professor dr.alaa etman md national heart institute professor dr.alaa etman md national heart...
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PROFESSOR Dr.ALAA ETMAN MD NATIONAL HEART INSTITUTE
PROFESSOR Dr.ALAA ETMAN MD NATIONAL HEART INSTITUTE
Get to Goal,
Achieve Control
Get to Goal,
Achieve Control
WHO World Health Report 2004
CV diseases
Cancer
Infectious and parasitic diseases
Other non-infectiousdiseases
Injuries
Respiratory diseases
Respiratory infections
Maternal and perinatal conditionsNutritional 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 yearsHypertension = 140/90mmHg threshold
Prevalence of Hypertension Increases with Age
Brown. BMJ 2006;332:8336
2039 4059 60
Prevalence of Hypertension (%)
Age (years)
Estimated non-institutionalized US adults, 19992002Adapted 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
Mort
ality
*
Usual SBP (mmHg)
50–59 y
60–69 y
70–79 y
80–89 y
StrokeAge 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% CIReproduced from The Lancet, 360, Lewington et al. pp. 1903–13. Copyright © 2002, with permission from Elsevier
Mort
ality
*
Usual SBP (mmHg)
50–59 y
60–69 y
70–79 y
80–89 y
StrokeAge 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% CIReproduced 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 2 mmHg decrease in decrease in mean SBPmean SBP 10% reduction in 10% reduction in
risk of stroke risk of stroke mortalitymortality
7% reduction in 7% reduction in risk of ischaemic risk of ischaemic heart disease heart disease mortalitymortality
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
SB
P,
mm
Hg
20 60 100 120 1408040
67% did not reach SBP goal
4%
13%
29%
54%
80
100
120
140
160
180
200
220
90
140
Not at SBPor 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
5Office
Home
24h
11-Year Increase in Risk of CV Death for 10 mmHg Increase 11-Year Increase in Risk of CV Death for 10 mmHg Increase in SBP at Different Baseline SBP Valuesin SBP at Different Baseline SBP Values
11-Year Increase in Risk of CV Death for 10 mmHg Increase 11-Year Increase in Risk of CV Death for 10 mmHg Increase in SBP at Different Baseline SBP Valuesin SBP at Different Baseline SBP Values
Sega et al., Circulation 2005Sega et al., Circulation 2005
Incr
ease
in r
isk
of
CV
dea
th (
%)
Incr
ease
in r
isk
of
CV
dea
th (
%)
Baseline SBP (mmHg)Baseline SBP (mmHg)
0.60.60.80.8
1.11.10.90.91.31.3
2.02.01.81.8
2.42.4
4.4.55
Evolution of Cardiovascular Risk in Hypertension
Low Risk Higher Risk Highest Risk
Clinical TrialTreatment 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 EndpointsSurrogate Endpoints
Drug Treatment
Atrial FibrillationSystolic DysfunctionDiastolic Dysfunction
Metabolic Syndrome to Diabetes
HypertensionDiabetes
DislipidemiaCentral Obesity
ArteriosclerosisVascular remodeling
LVH> IM thickness
Lacunar infarctsMicroalbuminuria
MI, AnginaStroke
Congestive Cardiac FailureRenal Failure
Periferal Artery DiseaseNon-fatalrecurrentevents
CRFDialysis
DementiaTreatment of Cardiovascular Risk
Factors
GenesLife style
DeathLife 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*VasoconstrictionVascular hypertrophy
LV hypertrophyFibrosisRemodelingApoptosis
Stroke
DEATH
GFRProteinuriaAldosterone releaseGlomerular sclerosis
Renal failure
Hypertension
Heart failureMI
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):313
Associated risk factors
Blood Pressure and Cardiovascular Risk: ESHESC Guidelines
Other RF, OD or disease
BP (mmHg)
NormalSBP 120–129or DBP 80–
84
High normal
SBP 130–139
or DBP 85–89
Grade 1 SBP 140–
159or DBP 90–
99
Grade 2SBP 160–179or 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 RFLow added
riskLow added
riskModerate 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 addedrisk
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 riskMS = metabolic syndrome
OD = subclinical organ damageRF = 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;25:1105-87LVH: Left ventricular hypertrophyIMT: 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;25:110587Chobanian et al. JAMA 2003;289:256072
*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
Cont…
Causes of Inadequate Responsiveness to Therapy….cont.
