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 Trialsঠwith 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…

Thank You