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Avoiding End Organ Damage
DR. SHAHBAZ AHMED KURESHIMBBS, MCPS, D. CARD, D. Med.Sc, FACC, FAHA, FACP, FPAMS
Consultant Cardiologist,Head Department of Cardiology and Nuclear Cardiology,
Federal Government Services Hospital, Islamabad
Destination <120/80
Lower is Better !
Thus, hypertension management is a public health priority1. WHO, 2002; 2. AHA, 2004
Hypertension Represents a Significant Burden on Healthcare
• Worldwide, hypertension is responsible for– 62% of strokes1
– 49% of heart attacks1
• Hypertension is the third leading risk factor for disease– Causes 7.1 million premature deaths each year1
– 4.5% of global burden of disease1
• Hypertension represents a high burden on healthcare expenditure– In 2004, the direct and indirect cost of high blood pressure
in the US was $55.5 billion; drug costs accounted for $21 billion2
National Health Survey• Circulatory diseases account for over
100,000 deaths a year or 12% of all cause mortality .
• Overall 18% of adults in Pakistan suffer from HBP, 21.5% in urban areas and 16.2% in rural areas.
• One in every 3 adults over age 45 suffer from hypertension.
• Very few Pakistanis with hypertension (<3%) have their B.P controlled.
PROCOR: 7/25/99 The National Health Survey in Pakistan published in 1998 by (PMRC) 1
Potentially Preventable Causes of Death
BP and increasing age
Kearney et al, Lancet 2005
Prevalence of hypertension is high
37.435.3
20.6
40.7
22 22.6
17
26.9
37.239.1
20.9
34.8
23.7
19.7
14.5
28.3
0
5
10
15
20
25
30
35
40
45
50
Men
Women
41.6
39.1
22.9
44.5
24
27.7
18.8
27
45.9
23.6
40.2
27 27
17.1
28.2
42,50
0
5
10
15
20
25
30
35
40
45
50
Establishedmarket
countries
Formersocialist
economies
India Latin Americaand the
Carribean
Middleeasterncrescent
China Other Asiaand islands
Sub-SaharanAfrica
2000
2025
Pre
vale
nce
of
hyp
erte
nsi
on
(%
)
Kearney PM et al.,Lancet. 2005;365:217-223.
Prevalence of hypertension in people aged 20 years and older
ESH-ESC guidelines, 2003, J Hypertens
Factors Necessary to Assess the Risk or Target Organ
DamageRisk stratification Target organ damage
Systolic / diastolic BPLeft ventricular hypertrophy
Men > 55; Women > 65 years Ultrasound: Evidence of thickening
Tobacco smoking or plaques
DyslipidemiaIncreased creatininemia
Family history +Microalbuminuria (malb/creat ratio)
Protein C-reactive > 6 mg/dl men: >2.5 mg/mmol
women: >3.5 mg/mmol
Hypertension is a leading cause for cardiovascular morbidity
9.5
3.3 2.45.0
2.0 3.5 2.1
45.4
21.3
12.4
6.29.9
7.3
13.9
6.3
22.7
0
10
20
30
40
50
Men Women Men Women Men Women Men Women
Normotensive
Hypertensive
Coronary Disease Stroke Peripheral Arterial Disease
Heart Failure
Bie
nn
ial
Ag
e-A
dju
sted
Rat
e p
er 1
,000
36-Year Follow-up in Patients Aged 35-64 Years1,2
1. Kannel W.B. et al., JAMA 1996; 275: 1571-15762. Kannel W.B. et al., J Hum Hypertens 2000; 14: 83-90
Vasan et al. Vasan et al. N Engl J Med.N Engl J Med. 2001 2001
High-Normal BP and CVD Risk
WomenWomen
1010
88
66
44
22
00
Time (years)Time (years)
00 22 44 66 88 1010 1212 1414
P<P<.001.001
MenMen
Cu
mu
lati
ve I
nci
den
ce (
%)
Cu
mu
lati
ve I
nci
den
ce (
%)
1414
1212
1010
88
66
44
22
00
Time (years)Time (years)
00 22 44 66 88 1010 1212 1414
PP<.001<.001
High normal 130-139/85-89 mm HgHigh normal 130-139/85-89 mm Hg Normal 120-129/80-84 mm HgNormal 120-129/80-84 mm Hg Optimal <120/80 mm HgOptimal <120/80 mm Hg
PrehypertensionPrehypertension
Lewington S et al. Lancet. 2002; 360:1903-1913.
