Transcript Get to Goal, Achieve - The 3rd Arab Diabetes Forum In

Get to Goal,
Achieve Control
PROFESSOR Dr.ALAA ETMAN MD
NATIONAL HEART INSTITUTE
Cardiovascular diseases leading causes of global
mortality
Maternal and perinatal conditions
Nutritional deficiencies
Other non-infectious
diseases
Infectious and
parasitic diseases
Injuries
Cancer
Respiratory diseases
Respiratory infections
CV diseases
WHO World Health Report 2004
Prevalence of Hypertension
30
25
20
10
13.6
India
China
6.07
12.08
5
22
20.4
26.3
% 15
0
Egypt
Bangladesh
USA
Candada
Proportion of Patients Treated/Not Treated
for Hypertension in Europe*
Patients (%)
England
Sweden
*Age adjusted; patients aged 35–64 years
Hypertension = 140/90mmHg threshold
Wolf-Maier et al. Hypertension 2004;43:10–17
Germany
Spain
Italy
Prevalence of Hypertension
Increases with Age
Prevalence of Hypertension (%)
Estimated non-institutionalized US adults, 19992002
Adapted from Centers for Disease Control and Prevention
2039
4059
Age (years)
Brown. BMJ 2006;332:8336
60
Stroke & IHD* Mortality Rate in Each
Decade of Age, vs Usual Systolic BP at the
Start of that Decade
Ischaemic Heart Disease
Stroke
Age at risk
256
80–89 y
128
80–89 y
256
70–79 y
70–79 y
128
60–69 y
64
60–69 y
50–59 y
32
50–59 y
16
16
40–49 y
8
8
4
4
2
2
64
Mortality*
Age at risk
32
1
1
0
0
120
140
160
180
Usual SBP (mmHg)
120
140
160
Usual SBP (mmHg)
*Floating absolute risk and 95% CI
Reproduced from The Lancet, 360, Lewington et al. pp. 1903–13. Copyright © 2002, with permission from Elsevier
*IHD= Ischaemic Heart Disease
180
Cardiovascular Mortality Risk Doubles with
Each 20/10 mmHg Increment in
Systolic/Diastolic BP*
Cardiovascular Mortality Risk
8
8X risk
6
4
4X risk
2
2X risk
0
1X risk
115/75
135/85
155/95
Systolic BP/Diastolic BP (mmHg)
*Individuals aged 40–69 years
Lewington et al. Lancet 2002;360:1903–13
175/105
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
Lewington et al. Lancet 2002;360:1903–13
7% reduction in risk
of ischaemic heart
disease mortality
10% reduction in risk
of stroke mortality
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
220
54%
13%
Not at SBP
or DBP goal
SBP, mmHg
200
67% did not reach
SBP goal
180
160
140
140
120
At SBP and
DBP goal
100
90
29%
4%
80
20
40
60
80
100
120
140
DBP, mmHg
Adapted from Lloyd-Jones DM, et al. Hypertension. 2000;36:594–599.
Predictive Power of Systolic BP on Cardiovascular Mortality
Systolic BP (mmHg)
Diastolic BP (mmHg)
<140
<90
140–159
90–99
160–179
100
≥180
0.5
1
1.5
2
2.5
0.5
Prognosis
worse
1.5
2
2.5
Relative risk
Relative risk
Prognosis
better
1
Prognosis
better
Prognosis
worse
Alli et al. Arch Intern Med 1999;159:1205–12
11-Year Increase in Risk of CV Death for 10 mmHg Increase
in SBP at Different Baseline SBP Values
Increase in risk of CV death (%)
5
4
Office
4.
