7th annual international diovan symposium

Sponsored by Novartis Pharma AG

7th Annual International Diovan Symposium

Lisbon, 3–5 February 2006


↓CVrisk = (BP↓Power +CV Protection)↑Compliance

Addressing the Variables:Solving the Formula to Reduce CV Risk


Host’s WelcomeCassiano Abreu-Lima

University of Porto School of MedicinePortugal

Prevalence of HF Stages in Porto

0

10

20

30

40

50

60

Low risk Stage A Stage B Stage C Stage D

AHA/ACC HF Stages

Perc

enta

ge

MEN (n=296)WOMEN (n=443)

Age 45 years

Azevedo et al. Heart, 2006

7.2%

69.4 %

0

10

20

30

40

50

60

70

Hypertension Diabetesmellitus

Obesity Coronary HD MetabolicSyndrome

Currentsmoking

Perc

enta

ge

MEN (n=296)WOMEN (n=443)

Heart Failure Risk Factors in Porto

Azevedo et al. Heart, 2006

Age 45 years

05

101520253035404550

Hypertensive Aware Treated Controlled

Perc

enta

ge

N=502318–90 years

42.1

N=2115

46.1

39.0

11.2

Hypertension in Portugal

Macedo et al. J Hypertension, 2005

Portugal Proportional Cardiovascular Disease Mortality

25%Other

Total CV mortality 38%

20%Coronary Artery Disease

55%Cerebrovascular Disease


Chairs’ Welcome and Objectives: Setting the Challenge

Victor DzauDuke University, Durham, USA

& Marc PfefferHarvard Medical School, USA

Introduction

Welcome to the 7th Annual International Diovan Symposium

700 hypertension, cardiology and lipidology experts from 44 countries as far apart as Nigeria, Saudi Arabia, Croatia and Japan

This year’s theme ‘Addressing the Variables: Solving the Formula to Reduce CV Risk’

The formula

↓CV risk=(BP↓Power + CV Protection)↑Compliance

Adapted from Feldman et al. Can Med Assoc J 1999;1611 (12 Suppl):S1–S17

↓CV risk = (BP↓Power + CV Protection)↑ComplianceGlobal risk reduction: the goal of HTN

management?

Can you stratify CV risk factors to develop treatment algorithms?

Metabolic syndrome: how relevant and useful is it as an entity?

How important is IGT and how prevalent is it?

How should HTN be defined and what is abnormal BP?

How important are BP guideline targets in clinical practice?

How low is low enough for BP?

Does it matter by what route BP is lowered (e.g. via the RAAS or via fluid balance)?

↓CV risk = (BP↓Power + CV Protection)↑Compliance

Protective benefits beyond BP lowering: what’s the evidence?

What is the relationship between BP and renopathology?

What are the mechanisms behind the reduction in new-onset diabetes seen with RAAS blockade?

Does the cause of heart failure impact clinical management?


Why are compliance and persistence rates so low in patients with HTN?

Is tolerability an important issue when selecting a RAAS blocker?

What can physicians do to improve patient compliance in hypertensive patients

What effect does improved compliance have on clinical outcomes?



From the Expert’s Files: Case Presentation

Marc PfefferHarvard Medical School, USA

Presentation

56-year-old British female

Presents to primary care physician for medical examination (new job)

Mother alive and well, father died from MI aged 70

No current meds

Smokes 20 cigarettes/day (30 pack-years)

Examination

Height: 1.65 m

Weight: 79 kg– BMI = 29

BP = 156/86 mmHg (confirmed on subsequent occasions)

Heart sounds normal, chest clear

Investigations

ECG = Normal

Electrolytes = Normal

Glucose = 5.8 mmol/L (104 mg/dL)

Dipstick protein +

Total cholesterol = 6.2 mmol/L (240 mg/dL)

LDL = 3.7 mmol/L (142 mg/dL)

HDL = 0.9 mmol/L (35 mg/dL)




VARIABLE 1: Hypertension

What is Normal and What is Abnormal Blood Pressure?

Toshiro Fujita

University of Tokyo

Conceptual Definition of Hypertension

Sir George Pickering decried the search for an arbitrary dividing line between normal and high blood pressure. In 1972 he restated his argument: “There is no dividing line between normal and high blood pressure. The relationship between arterial blood pressure and mortality is quantitative; the higher the pressure, the worse the prognosis.

