Transcript ΚΡΙΤΙΚΗ ΟΔΗΓΙΩΝ ΥΠΕΡΤΑΣΗΣ

ESH/ESC Guidelines:
Definitions and Classification of BP Levels (mmHg)
Category
Systolic
Diastolic
Optimal
Normal
High normal
Grade 1 hypertension (mild)
Grade 2 hypertension (moderate)
Grade 3 hypertension (severe)
Isolated systolic hypertension
< 120
120-129
130-139
140-159
160-179
≥ 180
≥ 140
< 80
80-84
85-89
90-99
100-109
≥ 110
< 90
When a patient’s SBP and DBP fall into different categories, the higher category should apply.
Isolated systolic hypertension can also be graded (grades 1, 2, 3) according to SBP values in the
ranges indicated, provided diastolic values are < 90
6254 M
Stroke and usual BP
CHD and usual BP
(in 5 categories defined by baseline
DBP)
7 prospective observational studies:
843 events
(in 5 categories defined by baseline
DBP)
9 prospective observational studies:
4856 events
4.00
4.00
Relative Risk
of Stroke
Relative Risk
of Stroke
2.00
2.00
1.00
1.00
0.50
0.50
0.25
0.25
Baseline
DBP category
Usual SBP
Usual DBP
1
2
3
4
5
123
76
136
84
148
91
162
99
175
105
Baseline
DBP category
Usual SBP
Usual DBP
1
2
3
4
5
123
76
136
84
148
91
162
99
175
105
Approximate mean usual BP
Approximate mean usual BP
(estimated from later remeasurements
in the Framingham Study)
(estimated from later remeasurements
in the Framingham Study)
Collins R and McMahon S, British Medical Bulletin 1994
3510
JNC 7
Individuals with
SBP of 120-139 or DBP of 80-89 mmHg should
be considered as prehypertensive
and require health promoting
lifestyle modifications to prevent CVD
4-Year Frequency (%) of Progression to HT
according to BP Values within Normal Range * (n = 9845, Framingham)
35-64 ys
65-94 ys
49.5
50
%
40
37.3
30
25.5
20
17.6
16.0
Optimum BP
<120/80 mmHg
Normal BP
120-129/80-84 mmHg
10
5.3
High normal BP
130-139/85-89 mmHg
0
* Data adjusted for sex, age, BMI, baseline examinations
7395 M
Vasan et al., Lancet 2001; 358: 1682
“Prehypertension” - Criticism
Progression to HT less frequent in several studies
“Hypertension” has an ominous significance by the layman
Anxiety over the term may create need for medical visits / lab
examinations
Several lifestyle changes must be preceded by / performed under
medical check / guidance
Lifestyle changes
- Not invariably devoid of cost
- Reflection on subject’s QoL, freedom etc.
8222 M
ESH/ESC Guidelines: Stratification of Risk to Quantify Prognosis
Blood Pressure (mmHg)
Normal
High Normal
Grade 1
Grade 2
Grade 3
Other Risk Factors
and Disease History
SBP 120-129
or DBP 80-84
SBP 130-139
or DBP 85-89
SBP 140-159
or DBP 90-99
SBP 160-179
or DBP 100-109
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
Associated Clinical
Conditions
High
added risk
Very high
added risk
Very high
added risk
Very high
added risk
Very high
added risk
7772 M
Low risk: < 15%; Medium risk: 15-20%; High risk: 20-30%; Very high risk: > 30%
ESH/ESC Guidelines: Factors Influencing Prognosis
Risk factors for CV disease used
for stratification
Target Organ Damage (TOD)
Diabetes Mellitus
Associated Clinical Conditions
(ACC)
Levels of SBP and DBP
Left ventricular hypertrophy
(electrocardiogram:
Sokolow-Lyons > 38 mm;
Cornell > 2440 mm*ms;
echocardiogram:
LVMI > 125, W > 110 g/m2)
Fasting plasma glucose
7.0 mmol/l (126 mg/dl)
Cerebrovascular disease:
ischaemic stroke;
cerebral haemorrhage;
transient ischaemic attack
Men > 55 years
Women > 65 years
Smoking
Dyslipidaemia
(total chol. > 250 mg/dl, or LDLchol. > 155 mg/dl, or HDL-chol.