5
Home
24h
3
2.4
2.0
2
1.8
1.3
1
0
1.1
0.9
0.8
0.6
120
130
140
Baseline SBP (mmHg)
Sega et al., Circulation 2005
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
Surrogate Endpoints
Drug
Treatment
Hard Endpoints
Atrial Fibrillation
Systolic Dysfunction
Diastolic Dysfunction
Metabolic Syndrome to Diabetes
Natural History of Cardiovascular Disease
Treatment of
Clinical Events
Treatment of
Silent Lesions
MI, Angina
Stroke
ToCongestive
Interrupt
Vascular
Cardiac
Failure
Renal
Failure
Disease
Progression
LVH
Periferal Artery Disease
> IM thickness
Lacunar infarcts
Microalbuminuria
Arteriosclerosis
Vascular remodeling
Hypertension
Diabetes
Dislipidemia
Central Obesity
Genes
Life style
Treatment of
Cardiovascular Risk
Factors
Life Style Changes
Non-fatal
recurrent
events
CRF
Dialysis
Dementia
Death
Angiotensin II Plays a Central Role in Organ
Damage
Stroke
Atherosclerosis*
Vasoconstriction
Vascular hypertrophy
A II
AT1 Receptor
LV hypertrophy
Fibrosis
Remodeling
Apoptosis
GFR
Proteinuria
Aldosterone release
Glomerular sclerosis
Hypertension
Heart failure
MI
DEATH
Renal failure
*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
Associated risk factors
Blood Pressure and Cardiovascular Risk: ESHESC
Guidelines
BP (mmHg)
Other RF,
OD or
disease
No other
RF
Normal
High normal
Grade 1
SBP 160–179
or DBP 100–
109
SBP 180
or DBP 110
Low added
risk
Moderate
added risk
High added
risk
SBP 120–129 SBP 130–139 SBP 140–159
or DBP 80–84 or DBP 85–89 or DBP 90–99
Average risk Average risk
Grade 2
Grade 3
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
Very high
CV or renal
added risk
disease
MS = metabolic syndrome
Very high
added risk
Very high
added risk
Very high
added risk
Very high
added risk
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
LVH: Left ventricular hypertrophy
IMT: Intima media thickness
Mancia G, et al. J Hypertens. 2007;25:1105-87
ESH/ESC & JNC 7 Summary:
Target BP Goals
Types of Hypertension
Uncomplicated
BP Goal (mmHg)
<140/90
Complicated
Diabetes mellitus
Kidney disease
Other high risk (stroke, myocardial
infarction)
*Lower if proteinuria is >1 g/day
Task Force of ESH–ESC. J Hypertens 2007;25:110587
Chobanian et al. JAMA 2003;289:256072
<130/80
<130/80*
<130/80
Blood Pressure Thresholds (mmHg)
for Definition of Hypertension with
Different Types of Measurement
SBP
DBP
140
90
24-hour
125-130
80
Day
130-135
85
Night
120
70
Home
130-135
85
Office or Clinic
Cont…
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
Wang TJ, Vasan RS. Circulation. 2005;112:1651-1662;
Chobanian AV, et al. JAMA. 2003;289:2560-2572.
•
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
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
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.
•
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”
Recommended Lifestyle Modifications
and Their Individual Effects on Blood
Pressure Approximate
Modifications*
Recommendation
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
Chobanian AV, et al. JAMA. 2003;289:2560-2572;
Blumenthal JA, et al. Arch Intern Med. 2000;160:1947-1958.
Causes of Essential Hypertension
Age
Overweight
Excess
Sodium
Consumption
Elevated
Systolic
and/or Diastolic
Excess
Alcohol
Consumption
Physical
Inactivity
Blood Pressure
Family
History
Stress
Pathophysiology of Hypertension
Pathophysiology of Hypertension
SALT
G1 P1
Salt Sensitivity
DIET
Kidney
G2 P2
Insulin Resistance
Brain
Hypertension
Skeletal muscle
G3 P3
Neurogenic
Hyper-Response
Vessels
STRESS
G4 P4
Vascular Structure
Sever P. J Cardiovasc Pharmacol . 1998;31(suppl 2):S1-S4.
