm Hg
Reduce dietary
sodium
<100 mmol (2-4 g)/day 28 mm Hg
Increase physical
activity
Aerobic activity >30 min/day
most days of the week
49 mm Hg
Moderate alcohol
consumption
Men: ≤ 2 drinks/day
Women: ≤ 1 drink/day
24 mm Hg
*Combining 2 or more of these modifications may or may not have an
additive
effect on blood pressure reduction.
SBP = systolic blood pressure; BMI = body mass index; DASH = Dietary
Approaches to Stop Hypertension

Causes of Essential Hypertension
Age
Excess
Sodium
Consumption
Overweight
Excess
Alcohol
Consumption
Physical
Inactivity
Elevated
Systolic
and/or Diastolic
Blood Pressure
Family
History Stress

Pathophysiology of Hypertension
Sever P. J Cardiovasc Pharmacol . 1998;31(suppl 2):S1-S4.
Pathophysiology of Hypertension
Vessels
Brain
Kidney
Skeletal muscle
Hypertension
Salt Sensitivity
G1 P1
Neurogenic
Hyper-Response
G3 P3
Insulin Resistance
G2 P2
Vascular Structure
P4
G4
STRESS
SALT
DIET

Hypertension Syndrome!!
It’s More Than Just Blood Pressure
Decreased
Arterial
Compliance Endothelial
Dysfunction
Abnormal
Glucose
Metabolism
Neurohormonal
Dysfunction
Renal-Function
Changes
Blood-Clotting
Mechanism
Changes
Obesity
Abnormal Insulin
Metabolism
LV Hypertrophy
and Dysfunction
Accelerated
Atherogenesis
Abnormal Lipid
Metabolism
Hypertension
Kannel WB. JAMA. 1996;275:1571-1576. Weber MA et al. J Hum Hypertens.
1991;5:417-423. Dzau VJ et al. J Cardiovasc Pharmacol. 1993;21(suppl 1):S1-S5.

Short Term Regulation of Blood Pressure: Pressure Natriuresis
Arterial pressure is a signal for regulation of NaCl excretion.
 Arterial pressure   NaCl reabsorbed in the proximal tubule  more NaCl to
Macula Densa  Tuboglomerular Feedback (TGF)  autoregulation RBF, GFR
2. Decrease PT NaCl reabsorption
3. Increase [NaCl] at macula
densa generates TGF signal
Natriuresis
Diuresis “Pressure Natriuresis”
1. Increase BP & renal
perfusion pressure
Increase NaCl
delivery to
distal nephron
4. Increase afferent arteriole resistance
5. Autoregulate RBF, GFR
40% increase volume
flow from PT
?
ECFV: Extracellular fluid volume, a function of Na+ reabsorption ; RBF: Renal blood flow; PT: Proximal tubule; GFR:
Glomerular filtration rate; TGF: tubuloglomerular feedback
• In addition, there is an
accompanying increase in
urine Na+, volume
output: pressure
natriuresis/diuresis.
• Pressure natriuresis can
normalize BP by
decreasing the effective
circulating volume – this
response connects BP and
ECFV.

Predicted Long-Term Effects of a Hypertensive
Stimulus
Renal function
curve
Predicted long-term effects of a hypertensive stimulus, caused by increased
total peripheral resistance (normal renal-pressure natriuresis mechanism).
Blood pressure is initially elevated (from point A to point B), but hypertension cannot
be sustained because sodium excretion exceeds intake, thereby reducing extracellular
fluid volume until blood pressure returns to normal and intake and output of sodium
are balanced.
Hall et al. Kidney Int Suppl, Volume 49 Supplement 55.June 1996.S-35-S-41

