Transcript Val-HeFT: Independent Predictors of AF Occurrence

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 Welcome
Cassiano Abreu-Lima
University of Porto School of Medicine
Portugal
Sponsored by
Novartis Pharma AG
Prevalence of HF Stages in Porto
69.4 %
60
MEN (n=296)
WOMEN (n=443)
50
Percentage
Age  45 years
40
30
20
7.2%
10
0
Low risk
Stage A
Stage B
Stage C
AHA/ACC HF Stages
Azevedo et al. Heart, 2006
Stage D
Heart Failure Risk Factors in Porto
70
MEN (n=296)
WOMEN (n=443)
60
Age  45 years
Percentage
50
40
30
20
10
0
Hypertension
Diabetes
mellitus
Obesity
Azevedo et al. Heart, 2006
Coronary HD
Metabolic
Syndrome
Current
smoking
Hypertension in Portugal
50
N=2115
45
N=5023
18–90 years
40
42.1
46.1
39.0
Percentage
35
30
25
20
15
10
11.2
5
0
Hypertensive
Aware
Macedo et al. J Hypertension, 2005
Treated
Controlled
Portugal Proportional Cardiovascular
Disease Mortality
Total CV mortality 38%
Other
25%
20%
Coronary Artery Disease
55%
Cerebrovascular Disease
Chairs’ Welcome and Objectives:
Setting the Challenge
Victor Dzau
Duke University, Durham, USA
& Marc Pfeffer
Harvard Medical School, USA
Sponsored by
Novartis Pharma AG
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)↑Compliance
 Global 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?
↓CV risk =
(BP↓Power + CV Protection)↑Compliance
 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?
From the Expert’s Files:
Case Presentation
Marc Pfeffer
Harvard Medical School, USA
Sponsored by
Novartis Pharma AG
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)
7th Annual
International Diovan
Symposium
Lisbon, 3–5 February 2006
VARIABLE 1:
Hypertension
Sponsored by
Novartis Pharma AG
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.
Correlation of Stroke Incidence
with Blood Pressure Levels
No Drug Intervention
18 years follow-up in Hisayama, Japan
Male
Female
1000 patient years
*p<0.01 (vs <120/80)
30
1000 patient years
*p<0.01 (vs <120/80)
30
24
24
18
12
*
6
*
Stroke Incidence
Stroke Incidence
*
0
Systolic BP<120 120 –130 –140 –160 –180 –mmHg
Diastolic BP<80 80 – 85 – 90 –100 –110 –mmHg
18
*
12
6
*
*
0
<120 120 –130 –140 –160 –180 – mmHg
<80
80 – 85 – 90 –100 –110 – mmHg
Classification of BP in Adult
JSH2004 (Japanese Guidelines)
Classification
Systolic BP
(mmHg)
Optimal BP
Normal BP
High Normal BP
<120
and
<130
and
130～139 or
Mild Hypertension
140～159
Moderate Hypertension 160～179
Severe Hypertension
>180
Systolic Hypertension
>140
Diastolic BP
(mmHg)
<80
<85
85～89
or 90～99
or 100～109
or
>120
and
<90
Classification of BP in Adult
JSH2004 (Japanese Guidelines)
Classification
Systolic BP
(mmHg)
Optimal BP
Normal BP
High Normal BP
<120
and
<130
and
130～139 or
Mild Hypertension
140～159
Moderate Hypertension 160～179
Severe Hypertension
>180
Systolic Hypertension
>140
Diastolic BP
(mmHg)
<80
<85
85～89
or 90～99
or 100～109
or
>120
and
<90
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
7
Usual BP at the Start of that Decade
Lewington S, et al: Lancet 2002; 360: 1903-13
(floating absolute risk)
IHD Mortality
128
80-89 years
70-79 years
128
80-89 years
70-79 years
32
32
60-69 years
60-69 years
8
8
50-59 years
2
50-59 years
2
40-49 years
40-49 years
0
120
140 160 180
SBP (mmHg)
0
70
80 90 100 110
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
CUMULATIVE INCIDENCE OF CV EVENTS IN MEN WITHOUT
HYPERTENSION ACCORDING TO BASELINE BLOOD PRESSURE
mmHg
mmHg
High normal
(130-139)
(130-139)
Normal
(121-129)
(121-129)
Optimal (< 120)
(< 120)
Last JM, et al: N Engl J Med 2001;345:1291-7
CHD Deaths in Men Screened for the MRFIT Study
Julius S: AJH 2000; 13: 11S-17S
Death
Excess Death
% Excess Death
Deaths
1500
20
1000
%
10
500
0
0
<110
110119
120129
130139
140139
150159
Systolic BP (mmHg)
160169
170179
>180
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
2003 WHO/ISH Statement: Journal of Hypertension 2003, 21:1983–1992
％ of population
Present distribution
Optimal distribution
High risk strategy focuses on
about 25% of the population
60
80
100
120
140 160 180 200 220 240
SBP (mmHg)
Distribution of systolic blood pressure in adults
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.