Sever P. J Cardiovasc Pharmacol . 1998;31(suppl 2):S1-S4.
Sever P. J Cardiovasc Pharmacol . 1998;31(suppl 2):S1-S4.
Hypertension Syndrome!!
It’s More Than Just Blood Pressure
Obesity
Decreased
Arterial
Compliance
Endothelial
Dysfunction
Abnormal
Glucose
Metabolism
Abnormal Lipid
Metabolism
Accelerated
Atherogenesis
Hypertension
LV Hypertrophy
and Dysfunction
Neurohormonal
Dysfunction
Renal-Function
Changes
Abnormal Insulin
Metabolism
Blood-Clotting
Mechanism
Changes
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.
Blood Pressure Regulation
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
1. Increase BP & renal
perfusion pressure
? 2.
Decrease PT NaCl reabsorption
40% increase volume
flow from PT
3. Increase [NaCl] at macula
densa generates TGF signal
4. Increase afferent arteriole resistance
•
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.
5. Autoregulate RBF, GFR
Increase NaCl
delivery to
distal nephron
Natriuresis
Diuresis “Pressure Natriuresis”
ECFV: Extracellular fluid volume, a function of Na+ reabsorption ; RBF: Renal blood flow; PT: Proximal tubule; GFR:
Glomerular filtration rate; TGF: tubuloglomerular feedback
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
The renin–angiotensin
system (RAS)
(RAAS)
Bradykinin/NO
Angiotensin I
Chymase
tPA
Cathepsin
ACE
Inactive fragments
Angiotensin II
AT1 RECEPTOR
AT2 RECEPTOR
Vasoconstriction
Sodium retention
SNS activation
Inflammation
Growth-promoting effects
Aldosterone
Apoptosis
Vasodilation
Natriuresis
Tissue regeneration
Inhibition of inappropriate cell growth
Differentiation
Anti-inflammation
Apoptosis
Hanon S., et al. J Renin
Angiotensin
Syst 2000;1:147–150;
Chen
R., et al. Hypertension
2003;42:542–547;
Hurairah
H., et al. Int J Clin Pract
Hanon
S., et al. JAldosterone
Renin Angiotensin
Aldosterone Syst
2000;1:147–150;
Chen R.,
et al. Hypertension
2003;42:542–547;
2004;58:173–183; Hurairah
Steckelings
U.M.,
e
t
al
.
Peptides
2005;26:1401–1409
H., et al. Int J Clin Pract 2004;58:173–183; Steckelings U.M., et al. Peptides 2005;26:1401–1409
ACE Inhibition
Bradykinin/NO
Angiotensin I
ACE
Inhibitor
Inactive fragments
Chymase
tPA
Cathepsin
Angiotensin II ‘Angiotensin II escape’
Vasodilation
Tissue protection
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
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
Selective AT1 Receptor Blockade (ARB)
Bradykinin/NO
Angiotensin I
Chymase
tPA
Cathepsin
ACE
Inactive fragments
Angiotensin II
Bradykinin?
ARB
AT1 RECEPTOR
Vasoconstriction
Sodium retention
SNS activation
Inflammation
Growth-promoting effects
Aldosterone
Apoptosis
NO?
AT2 RECEPTOR
Vasodilation
Natriuresis
Tissue regeneration
Inhibition of inappropriate cell growth
Differentiation
Anti-inflammation
Apoptosis
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
Rationale for Dual RAAS Blockade with
ACEI & ARB
Bradykinin/NO
Angiotensin I
Chymase
tPA
Cathepsin
ACE
Inhibitor
Inactive fragments
Vasodilation
Tissue protection
AT1 RECEPTOR
Vasoconstriction
Sodium retention
SNS activation
Inflammation
Growth-promoting effects
Aldosterone
Apoptosis
Angiotensin II ‘Angiotensin II escape’
Bradykinin?
ARB
NO?