The Renin Angiotensin Aldosterone System
(RAAS)
Hanon S., et al. J Renin Angiotensin Aldosterone Syst 2000;1:147–150; Chen R., et al. Hypertension 2003;42:542–547;
Hurairah H., et al. Int J Clin Pract 2004;58:173–183; Steckelings U.M., et al. Peptides 2005;26:1401–1409
The renin–angiotensin system (RAS)
Hanon S., et al. J Renin Angiotensin Aldosterone Syst 2000;1:147–150; Chen R., et al. Hypertension 2003;42:542–547; Hurairah H., et al. Int J Clin Pract
2004;58:173–183; Steckelings U.M., et al. Peptides 2005;26:1401–1409
Bradykinin/NO
Inactive fragments
ACE
Angiotensin I
Angiotensin II
Chymase
tPA
Cathepsin
AT1 RECEPTOR
Vasoconstriction
Sodium retention
SNS activation
Inflammation
Growth-promoting effects
Aldosterone
Apoptosis
AT2 RECEPTOR
Vasodilation
Natriuresis
Tissue regeneration
Inhibition of inappropriate cell growth
Differentiation
Anti-inflammation
Apoptosis

ACE Inhibition
S., et al. J Renin Angiotensin Aldosterone Syst–150; Chen R., et al. Hypertension 2003;42:542–547; Hurairah H., et al. Int J
Clin Pract 200H2000;1:147anon 4;58:173–183; Steckelings U.M., et al. Peptides 2005;26:1401–1409
Bradykinin/NO
Inactive fragments
Vasodilation
Tissue protection
ACE
Inhibitor
Angiotensin I
Angiotensin II
Chymase
tPA
Cathepsin
AT1 RECEPTOR
Vasoconstriction
Sodium retention
SNS activation
Inflammation
Aldosterone
Apoptosis
‘Angiotensin II escape’
AT2 RECEPTOR
Vasodilation
Natriuresis
Tissue regeneration
Differentiation
Anti-inflammation
Apoptosis

Selective AT1 Receptor Blockade (ARB)
Bradykinin/NO
Inactive fragments
ACE
Angiotensin I
Angiotensin II
Chymase
tPA
Cathepsin
ARB Bradykinin?
NO?
AT1 RECEPTOR
Vasoconstriction
Sodium retention
SNS activation
Inflammation
Aldosterone
Apoptosis
AT2 RECEPTOR
Vasodilation
Natriuresis
Tissue regeneration
Differentiation
Anti-inflammation
Apoptosis

Rationale for Dual RAAS Blockade with
ACEI & ARB
Bradykinin/NO
Inactive fragments
Vasodilation
Tissue protection
ACE
Inhibitor
Angiotensin I
Angiotensin II
Chymase
tPA
Cathepsin
AT1 RECEPTOR
Vasoconstriction
Sodium retention
SNS activation
Inflammation
Aldosterone
Apoptosis
‘Angiotensin II escape’
AT2 RECEPTOR
Vasodilation
Natriuresis
Tissue regeneration
Differentiation
Anti-inflammation
Apoptosis
ARB
Bradykinin?
NO?

Consider: BP level before treatment
Absence or presence of TOD and risk factors
Choose between
If goal BP not
achieved
If goal BP not
achieved
2–3-drug combination
at full doses
ESH/ESC
Algorithm for the Treatment of Hypertension
TOD = target organ damage
Marked BP elevation
High/very high CV risk
Lower BP target
Mild BP elevation
Low/moderate CV risk
Conventional BP target
Task Force of ESH/ESC. J Hypertens 2007;25:1105–87
2-drug combination
at low dose
Single agent at low dose
Previous
combination
at full dose
Add a third
drug at low
dose
Full-dose
monotherapy
2-3 drug
combination
at full dose
Previous
agent at full
dose
Switch to
different agent
at low dose

Advantages of Multiple-mechanism Therapy:
Efficacy
 Components with a different mechanism of action interact
on complementary pathways of BP control1
 Each component can potentially neutralize counter-
regulatory mechanisms, e.g.
• Diuretics reduce plasma volume, which in turn stimulates the renin
angiotensin system (RAS) and thus increases BP; addition of a RAS
blocker attenuates this effect1,2
 Multiple-mechanism therapy may result in BP reductions
that are additive2
1Sica. Drugs 2002;62:44362
2Quan et al. Am J Cardiovasc Drugs 2006;6:10313
Multiple-mechanism therapy results in a greater BP reduction
than seen with its single-mechanism components1,2