M < 40, W < 48 mg/dl
Family history of premature
CV disease (at age < 55 years M,
< 65 years W)
Abdominal obesity
(abdominal circumference > 102
cm, W > 88 cm)
C-reactive protein > 1 mg/dl
6250 M
Ultrasound evidence of arterial
wall thickening
(carotid IMT > 0.9 mm) or
atherosclerotic plaque
Slight increase in serum
creatinine
(M 115-133, W 107-124 mol/l; M
1.3-1.5, W 1.2-1.4 mg/dl)
Microalbuminuria
(30-300 mg/24h; albumincreatinine ratio M > 22, W > 31
mg/g; M > 2.5, W > 3.5 mg/mmol)
Postprandial plasma
glucose > 1.0 mmol/l
(198 mg/dl)
Heart disease:
myocardial infarction;
angina;
coronary revascularization;
congestive heart failure
Renal disease:
diabetic nephropathy;
renal impairment (serum
creatinine M > 1.5, W > 1.4
mg/dl)
proteinuria (> 300 mg/24h)
Peripheral vascular disease
Advanced retinopathy:
haemorrhages or exudates,
papilloedema
160
159
149
Stroke recurrency
HT
0
-10
RRR (%)
BP (mmHg)
140
120
100
94
80
-20
-30
90
-29
-32
60
-40
NT
160
8236 M
-10
127
100
60
CVD
136
120
80
Stroke recurrency
0
RRR (%)
BP (mmHg)
140
CVD
-20
-24
-30
79
-29
75
-40
PROGRESS, Lancet 2001
Mean BP 
(mmHg)
Favours
active
Favours
control
Relative Risk
(95% CI)
Stroke
More vs less
-4 / -3
0.77 (0.63-0.95)
CHD
More vs less
-4 / -3
0.86 (0.72-1.03)
Heart failure
More vs less
-4 / -3
0.84 (0.59-1.18)
Major CV events
More vs less
-4 / -3
0.86 (0.77-0.96)
CV death
More vs less
-4 / -3
0.93 (0.77-1.11)
Total mortality
More vs less
-4 / -3
0.96 (0.84-1.09)
0.5
8175 = 6397 alt. M
1.0
Relative risk
2.0
RR of CVD with Low-Dose Aspirin (vs Placebo) in HOT
On-treatment BP (mmHg)
~ 140/83
Medium risk
1.00
High / very high risk
0.78 *
* statistically significant
8247 M
Zanchetti et al., J Hypertens 2002; 20: 2309
On-Treatment BP and  Events with Atorvastatin (vs Placebo)
in ASCOT
All patients with ≥ 3 risk factors
8248 M
BP (mmHg)
~ 138/80
Stroke
-27%
CHD
-29%
CVD
-21%
Total mortality
-13% (NS)
Initiation of Antihypertensive Treatment
Blood Pressure (mmHg)
Normal
High Normal
Grade 1
Grade 2
Grade 3
SBP 120-129
SBP 130-139
SBP 140-159
SBP 160-179
SBP ≥ 180
or DBP 80-84
or DBP 85-89
or DBP 90-99
or DBP 100-109
or DBP ≥ 110
No BP
intervention
No BP
intervention
Lifestyle changes
for several months
Then drug
treatment if
preferred by the
patient and
resources available
Lifestyle changes
for several months
Then
drug treatment
Immediate drug
treatment and
lifestyle changes
Lifestyle
changes
Lifestyle
changes
Lifestyle changes
for several months
Then
drug treatment
Lifestyle changes
for several months
Then
drug treatment
Immediate drug
treatment and
lifestyle changes
3 or more risk factors
or TOD or diabetes
Lifestyle changes
Drug treatment
and
lifestyle changes
Drug treatment
and
lifestyle changes
Drug treatment
and
lifestyle changes
Immediate drug
treatment and
lifestyle changes
Associated clinical
conditions
Drug treatment
and
lifestyle changes
Immediate drug
treatment and
lifestyle changes
Immediate drug
treatment and
lifestyle changes
Immediate drug
treatment and
lifestyle changes
Immediate drug
treatment and
lifestyle changes
Other Risk Factors
and Disease History
No other risk factors
1-2 risk factors
Association of Hypertension with Other CAD Risk Factors:
Framingham Study
One
26%
None
19%
Four or more
8%
Men
2313
One
27%
Two
25%
Three
22%
Two
24%
None
17%
Four or more
12%
Three
20%
Women
Kannel, Am J Hypertens 2000; 13: 3S-10S
Echocardiography and US TSA in Low Risk Hypertensives
APROS STUDY RISK RE-CLASSIFICATION
Low
100
Medium
80
High
38
29
55
60
81
40
51
60
35
20
19
0
Routine
Cuspidi et al, J Hypertens 2002
10
11
11
After ECHO and US TSA
After ECHO
After US TSA
Risk Factors in Subjects of the SMOOTH Study with BP from Optimal to Untreated HT
 BMI
Smoking
 Ch
60
%
57.7
53.4
48.9
40
 TG
60.3
48.4
43.7
33.1
30.1
26.1
25.4
20
22.2
24.5
12.2
12.0
14.3
8.0
0

*
*
15
 HDL-Ch
 UA
DM
%
*
13.1
12.1
10
Optimal BP
Normal BP
High normal BP
5
6.0
6.3
6.3
5.2
5.2
Untreated HT
6.1
5.3
5.1
3.8
* P < 0.0001
 P < 0.0002
2.4
0
7637 M
NS
*
*
JNC VII: Classification and Management of Blood Pressure
for Adults Agfed 18 years and Older
Initial drug therapy
BP
classification
SBP*
mmHg
DBP*
mmHg
Lifestyle
modification
Normal
<120
Encourage
Prehypertension
120–
139
and
<80
or 80–
89
Stage 1
Hypertension
140–
159
or 90–
99
Yes
Stage 2
Hypertension
>160
or
>100
Yes
Yes
Without compelling
indication
No antihypertensive drug
indicated.