Patient-Related Barriers to EffectiveAntihypertensive 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 EffectiveAntihypertensive 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* RecommendationApproximate SBP Reduction
Reduce weight Maintain normal body weight
(BMI of 18.524.9 kg/m2)320 mm Hg
Adopt DASH dietRich in fruit, vegetables, and
low-fat dairy; reduced saturated and total fat content
814 mm Hg
Reduce dietary sodium
<100 mmol (2-4 g)/day 28 mm Hg
Increase physical activity
Aerobic activity >30 min/day most days of the week
49 mm Hg
Moderate alcohol consumption
Men: ≤ 2 drinks/dayWomen: ≤ 1 drink/day
24 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
ExcessSodium
ConsumptionOverweight
ExcessAlcohol
Consumption
Physical Inactivity
ElevatedSystolic
and/or Diastolic
Blood Pressure
Family History Stress
Pathophysiology of Hypertension
Sever P. J Cardiovasc Pharmacol . 1998;31(suppl 2):S1-S4.
Sever P. J Cardiovasc Pharmacol . 1998;31(suppl 2):S1-S4.
Pathophysiology of Hypertension
Sever P. J Cardiovasc Pharmacol . 1998;31(suppl 2):S1-S4.
Vessels
BrainKidney
Skeletal muscle
Hypertension
Salt Sensitivity
G1 P1
NeurogenicHyper-Response
G3 P3
Insulin Resistance
G2 P2
Vascular Structure
P4G4STRESS
SALT
DIET
Hypertension Syndrome!! It’s More Than Just Blood Pressure
DecreasedArterial
Compliance Endothelial Dysfunction
Abnormal Glucose
Metabolism
Neurohormonal Dysfunction
Renal-Function Changes
Blood-Clotting Mechanism
Changes
Obesity
Abnormal Insulin Metabolism
LV Hypertrophyand 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.
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
2. Decrease PT NaCl reabsorption
3. I ncrease [NaCl] at macula
densa generates TGF signal
Natriuresis
Diuresis “Pressure Natriuresis”
1. I ncrease BP & renal
perfusion pressure
I ncrease NaCl
delivery to
distal nephron
4. I ncrease aff erent arteriole resistance
5. Autoregulate RBF, GFR
40% increase volume flow f rom 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
ChymasetPA
Cathepsin
AT1 RECEPTOR
VasoconstrictionSodium retentionSNS activationInflammation
Growth-promoting effectsAldosteroneApoptosis
AT2 RECEPTOR
VasodilationNatriuresis
Tissue regenerationInhibition of inappropriate cell growth
DifferentiationAnti-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
VasodilationTissue protection
ACEInhibitor
Angiotensin I
Angiotensin II
ChymasetPA
Cathepsin
AT1 RECEPTOR
VasoconstrictionSodium retention
SNS activationInflammation
Growth-promoting effectsAldosteroneApoptosis
‘Angiotensin II escape’
AT2 RECEPTOR
VasodilationNatriuresis
Tissue regenerationInhibition of inappropriate cell
growthDifferentiation
Anti-inflammationApoptosis
Selective AT1 Receptor Blockade (ARB)
Bradykinin/NO
Inactive fragments
ACE
Angiotensin I
Angiotensin II
ChymasetPA
Cathepsin
ARB Bradykinin?
NO?