Classification of BP for Adults (mmHg)
JNC 7
SBP and DBP
ESH/ESC and JSH
Normal
<120 and <80
Optimal BP
120-9 or 80-4
Normal BP
130-9 or 85-9
High normal BP
140-59 or 90-9
Grade 1 hypertension
(mild)
Grade 2 hypertension
(moderate)
Grade 3 hypertension
(severe)
Prehypertension
Stage 1 hypertension
160-79 or 100-9
Stage 2 Hypertension
>180 or >110
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)
Risk
Group A
Risk
Group B
Risk
Group C
High Normal
(130-139/85-89)
486
36
21
Mild Hyperternsion
(140-159/90-99)
273
27
18
34
12
11
Moderate to Severe
Hypertension
(>160/>100)
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.
BP and relative Hazards of Cardiovascular Death in Subjects with
Impaired Glucose Tolerance (Igaku-no-ayumi 2004;210:717-8)
Systolic BP (mmHg)
Relative Hazard
16
Normal GT
*
12
*
IGT
*
*
8
*
P<0.05
vs
<120/Normal GT
*
4
0 <120 120- 130- 140- >160
129 139 159
<120 120- 130- 140- >160
129 139 159
Relative Hazard
Diastolic BP (mmHg)
10
8
Normal GT *
*
*
IGT
6
*
*
8084
8589
*
4
2
0 <80
8084
8589
90- >100
99
<80
90- >100
99
*
P<0.05
vs
<80/Normal GT
Stratification of Risk to Quantify Prognosis
BP
Other risk factors
and disease history
Normal
High Normal
SBP 120-129 SBP 130-139
or DBP 80-84 or DBP 85-89
Grade III
Grade I
Grade II
SBP 140-159 SBP 160-179 SBP>180
or DBP 90-99 or DBP 100-109or DBP>110
No other risk factors
Average
risk
Average
risk
Low
added
risk
Moderate
added
risk
High
added
risk
1-2 risk factors
Low
added
risk
Low
added
risk
Moderate
added
risk
Moderate
added
risk
Very high
added
risk
3 or more risk
factors or TOD or
diabetes
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
ACC
High
added
Drug Treatmentrisk
ACC: Associated clinical conditions; TOD: Target organ damage; SZBP systolic blood pressure
Journal of Hypertension 2003,Vol 21 No6：1011-1053
DBP: Diastolic blood pressure
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
(Units: mmHg)
JNC 7
ESH-ESC JSH 2004
Office BP
 140/90
Home
(self-measured)
BP
 135/85
24-hour
ambulatory BP
Awake
Asleep
 135/85
 120/75
 125/80
 135/80
Relative Hazards and 95% CI of Home Systolic/Diastolic
BP for Overall Mortality Ohasama Study (AJH 1997;10:409)
Systolic BP
<113 mmHg (n=380, 13 death)
113-120 mmHg (n=363, 22 death)
120-128 mmHg (n=375, 17 death)
128-138 mmHg (n=406, 27 death)
*
>138 mmHg (n=389, 62 death)
Diastolic BP
<67 mmHg (n=360, 32 death)
*
67-72 mmHg (n=362, 20 death)
72-77 mmHg (n=390, 21 death)
77-83 mmHg (n=381, 25 death)
*
>83 mmHg (n=420, 43 death)
0
1
Home BP: >135/>85 mmHg
2
3
4
5
Hypertension Relative Hazard
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
Cardiovascular Risk in Office and 24-Hour Ambulatory
Blood pressure in Elderly Systolic Hypertension (Syst-Eur)
0.20
2 Year Incidence Rate of
Cardiovascular Events
Nighttime BP
0.16
24-hour BP
0.12
Daytime BP
0.08
Office BP
0.04
0
90
110 130
150 170 190 210 230
Systolic BP （mmHg）
Staessen JA, et al.：JAMA.282；:539-546 (1999)
Prediction of Stroke by Self-Measurement BP at Home vs.