However, medical practice requires that some criteria be used to determine the need for workup and therapy. The criteria should be established on some rational basis that includes the risks of disability and death associated with various levels of blood pressure as well as the ability to decrease those risks by lowering the blood pressure.

Operational Definition of Hypertension

Evans JG and Rose G: Br Med Bull 1971:27:37-42‘Hypertension should be defined in terms of a BP level above which investigation and treatment do more good than harm’

Any numerical definition must be determined resulting from evidence of risk and availability of effective and well-tolerated drugs.

<120120 –130 –140 –160 –180 –Systolic BP mmHg

<80 80 – 85 – 90 –100 –110 –Diastolic BP mmHg

1000 patient years

<120 120 –130 –140 –160 –180 –mmHg

<80 80 – 85 – 90 –100 –110 –mmHg

30

24

18

12

6

0

Stro

ke In

cide

nce

**

*

*p<0.01 (vs <120/80) 30

24

18

12

6

0

**

*

*p<0.01 (vs <120/80)

Male Female1000 patient years

Correlation of Stroke Incidencewith Blood Pressure Levels

No Drug Intervention18 years follow-up in Hisayama, Japan

Stro

ke In

cide

nce

Classification of BP in AdultJSH2004 (Japanese Guidelines)

Classification

Optimal BPNormal BPHigh Normal BP

Mild HypertensionModerate HypertensionSevere Hypertension

Systolic Hypertension

Systolic BP (mmHg)

<120 <130

130 ～ 139

140 ～ 159 160 ～ 179

>180

>140

Diastolic BP (mmHg)

<80 <85

85 ～ 89

90 ～ 99 100 ～ 109

>120

<90

and and or

or or or

and


1. High Normal Blood Pressure

2. Total Individual Risk and Blood Pressure

3. Home and Ambulatory Blood Pressure

IHD Mortality Rate in each Decade of Age versus Usual BP at the Start of that Decade

Lewington S, et al: Lancet 2002; 360: 1903-13

0

2

8

32

128

120 140 160 180 0

2

8

32

128

70 80 90 100 110

IHD

Mor

talit

y(f

loat

ing

abso

lute

ris

k)

40-49 years40-49 years

50-59 years

50-59 years

60-69 years60-69 years

70-79 years

70-79 years

7

80-89 years 80-89 years

SBP (mmHg) DBP (mmHg)Death from both IHD (and stroke) increases progressively and linearly from BP levels as low as 115 mmHg SBP and 75 mmHg DBP.

Impact of High-Normal Blood Pressure on the Risk of Cardiovascular Disease

Last JM, et al: N Engl J Med 2001;345:1291-7

CUMULATIVE INCIDENCE OF CV EVENTS IN MEN WITHOUT HYPERTENSION ACCORDING TO BASELINE BLOOD PRESSURE

(130-139)

(121-129)

(< 120)

mmHg

(130-139)

(121-129)

(< 120)

mmHg

High normal

Normal

Optimal

0

500

1000

1500

0

10

20

CHD Deaths in Men Screened for the MRFIT StudyJulius S: AJH 2000; 13: 11S-17S

Dea

ths %

DeathExcess Death% Excess Death

<110 110-119

120-129

130-139

140-139

150-159

160-169

170-179

>180

Systolic BP (mmHg)

BP to Initiate Antihypertensive Drug Therapy(Julius S: AJH 2000; 13: 11S-17S)

Very conservative recommendations about starting treatment in stage 1 hypertension have been made in New Zealand and Norway. In both countries the health care system is government funded and within such a modus operandi, cost containment is at a premium.

However, early intervention may be more beneficial than late treatment and treating mild hypertension may have a major positive impact on public health.

Strategies Aimed at Diets and Physical Activity of the Population Shifts the BP Distribution of the Whole Population to the Left

Present and optimal systolic blood pressure distribution of the population. These smoothed curves portray the present distribution (blue line) and the optimal distribution (yellow line) of systolic blood pressure in adults. A combination of population and high-risk strategies of blood pressure control is necessary to achieve the optimal blood pressure distribution.