Drug(s) for
compelling
indications. ‡
Thiazide-type diuretics for Drug(s) for the
most. May consider ACEI, compelling
ARB, BB, CCB, or
indications.‡
combination.
Other
antihypertensive
Two-drug combination for drugs (diuretics,
most† (usually thiazide-type ACEI, ARB, BB,
diuretic and ACEI or ARB CCB) as needed.
or BB or CCB).
*Treatment determined by highest BP category.
†Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension.
‡Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg.
6273 M
With compelling
indications
Clinical Outcomes (6 yr rate .100 persons) in ALLHAT
4673 M
C
A
L
CHD
11.5
11.3
11.4
Stroke
5.6
5.4
6.3*
CHF
7.7
10.2**
8.7**
ESRF
1.8
2.1
2.0
* P < 0.02
** P < 0.01
Comparison of ACEI-based therapy and calcium-antagonist-based therapy
vs placebo
Favours Favours
RR
ACEI placebo (95% CI)
Favours Favours
RR
CA placebo (95% CI)
Stroke
0.70 (0.57-0.85)
0.61 (0.44-0.85)
CHD
0.80 (0.72-0.89)
0.79 (0.59-1.06)
CHF
0.84 (0.68-1.04)
0.72 (0.48-1.07)
CV events
0.79 (0.73-0.86)
0.72 (0.59-0.87)
CV death
0.74 (0.64-0.85)
0.72 (0.52-0.98)
Total mortality
0.84 (0.76-0.94)
0.87 (0.70-1.09)
0.5
1.0
1.0
2.0
Relative risk
0.5
1.0
2.0
2.0
Relative risk
1816
1816
Trials on “New” vs “Old” Treatments
Primary Endpoints (RR + 95% CI)
CAPPP*
STOP2*
ANBP2*
ALLHAT°
STOP2*
NORDIL*
INSIGHT*
ALLHAT°
INVEST*
ALLHAT°
SCOPE*
LIFE*
* CVD; ° CHD
5487 M
ACE-I
ACE-I
ACE-I
ACE-I
CCB
CCB
CCB
CCB
CCB
B
ARB
ARB
0.5
1.0
New better
2.0
1.05 (0.90-1.22)
1.01 (0.84-1.22)
0.89 (0.79-1.00)
0.99 (0.91-1.08)
0.97 (0.80-1.17)
1.00 (0.87-1.15)
1.10 (0.91-1.34)
0.98 (0.90-1.07)
0.98 (0.90-1.06)
1.03 (0.90-1.17)
0.89 (0.75-1.06)
0.87 (0.77-0.98)
n = 10985
n = 4418
n = 6083
n = 9054
n = 4209
n = 10881
n = 6321
n = 9048
n = 22599
n = 24335
n = 4506
n = 9193
Old better
Mancia G. et al., 2003
ANBP2: Primary End-Points among All, Male, and Female Subjects
All Subjects
ACE-I superior
0.2
End Point
Hazard Ratio (95% CI)
All CV events or death from any cause
0.89 (0.79-1.00)
First CV event or death from any cause
0.89 (0.79-1.01)
Death from any cause
0.90 (0.75-1.09)
ACE-I superior
0.2
5370 M
5.0
Diuretics superior
1.0
5.0
P Value
0.02
0.02
0.14
Female Subjects
End Point
Hazard Ratio (95% CI)
All CV events or death from any cause
1.00 (0.83-1.21)
First CV event or death from any cause
1.00 (0.83-1.20)
Death from any cause
1.01 (0.76-1.35)
1.0
P Value
0.05
0.06
0.27
Male Subjects
End Point
Hazard Ratio (95% CI)
All CV events or death from any cause
0.83 (0.71-0.97)
First CV event or death from any cause
0.83 (0.71-0.97)
Death from any cause
0.83 (0.66-1.06)
Diuretics superior
ACE-I superior
P Value
