7th Annual International Diovan Symposium
description
Transcript of 7th Annual International Diovan Symposium
Sponsored by Novartis Pharma AG
7th Annual International Diovan Symposium
Lisbon, 3–5 February 2006
Sponsored by Novartis Pharma AG
↓CVrisk = (BP↓Power +CV Protection)↑Compliance
Addressing the Variables:Solving the Formula to Reduce CV Risk
Sponsored by Novartis Pharma AG
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
Sponsored by Novartis Pharma AG
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?
↓CV risk = (BP↓Power + CV Protection)↑Compliance
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?
↓CV risk = (BP↓Power + CV Protection)↑Compliance
Sponsored by Novartis Pharma AG
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)
Sponsored by Novartis Pharma AG
7th Annual International Diovan Symposium
Lisbon, 3–5 February 2006
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
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
What is Normal and What is Abnormal Blood Pressure?
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.
What is Normal and What is Abnormal Blood Pressure?
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
3. Home and Ambulatory 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
Very high added risk
Very high added risk
Very high added risk
Very high added risk
Very 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
What is Normal and What is Abnormal Blood Pressure?
1. High normal blood pressure had better be controlled for risk reduction: a major positive impact on public health.
2. Total individual risk should determine the real threshold for high blood pressure.
3. Home and Ambulatory 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
Diagnosis of Hypertension
Diagnosis of Hypertension
Diagnosis of Hypertension
Diagnosis of Hypertension
continue tofollow-up
continue tofollow-up
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~
What is Normal and What is Abnormal Blood Pressure?
1. High normal blood pressure had better be controlled for risk reduction: a major positive impact on public health.
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.
Sponsored by Novartis Pharma AG
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
Sponsored by Novartis Pharma AG
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
Stage 1 hypertension
Grade 1 hypertension
(mild)
140–159
140–159
or
90–99
90–99
Stage 2 hypertension
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
Minimum = 138.5 mmHg10
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
Minimum = 82.6 mmHg20
15
10
5
0
Maj
or C
Veve
nts/
1,00
0pa
tient
-yea
rs
Minimum = 86.5 mmHg10
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)
Sponsored by Novartis Pharma AG
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
Sponsored by Novartis Pharma AG
7th Annual International Diovan Symposium
Lisbon, 3–5 February 2006
The Rebuttals
Sponsored by Novartis Pharma AG
RebuttalMatthew R Weir
University of Maryland School of Medicine, USA
Presyncope??