7th Annual International Diovan Symposium

1
7th Annual International Diovan Symposium

• Lisbon, 35 February 2006

2
??CVrisk (BP?Power CV Protection)?Compliance

• Addressing the Variables
• Solving the Formula to Reduce CV Risk

3
Hosts Welcome

• Cassiano Abreu-Lima
• University of Porto School of MedicinePortugal

4
Prevalence of HF Stages in Porto
Age ? 45 years
Azevedo et al. Heart, 2006
5
Heart Failure Risk Factors in Porto
Age ? 45 years
Azevedo et al. Heart, 2006
6
Hypertension in Portugal
N2115
N5023 1890 years
46.1
42.1
39.0
11.2
Macedo et al. J Hypertension, 2005
7
Portugal Proportional Cardiovascular Disease
Mortality
Total CV mortality 38
Other
25
20
Coronary Artery Disease
8
Chairs Welcome and Objectives Setting the
Challenge

• Victor Dzau
• Duke University, Durham, USA
• Marc Pfeffer
• Harvard Medical School, USA

9
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 years theme Addressing the Variables
  Solving the Formula to Reduce CV Risk

10
The formula

• ??CV risk
• (BP?Power CV Protection)?Compliance

Adapted from Feldman et al. Can Med Assoc J
19991611 (12 Suppl)S1S17
11
??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?

12
??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)?

13
??CV risk
(BP?Power CV Protection)?Compliance

• Protective benefits beyond BP lowering whats
  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?

14
??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?

15
From the Experts Files Case Presentation

• Marc Pfeffer
• Harvard Medical School, USA

16
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)

17
Examination

• Height 1.65 m
• Weight 79 kg
• BMI 29
• BP 156/86 mmHg (confirmed on subsequent
  occasions)
• Heart sounds normal, chest clear

18
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)

19
7th Annual International Diovan Symposium

• Lisbon, 35 February 2006

VARIABLE 1 Hypertension
20
What is Normal and What is Abnormal Blood
Pressure?
Toshiro Fujita University of Tokyo
21
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.

22

• 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.

23
Operational Definition of Hypertension
Evans JG and Rose G Br Med Bull
19712737-42 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.
24
Correlation of Stroke Incidencewith Blood
Pressure Levels
No Drug Intervention 18 years follow-up in
Hisayama, Japan
Male
Female
1000 patient years
1000 patient years
plt0.01 (vs lt120/80)
plt0.01 (vs lt120/80)
30
30
Stroke Incidence
Stroke Incidence

24
24
18
18

12
12



6
6

0
0
lt120
120
130
140
160
180
Systolic BP
mmHg
lt120
120
130
140
160
180
mmHg
lt80
80
85
90
100
110
Diastolic BP
mmHg
lt80
80
85
90
100
110
mmHg
25
Classification of BP in Adult JSH2004 (Japanese
Guidelines)
Classification Optimal BP Normal BP High Normal
BP Mild Hypertension Moderate Hypertension Severe
Hypertension Systolic Hypertension
Systolic BP (mmHg) lt120 lt130 130139
140159 160179 gt180 gt140
Diastolic BP (mmHg) lt80 lt85 8589 9099
100109 gt120 lt90
and and or or or or and
26
Classification of BP in Adult JSH2004 (Japanese
Guidelines)
Classification Optimal BP Normal BP High Normal
BP Mild Hypertension Moderate Hypertension Severe
Hypertension Systolic Hypertension
Systolic BP (mmHg) lt120 lt130 130139
140159 160179 gt180 gt140
Diastolic BP (mmHg) lt80 lt85 8589 9099
100109 gt120 lt90
and and or or or or and
27

• What is Normal and What is Abnormal Blood
  Pressure?
• High Normal Blood Pressure
• Total Individual Risk and Blood Pressure
• Home and Ambulatory Blood Pressure

28
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
7
80-89 years
80-89 years
128
128
70-79 years
70-79 years
32
32
IHD Mortality (floating absolute risk)
60-69 years
60-69 years
8
8
50-59 years
50-59 years
2
2
40-49 years
40-49 years
0
0
120
140
160
180
70
80
90
100
110
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.
29
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
(lt 120)
(lt 120)
Last JM, et al N Engl J Med 20013451291-7
30
CHD Deaths in Men Screened for the MRFIT
Study Julius S AJH 2000 13 11S-17S
Death Excess Death Excess Death
1500
20
1000