0.98
0.98
0.94
0.2
Diuretics superior
1.0
Wing et al., N Engl J Med 2003; 348: 583-92
5.0
All Cardiovascular Events
Number of events / patients
Trials
MIDAS/NICS/VHAS
STOP2/CCBs
NORDIL
INSIGHT
ALLHAT/Aml
ELSA
CCBs without CONVINCE
CONVINCE
All CCBs
Het. p = 0.86
UKPDS
STOP/ACEIs
CAPPP
ALLHAT/Lis
ANBP2
All ACEIs
Het. p = 0.006
LIFE
SCOPE
All ARBs
Het. p = 0.69
ALLHAT/Dox
All Trials
Het. p < 0.0001
Het. p = 0.78
Difference
(SD)
Odds ratios
(95% CIs)
Old
New
37/ 1358
637/ 2213
453/ 5471
397/ 3164
3941/15255
33/ 1157
5498/28618
39/ 1353
636/ 2196
466/ 5410
383/ 3157
2432/ 9048
27/ 1177
3983/22341
365/ 8297
5863/36915
364/ 8179
4347/30520
3.4% (2.3) 2p = 0.15
78/ 358
637/ 2213
401/ 5493
3941/15255
429/ 3039
5486/26358
107/ 400
586/ 2205
438/ 5492
2514/ 9054
394/ 3044
4039/20195
2.6% (3.6) 2p = 0.59
588/ 4588
268/ 2460
856/ 7048
508/ 4605
242/ 2477
750/ 7082
-14.3% (5.5) 2p = 0.004
2245/15268
1592/ 9067
7627/53279
10728/67295
.
.
3.6% (2.4) 2p = 0.14
1.4% (4.8) 2p = 0.69
0
1
2
New drugs better
Old drugs better
5563 M
3
Staessen, J Hypertens 2003
CVD and HTN
Antihypertensive T reduces CVD
Benefit with a variety of drug classes
D
BB
ACEI
CA
ARB
BP reduction per se major factor
4662 M
Relative risk of outcome event
1.50
1.25
1.50
1.50
Stroke
Major CVD
CHD
1.25
1.25
1.00
1.00
1.00
0.75
0.75
0.75
0.50
0.50
0.50
0.25
0.25
0.25
-10
-8
-6
-4
-2
0
2
4
-10
1.50
1.25
-8
-6
-4
-2
0
2
4
-10
-8
-6
-2
1.50
CVD death
Total mortality
1.25
1.00
1.00
0.75
0.75
0.50
0.50
0.25
0.25
-10
-8
-6
-4
-2
0
2
4
-10
-8
-6
-4
-2
0
SBP difference between randomized groups (mmHg)
7939 = 6398 M mod.
-4
2
4
0
2
4
Risk of CVD according to SBP Control by Treatment
CHF
40
No
Yes
30.2
30
Prior MI
No
Yes
Diabetes
No
Yes
Prior
Stroke / TIA
No
Yes
Renal
Impairment
No
*
29.8


21.0
20
10
*
12.4
7.4
11.9
6.4
20.3

12.4*
6.7
> 70
†
18.9
18.7

≤ 70
24.6
24.1
*
13.5
Yes
Age
17.4
13.6
†
14.8
14.0
11.9
10.8
7.4
7.9
5.1
0
8273 M
≥ 140 mmHg
< 140 mmHg
* P < 0.001;  P = 0.03; † P = 0.04
Pepine, Koney, Kupfer, Benetos, Mancia et al., 2004
Hypertension in High-Risk Patients: Number
of Agents Required to Achieve BP Goal
UKPDS (<85 mm Hg, diastolic)
MDRD (92 mm Hg, MAP)
HOT (<80 mm Hg, diastolic)
AASK (<92 mm Hg, MAP)
RENAAL (<140/90 mm Hg)
IDNT (135/85 mm Hg)
1
2
3
Number of BP Medications
4
UKPDS=United Kingdom Prospective Diabetes Study; MDRD=Modification of Diet in Renal Disease;
HOT=Hypertension Optimal Treatment; AASK=African American Study of Kidney Disease; RENAAL=Reduction of Endpoints in
NIDDM with the Angiotensin II Antagonist Losartan; IDNT=Irbesartan Diabetic Nephropathy Trial; MAP=mean arterial pressure.