Relationship between (a) systolic blood pressure (SBP) and (b) diastolic blood pressure (DBP) and ischaemic heart disease mortality in one million individuals in the general population.CI, confidence interval.
Blood pressure, heart disease and age correlate closely
70 80 90 100 110
256
128
64
32
16
8
4
2
1
256
128
64
32
16
8
4
2
1
80–89 years
70–79 years
60–69 years
50–59 years
40–49 years
80–89 years
70–79 years
60–69 years
50–59 years
40–49 years
120 140 160 180
Age at risk: Age at risk:
Usual SBP (mmHg) Usual DBP (mmHg)
Isch
aem
ic h
eart
dis
ease
mor
talit
y(f
loat
ing
abso
lute
ris
k a
nd 9
5% C
I)
Isch
aem
ic h
eart
dis
ease
mor
talit
y(f
loat
ing
abso
lute
ris
k a
nd 9
5% C
I)
a b
CV Mortality Risk Doubles with Each 20/10 mm Hg BP Increment*
*Individuals aged 40-70 years, starting at BP 115/75 mm Hg.CV, cardiovascular; SBP, systolic blood pressure; DBP, diastolic blood pressure
Lewington S, et al. Lancet. 2002; 60:1903-1913. JNC 7. JAMA. 2003;289:2560-2572.
CVmortality
risk
SBP/DBP (mm Hg)
0
1
2
3
4
5
6
7
8
115/75 135/85 155/95 175/105
Absolute Risk Of Coronary Artery Disease And Stroke Mortality
Curvilinear Relation Of Blood Pressure And Cardiovascular Risk
Geographical Variation In Hypertension Prevalence In Population Of African And European Ancestry
Age- Dependent Changes In Systolic and Diastolic Blood Pressure In USA
Vascular Remodeling Of Small And Large Arteries
The Renin- Angiotensin- Aldosterone System
Schematic Representation Of The Central Role Played By Angiotensin 1 Receptor (AT1R)
Superiority Of Ambulatory Over Office Blood Pressure Measurements
24-Hour Ambulatory Blood Pressure Recording
Relation Between Systolic Blood Pressure And The Rate Of Progression Of Coronary Atheroma
Blood Pressure Risk Stratification (ESH/ESC
2007)
Mancia G et al., J Hypertens 2007;25:1105–87
Blood pressure reductions of as little as 2 mmHg reduce the risk of
cardiovascular events by up to 10%1
• Meta-analysis of 61 prospective, observational studies• One million adults• 12.7 million person-years
2 mmHg decrease in mean systolic blood
pressure10% reduction in risk of stroke mortality
7% reduction in risk of ischemic heart disease mortality
1. Lewington S et al. Lancet. 2002;360:1903–1913.
Fatal and non-fatal events
Mortality Fatal and non-fatal events
Mortality10
-40
-30
-20
-10
0
-50
Isolated systolic hypertension
Stroke CHDAll
Causes CV Non CV Stroke CHDAll
Causes CV Non CV
Systolic–diastolic hypertension
<0.001
<0.001
<0.001
<0.001
<0.01 <0.01
NSNS
0.02
0.01
Event reduction in patients on active antihypertensive treatment vs placebo or no treatment
CHD: coronary heart disease; CV: cardiovascular
Effective blood pressure control reduces cardiovascular morbidity
and mortality
Cifkova R, et al. J Hypertens. 2003;21:1011–1053.
Rel
ati
ve
Ris
k R
ed
uct
ion
(%
)
ESH/ESC guidelines consider systolic values of <139 mmHg and diastolic values of <89 mmHg to be normal
Relations Between Achieved Blood Pressure Control And Declines In Glomerular Filtration Rate
Absolute Benefits For The Prevention Of Fatal Nonfatal Cardiovascular Events
Odds Ratio For Cardiovascular Events And Systolic Blood Pressure
Trials Comparing The Effect On Primary End Point Of Treatment Based On Different
Antihypertensive Drugs
Bakris et al. Bakris et al. Am J Kidney DisAm J Kidney Dis. 2000;36:646-661; Bakris et al. . 2000;36:646-661; Bakris et al. Arch Intern Med.Arch Intern Med. 2003;163:1555- 2003;163:1555-1565; Lewis et al. 1565; Lewis et al. N Engl J MedN Engl J Med. 2001;345:851-860.. 2001;345:851-860.