Casual Screening BP: The Ohasama Study (Stroke 2004;35:2356)
Risk of First Stroke
Relative Hazard and 95%CI*
Home BP
Office BP
4
2
Trend p<0.0001
1
Trend p<0.0009
2
3
4
2
3
4
Group
*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
Diagnosis of Masked Hypertension
ABP
Masked Hypertension
Hypertension
Normal BP
White-coat HT
135/80 mmHg
Homed BP
135/85 mmHg
Clinic BP
140/90 mmHg
Jichii Morning-Hypertension Research-J-MORE study
Morning
Systolic
Pressure
(mmHg)
200
23% -MMH
38% -PCH
180
160
150
r=0.25
n=969
135
120
100
90
21% -WCH
100
120
18% -WCHT
140
160
180
200
220
Clinic systolic pressure (mmHg)
(Kario Circulation 2003,108:72e-73e)
Patients with Masked Hypertension have
High Cardiovascular Risk
(/1,000 person x
year)
40
30.6
30
25.6
CV Events
20
10
11.1
12.1
0
Normal BP White-coat HT Masked HT Sustained HT
n=685
n=656
n=462
n=3,125
(Bobrie G et al. JAMA 291:1342-1349,2004)
Canadian Hypertension Education Program Algorithm for Diagnosis of Hypertension
Am J Hypertens 2005;18:1369-1374
Elevated Out of
Office BP
Elevated Random
Office BP
Hypertensive Urgency/
Emergency
Hypertension Visit 1
BP Measurement, History, Physical
Diagnostic tests at visit 1 or 2
Hypertension Visit 2
Within 1 month
BP>140/90+target organ damage
or diabetes or renal disease
BP>180/110
Diagnosis of
Hypertension
Yes
No
Office BPM
Hypertension Visit 3
>160 SBP or
>100 DBP
Diagnosis of
Hypertension
ABPM or SBPM
if available
<160/100
or
Hypertension Visit 4-5
>140 SBP or
>90 DBP
<140/90
Diagnosis of
Hypertension
continue to
follow-up
BP:140-179/90-109
ABPM (if available)
Awake
<135/85 or
24-hour
<130/80
continue to
follow-up
Awake
>135 SBP or >85 DBP
or 24-hour
>130 SBP or >80 DBP
Diagnosis of
Hypertension
SBPM (if available)
<135/85
>135 SBP or
>85 DBP
continue to
follow-up
Diagnosis of
Hypertension
or
Office BPM: Office BP monitoring; ABPM: Ambulatory BP monitoring; SBPM: Self BP monitoring
Home Blood Pressure and Antihypertensive Therapy
~Japanese HT Guideline~
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 .
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.
Point-Counterpoint
BP goal: do the guidelines go
low enough?