5129 M
Bakris et al. Am J Kidney Dis. 2000;36:646-661; Brenner et al. N Engl J Med. 2001;345:861-869;
Lewis et al. N Engl J Med. 2001;345:851-860
2003 ESH/ESC Guidelines
Diuretics
AT1-receptor
blockers
ß-blockers
Calcium
antagonists
1-blockers
ACE inhibitors
6220 M
2003 ESH/ESC Guidelines
Consider:
Untreated BP level
Absence or presence of TOD and risk
factors
Single agent
at low dose
Choose between
Two-drug combination
at low dose
If goal BP not achieved
Previous agent
at full dose
Two-three drug
combination
6219 M
Switch to different
agent at low dose
Previous combination Add a third drug
at full dose
at low dose
If goal BP not achieved
Full dose
Two-three drug combination
monotherapy
at effective doses
ESH/ESC Guidelines
Particular attention should be given to adverse
events, even primarily subjective disturbances,
because they may be an important cause of noncompliance
Pts should always be asked about adverse effects and
doses or drugs changed accordingly
6375 M
ESH/ESC Guidelines - Specific Indications for Drug Classes
6372 M
Thiazides
CHF / Elderly / ISH / Blacks
Loop diuretics
Renal insufficiency / CHF
Antialdosterone D
CHF / Post-MI
B
Angina / Post-MI / CHF / Pregnancy / Tachyarrhythmias
CCB (DHP)
Elderly / ISH / Angina / PVD / Ca atherosclerosis / Pregnancy
CCB (non-DHP)
Angina / Ca atherosclerosis / Suprav. tachycardia
ACEI
CHF / LV dysfunction / Post-MI / Non-DN / Type I DN / Proteinuria
ARB
Type 2 DN / Diabetic microalbuminuria / Proteinuria / LVH / ACEI-cough
B
BPH / Hyperlipidaemia
1993 ESH/ESC Guidelines:
Antihypertensive Treatment in DM
Non-pharmacological measures (particularly weight loss and  Na intake)
in all patients
BP goal a 130/80 mmHg
Combination T required most often
Use of all effective / well tolerated agents recommended
Renoprotection benefits from regular inclusion in combination T of
- ACEI in type I DM
- ARB in type II DM
In type II DM with normal BP use first a RAS blocker
Microalbuminuria (type I/II DM) is an indication for T, especially with
RAS blocker, irrespective of BP values
6262 M
Risk
Factors
Subclinical
Organ
Damage
Not surrogate
but
“intermediate” end-point
7997 M
Events
LVH Regression by Different Classes of Antihypertensive Drugs
Diuretics
-Blockers
Calcium
antagonists
ACE-I
Ag IIBlockers
Reduction of LVM (%)
0
-5
-10
p < 0.01
-15
p < 0.01
p < 0.05
-20
6362 M
Klingbeil A, Schmieder RE, Curr Cardiol Report 2003
HOPE:
Reduction in Primary Outcome with Regression/Prevention of
LVH
Proportion of 0.20
all patients
with primary outcome
(CV death, MI, 0.15
stroke)
P = 0.0061
Development / Persistence
0.10
0.05
0.00
Regression / Prevention
0
500
1000
Days of follow-up
1500
2000
* whether or not hospitalized
5811 M
Mathew J et al., Circulation 2001; 104: 1615-1621
New DM in Antihypertensive Drugs Trials
CAPPP STOP-2 ALLHAT HOPE
ACEI
vs
Conv
ACEI
vs
Conv
ACEI
vs
D
ACEI
vs
PL
STOP-2 INVEST INSIGHT ALLHAT STOP-2
LIFE
CA
vs
D
ARB
vs
BB
CA
vs
Conv
CA
vs
Conv
CA
vs
D
ACEI
vs
CA
SCOPE CHARM
ARB
vs
Conv
ARB
vs
PL
0
-2
-2
-4
-10
-16**
-14
-16
-20
-30
-20
-23
-30**
-25*
-34
-40
-40*
* T, 2 yrs; ** T, 4 yrs