Deaths
10
500
0
0
lt110
110- 119
120- 129
130- 139
140- 139
150- 159
160- 169
170- 179
gt180
Systolic BP (mmHg)
31
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.
32
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, 2119831992
Present distribution Optimal distribution
of population
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.
33
Classification of BP for Adults (mmHg)
ESH/ESC and JSH Optimal BP Normal BP High
normal BP Grade 1 hypertension (mild) Grade 2
hypertension (moderate) Grade 3
hypertension (severe)
JNC 7 Normal Prehypertension Stage 1
hypertension Stage 2 Hypertension
SBP and DBP lt120 and lt80 120-9 or 80-4 130-9
or 85-9 140-59 or 90-9 160-79 or 100-9 gt180 or
gt110

34
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.
35

• What is Normal and What is Abnormal Blood
  Pressure?
• High normal blood pressure had better be
  controlled for risk reduction a major positive
  impact on public health.
• Total Individual Risk and Blood Pressure
• Home and Ambulatory Blood Pressure

36
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. 200035539 )
Baseline SBP/DBP (mmHg) High Normal (130-139/85-8
9) Mild Hyperternsion (140-159/90-99) Moderate
to Severe Hypertension (gt160/gt100)
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.
37
BP and relative Hazards of Cardiovascular Death
in Subjects with Impaired Glucose Tolerance
(Igaku-no-ayumi 2004210717-8)
Systolic BP (mmHg)

16
Normal GT
IGT




Plt0.05 vs lt120/Normal GT
12
Relative Hazard

8
4
0
lt120
120- 129
130- 139
140- 159
gt160
lt120
120- 129
130- 139
140- 159
gt160
Diastolic BP (mmHg)

10
Normal GT
IGT



8

Plt0.05 vs lt80/Normal GT


6
Relative Hazard
4
2
0
lt80
80- 84
85- 89
90- 99
gt100
lt80
80- 84
85- 89
90- 99
gt100
38
Stratification of Risk to Quantify Prognosis
BP
Other risk factors and disease history
Normal SBP 120-129 or DBP 80-84
High Normal SBP 130-139 or DBP 85-89
Grade I SBP 140-159 or DBP 90-99
Grade II SBP 160-179 or DBP 100-109
Grade III SBPgt180 or DBPgt110
Low added risk
Moderate added risk
High added risk
Average risk
Average risk
No other risk factors
Low added risk
Low added risk
Moderate added risk
Very high added risk
Moderate added risk
1-2 risk factors
High added risk
High added risk
3 or more risk factors or TOD or diabetes
Moderate added risk
High added risk
Very high added risk
High added risk
Very high added risk
Very high added risk
Very high added risk
Very high added risk
ACC

Drug Treatment
ACC Associated clinical conditions TOD Target
organ damage SZBP systolic blood pressure DBP
Diastolic blood pressure
Journal of Hypertension 2003,Vol 21 No61011-1053
39

• What is Normal and What is Abnormal Blood
  Pressure?
• High normal blood pressure had better be
  controlled for risk reduction a major positive
  impact on public health.
• Total individual risk should determine the real
  threshold for high blood pressure.
• Home and Ambulatory Blood Pressure

40
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.
41
Criteria for Hypertension
(Units mmHg)
JNC 7
JSH 2004
ESH-ESC
? 140/90
Office BP
? 135/85
Home (self-measured) BP
24-hour ambulatory BP
Awake
? 135/85
? 125/80
? 135/80
Asleep
? 120/75
42
Relative Hazards and 95 CI of Home
Systolic/Diastolic BP for Overall Mortality
Ohasama Study (AJH 199710409)
Systolic BP
lt113 mmHg (n380, 13 death)
113-120 mmHg (n363, 22 death)
120-128 mmHg (n375, 17 death)
128-138 mmHg (n406, 27 death)

gt138 mmHg (n389, 62 death)
Diastolic BP
lt67 mmHg (n360, 32 death)

67-72 mmHg (n362, 20 death)
72-77 mmHg (n390, 21 death)
77-83 mmHg (n381, 25 death)