AT2 RECEPTOR
Vasodilation
Natriuresis
Tissue regeneration
Inhibition of inappropriate cell growth
Differentiation
Anti-inflammation
Apoptosis
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
ESH/ESC
Algorithm for the Treatment of Hypertension
Consider: BP level before treatment
Absence or presence of TOD and risk factors
Mild BP elevation
Low/moderate CV risk
Conventional BP target
Choose between
Marked BP elevation
High/very high CV risk
Lower BP target
2-drug combination
at low dose
Single agent at low dose
If goal BP not
achieved
Previous
agent at full
dose
Switch to
different agent
at low dose
Previous
combination
at full dose
Add a third
drug at low
dose
If goal BP not
achieved
2-3 drug
combination
at full dose
Full-dose
monotherapy
Task Force of ESH/ESC. J Hypertens 2007;25:1105–87
2–3-drug combination
at full doses
TOD = target organ damage
Advantages of Multiple-mechanism Therapy:
Efficacy
Multiple-mechanism therapy results in a greater BP reduction
than seen with its single-mechanism components1,2
 Components with a different mechanism of action interact
on complementary pathways of BP control1
 Each component can potentially neutralize counterregulatory 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.
2Quan
Drugs 2002;62:44362
et al. Am J Cardiovasc Drugs 2006;6:10313
Advantages of Multiple-mechanism Therapy:
Safety/Tolerability
Multiple-mechanism therapy may have an improved tolerability
profile compared with its single-mechanism components1,2
 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.
2Quan
Drugs 2002;62:44362
et al. Am J Cardiovasc Drugs 2006;6:10313
Advantages of Fixed Versus Free Combinations of Two
Antihypertensive Drugs
Fixed
Free
Simplicity of treatment
+
–
Compliance
+
–
Efficacy
+
+
Tolerability
+*
–
Price
+
–
Flexibility
–
+
*Lower doses generally used in fixed-dose combinations
+ = potential advantage
Better Compliance with Antihypertensive Drugs Leads to
a Lower Risk of Hospitalization
Level of compliance (%)
80–100
n=5,804
60–79
n=921
40–59
n=562
20–39
n=344
1–19
n=350
0
27
30*
36 *
39*
44 *
10
20
30
40
50
All-cause hospitalization risk (%)
*p<0.05 vs 80–100% compliant group
Sokol et al. Med Care 2005;43:521–30
Multiple Antihypertensive Agents are Needed to Reach BP Goal
Trial (SBP achieved)
MDRD (132 mmHg)
HOT (138 mmHg)
RENAAL (141 mmHg)
AASK (128 mmHg)
ABCD (132 mmHg)
IDNT (138 mmHg)
UKPDS (144 mmHg)
ASCOT-BPLA (136.9 mmHg)
ALLHAT (138 mmHg)
ACCOMPLISH* (132 mmHg)
Initial 2-drug combination therapy
*Interim 6-month data
1
2
3
4
Average no. of antihypertensive medications
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
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
Natriuresis
Vasodilation
Arterial
Arterial +
Venous
CCB
ARB
↑ RAS
RAS ↓
↑ SNS
SNS ↓
CCB/ARB: Synergy of Counter-regulation
CCB
 Arteriodilation
 Peripheral edema
 Effective in low-renin patients
 Reduces cardiac ischemia
ARB
 Venodilation
 Attenuates peripheral edema
 Effective in high-renin patients
 No effect on cardiac ischemia
ARB
 RAS blockade
 Congestive heart
failure and renal
benefits
CCB
 RAS activation
 No renal or
congestive heart
failure benefits
Tolerability and Risk Factor Modification: CCB-induced
Peripheral Edema Minimized by the ARB
CCB dilates
arteries
Veins remain
constricted
ARB dilates arteries and
veins
Capillary
overload
forces fluid
into
surrounding
tissue
Reduces
CCB-induced
peripheral
edema
Single mode of action of the
CCB
Dual mode of action of the
CCB/ARB
Illustration modified from www.lotrel.com
Messerli et al. Am J Hypertens 2001;14:978–9
The importance of BP control for CV protection
calls for use of effective antihypertensive drugs
in the context of
effective antihypertensive treatment strategies
12418 M
Choose the treatment…!!!