-50
8092 M = 4850 new
-25
-21
Rate of Metabolic Syndrome and New Onset Diabetes
in ALPINE after 1 Year T
Metabolic Syndrome
B
T
8270 M
Diabetes
Candesartan
13 (6.6%)
5 (2.6%)
1 (0.5%)
HCTZ
12 (6.1%)
18 (9.2%)
8 (4.1%)
Lindholm et al., J Hypertens 2003; 21: 1563
Importance (Hazard Ratio) of  Blood Glucose at Age 50 to 60
on Risk of MI after 60
Antihypertensive T (mainly D/BB)
 Glucose
Glucose
 BMI
BMI
 SBP
SBP
 DBP
DBP
6232 M
* P = 0.0004; ° P = 0.02; † P = 0.01
Yes
(n = 291)
No
(n = 1358)
1.37*
1.04
0.88
0.11
0.96
0.99
0.85
0.92
1.14
1.16
0.98
1.19°
1.25
1.27†
1.01
1.26 °
Dunder et al., BMJ 2003, 326
Association of Systolic BP and Cardiovascular Death
in Type 2 Diabetes
250
Cardiovascular
mortality
rate/10,000
person-yr 200
Nondiabe tic
Diabetic
150
100
50
0
< 120
180-199
120-139
140-159
160-179
Systolic blood pressure (mmHg)
•
200
Stamler J et al. Diabetes Care 1993; 16: 434-444
1625
JNC 7 - Stage I Hypertension
6701 M
As it is
Thiazide diuretics for most
May consider ACEI / ARB / CCB or combination
Improved
Thiazide diuretics
For most may consider ACEI / ARB / CCB or combination
Further
improvement
Thiazide diuretics
For most may consider ACEI / ARB / CCB / BB or,
more frequently, combination T
Ideal
ESH/ESC Guidelines
Percent of Italian Hypertensives with BP Control (<140/90 mmHg)
after Year 2000
Forlife 
(n = 12792)
SMOOTH
(n = 2144 *)
12.2
21.7
14.0
Practitioners
Specialists
Practitioners

Mancia et al. 
J Hypertension 2004, 2
(n = 3812)
Hypertensives enrolled by physicians across Italian territory
* Population survey in San Marino - n refers to hypertensive fraction
8234 M
Log change from baseline
Effects of antihypertensive agents on changes in proteinuria and albuminuria
in patients with type 1 and 2 diabetes mellitus
(meta-regression analysis, 100 studies, 2494 patients)
0.2
-0.0
Proteinuria
Albuminuria
*
p < 0.05 vs control
* *
-0.2
-0.4
-0.6
ACE
Inhibitors
Calcium
Channel
Blockers
-blockers
Control
Kasiske et al Ann Intern Med 1993
5993 M
CBMmax: Final Scan versus Baseline Scan
0.06
Mean Change
(mm)
0.05
Atenolol
Lacidipine
0.04
0.03
0.02
0.01
0
ITT
PP 1
PP 2
Compl.
Ratios of Mean Changes and 95% CI
ITT
PP 1
PP 2
Compl.
0.2
8290 M
0.4
0.6
0.8
Lacidipine better
1
1.2
Atenolol better
1.4
ESH/ESC vs JNC 7 - Major Agreements
Benefits of antihypertensive T
Avoidance of complex lab examinations
BP measurement procedure
Use / value of ABPM / home BP
Use of antiplatelet / lipid lowering drugs
BP targets (and thresholds?)
Follow-up strategies
Value of fixed / long-acting / low dose combinations
Compelling drug indications ( more of format than of substance)
Combination T (as above)
Treatment of most specific conditions
6705 M
Progression of non-diabetic renal disease
150
Not including ACE-inhibitors
Urinary protein excretion
140
139/85 vs 144/87
130
95
p<0.001
90
85
80
1.0
Survival without ESRD
Including ACE-inhibitors
Blood Pressure
Survival without end-stage renal disease
0.8
0.6
0.4
0.2
0.0
Patient, n
Control
ACEI
p<0.003
0
12
919
941
752
770
24
36
48
632
657
404
450
63
56
Follow-up (mo)
Jafar TH, Ann Int Med 2001;135:73-87.
