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