Advantages of Multiple-mechanism Therapy:
Safety/Tolerability
 Components of multiple-mechanism therapy can be given
at lower dosages to achieve BP goal than those required
as monotherapy therefore better tolerated1,2
 Compound-specific adverse events can be attenuated,
e.g.,1,2
• RAS blockers may attenuate the edema that is caused by CCBs
1Sica. Drugs 2002;62:44362
2Quan et al. Am J Cardiovasc Drugs 2006;6:10313
Multiple-mechanism therapy may have an improved tolerability
profile compared with its single-mechanism components1,2

*Lower doses generally used in fixed-dose combinations
+ = potential advantage
Advantages of Fixed Versus Free Combinations of Two
Antihypertensive Drugs
Fixed Free
Simplicity of treatment + –
Compliance + –
Efficacy + +
Tolerability +* –
Price + –
Flexibility – +

Better Compliance with Antihypertensive Drugs Leads to
a Lower Risk of Hospitalization
44
39
36
30
27
0 10 20 30 40 50
1–19
20–39
40–59
60–79
80–100
Level
of
compliance
(%)
All-cause hospitalization risk (%)
*p<0.05 vs 80–100% compliant group
n=5,804
n=921
n=562
n=344
n=350 *
*
*
Sokol et al. Med Care 2005;43:521–30
*

Average no. of antihypertensive medications
1 2 3 4
Multiple Antihypertensive Agents are Needed to Reach BP Goal
Trial (SBP achieved)
Bakris et al. Am J Med 2004;116(5A):30S–8
Dahlöf et al. Lancet 2005;366:895–906; Jamerson et al. Blood Press 2007;16:80–6
ASCOT-BPLA (136.9 mmHg)
ALLHAT (138 mmHg)
IDNT (138 mmHg)
RENAAL (141 mmHg)
UKPDS (144 mmHg)
ABCD (132 mmHg)
MDRD (132 mmHg)
HOT (138 mmHg)
AASK (128 mmHg)
ACCOMPLISH* (132 mmHg)
Initial 2-drug combination therapy
*Interim 6-month data

Recommendations for Multiple-mechanism Therapy:
What the Treatment Guidelines Say: ESH–ESC
 More than one agent is necessary to achieve target BP in the
majority of patients
 Treatment can be initiated with monotherapy or a combination
of two drugs at low doses
 Drug dose or number of drugs may be increased if necessary
 A combination of two drugs at low doses preferred 1st step
when
 Initial BP in grade 2–3 range
 Total CV risk high/very high
 Fixed combinations of two drugs simplify treatment/favor
compliance
Task Force of ESH/ESC. J Hypertens 2007;25:1105–87

Interaction of CCBs and ARBs on Vascular and Renal Function,
SNS and RAS Activity
CCB ARB
Vasodilation
Natriuresis
Arterial Arterial +
Venous
RAS ↓
SNS ↓
↑ RAS
↑ SNS

CCB
 Arteriodilation
 Peripheral edema
 Effective in low-renin patients
 Reduces cardiac ischemia
CCB
 RAS activation
 No renal or
congestive heart
failure benefits
CCB/ARB: Synergy of Counter-regulation
ARB
 Venodilation
 Attenuates peripheral edema
 Effective in high-renin patients
 No effect on cardiac ischemia
ARB
 RAS blockade
 Congestive heart
failure and renal
benefits

Tolerability and Risk Factor Modification: CCB-induced
Peripheral Edema Minimized by the ARB
Single mode of action of the
CCB
Dual mode of action of the
CCB/ARB
Illustration modified from www.lotrel.com
ARB dilates arteries and
veins
Reduces
CCB-induced
peripheral
edema
Capillary
overload
forces fluid
into
surrounding
tissue
CCB dilates
arteries
Veins remain
constricted
Messerli et al. Am J Hypertens 2001;14:978–9

12418 M
The importance of BP control for CV protection
calls for use of effective antihypertensive drugs
in the context of
effective antihypertensive treatment strategies