AT1 RECEPTOR
VasoconstrictionSodium retention
SNS activationInflammation
Growth-promoting effectsAldosteroneApoptosis
AT2 RECEPTOR
VasodilationNatriuresis
Tissue regenerationInhibition of inappropriate cell
growthDifferentiation
Anti-inflammationApoptosis
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 withACEI & ARB
Bradykinin/NO
Inactive fragments
VasodilationTissue protection
ACEInhibitor
Angiotensin I
Angiotensin II
ChymasetPA
Cathepsin
AT1 RECEPTOR
VasoconstrictionSodium retention
SNS activationInflammation
Growth-promoting effectsAldosteroneApoptosis
‘Angiotensin II escape’
AT2 RECEPTOR
VasodilationNatriuresis
Tissue regenerationInhibition of inappropriate cell
growthDifferentiation
Anti-inflammationApoptosis
ARBBradykinin?
NO?
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
Consider: BP level before treatmentAbsence or presence of TOD and risk factors
Choose between
If goal BP not achieved
If goal BP not achieved
2–3-drug combinationat full doses
ESH/ESCAlgorithm for the Treatment of
Hypertension
TOD = target organ damage
Marked BP elevationHigh/very high CV riskLower BP target
Mild BP elevationLow/moderate CV
riskConventional 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 monotherap
y
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;62:443622Quan et al. Am J Cardiovasc Drugs 2006;6:10313
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;62:443622Quan et al. Am J Cardiovasc Drugs 2006;6:10313
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*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
Leve
l of
com
plia
nce
(%)
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 medications1 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
CCBCCB ARBARB
Vasodilation Vasodilation
NatriuresisNatriuresis
ArterialArterial Arterial +Arterial +VenousVenous
RAS ↓RAS ↓
SNS ↓SNS ↓
↑ ↑ RASRAS
↑ ↑ SNSSNS
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
ReducesCCB-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 M12418 M
The importance of BP control for CV protectionThe importance of BP control for CV protectioncalls for use of calls for use of effective antihypertensive drugseffective antihypertensive drugs
in the context of in the context of effective antihypertensive treatment strategieseffective antihypertensive treatment strategies
Choose the treatment…!!!
Maximum home blood pressure: a novel indicator of target-organ damage in hypertensionMaximum 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 dayMaximum home systolic blood pressure measurements were observed up to 50 times per day
Num
ber
of e
piso
des
per/
day
Matsui Y et al. Hypertens. 2011;57: in press
High incidence of maximum home systolic blood pressure is associated with a high High incidence of maximum home systolic blood pressure is associated with a high degree of cardiac and vascular remodelingdegree of cardiac and vascular remodeling
Matsui Y et al. Hypertens. 2011;57: in press
ConclusionConclusion
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 ARBFavours
ACE inhibitor
Reboldi et al. J Hypertension 2008;26:1282–1289
Studies (N=63,409N=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*
*Expectedenrolment
‡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
Nu
mb
er o
f p
atie
nts
Valsartan Telmisartan Losartan Candesartan Irbesartan Olmesartan Eprosartan
57,78152,896
24,841 23,940
6,577
1,405
15,693
1
2
5
4
3
78
6
9
10
16
12
11
1718
15
13
14
2223
25
19
20
3431
30
3233
29
28
2726
24
35. NAGOYA Heart S
35
VALUE: Incidence of New-onset DiabetesN
ew-o
nset
dia
bete
s (%
of p
atien
ts in
tr
eatm
ent g
roup
)
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†1.94.4
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 indexFogari et al. Hypertens Res 2005;28:209-214
Chan
ge fr
om b
asel
ine
(%)
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*§
Chan
ge in
pla
sma
leve
lsfr
om b
asel
ine
to 1
2 w
eeks
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. baselineFogari 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/symptoms28% 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 + angina33% 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 angina27% 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 procedures30% new-onset diabetes27% stroke11% 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. lisinopril6% combined CVD23% 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 compositeendpoint
Cardiac mortality
Cardiac morbidity
All MI
All congestive heart failure
All stroke
All-cause death
New-onset diabetes
1
VALUE trial2
Favorsvalsartan
Favorsamlodipine
Development of diabetes
1Dahlöf et al. Lancet 2005;366:895–906; 2Julius et al. Lancet 2004;363:2022–31
Exforge Clinical data
Page 70
Amlodipine/Valsartan: BP Reductions Across All Grades of Hypertension - (Exzellent Trial1)
DBP ↓ (mmHg) –17 –18 –29 DBP ↓ (mmHg) –17 –18 –29
n = n = 18001800
n = n = 22932293
n = n = 890890
1Schrader J et al. PS38 Late Breaking Abstracts Session. ESH/ISH Congress, 14 June 2008.