Sponsored by
Novartis Pharma AG
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;289:2560–72
Guidelines Committee. J Hypertens 2003;21:1011–53
2ESH/ESC
BP Goal: Do the Guidelines Go
Low Enough? Yes
Matthew R Weir
University of Maryland School of Medicine, USA
Sponsored by
Novartis Pharma AG
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
A definition is required to avoid confusion and enhance the case for tight BP control
BP classification
Systolic pressure
(mmHg)
JNC7
ESC-ESH
JNC7
ESC-ESH
Normal
Normal
<120
120–129
Pre-hypertension
High normal
120–139
Stage 1
hypertension
Grade 1
hypertension
(mild)
Grade 2
hypertension
(moderate)
Stage 2
hypertension
Grade 3
hypertension
(severe)
Diastolic pressure
(mmHg)
JNC7
ESH-ESH
and
<80
80–84
130–139
or
80–89
85–89
140–159
140–159
or
90–99
90–99
160
160–179
or
100
100–109
180
or
Both sets of guidelines define hypertension as a BP ≥140/90 mmHg
Chobanian et al. JAMA 2003;289:2560–72
ESC Guidelines Committee. J Hypertens 2003;21:1011–53
110
High–normal BP Increases the Risk of CVD in
Men but That Risk is Still Low
mmHg
Cumulative incidence (%)
14
High–normal
(130–139)
Normal
(121–129)
Optimal
(<120)
12
10
8
6
4
2
0
0
2
4
6
8
Time (years)
10
Vasan et al. N Engl J Med 2001;345:1291–7
12
14
Lewington S, Clarke R, Qizilbash N, Peto R,
Collins R.
Age-specific relevance of usual blood pressure to
vascular mortality; a meta-analysis of individual data for
one 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
Age at risk:
80–89 years
128
70–79 years
64
60–69 years
32
50–59 years
16
8
4
2
1
256
IHD mortality
(floating absolute risk and 95%CI)
IHD mortality
(floating absolute risk and 95% CI)
256
128
0
64
Age at risk:
80–89 years
70–79 years
60–69 years
32
50–59 years
16
8
4
2
1
0
120
140 160 180
Usual systolic blood
pressure (mmHg)
Lewington et al. Lancet 2002;360:1903–13
70 80 90 100 110
Usual diastolic blood
pressure (mmHg)
Total CV Risk According to BP, Other Risk Factors and
Disease History: The ESH-ESC Guidelines
Definition must be flexible taking into account CV risk profile
Blood pressure (mmHg)
Other risk factors
and disease history
Normal
SBP 120–129
or DBP 80–84
High–normal
SBP 130–139
or DBP 85–89
Grade 1
SBP 140–159
or 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 added
risk
Moderate
added risk
High added
risk
1–2 risk factors
Low added
risk
Low added
risk
Moderate
added risk
Moderate
added risk
Very high
added risk
3 or more risk factors
or TOD or diabetes
Moderate
added risk
High added
risk
High added
risk
High added
risk
Very high
added risk
ACC
High added
risk
Very high
added risk
Very high
added risk
Very high
added risk
Very high
added risk
TOD = target organ damage; ACC = associated clinical conditions
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)
Table modified from ESC Guidelines Committee. J Hypertens 2003;21:1011–53
Anderson et al. Circulation 1991;83:356–362
Lower is an Unachievable Goal: Patients Are
Not Reaching the Current Target
 Current control rates (to <140/90 mmHg), although improved,
Trends in awareness,
treatment and control of high
blood pressure 1976–2000
are still far below the Healthy People 2010 goal of 50%1
80
Awareness
Treatment
Control*
60
40
20
0
1976–1980
1988–1991
1991–1994
1999–2000
Percentage of adults aged 18–74 years with SBP of 140 mmHg or greater, DBP of 90 mmHg or
greater, or taking antihypertensive medication
*SBP below 140 mmHg and DBP below 90 mmHg and receiving antihypertensive medication
1Chobanian
et al. Hypertension 2003;42:1206–52
Are There Additional Benefits, or Risks, in
Lowering SBP to Fully Normotensive Levels?