Maximum home blood pressure: a novel indicator of target-organ damage in hypertension
 Blood pressure variability has recently been shown to be a
strong predictor of stroke and cardiovascular events,
independently of the mean systolic blood pressure level.1
 The clinical implication of variability in blood pressure, as
measured by home blood pressure monitoring, has never been
reported.
 A new study has investigated the association between
maximum home blood pressure and target-organ damage in
356 never-treated hypertensive subjects.
1. Rothwell PM et al. Lancet. 2010;375:938-948. 2. Matsui Y et al. Hypertens, 2011;57: in press

Maximum home systolic blood pressure measurements were observed up to 50 times per day
Number
of
episodes
per/day
Matsui Y et al. Hypertens. 2011;57: in press

High incidence of maximum home systolic blood pressure is associated with a high degree of
cardiac and vascular remodeling
Matsui Y et al. Hypertens. 2011;57: in press

Conclusion
This study provides additional information on the importance of blood
pressure stabilization to prevent cardiovascular complication in hypertensive
patients:
Transiently high blood pressure readings at home should be taken seriously
as meaningful indicators for hypertensive damage in the heart and artery.1
The variability in systolic blood pressure can be simply assessed by home
blood pressure measurements.1
This study confirms, that effective antihypertensive treatment should not
only reduce, but also stabilize blood pressure.2
1. Matsui Y et al. Hypertens. 2011;57: in press; 2.Rothwell PM. et al. Lancet. 2010;375:938-948.

Conditions favoring use of some antihypertensive drugs
versus others:

Effects of RAS blockade on stroke: meta-analysis of
ARBs and ACE inhibitors
MI
Cardiovascular mortality
All-cause mortality
Stroke
Favours ARB
Favours
ACE inhibitor
Reboldi et al. J Hypertension 2008;26:1282–1289
Studies (N=63,409 ): ELITE; ELITE-II; OPTIMAAL; DETAIL; VALIANT; ONTARGET

Better stroke protection with ARBs than with ACEIs
Suggests AT2-receptor mediated
cerebroprotection

 Spansk studie ARB less severe strokes
The multiple regression analysis
showed that
Previous treatment with ARB was
independently associated with reduced
stroke severity:
OR: 0.40; 95% CI 0.24—0.65, p<0.001
and against poor outcome:
OR: 0.41; 95%CI 0.23-0.78, p=0.003

There is no such thing as a simple Class Effect that
explains ,all about a particular molecule
Every molecule is unique