2003 WHO/ISH Statement: Journal of Hypertension 2003, 21:1983–1992

Distribution of systolic blood pressure in adultsSBP (mmHg)

60 80 100 120 140 160 180 200 220 240

％ o

f pop

ulat

ion

Present distributionOptimal distribution

High risk strategy focuses on about 25% of the population

ESH/ESC and JSH

Optimal BP

Normal BP

High normal BP

Grade 1 hypertension(mild)

Grade 2 hypertension(moderate)

Grade 3 hypertension(severe)

SBP and DBP

<120 and <80

120-9 or 80-4

130-9 or 85-9

140-59 or 90-9

160-79 or 100-9

>180 or >110

Classification of BP for Adults (mmHg)

JNC 7

Normal

Prehypertension

Stage 1 hypertension

Stage 2 Hypertension

Classification of BP in ESH/ESC

Although it would be appropriate to use a classification of BP without term ‘hypertension’, this could be confusing.

Thus, the classification has been retained with the reservation that the real threshold for hypertension must be considered as flexible, being higher or lower based on the total cardiovascular risk profile of each individuals.


1. High normal blood pressure had better be controlled for risk reduction: a major positive impact on public health.

2. Total Individual Risk and Blood Pressure


Estimated Effect of a 12 mm Hg Reduction in SBP Over 10 Years on the Number-Needed-to-Treat to Prevent a Cardiovascular Death

NHANES I Epidemiologic Follow-Up Study (Ogden LG, et al: Hypertension. 2000;35:539 )

Baseline SBP/DBP(mmHg)

High Normal(130-139/85-89)

Mild Hyperternsion(140-159/90-99)

Moderate to Severe Hypertension(>160/>100)

Risk Group A

486

273

34

Risk Group B

36

27

12

Risk Group C

21

18

11

Corrected for regression dilution bias using a reliability coefficient of 0.53 to correct for imprecision in the measurement of SBP. Risk group A includes participants with no evidence of target organ damage, clinical cardiovascular disease, or additional major risk factors for cardiovascular disease. Risk group B includes participants who were men or postmenopausal women 60 years of age, current smokers, or had a serum total cholesterol 240 mg/dL. Risk group C includes participants who had a self-reported history of diabetes, heart attack, heart failure, stroke, or renal disease at baseline or had used medication for these conditions during the preceding 6 months.

02468

10

<80 80-84

85-89

90-99

>100 <80 80-84

85-89

90-99

>100

0

4

8

12

16

<120 120-129

130-139

140-159

>160 <120 120-129

130-139

140-159

>160

* **

**

* *

* **

*

Normal GT

Normal GT

IGT

IGT

Systolic BP (mmHg)

Diastolic BP (mmHg)

Rel

ativ

e H

azar

dR

elat

ive

Haz

ard

*P<0.05vs<120/Normal GT

*P<0.05vs<80/Normal GT

BP and relative Hazards of Cardiovascular Death in Subjects with Impaired Glucose Tolerance (Igaku-no-ayumi 2004;210:717-8)

Moderate added risk

NormalSBP 120-129or DBP 80-84

High NormalSBP 130-139or DBP 85-89

Grade ISBP 140-159or DBP 90-99

Grade IISBP 160-179or DBP 100-109

Grade IIISBP>180or DBP>110

ACC: Associated clinical conditions; TOD: Target organ damage; SZBP systolic blood pressure DBP: Diastolic blood pressure

Average risk

Average risk

Low added risk

Moderate added risk

High added risk

Low added risk

Low added risk

Moderate added risk

Very high added risk

Moderate added risk

High added risk

High added risk

High added risk






High added risk

Stratification of Risk to Quantify Prognosis

Other risk factors and disease history

BP

No other risk factors

1-2 risk factors

3 or more risk factors or TOD or diabetes

ACC

Journal of Hypertension 2003,Vol 21 No6 ： 1011-1053

Drug Treatment



2. Total individual risk should determine the real threshold for high blood pressure.


Home and Ambulatory BP Monitoring

Measuring blood pressure at home is becoming increasingly popular for both doctors and patients. Usual office blood pressure is significantly higher than daytime home blood pressure, and usual office blood pressure measurement often leads to significant overestimation of BP and thereby overdiagnosis of hypertension: white-coat hypertension. Ambulatory BP monitoring and home BP monitoring are useful for the evaluation of white-coat hypertension. Moreover, this method gives a more comprehensive representation of the vascular burden of hypertension than a small number of BP readings in the office of a clinician.