gt83 mmHg (n420, 43 death)
0
1
2
3
4
5
Relative Hazard
Home BP gt135/gt85 mmHg Hypertension
43
Relative Hazards and 95 CIs of 24-hour Systolic
and Diastolic BP Values for Overall
Mortality Ohasama Study (Hypertension
199832255)
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 gt135/gt80 mmHg
Hypertension
44
Cardiovascular Risk in Office and 24-Hour
Ambulatory Blood pressure in Elderly Systolic
Hypertension (Syst-Eur)
0.20
Nighttime BP
0.16
24-hour BP
0.12
2 Year Incidence Rate of Cardiovascular Events
Daytime BP
0.08
Office BP
0.04
0
130
210
90
110
150
170
190
230
Systolic BP (mmHg)
Staessen JA, et al.JAMA.282539-546 (1999)
45
Prediction of Stroke by Self-Measurement BP at
Home vs. Casual Screening BP The Ohasama Study
(Stroke 2004352356)
Risk of First Stroke
Home BP
Office BP
4
Relative Hazard and 95CI
2
Trend plt0.0001
1
Trend plt0.0009
2
3
4
2
3
4
Group
Adjusted for age, sex, diabetes,
hypercholesterolemia, smoking, history of
cardiovascular disease Group 1 normotensive
(relative hazard1), Group 2 prehypertensive
Group 3 stage 1 hypertensive Group 4 stage 2
hypertensive
46
Diagnosis of Masked Hypertension
Masked Hypertension
Hypertension
ABP 135/80 mmHg Homed BP 135/85 mmHg
Normal BP
White-coat HT
Clinic BP 140/90 mmHg
47
Jichii Morning-Hypertension Research-J-MORE study
Morning Systolic Pressure (mmHg)
200 180 160 150 135 120 100 90
38 -PCH
23 -MMH


r0.25 n969















21 -WCH
18 -WCHT
100 120 140 160
180 200 220
Clinic systolic pressure (mmHg)
(Kario Circulation 2003,10872e-73e)
48
Patients with Masked Hypertension have High
Cardiovascular Risk
(/1,000 person x year)
40 30 20 10 0
CV Events
30.6
25.6
12.1
11.1
Normal BP n685
White-coat HT n656
Masked HT n462
Sustained HT n3,125
(Bobrie G et al. JAMA 2911342-1349,2004)
49
Canadian Hypertension Education Program Algorithm
for Diagnosis of Hypertension Am J Hypertens
2005181369-1374
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
BPgt140/90target organ damage or diabetes or
renal disease BPgt180/110
Diagnosis of Hypertension
Yes
No
BP140-179/90-109
Office BPM
Hypertension Visit 3
Diagnosis of Hypertension
ABPM (if available)
SBPM (if available)
gt160 SBP or gt100 DBP lt160/100
ABPM or SBPM if available
Awake lt135/85 or 24-hour lt130/80
lt135/85
gt135 SBP or gt85 DBP
Awake gt135 SBP or gt85 DBP or 24-hour gt130 SBP or
gt80 DBP
or
or
Hypertension Visit 4-5
Diagnosis of Hypertension
gt140 SBP or gt90 DBP lt140/90
continue to follow-up
Diagnosis of Hypertension
Diagnosis of Hypertension
continue to follow-up
continue to follow-up
Office BPM Office BP monitoring ABPM
Ambulatory BP monitoring SBPM Self BP monitoring
50
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 .
51

• What is Normal and What is Abnormal Blood
  Pressure?
• High normal blood pressure had better be
  controlled for risk reduction a major positive
  impact on public health.
• Total individual risk should determine the real
  threshold for high blood pressure.
• Home/ambulatory blood pressure more greatly
  affect cardiovascular risk the widely-accepted
  and evidence-based criteria of home/ambulatory
  hypertension should be required.

52
Point-CounterpointBP goal do the guidelines go
low enough?
53
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
  mmHg1
• 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 diabetics2

1JNC 7 Report. JAMA 2003289256072 2ESH/ESC
Guidelines Committee. J Hypertens 200321101153
54
BP Goal Do the Guidelines Go Low Enough? Yes

• Matthew R Weir
• University of Maryland School of Medicine, USA

55
Overview

• How low should you go?
• What drugs should you use?
• How are you going to get there?

56
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

57
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
Both sets of guidelines define hypertension as a
BP 140/90 mmHg
Chobanian et al. JAMA 2003289256072ESC
Guidelines Committee. J Hypertens 200321101153
58
Highnormal BP Increases the Risk of CVD in Men
but That Risk is Still Low
mmHg
14 12 10 8 6 4 2 0
(130139)
Highnormal
(121129)
Normal
Cumulative incidence ()
(lt120)
Optimal
0 2 4 6 8 10 12 14
Time (years)
Vasan et al. N Engl J Med 200134512917
59
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 2002360190313
• 61 prospective trials
• 1,000,000 individuals
• 12,700,000 person-years