0
10,000
20,000
30,000
40,000
50,000
60,000
21
1. VALUE
2. VALIANT
3. NAVIGATOR
4. Val-HeFT
5. JIKEI HEART
6. KYOTO HEART*
7. VART*
8. VALISH*
27. IDNT
28. ACTIVE-I*
29. NID-2
30. SUPPORT*
31. COLM*
32. OSCAR*
33. ORIENT*
34. MOSES
Julius et al. 2004; 2. Pfeffer et al. 2003; 3. Califf et al 2008; 4. Cohn et al. 2001; 5. Mochizuki et al. 2007;
6. http://clinicaltrials.gov (NCT00149227); 7. Nakayama et al. 2008; 8. NCT00151229; 9. ONTARGET Investigators 2008; 10. Yusuf et al 2008; 11. TRANSCEND Investigators 2008; 12. http://clinicaltrials.gov (NCT00283686); 13. Dahlöf et
al. 2002; 14. Dickstein et al. 2002; 15. Pitt et al. 2000; 16. Brenner et al. 2001; 17. http://clinicaltrials.gov (NCT00090259); 18. http://clinicaltrials.gov (NCT00555217); 19. Pfeffer et al 2003; 20. Papademetriou et al. 2004; 21.
http://clinicaltrials.gov (NCT00120003); 22. Ogihara et al. 2008; 23. http://clinicaltrials.gov (NCT00108706); 24. Laufs et al. 2008; 25. Suzuki et al. 2005; 26. Massie et al 2008; 27. Lewis et al. 2001; 28. http://clinicaltrials.gov
(NCT00249795); 29. http://clinicaltrials.gov (NCT00535925); 30. http://clinicaltrials.gov (NCT00417222); 31. http://clinicaltrials.gov (NCT00454662); 32. http://clinicaltrials.gov (NCT00134160); 33. http://clinicaltrials.gov (NCT00141453);
34. Schrader et al. 2005...35. Kunihiro Matsushita ,et al , J of Cardiology Volume 56, Issue 1, July 2010, Pages 111-117
1.
9. ONTARGET
10. PRoFESS
11. TRANSCEND
12. HALT-PKD*
13. LIFE
14. OPTIMAAL
15. ELITE II
16. RENAAL
17. NCT00090259*
*Expected
enrolment
‡Ongoing and completed randomized
controlled trials with death or hard CV
events as or part of the primary
endpoint
¶Valid as of January 2009
Mortality and Morbidity Endpoint Trials‡¶ with ARBs
18. VA NEPHRON-D*
19. CHARM
20. SCOPE
21. SCAST*
22. CASE-J
23. ACCOST
24. HIJ-CREATE
25. E-COST
26. I-PRESERVE
Number
of
patients
Valsartan Telmisartan Losartan Candesartan Irbesartan Olmesartan Eprosartan
57,781
52,896
24,841 23,940
6,577
1,405
15,693
1
2
5
4
3
7
8
6
9
10
16
12
11
17
18
15
13
14
22
23
25
19
20
34
31
30
32
33
29
28
27
26
24
35. NAGOYA
Heart S
35

VALUE: Incidence of New-onset Diabetes
New-onset
diabetes
(%
of
patients
in
treatment
group)
Julius S et al. Lancet. June 2004;363.
0
2
4
6
8
10
12
14
Valsartan-based regimen
(n = 7,649)
Amlodipine-based
regimen
(n = 7,596)
13.1%
16.4%
23% risk reduction
with valsartan
16
18
P < 0.0001

Valsartan Improves Insulin Sensitivity in Hypertensive
Patients*
*All patients in study group received valsartan 80 mg once daily. †P <0.001 vs hypertensive pretreatment.
HOMA-IR = homeostasis model assessment – estimated insulin resistance.
Top C et al. J Int Med Res. 2002;30:15-20.
Normotensive (n = 20)
Hypertensive pretreatment (n = 20)
Hypertensive posttreatment (n = 20)
HOMA-IR
0
5
10
15
20
25
9.8†
19.6
8.7
2.2†
1.9
4.4
0
5
10
15
20
25
Fasting Insulin
(µlU/mL)

Valsartan® Improves Insulin Sensitivity & Decreases
Leptin in Obese Patients with HTN
Results from a 16-week study in 91 obese† patients with mild-to-moderate
essential HTN‡
†BMI ≥30kg/m2; ‡DBP >90 and <110 mmHg; *p<0.01, **p<0.05, ***p=NS vs. placebo; §p<0.01 vs. DIOVAN;
BMI=Body mass index; HOMA-IR=Homeostasis model assessment of insulin resistance index
Fogari et al. Hypertens Res 2005;28:209-214
Change
from
baseline
(%)
BMI Plasma
Leptin
HOMA-IR Plasma
norepinephrine
DIOVAN 80-160 mg od (n=46)
Felodipine 5-10 mg od (n=45)
*
†
-20
-10
0
10
20
30
40
-4.7*
0.1
-10.1**
0.6
-20.0**
-3.8
-13.8***
38.8*§

Change
in
plasma
levels
from
baseline
to
12
weeks
Adiponectin
(ng/mL)
Resistin
(ng/mL)
Leptin
(ng/mL)
DIOVAN 160 mg/day (n=36)
Valsartan® Significantly Increases Adiponectin in
Obese Patients with HTN
Results from a 12-week study in 72 obese§ patients with mild-to-moderate HTN#
§BMI ≥30kg/m2; #DBP >90 mmHg and <110 mmHg; *p<0.05 vs. baseline
Fogari et al. Am J Hypertens 2005;18:196A (abstract P-521)
Amlodipine 10 mg/day (n=36)
-4
-3
-2
-1
0
1
2
1.1*
0.3
-0.3
-3.7*
-0.2
-1.1*
-0.2
-1.0*
HOMA-IR