Estimated incidence (95% Confidence Interval) of CV
events in relation to achieved mean SBP
Minimum = 138.8 mmHg
Minimum = 138.5 mmHg
10
CV mortality/1,000
patient-years
Major CVevents/1,000
patient-years
20
15
10
5
0
8
6
4
2
0
120130 140 150 160 170 180 190
Mean SBP
120130 140 150 160 170 180 190
Mean SBP
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 risk
Hansson et al. Lancet 1998;351:1755–62
Are There Additional Benefits, or Risks, in
Lowering DBP to Fully Normotensive Levels?
Estimated incidence (95% Confidence Interval) of CV
events in relation to achieved mean DBP
Minimum = 82.6 mmHg
Minimum = 86.5 mmHg
10
CV mortality/1,000
patient-years
Major CVevents/1,000
patient-years
20
15
10
5
0
8
6
4
2
0
70 75 80 85 90 95 100 105
Mean DBP
70 75 80 85 90 95 100 105
Mean DBP
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 risk
Hansson et al. Lancet 1998;351:1755–62
Majority of US Hypertensive Patients Are Not
at SBP Goal of <140 mmHg
14
Population (millions)
12
10
8
6
Not meeting goal
4
2
0
SBP range (mmHg)
Adapted from Lapuerta and L’Italien. Am J Hypertens 1999;12:92A
Let Us Not Be Greedy!
What May be a More Important
Question is Whether Every
Patient Who Needs BP
Reduction Should be
on a RAAS Blocker?
Angiotensin II Dichotomy
Angiotensin II
Vasoconstriction
Vascular structure and
function
Modification of SNS
Modification of disease
Renal salt and water
retention
BP homeostasis
Progression
LVH
Atherogenesis Glomerular
sclerosis
Angiotensin II Formation
Angiotensinogen
Renin
Angiotensin I
Alternate pathways*
CAGE
T-PA
Cathepsin G
Cathepsin G
Chymase
Tonin
ACE
Angiotensin II
Angiotensin II receptors
*The clinical significance of alternate pathways is unknown
Dzau et al. J Hypertens 1993;11:S13–18
Proposed Angiotensin II Influences on the
Blood Vessel
BP
Vascular injury
Induction of angiotensin II pathways at the
tissue level
Local angiotensin II production
Vascular remodelling
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
Population with BP controlled
to DBP 90 mmHg (%)
100
80
60
40
20
0
HOT Study1
1Hansson.
2Hyman
NHANES2
J Hypertens Suppl 1999;S9–13
and Pavlick. N Engl J Med 2001;345:479–86
Predictors of Uncontrolled Hypertension in
Ambulatory Patients
Odds of poor
control
95% CI
Age group (years)
55–64
65–74
75
1.26
2.50
2.56
0.71–2.24
1.49–4.19
1.45–4.52
No. of antihypertensive drugs
during the study period
0
2
3
4 or 5
0.90
1.91
2.53
4.70
0.41–1.98
1.25–2.91
1.50–4.28
2.22–9.95
Lack of knowledge of appropriate SBP
1.55
1.09–2.20
Attributed a specific side effect to a
specific antihypertensive medication
2.06
1.41–3.01
Variable
Knight et al. Hypertension 2001;38:809–14
Poor BP Control Resulting From Lack of
Patient Compliance
 Compliance, even to a simple dose regimen, decreases progressively in patients
Proportion of
participants (%)
with hypertension1
100
Medication taken 6–7 days per week
80
Medication taken 4–5 days per week
Medication taken 0–4 days per week
60
Dropped medical follow-up
40
Data not available
20
0
1
2
3
4 5 6 7 8 9
Month of follow-up
10 11 12
 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
1Bovet
2Moser
et al. Bull World Health Organ 2002;80:33–9
and Black. Am J Hypertens 1998;11(6 Pt 2):73S–78S
Poor BP Control is at Least in Part Related to
Physician 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