Survival without doubling of
baseline serum Creatinine
concentration of ESRD Urinary protein excretion g/d
Diastolic BP
(mmHg)
Systolic BP
(mmHg)
A meta-analysis of data on 1860 pts on antihypertensive regimens
2.0
1.8
1.6
1.4
1.2
1.0
1.0
p<0.001
Doubling of baseline serum creatinine
concentration or ESD
0.8
0.6
0.4
0.2
0.0
p<0.001
0
12
24
Follow-up (mo)
36
48
Results of IDNT: Primary Objective
% doubling of serum creatinine, ESRD, death
50
Blood Pressure
40
30
41
39
32
Irbesartan
Amlodipine
Placebo
140/77
141/77
144/80
20
10
RR p-value
0
2283
Irbesartan
Amlodipine
Placebo
irbesartan vs placebo
0.77
amlodipine vs placebo
1.07
irbesartan vs amlodipine 0.71
0.011
ns
0.001
ASH 2001
Effect of Antihypertensive Treatment (n = 10)
125
MAP
(mmHg)
Start of treatment
115
105
95
105
GFR
(ml/min/1.73 m2) 95
85
75
65
1250
Albuminuria
(g/min)
750
250
-30
4826 M
-24
-18
-12
-6
0
6
12
18
24
30
36 Months
Parving et al., Lancet 1983
Mean BP 
(mmHg)
Favours first
listed
Favours second
listed
Relative Risk
(95% CI)
Stroke
ACEI vs D/BB
CA
vs D/BB
ACEI vs CA
+2 / 0
0/ 0
+1 / +1
1.09 (1.00-1.18)
0.93 (0.86-1.01)
1.12 (1.01-1.25)
CHD
ACEI vs D/BB
CA
vs D/BB
ACEI vs CA
+2 / 0
0/ 0
+1 / +1
0.98 (0.91-1.05)
1.01 (0.94-1.08)
0.96 (0.88-1.05)
Heart failure
ACEI vs D/BB
CA
vs D/BB
ACEI vs CA
+2 / 0
0/ 0
+1 / +1
1.07 (0.96-1.19)
1.34 (1.22-1.47)
0.82 (0.73-0.92)
Major CV events
ACEI vs D/BB
CA
vs D/BB
ACEI vs CA
+2 / 0
0/ 0
+1 / +1
1.02 (0.98-1.07)
1.04 (0.99-1.08)
0.97 (0.92-1.03)
CV death
ACEI vs D/BB
CA
vs D/BB
ACEI vs CA
+2 / 0
0/ 0
+1 / +1
1.03 (0.95-1.11)
1.04 (0.97-1.12)
1.03 (0.94-1.13)
Total mortality
ACEI vs D/BB
CA
vs D/BB
ACEI vs CA
+2 / 0
0/ 0
+1 / +1
1.00 (0.95-1.05)
0.99 (0.94-1.04)
1.04 (0.98-1.10)
0.5
6396 M
1.0
Relative risk
2.0
Intermediate Outcomes: Biochemical Changes at 4 years
Potassium - mmol/L
5209 M
Chlorthalidone
Amlodipine
Lisinopril
4.1
4.4
4.5
P<.001
P<.001
% < 3.5mmol/L
Chlorthalidone
Amlodipine
Lisinopril
8.5
1.9
0.8
P<.001
P<.001
ALLHAT - K+ Supplementation Analysis
8081 M
C
A
L
8%
4%
2%
Diuretic-Induced Hypokalemia
Common
More lab examinations?
 Sudden death?
 Protection by antihypertensive treatment?
8097 M
Hazard Ratio of CVD According to Serum K+ of Treated Patients
at 1 Year in SHEP
CVD
CHD
Stroke
0.1
1.18 (0.73-1.76)
0.61 (0.50-0.75)
1.46 (0.79-2.67)
0.75 (0.56-1.01)
1.43 (0.74-2.74)
0.51 (0.36-0,71)
0.5
Treatment better
4851
K+ < 3.5 mEq/l
K+ ≥ 3.5 mEq/l
1
2
Placebo better
5
10
ESH/ESC Guidelines - Choice of Antihypertensive Drugs
Choice influenced by
- Previous patient’s experience
- Cost (to individual / health provider) *
- Risk profile / TOD
- CVD / Renal disease
- Diabetes
- Coexisting disorders / Drugs interactions
- Patient’s preference
Emphasis on 1st choice drugs outdated (predominance of
combination T)
Cost consideration should not predominate over efficacy / tolerability in
any individual patients
6407 M
Dysmetabolic Effect of Diuretics (± BB)
 CVD / Nephropathy / ESRF
More med. visits / lab examinations
More patients under antidiabetic drugs
More antihypertensive drugs (lower BP targets)
More antihypertensive drugs in diabetics
8096 M
Changes in OGT Test (2h) after 12 Months Antihypertensive T