Valsartan: Wealth of CV Outcomes Data
1Julius et al. Lancet 2004;363:2022–31; 2Pfeffer et al. N Engl J Med 2003;349:1893–906; 3Maggioni et al. Am Heart J
2005;149:548–57; 4Wong et al. J Am Coll Cardiol 2002;40:970–5; 5Cohn et al. N Engl J Med 2001;345:1667–7;
6Mochizuki et al. Lancet 2007;369:1431–9
VALUE1
15,245 high-risk HTN patients; Double-blind,
randomized study vs. amlodipine
No difference in composite of cardiac mortality and
morbidity (primary)
23%  new-onset diabetes
VALIANT2
14,703 post-myocardial infarction patients; Double-
blind, randomized study vs. captopril and vs.
captopril + valsartan
No difference vs. captopril in all-cause mortality
(primary)
(valsartan is as effective as standard of care)
Val-HeFT3–5
5,010 heart failure II–IV patients; Double-blind,
randomized study vs. placebo
13%  morbidity and mortality (primary)
 left ventricular remodeling
37%  atrial fibrillation occurrence
 heart failure signs/symptoms
28%  heart failure hospitalization
JIKEI HEART6
3,081 Japanese patients on conventional treatment
for hypertension, coronary heart disease, heart
failure or combination of these; Multicenter,
randomized, controlled trial comparing addition of
valsartan vs. non-ARB to conventional treatment
39%  composite CV mortality and morbidity
40%  Stroke/transient ischemic attack
47%  Hospitalization for heart failure
65%  Hospitalization for angina

Amlodipine: Wealth of CV Outcomes Data
1Pitt et al. Circulation 2000;102:1503–10; 2Nissen et al. JAMA 2004;292:2217–26; 3Dahlof et al. Lancet 2005;366:895–906
4Williams et al. Circulation 2006;113:1213–25; 5Leenen et al. Hypertension 2006;48:374–84
PREVENT1
825 CAD patients (≥30%): Multicenter,
randomized, placebo controlled
Primary outcome: No difference in mean 3 yr
coronary angiographic changes vs. placebo
35%  hospitalization for heart failure + angina
33%  revascularization procedures
CAMELOT2
1,991 CAD patients (>20%): Double-blind,
randomized study vs. placebo and enalapril 20 mg
Primary outcome: 31%  in CV events vs. placebo
41%  hospitalization for angina
27%  coronary revascularization
ASCOT-BPLA/CAFE3,4
19,257 HTN patients: Multicenter, randomized,
prospective study vs. atenolol
Primary outcome: 10%  in non-fatal MI & fatal CHD
16%  total CV events and procedures
30%  new-onset diabetes
27%  stroke
11%  all-cause mortality
 central aortic pressure by 4.3 mmHg
ALLHAT5
18,102 HTN patients: Randomized, prospective
study vs. lisinopril
Primary outcome: No difference in composite of fatal
CHD + non-fatal MI vs. lisinopril
6%  combined CVD
23%  stroke

Non-fatal MI (excluding
silent) + fatal CHD
Total coronary endpoint
Total CV events and procedures
All-cause mortality
CV mortality
Fatal/non-fatal stroke
Fatal/non-fatal HF
Development of renal impairment
0.5 1 2
ASCOT BPLA1
Amlodipine-based
better
Atenolol-based
better
Valsartan and Amlodipine in High-risk Hypertension Have Proven
Endpoint Benefits
0.5 2
Primary cardiac composite
endpoint
Cardiac mortality
Cardiac morbidity
All MI
All congestive heart failure
All stroke
All-cause death
New-onset diabetes
1
VALUE trial2
Favors
valsartan
Favors
amlodipine
Development of diabetes
1Dahlöf et al. Lancet 2005;366:895–906; 2Julius et al. Lancet 2004;363:2022–31