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
Number of episodes per/day
Maximum home systolic blood pressure measurements were observed up to 50 times 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
Studies (N=63,409 ): ELITE; ELITE-II; OPTIMAAL; DETAIL; VALIANT; ONTARGET
Reboldi et al. J Hypertension 2008;26:1282–1289
Favours
ACE inhibitor
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
Mortality and Morbidity Endpoint Trialsঠwith ARBs
Number of patients
60,000
57,781
35
52,896
8
7
50,000
12
6
5
11
4
40,000
1. VALUE
2. VALIANT
3. NAVIGATOR
4. Val-HeFT
5. JIKEI HEART
6. KYOTO HEART*
7. VART*
8. VALISH*
10
3
30,000
24,841
18
17
16
15
2
20,000
14
10,000
9
1
0
Valsartan
13
9. ONTARGET
10. PRoFESS
11. TRANSCEND
12. HALT-PKD*
13. LIFE
14. OPTIMAAL
15. ELITE II
16. RENAAL
17. NCT00090259*
18. VA NEPHRON-D*
19. CHARM
20. SCOPE
21. SCAST*
22. CASE-J
23. ACCOST
24. HIJ-CREATE
25. E-COST
26. I-PRESERVE
27. IDNT
28. ACTIVE-I*
29. NID-2
30. SUPPORT*
31. COLM*
32. OSCAR*
33. ORIENT*
34. MOSES
35. NAGOYA
Heart S
23,940
25
24
15,693
23
22
29
21
20
28
19
27
26
6,577
31
33
32
1,405
30
34
Telmisartan Losartan Candesartan Irbesartan Olmesartan Eprosartan
*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
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.
VALUE: Incidence of New-onset Diabetes
23% risk reduction
with valsartan
18
New-onset diabetes
(% of patients in
treatment group)
16
P < 0.0001
14
12
10
8
6
16.4%
13.1%
4
2
0
Amlodipine-based
regimen
(n = 7,596)
Julius S et al. Lancet. June 2004;363.
Valsartan-based regimen
(n = 7,649)
Valsartan Improves Insulin Sensitivity in Hypertensive
Patients*
Normotensive (n = 20)
Hypertensive pretreatment (n = 20)
Hypertensive posttreatment (n = 20)
25
25
19.6
20
15
Fasting Insulin
(µlU/mL)
10
20
8.7
9.8†
HOMA-IR
15
10
5
5
0
0
4.4
1.9
*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.
2.2†
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
Plasma
Leptin
HOMA-IR
Plasma
norepinephrine
38.8*§
40
Change from baseline (%)
30
DIOVAN 80-160 mg od (n=46)
Felodipine 5-10 mg od (n=45)
20
10
0.6
0.1
0
-10
*
-4.7*
-3.8
-10.1**
-20
-13.8***
†
-20.0**
≥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
†BMI
Valsartan® Significantly Increases Adiponectin in
Obese Patients with HTN
Results from a 12-week study in 72 obese§ patients with mild-to-moderate HTN#
2
Adiponectin
(ng/mL)
Leptin
(ng/mL)
Resistin
(ng/mL)
HOMA-IR
-0.2
-0.2
1.1*
Change in plasma levels
from baseline to 12 weeks
1
0.3
0
-0.3
-1
-1.1*
-2
DIOVAN 160 mg/day (n=36)
-3
-4
§BMI
-1.0*
Amlodipine 10 mg/day (n=36)
-3.7*
≥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)
Valsartan: Wealth of CV Outcomes Data
VALUE1
No difference in composite of cardiac mortality and
morbidity (primary)
15,245 high-risk HTN patients; Double-blind,
randomized study vs. amlodipine
23%  new-onset diabetes
VALIANT2
No difference vs. captopril in all-cause mortality
(primary)
14,703 post-myocardial infarction patients; Doubleblind, randomized study vs. captopril and vs.