60
Lower is Better IHD Rates by SBP, DBP and Age
Age at risk
Age at risk
256 128 64 32 16 8 4 2 1 0
256 128 64 32 16 8 4 2 1 0
8089 years
8089 years
7079 years
7079 years
6069 years
6069 years
5059 years
5059 years
IHD mortality(floating absolute risk and 95 CI)
IHD mortality(floating absolute risk and 95CI)
120 140 160 180
70 80 90 100 110
Usual systolic bloodpressure (mmHg)
Usual diastolic bloodpressure (mmHg)
Lewington et al. Lancet 2002360190313
61
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) Blood pressure (mmHg) Blood pressure (mmHg) Blood pressure (mmHg) Blood pressure (mmHg)
Other risk factorsand disease history NormalSBP 120129or DBP 8084 Highnormal SBP 130139or DBP 8589 Grade 1 SBP 140159or DBP 9099 Grade 2 SBP 160179or DBP 100109 Grade 3 SBP gt180or DBP gt110
No other risk factors Average risk Average risk Low addedrisk Moderateadded risk High addedrisk
12 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
TOD target organ damage ACC associated
clinical conditions
JNC7 and ESH-ESC guidelines recommend a target BP
of lt140/90 mmHg for patients with uncomplicated
hypertension since this is associated with
average CV risk (Framingham)
Table modified from ESC Guidelines Committee. J
Hypertens 200321101153Anderson et al.
Circulation 199183356362
62
Lower is an Unachievable Goal Patients Are Not
Reaching the Current Target

• Current control rates (to lt140/90 mmHg), although
  improved, are still far below the Healthy People
  2010 goal of 501

80 60 40 20 0
Awareness Treatment Control
Trends in awareness,treatment and control of
highblood pressure 19762000
19761980 19881991 19911994 19992000
Percentage of adults aged 1874 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 200342120652
63
Are There Additional Benefits, or Risks,
inLowering 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 8 6 4 2 0
20 15 10 5 0
CV mortality/1,000patient-years
Major CVevents/1,000patient-years
120 130 140 150 160 170 180 190
120 130 140 150 160 170 180 190
Mean SBP
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 1998351175562
64
Are There Additional Benefits, or Risks,
inLowering 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 8 6 4 2 0
20 15 10 5 0
CV mortality/1,000patient-years
Major CVevents/1,000patient-years
70 75 80 85 90 95 100 105
70 75 80 85 90 95 100 105
Mean DBP
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 1998351175562
65
Majority of US Hypertensive Patients Are Not at
SBP Goal of lt140 mmHg
14 12 10 8 6 4 2 0
Population (millions)
Not meeting goal
8190
91100
171180
181190
191200
201210
211220
221230
231240
241250
161170
151160
141150
131140
121130
111120
101110
SBP range (mmHg)
Adapted from Lapuerta and LItalien. Am J
Hypertens 19991292A
66
Let Us Not Be Greedy!
67
What May be a More ImportantQuestion is Whether
EveryPatient Who Needs BPReduction Should beon
a RAAS Blocker?
68
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
69
Angiotensin II Formation
Alternate pathways
Angiotensinogen
Renin
T-PA Cathepsin G Tonin
CAGE Cathepsin G Chymase
Angiotensin I
ACE
Angiotensin II
Angiotensin II receptors
The clinical significance of alternate pathways
is unknown Dzau et al. J Hypertens 199311S1318
70
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
199322S19
71
(No Transcript)
72
Optimal Vascular Protection
Earlier and more aggressive BP control
Pharmacologic blockade of the RAAS
73
BP Control Rates in Trial and Community Settings
100 80 60 40 20 0
Population with BP controlled to DBP 90 mmHg ()
HOT Study1
NHANES2
1Hansson. J Hypertens Suppl 1999S913 2Hyman and
Pavlick. N Engl J Med 200134547986
74
Predictors of Uncontrolled Hypertension in
Ambulatory Patients
Variable Odds of poor control 95 CI
Age group (years)55646574³75 1.262.502.56 0.712.241.494.191.454.52
No. of antihypertensive drugs during the study period0234 or 5 0.901.912.534.70 0.411.981.252.911.504.282.229.95
Lack of knowledge of appropriate SBP 1.55 1.092.20
Attributed a specific side effect to a specific antihypertensive medication 2.06 1.413.01
Knight et al. Hypertension 20013880914
75
Poor BP Control Resulting From Lack of Patient
Compliance

• Compliance, even to a simple dose regimen,
  decreases progressively in patients with
  hypertension1

100 80 60 40 20 0
Medication taken 67 days per week Medication
taken 45 days per week Medication taken 04 days
per week Dropped medical follow-up Data not
available
Proportion of participants ()
1 2 3 4 5 6 7 8 9 10 11 12
Month of follow-up