Amlodipine/Valsartan: BP Reductions Across All Grades
of Hypertension - (Exzellent Trial1)
DBP ↓ (mmHg) –17 –18 –29
n =
1800
n =
2293
n =
890
1Schrader J et al. PS38 Late Breaking Abstracts Session. ESH/ISH Congress, 14 June 2008.
-19
-32
-49

Amlodipine/Valsartan FDC: BP Reductions for Patients
with Diabetes– (Exzellent Trial1)
n =
639
n =
795 n =
295
1Schrader J et al. PS38 Late Breaking Abstracts Session. ESH/ISH Congress, 14 June 2008.
-19
-32
-48
DBP ↓ (mmHg) –11 –15 –18
syst.BP
reduction
(mmHg)

Amlodipine/Valsartan: Powerful SBP Drops of Over 40
mmHg in Patients with Baseline MSSBP ≥180 mmHg
LSM Change in MSSBP from baseline (mmHg) LSM Change in MSSBP from baseline (mmHg)
p=0.1
−20
−10
0
Amlodipine/Valsartan
10/160 mg
Amlodipine
10 mg
p=0.0018
−40
−30
N=55
−31.7
N=46
–40.1
LSM=least square mean
MSSBP=mean sitting systolic blood pressure
EX-EFFeCTS1
Patients with Stage 2 Hypertension
−20
−10
0
N=42
Amlodipine/Valsartan
10/160–320 mg
Amlodipine
10 mg
–43.5
−40
−30
−50
−37.2
N=38
EX-STAND2
Black Patients with Stage 2 Hypertension
1.Destro et al. J Am Soc Hypertens 2008;2:294–302
2.Flack et al. J Hum Hypertens 2009 (E-pub ahead of print).

Amlodipine/Valsartan: Up to 9 Out of 10 Patients
Reach BP Goal <140/90 mmHg
77.1
84.4
78.4
85.2
69.7
80
0
20
40
60
80
100
All patients Non-diabetic patients Diabetic patients
Amlodipine/Valsartan 5/160 mg Amlodipine/Valsartan 10/160 mg
Diabetic patients with BP <130/80 mmHg at Week 8 were 47.0% and
49.2% for 5/160 mg and 10/160 mg doses, respectively
Patients
(%)
Data shown are at Week 8
No hydrochlorothiazide add-on was permitted until after Week 8
Randomized, double-blind, multinational, parallel-group, 16-week study
n=440 n=369 n=71 n=449 n=375 n=74
80.0
Adapted from
Allemann et al. J Clin Hypertens 2008;10:185–94

96.6
89.3
82.3
80
90
100
Mean
diastolic
BP
(mmHg)
136
151.4
166.7
120
140
160
180
Mean
systolic
BP
(mmHg)
Amlodipine/Valsartan: Additional BP Drops in Non-
responders to Ramipril/Felodipine
–30.7 mmHg
–14.3 mmHg
–15.4 mmHg
p<0.0001 –7.0 mmHg
p<0.0001
Week 0 5 10
N=133
After
Amlo/Val 10/160
After Ram
5 + Fel 5
Open, sequential, non-
responder, 10-week study
After
Amlo/Val 10/160
After Ram
5 + Fel 5
Week 0 5 10
Trenkwalder et al. J Hypertens 2007;25(Suppl. 2):S228 (abstract P24.261)

*p<0.01 vs. amlodipine
Fogari et al. J Hum Hypertens 2007;21:220-4
EXFORGE® Significantly Reduces Fluid Retention
Vs Amlodipine Monotherapy
*
6.8
23.0
25
20
15
10
5
0
Ankle-foot
volume
increase
(%)
Amlodipine 10 mg EXFORGE®
10/160 mg
n=80
70%
difference