Criteria for Hypertension

JNC 7 JSH 2004ESH-ESC

140/90Office BP

24-hourambulatory BP

Awake 135/85

Asleep 120/75 125/80 135/80

Home(self-measured)BP

135/85

(Units: mmHg)

Relative Hazards and 95% CI of Home Systolic/Diastolic BP for Overall Mortality Ohasama Study (AJH 1997;10:409)

0 1 2 3 4 5>83 mmHg (n=420, 43 death)

77-83 mmHg (n=381, 25 death)

72-77 mmHg (n=390, 21 death)

67-72 mmHg (n=362, 20 death)

<67 mmHg (n=360, 32 death)

>138 mmHg (n=389, 62 death)

128-138 mmHg (n=406, 27 death)

120-128 mmHg (n=375, 17 death)

113-120 mmHg (n=363, 22 death)

<113 mmHg (n=380, 13 death)

Relative Hazard

Systolic BP

Diastolic BP

*

*

*

Home BP: >135/>85 mmHg Hypertension

Relative Hazards and 95% CIs of 24-hour Systolic and Diastolic BP Values for Overall Mortality

Ohasama Study (Hypertension 1998;32:255)

The curves fitted to the second-degree equation determined by the Cox proportional hazards model adjusted for age, gender, smoking status, use of antihypertensive medication at baseline, and history of cardiovascular disease, diabetes, and hypercholesterolemia.

24 hr BP: >135/>80 mmHg Hypertension

Staessen JA, et al. ： JAMA.282 ； :539-546 (1999)

90 110 130 150 170 190 0

0.04

0.08

0.12

0.16

0.20

Systolic BP （ mmHg ） 210 230

24-hour BP

Nighttime BP

Office BP

Daytime BP

Cardiovascular Risk in Office and 24-Hour Ambulatory Blood pressure in Elderly Systolic Hypertension (Syst-Eur)

2 Y

ear

Inci

denc

e R

ate

of

Car

diov

ascu

lar

Eve

nts

Prediction of Stroke by Self-Measurement BP at Home vs. Casual Screening BP: The Ohasama Study (Stroke 2004;35:2356)

Rel

ativ

e H

azar

d an

d 95

%C

I*

*Adjusted for age, sex, diabetes, hypercholesterolemia, smoking, history of cardiovascular disease; Group 1: normotensive (relative hazard=1), Group 2: prehypertensive; Group 3: stage 1 hypertensive; Group 4: stage 2 hypertensive

Risk of First Stroke

Trend p<0.0001

Trend p<0.0009

2 3 4 2 3 4

1

2

4

Home BP Office BP

Group

Diagnosis of Masked Hypertension

Masked Hypertension

Normal BP White-coat HT

ABP

135/80 mmHg

Homed BP

135/85 mmHg

Clinic BP

140/90 mmHg

Hypertension

Jichii Morning-Hypertension Research-J-MORE study

(Kario Circulation 2003,108:72e-73e)

200

180

160150

135

120

10090

100 120 140 160 180 200 220

Clinic systolic pressure (mmHg)

MorningSystolic

Pressure(mmHg)

38% -PCH

r=0.25n=969

23% -MMH

21% -WCH 18% -WCHT

Patients with Masked Hypertension have High Cardiovascular Risk

(Bobrie G et al. JAMA 291:1342-1349,2004)

40

30

20

10

0

CV

Events

(/1,000 person x year)

Normal BPn=685

White-coat HTn=656

Masked HTn=462

Sustained HTn=3,125

11.112.1

30.6

25.6

Hypertensive Urgency/Emergency

Diagnosis of Hypertension

Yes

BP>140/90+target organ damage or diabetes or renal disease

BP>180/110

BP:140-179/90-109Office BPM

ABPM or SBPMif available

continue tofollow-up

ABPM (if available) SBPM (if available)

Awake<135/85 or

24-hour<130/80

<135/85 >135 SBP or>85 DBP

Hypertension Visit 2Within 1 month

Hypertension Visit 3

Hypertension Visit 4-5

Elevated Out ofOffice BP

Elevated RandomOffice BP

Hypertension Visit 1BP Measurement, History, Physical

Diagnostic tests at visit 1 or 2

No

>160 SBP or>100 DBP

<160/100

>140 SBP or>90 DBP

<140/90







Awake>135 SBP or >85 DBP

or 24-hour>130 SBP or >80 DBP

or

Canadian Hypertension Education Program Algorithm for Diagnosis of HypertensionAm J Hypertens 2005;18:1369-1374

or

Office BPM: Office BP monitoring; ABPM: Ambulatory BP monitoring; SBPM: Self BP monitoring

The normotensive value of the home blood pressure differs from the target level of the home blood pressure during antihypertensive therapy.