Increasing the Patient Pool: Diluting the
Resources
60
80
100
120
High normal
Normal
Population (%)
Distribution of systolic blood pressure in adults
Grade I
140
Grade II
160
Grade III
180
SBP (mmHg)
Chobanian et al. Hypertension 2003;42:1206–52
Burt et al. Hypertension 1995;26:60–9
200
220
240
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
Sponsored by
Novartis Pharma AG
The Lower The Better
Age at risk:
80–89 years
128
70–79 years
64
60–69 years
32
50–59 years
16
8
4
2
1
256
IHD mortality
(floating absolute risk and 95%CI)
IHD mortality
(floating absolute risk and 95%CI)
256
128
0
64
Age at risk:
80–89 years
70–79 years
60–69 years
32
50–59 years
16
8
4
2
1
0
120
140 160 180
Usual systolic blood
pressure (mmHg)
Lewington et al. Lancet 2002;360:1903–13
70 80 90 100 110
Usual diastolic blood
pressure (mmHg)
10
High
normal
8
6
4
Normal
2
Optimal
0
Cumulative incidence (%)
Cumulative incidence (%)
Even in the US…
14
12
High
normal
10
Normal
8
6
Optimal
4
2
0
0
2
4
6
8
10
Time (year)
12
No. at risk
Optimal
1875 1967 1951 1839 1821 1734 887
Normal
1126 1115 1097 1084 1061 974 649
High-normal 891 874 809 840 812 722 520
14
0
2
4
6
8
10
Time (year)
No. at risk
Optimal
1005 995 973 962
Normal
1059 1039 1012 982
High-normal 903 879 857 819
High–normal = 130–139/85–89 mmHg
Normal
= 120–129/80–84 mmHg
Optimal
= <120/80 mmHg
Vasan et al. New Engl J Med 2001;345:1291–7
934
952
795
992
992
726
12
454
520
441
14
Benefits of Antihypertensive Treatment Are
Proportional to Reduction in BP
1.50
ACE/CA
ACE/D/BB
1.25
Relative
risk of
stroke
1.00
ACE/placebo
ARB/other
0.75
CA/D/BB
More/less
0.50
CA/placebo
0.25
–10
–8
–6
–4
–2
0
2
4
Systolic blood pressure difference
between randomised groups (mmHg)
Results of prospectively designed overviews of randomised trials
Turnbull et al. Lancet 2003;362:1527–35
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?
The evidence
Treatment
Baseline DBP (mmHg)
Reduction DBP (mmHg)
Reduction CV risk (%)
HOPE
EUROPA
CAMELOT
ACEI
ACEI
CCB
79
82
79
2
2
3
22
20
31
Fox et al. Lancet 2003;362:782–8;
HOPE Investigators. N Engl J Med 2000;342:145–153
Nissen et al. JAMA 2004;292:2217–26
HOT Trial: Diabetes Population
Major CV events/1,000 patients year
Hypertension optimal treatment
25
20
15
10
5
0
90 mmHg
85 mmHg
Hansson et al. Lancet 1998;351:1775–62
80 mmHg
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
Slower Decline in Renal Function With Lower
Blood Pressure Goals
Mean arterial pressure (mmHg)
98
0
GFR decline
(ml/min/year)
−2
100
102
104
106
108
110
r=0.66; p<0.05
−4
−6
−8
−10
Results of studies 3 years in patients with type 2 diabetic nephropathy
Bakris. Diabetes Res Clin Pract 1998;39:S35–42
HOT: Change in QoL Total Score from Baseline
to 6 Months vs DBP at 6 Months (Mean ± SEM)
3.5
Mean change
2.5
1.5
0.5
–0.5
n=108
n=184
n=133
n=108
DBP <80
DBP <81–85
DBP 86–90
–1.5
–2.5
–3.5
Fletcher A et al. J Hypertens 1999
DBP >91
QOL: US Data
TOMHS follow up
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
Grimm et al. Arch Intern Med 1997;157:638–48
7th Annual
International Diovan
Symposium
Lisbon, 3–5 February 2006
The Rebuttals
Sponsored by
Novartis Pharma AG
Rebuttal
Matthew R Weir
University of Maryland School of Medicine, USA
Sponsored by
Novartis Pharma AG
Presyncope??