–43.0
*
–31.2
†
Amlodipine/Valsartan: Powerful SBP Drops of 43 mmHg in Patients
with a Baseline MSSBP 180 mmHg
*p<0.001; †p<0.002 vs.
baseline
Change
from
baseline
in
MSSBP
at
6-week
endpoint
(mmHg)
Endpoint BP
(mean)
0
–10
–20
–30
–40
–50
Amlodipine (5–10 mg)
+ valsartan (160 mg)
145.4 mmHg 157.4 mmHg
Lisinopril (10–20 mg) +
HCTZ (12.5 mg)
n=15 n=11
Change in MSDBP (mmHg) –26.1* –21.7*
Poldermans et al. Clin Ther 2007;29:279–89
Baseline mean sitting systolic BP (MSSBP): 188 mmHg
Baseline mean sitting diastolic BP (MSDBP): 113 mmHg
Randomized, double-blind, multicenter, active-controlled study

Blood Pressure and Cardiovascular Risk:
ESHESC Guidelines
Other RF,
OD or
disease
BP (mmHg)
Normal
SBP 120–129
or DBP 80–84
High normal
SBP 130–139
or DBP 85–89
Grade 1
SBP 140–159
or DBP 90–99
Grade 2
SBP 160–179
or DBP 100–109
Grade 3
SBP 180
or DBP 110
No other RF Average risk Average risk
Low added
risk
Moderate
added risk
High added
risk
1–2 RF
Low added
risk
Low added
risk
Moderate
added risk
Moderate
added risk
Very high
added risk
3 RF, MS,
OD or
diabetes
Moderate
added risk
High added
risk
High added
risk
High added
risk
Very high
added risk
Established
CV or renal
disease
Very high
added risk
Very high
added risk
Very high
added risk
Very high
added risk
Very high
added risk
MS = metabolic syndrome
OD = subclinical organ damage
RF = risk factors
Reproduced from the Task Force of ESH–ESC. J Hypertens 2007;25:1105–87
Copyright © 2007, with permission from Lippincott Williams and Wilkins

Summary of Amlodipine/Valsartan Clinical Data
 Amlodipine/Valsartan – the first antihypertensive agent available
to physicians that reduces BP via dual calcium channel and
angiotensin receptor blockade
 Data on Amlodipine/Valsartan demonstrate
 Powerful BP reductions across all grades of hypertension1,2
 Up to 43 mmHg drop in patients with a mean sitting systolic BP
(SBP) 180 mmHg2
 Incremental BP drops over reductions achieved with previous
medications
 ~21 mmHg SBP drop in patients uncontrolled on monotherapy3
 ~15 mmHg SBP drop in patients uncontrolled on combination
therapy4
1 Smith et al. J Clin Hypertens 2007;9:355–64; 2 Poldermans et al. Clin Ther 2007;29:279–89
3Allemann et al. J Clin Hypertens 2007 (In press); 4Trenkwalder et al. J Hypertens 2007;25(Suppl. 2):S228
(abstract P24.261); 5Philipp et al. Clin Ther 2007;29:563–80

Summary of Amlodipine/Valsartan Clinical Data
 Up to 9 out of 10 patients achieved BP <140/90 mmHg3
 Well tolerated with a reduction in the incidence of peripheral
edema compared with amlodipine monotherapy5
• ARB at least the same efficacy as ACEI but better
tolerability/safety and potentially a stroke benefit
• Valsartan can preferably be combined with Amlodipine, HCTZ
and Aliskiren SPC to a majority
1 Smith et al. J Clin Hypertens 2007;9:355–64; 2 Poldermans et al. Clin Ther 2007;29:279–89
3Allemann et al. J Clin Hypertens 2007 (In press); 4Trenkwalder et al. J Hypertens 2007;25(Suppl. 2):S228
(abstract P24.261); 5Philipp et al. Clin Ther 2007;29:563–80

The Best Marker to Monitor in Treating Blood
Pressure …. Is Blood Pressure Itself

Every two seconds,
one person dies from cardiovascular
disease

…are
frightened to
death of cancer
and AIDS…or
H1N1
…and ultimately die of
cardiovascular diseases
The Paradox of Diseases
The majority of people continuously
complain of allergic problems…

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