The intervention studies using home BP measurement are needed for the determination of the target BP level .

Home Blood Pressure and Antihypertensive Therapy~Japanese HT Guideline~



2. Total individual risk should determine the real threshold for high blood pressure.

3. Home/ambulatory blood pressure more greatly affect cardiovascular risk: the widely-accepted and evidence-based criteria of home/ambulatory hypertension should be required.


Point-CounterpointBP goal: do the guidelines go low enough?

BP Goal: The Guidelines JNC 7: “Treating systolic BP and diastolic BP to targets

that are less than 140/90 mmHg is associated with a decrease in CVD complications. In patients with hypertension and diabetes or renal disease, the BP goal is less than 130/80 mmHg”1

ESH/ESC: “…blood pressure, both systolic or diastolic, be intensively lowered at least below 140/90 mmHg and to definitely lower values, if tolerated, in all hypertensive patients, and below 130/80 mmHg in diabetics…”2

1JNC 7 Report. JAMA 2003;289:2560–722ESH/ESC Guidelines Committee. J Hypertens 2003;21:1011–53


BP Goal: Do the Guidelines Go Low Enough? Yes

Matthew R WeirUniversity of Maryland School of Medicine, USA

Overview

How low should you go?

What drugs should you use?

How are you going to get there?

What is Your Definition of ‘Hypertension’?

We must delete the word ‘hypertension’ – it has no meaning

The blood pressure goal should be established for each patient

US and European Classification of BP in Adults: JNC 7 and ESH-ESC Guidelines

BP classification

Systolic pressure (mmHg)

Diastolic pressure (mmHg)

JNC7 ESC-ESH JNC7 ESC-ESH JNC7 ESH-ESH

Normal Normal <120 120–129 and <80 80–84

Pre-hypertension High normal 120–139 130–139 or 80–89 85–89


Grade 1 hypertension

(mild)

140–159

140–159

or

90–99

90–99


Grade 2 hypertension (moderate)

Grade 3 hypertension

(severe)

160

160–179

180

or

or

100

100–109

110

Both sets of guidelines define hypertension as a BP ≥140/90 mmHg

Chobanian et al. JAMA 2003;289:2560–72ESC Guidelines Committee. J Hypertens 2003;21:1011–53

A definition is required to avoid confusion and enhance the case for tight BP control

High–normal BP Increases the Risk of CVD in Men but That Risk is Still Low

Vasan et al. N Engl J Med 2001;345:1291–7

(130–139)

(121–129)

(<120)

mmHg14

12

10

8

6

4

2

0

Cum

ulat

ive

inci

denc

e (%

)

0 2 4 6 8 10 12 14

High–normal

Normal

Optimal

Time (years)

Lewington S, Clarke R, Qizilbash N, Peto R, Collins R.

Age-specific relevance of usual blood pressure tovascular mortality; a meta-analysis of individual data forone million adults in 61 prospective studies

Lancet 2002;360:1903–13

61 prospective trials 1,000,000 individuals 12,700,000 person-years

Lower is Better: IHD Rates by SBP, DBP and Age

256

128

64

32

16

8

4

2

1

0

IHD

mor

talit

y(fl

oatin

g ab

solu

te ri

sk a

nd 9

5% C

I)

120 140 160 180Usual systolic blood

pressure (mmHg)

256

128

64

32

16

8

4

2

1

0

IHD

mor

talit

y(fl

oatin

g ab

solu

te ri

sk a

nd 9

5%C

I)

70 80 90 100 110Usual diastolic blood

pressure (mmHg)

80–89 years

70–79 years

60–69 years

50–59 years

Age at risk:80–89 years

70–79 years

60–69 years

50–59 years

Age at risk:

Lewington et al. Lancet 2002;360:1903–13

Total CV Risk According to BP, Other Risk Factors and Disease History: The ESH-ESC Guidelines

Table modified from ESC Guidelines Committee. J Hypertens 2003;21:1011–53Anderson et al. Circulation 1991;83:356–362