-19
-32
-49
Page 71
Amlodipine/Valsartan FDC: BP Reductions for Patients with Diabetes– (Exzellent Trial1)
n = n = 639639
n = n = 795795 n = n =
295295
1Schrader J et al. PS38 Late Breaking Abstracts Session. ESH/ISH Congress, 14 June 2008.
-19
-32
-48
DBP ↓ (mmHg) –11 –15 –18 DBP ↓ (mmHg) –11 –15 –18
syst
.BP
red
uctio
n (m
mH
g)
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/Valsartan10/160 mg
Amlodipine10 mg
p=0.0018
−40
−30
N=55
−31.7
N=46
–40.1
LSM=least square meanMSSBP=mean sitting systolic blood pressure
EX-EFFeCTS1
Patients with Stage 2 Hypertension
−20
−10
0N=42
Amlodipine/Valsartan10/160–320 mg
Amlodipine10 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;2:294–3022.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
77.184.4
78.485.2
69.7
80
0
20
40
60
80
100All 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
Pat
ien
ts (
%)
Data shown are at Week 8No hydrochlorothiazide add-on was permitted until after Week 8Randomized, double-blind, multinational, parallel-group, 16-week study
n=440 n=369 n=71 n=449 n=375 n=74
80.0
Adapted fromAllemann et al. J Clin Hypertens 2008;10:185–94
96.6
89.3
82.380
90
100
Me
an
dia
sto
lic
BP
(m
mH
g)
136
151.4
166.7
120
140
160
180
Me
an
sy
sto
lic
BP
(m
mH
g)
Amlodipine/Valsartan: Additional BP Drops in Non-responders to Ramipril/Felodipine
–30.7 mmHg–14.3 mmHg
–15.4 mmHgp<0.0001 –7.0 mmHg
p<0.0001
Week 0 5 10
N=133
AfterAmlo/Val 10/160
After Ram 5 + Fel 5
Open, sequential, non-responder, 10-week study
AfterAmlo/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)
Page 75
*p<0.01 vs. amlodipineFogari et al. J Hum Hypertens 2007;21:220-4
EXFORGE® Significantly Reduces Fluid Retention Vs Amlodipine Monotherapy
*6.8
23.025
20
15
10
5
0
An
kle-
foo
t vo
lum
e in
crea
se (
%)
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
Ch
ang
e fr
om
bas
elin
e in
M
SS
BP
at
6-w
eek
end
po
int
(mm
Hg
)
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 mmHgBaseline mean sitting diastolic BP (MSDBP): 113 mmHgRandomized, double-blind, multicenter, active-controlled study
Page 77
Blood Pressure and Cardiovascular Risk: ESHESC Guidelines
Other RF, OD or disease
BP (mmHg)
NormalSBP 120–129or DBP 80–84
High normalSBP 130–139or DBP 85–89
Grade 1 SBP 140–159or DBP 90–99
Grade 2SBP 160–179
or DBP 100–109
Grade 3 SBP 180
or DBP 110
No other RF Average risk Average riskLow added
riskModerate
added riskHigh added
risk
1–2 RFLow added
riskLow added
riskModerate
added riskModerate
added riskVery high added risk
3 RF, MS, OD or diabetes
Moderate added risk
High added risk
High added risk
High addedrisk
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 syndromeOD = subclinical organ damageRF = risk factors
Reproduced from the Task Force of ESH–ESC. J Hypertens 2007;25:1105–87Copyright © 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
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 DiseasesThe majority of people continuously complain of allergic problems…
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