captopril + valsartan
(valsartan is as effective as standard of care)
Val-HeFT3–5
13%  morbidity and mortality (primary)
5,010 heart failure II–IV patients; Double-blind,
randomized study vs. placebo
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
1Julius
 left ventricular remodeling
37%  atrial fibrillation occurrence
 heart failure signs/symptoms
28%  heart failure hospitalization
39%
40%
47%
65%




composite CV mortality and morbidity
Stroke/transient ischemic attack
Hospitalization for heart failure
Hospitalization for angina
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
Amlodipine: Wealth of CV Outcomes Data
PREVENT1
825 CAD patients (≥30%): Multicenter,
randomized, placebo controlled
CAMELOT2
1,991 CAD patients (>20%): Double-blind,
randomized study vs. placebo and enalapril 20 mg
ASCOT-BPLA/CAFE3,4
19,257 HTN patients: Multicenter, randomized,
prospective study vs. atenolol
ALLHAT5
18,102 HTN patients: Randomized, prospective
study vs. lisinopril
1Pitt
Primary outcome: No difference in mean 3 yr
coronary angiographic changes vs. placebo
35%  hospitalization for heart failure + angina
33%  revascularization procedures
Primary outcome: 31%  in CV events vs. placebo
41%  hospitalization for angina
27%  coronary revascularization
Primary outcome: 10%  in non-fatal MI & fatal CHD
16%
30%
27%
11%
 total CV events and procedures
 new-onset diabetes
 stroke
 all-cause mortality
 central aortic pressure by 4.3 mmHg
Primary outcome: No difference in composite of fatal
CHD + non-fatal MI vs. lisinopril
6%  combined CVD
23%  stroke
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
Valsartan and Amlodipine in High-risk Hypertension Have Proven
Endpoint Benefits
ASCOT BPLA1
VALUE trial2
Non-fatal MI (excluding
silent) + fatal CHD
Primary cardiac composite
endpoint
Total coronary endpoint
Cardiac mortality
Total CV events and procedures
Cardiac morbidity
All-cause mortality
All MI
CV mortality
All congestive heart failure
Fatal/non-fatal stroke
Fatal/non-fatal HF
All stroke
Development of renal impairment
All-cause death
Development of diabetes
New-onset diabetes
0.5
1
2
Amlodipine-based Atenolol-based
better
better
1Dahlöf
0.5
2
1
Favors
valsartan
Favors
amlodipine
et al. Lancet 2005;366:895–906; 2Julius et al. Lancet 2004;363:2022–31
Exforge Clinical data
Amlodipine/Valsartan: BP Reductions Across All Grades
of Hypertension - (Exzellent Trial1)
n=
1800
n=
2293
-19
-32
n=
890
-49
DBP ↓ (mmHg)
Page 70
–17
–18
1Schrader
–29
J et al. PS38 Late Breaking Abstracts Session. ESH/ISH Congress, 14 June 2008.
syst.BP reduction (mmHg)
Amlodipine/Valsartan FDC: BP Reductions for Patients
with Diabetes– (Exzellent Trial1)
DBP ↓ (mmHg)
n=
639
n=
795
-19
n=
295
-32
-48
–11
–15
–18
Page 71
1Schrader
J et al. PS38 Late Breaking Abstracts Session. ESH/ISH Congress, 14 June 2008.