Definition must be flexible taking into account CV risk profile

JNC7 and ESH-ESC guidelines recommend a target BP of <140/90 mmHg for patients with uncomplicated hypertension since this is associated with average CV risk (Framingham)

TOD = target organ damage; ACC = associated clinical conditions

Blood pressure (mmHg)

Other risk factorsand disease history

NormalSBP 120–129or DBP 80–84

High–normal SBP 130–139or DBP 85–89

Grade 1 SBP 140–159or DBP 90–99

Grade 2 SBP 160–179

or DBP 100–109

Grade 3 SBP >180

or DBP >110

No other risk factors Average risk Average risk Low addedrisk

Moderateadded risk

High addedrisk

1–2 risk factors Low addedrisk

Low addedrisk

Moderateadded risk

Moderateadded risk

Very highadded risk

3 or more risk factors or TOD or diabetes

Moderateadded risk

High addedrisk

High addedrisk

High addedrisk

Very highadded risk

ACC High addedrisk

Very highadded risk

Very highadded risk

Very highadded risk

Very highadded risk

Lower is an Unachievable Goal: Patients Are Not Reaching the Current Target Current control rates (to <140/90 mmHg), although improved,

are still far below the Healthy People 2010 goal of 50%1

1Chobanian et al. Hypertension 2003;42:1206–52

AwarenessTreatmentControl*

80

60

40

20

0

Tren

ds in

aw

aren

ess,

trea

tmen

t and

con

trol

of h

igh

bloo

d pr

essu

re 1

976–

2000

1976–1980 1988–1991 1991–1994 1999–2000

*SBP below 140 mmHg and DBP below 90 mmHg and receiving antihypertensive medication

Percentage of adults aged 18–74 years with SBP of 140 mmHg or greater, DBP of 90 mmHg or greater, or taking antihypertensive medication

Are There Additional Benefits, or Risks, inLowering SBP to Fully Normotensive Levels?

Benefits shown for lowering SBP to 140 mmHg but additional lowering to 120 mmHg appears to give little further benefit, although does not cause any significant additional

riskHansson et al. Lancet 1998;351:1755–62

Estimated incidence (95% Confidence Interval) of CV events in relation to achieved mean SBP

120130140 150160170180190Mean SBP

Minimum = 138.8 mmHg20

15

10

5

0

Maj

or C

Veve

nts/

1,00

0pa

tient

-yea

rs


8

6

4

2

0C

V m

orta

lity/

1,00

0pa

tient

-yea

rs120130140 150160170180190

Mean SBP

Are There Additional Benefits, or Risks, inLowering DBP to Fully Normotensive Levels?

Benefits shown for lowering DBP to ≤85 mmHg but additional lowering to 70 mmHg appears to give little further benefit, although does not cause any significant additional

riskHansson et al. Lancet 1998;351:1755–62

Estimated incidence (95% Confidence Interval) of CV events in relation to achieved mean DBP


15

10

5

0

Maj

or C

Veve

nts/

1,00

0pa

tient

-yea

rs


8

6

4

2

0C

V m

orta

lity/

1,00

0pa

tient

-yea

rs70 75 80 85 90 95 100105

Mean DBP70 75 80 85 90 95 100 105

Mean DBP

Majority of US Hypertensive Patients Are Not at SBP Goal of <140 mmHg

Adapted from Lapuerta and L’Italien. Am J Hypertens 1999;12:92A

SBP range (mmHg)

Popu

latio

n (m

illio

ns)

Not meeting goal

14

12

10

8

6

4

2

0

171–

180

181–

190

191–

200

201–

210

211–

220

221–

230

231–

240

241–

250

161–

170

151–

160

141–

150

131–

140

121–

130

111–

120

101–

110

91–1

0081

–90

Let Us Not Be Greedy!

What May be a More ImportantQuestion is Whether Every

Patient Who Needs BPReduction Should beon a RAAS Blocker?