Number of BP Medications
Antihypertensive Therapy: Number of Agents Required to Achieve BP Goal
UKPDS (<85 mm Hg, diastolic)
4321
MDRD (<92 mm Hg, MAP)
HOT (<80 mm Hg, diastolic)
AASK (<92 mm Hg, MAP)
RENAAL (<140/90 mm Hg)
IDNT (135/85 mm Hg)
An Algorithm For The decision To Manage Patients With Different Average Blood
Pressure Levels
Algorithm For Therapy Of Hypertension
Get patients to BP goal Provides 24 hour BP control Has good tolerability Has ‘added’ protection
What qualities do you want to see in an effective Anti Hypertensive agent?
45
46
47
48
ConclusionIn patients with MI complicated by heart failure, leftventricular dysfunction or both:• Valsartan is as effective as a proven dose of captopril in
reducing the risk of:– Death– CV death or nonfatal MI or heart failure admission
• Combining valsartan with a proven dose of captopril produced no further reduction in mortality—and more adverse drug events.
Implications:In these patients, valsartan is a clinically effectivealternative to an ACE inhibitor.
Treatment Enables Retardation of the Progression of Renal Disease
Early stage Late stage Terminal stage
Severity of renal disease
IRMA 2
MARVAL
IDNT
RENAAL
Microalbuminuria Macroalbuminuria ESRD
Prevention ProtectionBenedict
study
Cardiovascular morbidity and mortality
Conclusions
• In type 2 diabetic pts with microalbuminuria arterial BP was reduced to the same extent in the valsartan and amlodipine groups
• AER was significantly reduced in the valsartan group compared with the amlodipine group.
• Significantly more pts regressed to normoalbuminuria in
the valsartan group
• The effect of valsartan on AER was similar in both the normotensive and hypertensive subgroups
“First do no harm”
The Mechanisms By Which Chronic Diuretic Therapy May Lead TO Various Complications
Theoretical Therapeutic And Toxic Logarithmic And Linear Dose Response Curve
Classification Of Beta- Adrenoreceptor Blockers On The Basic Of Cardioselectivity And Intrinsic
Sympathomimetic Activity
USA53.1
Canada41.0
Mexico21.8
Germany33.6
Greece49.5
England29.2
Egypt33.5
South Africa*47.6
Japan*55.7
Taiwan18.0
China28.8
Worldwide blood pressure control rates in treated
hypertensive patients are low
Kearney P.M. et al., J Hypertens 2004; 22: 11–19; * Data for men only
Turkey19.8
Simplified Schematic View Of The Adrenergic Nerve
Angiotensinogen
Angiotensin I Angiotensin IICE
Renin
Chymase
Bradykinin Inactive
K+Na+
ACTHOther
Adapted from Unger T. Am J Cardiol 2002; 89 (suppl):3A-10A.
RAA system targets multiple receptor sites
Aldosterone
Kaplan NM & Opie LH. Lancet 2006; 367:168-176.
• Major mechanisms– (1) increased adrenergic
drive, as often found in young people (aged 30–49 years);
– (2) high-renin hypertension, as seen in individuals with renal dysfunction;
– (3) low-renin hypertension, as recorded in individuals with inherently raised aldosterone concentrations;
– (4) increased peripheral vascular resistance (PVR), as seen in elderly patients. CO=cardiac output. β=β-adrenergic stimulation α=α-adrenergic stimulation. AII=angiotensin II.
Hypertension has a multifactorial origin
Renin
ACE
Non-ACE
Pathways*
Angiotensinogen
Angiotensin II
Angiotensin I
AT1 receptor
ARB Blockade
AT2 receptor
*not affected by ACE inhibitors
• Vasoconstriction
• Hypertrophy and Proliferation
• Oxidation and Inflammation
• PAI-1 expression and release
• Vasodilation
• Nitric Oxide release
• Antiproliferation
Blockade of AT1 receptor
Activation of AT2 receptor
Vascular Protection
Adapted from:Kaschina E and Unger T. Blood Press 2003;12:70-88.Unger T. J Hypertens 1999;17:1775-1786.
Angiotensin (AT1) receptor blockade provides vascular protection
Renin profile correlates with CV risk
Alderman MH et al. N Engl J Med. 1991;324:1098-1104.
18.8
13.310.6
2.85.0
2.0
Smoking
Events per 1000
person-years
LowNormal
High
NoYes
Renin Profile 48.5
11.712.4
4.6
24.4
2.1
FastingBloodGlucose(mmol/L)
Events per 1000
person-years
LowNormal
High
7.87.8
Renin ProfileCholesterol(mmol/L)
Events per 1000
person-years
LowNormal
High
6.36.3
Renin Profile
34.5
8.410.2
3.28.4
0.9