Amlodipine/Valsartan: Powerful SBP Drops of Over 40
mmHg in Patients with Baseline MSSBP ≥180 mmHg
EX-EFFeCTS1
EX-STAND2
Patients with Stage 2 Hypertension
Black Patients with Stage 2 Hypertension
Amlodipine/Valsartan
10/160 mg
Amlodipine
10 mg
N=46
N=55
0
Amlodipine/Valsartan
10/160–320 mg
Amlodipine
10 mg
0
N=42
N=38
−10
−10
−20
−20
−30
−30
−31.7
−40
−40
–40.1
p=0.0018
−37.2
–43.5
−50
p=0.1
LSM Change in MSSBP from baseline (mmHg)
LSM Change in MSSBP from baseline (mmHg)
LSM=least square mean
MSSBP=mean sitting systolic blood pressure
2.Flack
1.Destro et al. J Am Soc Hypertens 2008;2:294–302
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
All patients
Non-diabetic patients
Diabetic patients
100
84.4
Patients (%)
80
77.1
85.2
78.4
80
80.0
69.7
60
n=440
n=369
n=71
n=449
n=375
n=74
40
20
0
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
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
Adapted from
Allemann et al. J Clin Hypertens 2008;10:185–94
Amlodipine/Valsartan: Additional BP Drops in Nonresponders to Ramipril/Felodipine
N=133
160
–30.7 mmHg
166.7
–14.3 mmHg
100
–15.4 mmHg
p<0.0001
151.4
140
136
Mean diastolic BP (mmHg)
Mean systolic BP (mmHg)
180
96.6
–7.0 mmHg
p<0.0001
90
89.3
82.3
120
Week
80
0
Open, sequential, nonresponder, 10-week study
5
10
After Ram
After
5 + Fel 5 Amlo/Val 10/160
Week
0
5
10
After Ram
After
5 + Fel 5 Amlo/Val 10/160
Trenkwalder et al. J Hypertens 2007;25(Suppl. 2):S228 (abstract P24.261)
EXFORGE® Significantly Reduces Fluid Retention
Vs Amlodipine Monotherapy
Ankle-foot volume increase (%)
25
n=80
23.0
20
70%
difference
15
10
*
6.8
5
0
Amlodipine 10 mg
10/160 mg
*p<0.01 vs. amlodipine
Page 75
EXFORGE®
Fogari et al. J Hum Hypertens 2007;21:220-4
Amlodipine/Valsartan: Powerful SBP Drops of 43 mmHg in Patients
with a Baseline MSSBP 180 mmHg
Change from baseline in
MSSBP at 6-week
endpoint (mmHg)
Endpoint BP
(mean)
0
Amlodipine (5–10 mg)
+ valsartan (160 mg)
145.4 mmHg
Lisinopril (10–20 mg) +
HCTZ (12.5 mg)
157.4 mmHg
n=15
n=11
–10
–20
–30
–31.2
†
–40
–50
Change in MSDBP (mmHg)
–43.0
*
–26.1*
–21.7*
*p<0.001; †p<0.002 vs.
baseline
Baseline mean sitting systolic BP (MSSBP): 188 mmHg
Baseline mean sitting diastolic BP (MSDBP): 113 mmHg
Randomized, double-blind, multicenter, active-controlled study
Poldermans et al. Clin Ther 2007;29:279–89
Blood Pressure and Cardiovascular Risk:
ESHESC Guidelines
BP (mmHg)
Other RF,
OD or
disease
Normal
High normal
Grade 1
Grade 2
SBP 120–129
or DBP 80–84
SBP 130–139
or DBP 85–89
SBP 140–159
or DBP 90–99
SBP 160–179
or DBP 100–109
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
Page 77
Grade 3
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
3Allemann
et al. J Clin Hypertens 2007;9:355–64; 2 Poldermans et al. Clin Ther 2007;29:279–89
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
3Allemann
et al. J Clin Hypertens 2007;9:355–64; 2 Poldermans et al. Clin Ther 2007;29:279–89
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
The Paradox of Diseases
The majority of people continuously
complain of allergic problems…
…are
frightened to
death of cancer
and AIDS…or
H1N1
…and ultimately die of
cardiovascular diseases
Thank You