Angiotensin II Dichotomy

Angiotensin II

Vasoconstriction

Modification of SNS

Renal salt and water retention

Vascular structure and function

Modification of disease

Progression

BP homeostasis LVH Atherogenesis Glomerular sclerosis

Angiotensin II Formation

Angiotensinogen

Angiotensin I

Angiotensin II

Angiotensin II receptors

Renin

ACE

CAGE

Cathepsin G

Chymase

T-PA

Cathepsin G

Tonin

Alternate pathways*

*The clinical significance of alternate pathways is unknownDzau et al. J Hypertens 1993;11:S13–18

Proposed Angiotensin II Influences on the Blood Vessel

Induction of angiotensin II pathways at the tissue level

Local angiotensin II production

Vascular remodelling

Vascular injury BP

Adapted from Dzau. J Cardiovasc Pharmacol 1993;22:S1–9

Optimal Vascular Protection

Earlier and more aggressive BP control

Pharmacologic blockade of the RAAS

BP Control Rates in Trial and Community Settings

1Hansson. J Hypertens Suppl 1999;S9–132Hyman and Pavlick. N Engl J Med 2001;345:479–86

HOT Study1 NHANES2

100

80

60

40

20

0

Popu

latio

n w

ith B

P co

ntro

lled

to D

BP

90

mm

Hg

(%)

Predictors of Uncontrolled Hypertension in Ambulatory Patients

Knight et al. Hypertension 2001;38:809–14

VariableOdds of poor

control 95% CIAge group (years)

55–6465–7475

1.262.502.56

0.71–2.241.49–4.191.45–4.52

No. of antihypertensive drugsduring the study period

0234 or 5

0.901.912.534.70

0.41–1.981.25–2.911.50–4.282.22–9.95

Lack of knowledge of appropriate SBP 1.55 1.09–2.20Attributed a specific side effect to a specific antihypertensive medication 2.06 1.41–3.01

Medication taken 6–7 days per weekMedication taken 4–5 days per weekMedication taken 0–4 days per weekDropped medical follow-upData not available

Poor BP Control Resulting From Lack of Patient Compliance Compliance, even to a simple dose regimen, decreases progressively in patients with

hypertension1

1Bovet et al. Bull World Health Organ 2002;80:33–92Moser and Black. Am J Hypertens 1998;11(6 Pt 2):73S–78S

More than 50% of patients require a combination of two or more antihypertensive drugs to achieve BP goal <140/90 mmHg2

This adds to patients’ pill burden, reduces convenience and increases confusion, particularly in elderly patients who are most likely to require multiple drug therapy

100

80

60

40

20

0

Prop

ortio

n of

part

icip

ants

(%)

1 2 3 4 5 6 7 8 9 10 11 12Month of follow-up

Poor BP Control is at Least in Part Related toPhysician Factors A large study showed patients who had more intensive

therapy had significantly (p<0.01) better control of BP1

Inadequate guideline awareness,2,3 or physicians familiar with JNC guidelines but satisfied with achieved BP despite not being at goal3,4

Physicians appear to be especially reluctant to treat older patients to BP goal,3 plus uncertainty about importance of SBP in the elderly

Physicians don’t always feel that patients included in the clinical trials are representative of their own patient population

1Berlowitz et al. N Engl J Med 1998;339:1957–63; 2Hagemeister et al. J Hypertens 2001;19:2079–86; 3Hyman and Pavlik. Arch Intern Med 2000;160:2281–6; 4Oliveria et al. Arch Intern Med 2002;162:413–20

Distribution of systolic blood pressure in adults

SBP (mmHg)

60 80 100 120 140 160 180 200 220 240

Popu

latio

n (%

)Increasing the Patient Pool: Diluting the Resources

Nor

mal

Hig

h no

rmal

Grade I Grade II Grade III

Chobanian et al. Hypertension 2003;42:1206–52Burt et al. Hypertension 1995;26:60–9

Conclusions

Benefits shown for lowering BP to <140 and <80 mmHg, but we have no prospective data evaluating the benefits of lower BP goals in the general population

If patients are not achieving current BP goals, why recommend lower goals?

Focus more attention on physician awareness and patient compliance – lowering the BP target will not improve the attainment of lower BP goals!

Consider fixed-dose combination therapy!