• More than 50 of patients require a combination
  of two or more antihypertensive drugs to achieve
  BP goal lt140/90 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 et al. Bull World Health Organ
2002803392Moser and Black. Am J Hypertens
199811(6 Pt 2)73S78S
76
Poor BP Control is at Least in Part Related
toPhysician Factors

• A large study showed patients who had more
  intensive therapy had significantly (plt0.01)
  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 dont always feel that patients
  included in the clinical trials are
  representative of their own patient population

1Berlowitz et al. N Engl J Med 1998339195763
2Hagemeister et al. J Hypertens 200119207986
3Hyman and Pavlik. Arch Intern Med
200016022816 4Oliveria et al. Arch Intern Med
200216241320
77
Increasing the Patient Pool Diluting the
Resources
Distribution of systolic blood pressure in adults
Population ()
High normal
Normal
Grade I
Grade II
Grade III
60
80
100
120
140
160
180
200
220
240
SBP (mmHg)
Chobanian et al. Hypertension 200342120652 Bur
t et al. Hypertension 199526609
78
Conclusions

• Benefits shown for lowering BP to lt140 and lt80
  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!

79
Conclusions (Contd)

• 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)

80
Do the Guidelines Go Low Enough? No

• Gordon McInnes
• Western Infirmary, Glasgow, UK

81
The Lower The Better
Age at risk
Age at risk
256 128 64 32 16 8 4 2 1 0
256 128 64 32 16 8 4 2 1 0
8089 years
8089 years
7079 years
7079 years
6069 years
6069 years
5059 years
5059 years
IHD mortality(floating absolute risk and 95CI)
IHD mortality(floating absolute risk and 95CI)
120 140 160 180
70 80 90 100 110
Usual systolic bloodpressure (mmHg)
Usual diastolic bloodpressure (mmHg)
Lewington et al. Lancet 2002360190313
82
Even in the US
10 8 6 4 2 0
14 12 10 8 6 4 2 0
Highnormal
Highnormal
Normal
Cumulative incidence ()
Cumulative incidence ()
Optimal
Normal
Optimal
0 2 4 6 8 10 12 14
0 2 4 6 8 10 12 14
Time (year)
Time (year)
No. at risk Optimal 1875 1967 1951 1839 1821 1734
887 Normal 1126 1115 1097 1084 1061 974 649 High-n
ormal 891 874 809 840 812 722 520
No. at risk Optimal 1005 995 973 962 934 992 454 N
ormal 1059 1039 1012 982 952 992 520 High-normal 9
03 879 857 819 795 726 441
Highnormal 130139/8589 mmHg Normal
120129/8084 mmHg Optimal lt120/80 mmHg
Vasan et al. New Engl J Med 200134512917
83
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
ARB/other
ACE/placebo
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
2003362152735
84
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 2005112165162
85
Is Low DBP a Risk in CHD?
The evidence
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
Fox et al. Lancet 20033627828 HOPE
Investigators. N Engl J Med 2000342145153Nisse
n et al. JAMA 2004292221726
86
HOT Trial Diabetes Population
Hypertension optimal treatment
25 20 15 10 5 0
Major CV events/1,000 patients year
90 mmHg 85 mmHg 80 mmHg
Hansson et al. Lancet 1998351177562
87
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
2001358103341
88
Slower Decline in Renal Function With Lower Blood
Pressure Goals
Mean arterial pressure (mmHg)
98
100
102
104
106
108
110
0
r0.66 plt0.05
-2
-4
GFR decline(ml/min/year)
-6
-8
-10
Results of studies ³3 years in patients with type
2 diabetic nephropathy
Bakris. Diabetes Res Clin Pract 199839S3542
89
HOT Change in QoL Total Score from Baseline to
6 Months vs DBP at 6 Months (Mean SEM)
3.5 2.5 1.5 0.5 0.5 1.5 2.5 3.5
n108
Mean change
n184
n133
n108
DBP lt80 DBP lt8185 DBP 8690 DBP gt91
Fletcher A et al. J Hypertens 1999
90
QOL US Data
TOMHS follow up
SBP (mmHg) Active Placebo
lt120 476.1 464.1
120129 447.6 439.8
130139 434.5 411.1
³140 408.3 399.3
Grimm et al. Arch Intern Med 199715763848
91
7th Annual International Diovan Symposium

• Lisbon, 35 February 2006

The Rebuttals
92
Rebuttal

• Matthew R Weir
• University of Maryland School of Medicine, USA

93
Presyncope??