Conclusions (Cont’d)

Focus efforts and resources on optimising the number of hypertensive patients who achieve the current goal rather than reducing the BP target any further

Ensure patients achieve appropriate BP goals and receive RAAS blockade (unless contraindicated)


Do the Guidelines Go Low Enough? No

Gordon McInnes Western Infirmary, Glasgow, UK

The Lower The Better256

128

64

32

16

8

4

2

1

0

IHD

mor

talit

y(fl

oatin

g ab

solu

te ri

sk a

nd 9

5%C

I)

120 140 160 180Usual systolic blood

pressure (mmHg)

256

128

64

32

16

8

4

2

1

0

IHD

mor

talit

y(fl

oatin

g ab

solu

te ri

sk a

nd 9

5%C

I)

70 80 90 100 110Usual diastolic blood

pressure (mmHg)

80–89 years

70–79 years

60–69 years

50–59 years

Age at risk:80–89 years

70–79 years

60–69 years

50–59 years

Age at risk:

Lewington et al. Lancet 2002;360:1903–13

Even in the US…

High–normal = 130–139/85–89 mmHgNormal = 120–129/80–84 mmHgOptimal = <120/80 mmHg

Vasan et al. New Engl J Med 2001;345:1291–7

Cum

ulat

ive

inci

denc

e (%

) 10

8

6

4

2

00 2 4 6 8 10 12 14

Time (year)No. at riskOptimal 1875 1967 1951 1839 1821 1734 887Normal 1126 1115 1097 1084 1061 974 649High-normal 891 874 809 840 812 722 520

Cum

ulat

ive

inci

denc

e (%

) 14

12

10

8

6

4

2

00 2 4 6 8 10 12 14

Time (year)No. at riskOptimal 1005 995 973 962 934 992 454Normal 1059 1039 1012 982 952 992 520High-normal 903 879 857 819 795 726 441

Highnormal

Normal

Optimal

Highnormal

Normal

Optimal

Benefits of Antihypertensive Treatment Are Proportional to Reduction in BP

Systolic blood pressure difference between randomised groups (mmHg)

Relative risk of stroke

CA/placebo

Results of prospectively designed overviews of randomised trials Turnbull et al. Lancet 2003;362:1527–35

0.25

0.50

0.75

1.00

1.25

1.50

–10 –8 –6 –4 –2 0 2 4

ACE/placebo

More/less

ARB/other

ACE/CA

CA/D/BB

ACE/D/BB

Causes of Failure in US

Physician factors

Concern about J-curve

Concern about side effects

Lack of knowledge

Lack of time

Wang et al. Circulation 2005;112:1651–62

Is Low DBP a Risk in CHD?

Fox et al. Lancet 2003;362:782–8; HOPE Investigators. N Engl J Med 2000;342:145–153Nissen et al. JAMA 2004;292:2217–26

HOPE EUROPA CAMELOT

Treatment ACEI ACEI CCB

Baseline DBP (mmHg) 79 82 79

Reduction DBP (mmHg) 2 2 3

Reduction CV risk (%) 22 20 31

The evidence

HOT Trial: Diabetes Population

25

20

15

10

5

0Maj

or C

V ev

ents

/1,0

00 p

atie

nts

year

90 mmHg 85 mmHg 80 mmHg

Hypertension optimal treatment

Hansson et al. Lancet 1998;351:1775–62

Low Blood Pressure in Stroke

PROGRESS

BP reduction 12/5 mmHg

Stroke reduction 28%

Similar reduction in hypertension and normotension

Stroke has killed 11 US presidents

Lower targets might save George Bush!

PROGRESS Collaborative Group. Lancet 2001;358:1033–41

Bakris. Diabetes Res Clin Pract 1998;39:S35–42

GFR

dec

line

(ml/m

in/y

ear)

Results of studies 3 years in patients with type 2 diabetic nephropathy

Mean arterial pressure (mmHg)

−8

−6

−4

−2

098 100 102 104 106 108 110

r=0.66; p<0.05

−10

Slower Decline in Renal Function With Lower Blood Pressure Goals

n=184 n=133 n=108

n=108

HOT: Change in QoL Total Score from Baseline to 6 Months vs DBP at 6 Months (Mean ± SEM)

Mea

n ch

ange

3.5

2.5

1.5

0.5

–0.5

–1.5

–2.5

–3.5DBP <80 DBP <81–85 DBP 86–90 DBP >91

Fletcher A et al. J Hypertens 1999

QOL: US Data

Grimm et al. Arch Intern Med 1997;157:638–48

SBP (mmHg) Active Placebo

<120 476.1 464.1

120–129 447.6 439.8

130–139 434.5 411.1

140 408.3 399.3

TOMHS follow up




The Rebuttals


RebuttalMatthew R Weir

University of Maryland School of Medicine, USA

Presyncope??

7th annual international diovan symposium

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