in ALPINE (n = 49)
S-Insulin
% 50
°
P-glucose
S-Ins / P-Gluc
47.7
40
Candesartan, 16 mg
HCTZ, 25 mg
30
20
°
13.1
†
10
0
3.5
° p < 0.001
† p = 0.006
-1
-10
8272 M
-6.3
-10
Lindholm et al., J Hypertens 2003; 21: 1563
ALLHAT
Biochemical Results – Fasting Glucose (mg/dL)
Chlorthalidone
Amlodipine
Lisinopril
123.5 (58.3)
126.3 (55.6)
123.1 (57.0)
123.7 (52.0)
122.9 (56.1)
121.5 (51.3)*
Among baseline nondiabetics with baseline <126 mg/dL
Baseline
93.1 (11.7)
93.0 (11.4)
4 Years
104.4 (28.5)
103.1 (27.7)
93.3 (11.8)
100.5 (19.5)*
Total
Baseline
4 Years
Diabetes Incidence (follow-up fasting glucose  126 mg/dL)
4 Years
*p<.05 compared to chlorthalidone
5246 M
11.6%
9.8%*
8.1%*
Systolic vs Diastolic BP Control in Trials on Diabetic Hypertensives
200
120
mmHg
mmHg
SBP
DBP
Micro HOPE
190
CAPPP
110
INSIGHT
180
VALUE
HOT
170
100
UKPDS
STOP-2
160
90
FACET
150
LIFE
RENAAL
80
IDNT
140
IRMA
70
130
ABCD
120
1186 G
B
T
60
B
T
Mancia G., Grassi G., J Hypertension 2002
Cumulative Yearly Rates of Development of Sight-Threatening
Diabetic Retinopathy in 4770 Patients with Type 2 Diabetes
80
Cumulative
incidence 70
(%)
Leve l 30
p = 0.0012 (for trend)
Leve l 20
60
Leve l 10
50
40
30
20
10
0
0
Patients at risk
Level 30
217
Level 20
810
Level 10
3743
7148 M
1
2
3
4
Observation period (years)
217
810
3743
175
732
3568
116
531
2558
69
355
1584
5
6
33
218
943
18
149
630
Younis N et al., Lancet 2003; 361: 195
Prevalence (%) of Different Stages of Nephropathy
with Increasing Duration of Diabetes
Time Microalbuminuria
(years)
or worse
7156 M
Macroalbuminuria
 SCr /
or worse
renal replacement
0
7.3
0.7
0.0
5
17.3
2.8
0.4
10
24.9
5.1
0.8
15
28.0
7.6
2.3
20
34.3 (model)
10.0 (model)
Adler et al. - UKPDS, Kidney Int 2003; 63: 225
RR of New Onset Diabetes in CAS (vs NCAS) Patients
in INVEST
Trandolapril
2
No
Yes
(2)
Yes
(4)
HCTZ
No
Yes
(25)
RR
1.36
1.17
0.95
1
0
7542 M
Yes
(50.0)
0.95
0.86
0.77
Cardiovascular Events in Hypertensive Subjects with Regression
versus Persistence or New Development of Left Ventricular Hypertrophy*
Study
LVH
LVH
regression persistence/new
Odds Ratio
(95% CI)
Odds Ratio
(95% CI)
Muiesan (1995)
4/ 32
15/ 41
0.24 (0.07-0.84)
Verdecchia (1998)
3/ 52
13/100
0.41 (0.11-1.51)
Cipriano (2001)
5/ 52
17/134
0.73 (0.25-2.10)
Koren (2002)
1/ 16
12/ 42
0.17 (0.02-1.40)
13/152
57/317
0.41 (0.21-0.78)
Total
Heterogeneity: 2 = 2.50; df = 3; p = 0.48
Z = -2.71 p = 0.0068
8010 M
* LVH detected by echocardiography
0.1
0.2
0.5
Favours
LVH regression
1
2
5
Favours
LVH persistence/new
n = 1064
FU 2.8-10.0 ys
LVH at B 22%
Verdecchia P et al., Am J Hypertens 2003; 16: 895
Low-Dose Diuretics as 1st Choice 1993 WHO/ISH Statement
It is contradictory to emphasize the need for treatment
to address “global” CV risk and recommend as 1st
choice treatments that may increase it.
8094 M
Goal(s) of Treatment
In young / middle age / not high risk patients
treatment goal is not to prevent an (unlikely) event
in few years but to prevent progression (or achieve
regression) of silent organ damage that will cause
an event many years later.
7998 M
Superior Effect of New vs Conventional Drugs on Markers of TOD
(Intermediate End-Points)
6073 M
LV hypertrophy
ACEI / CA / ARB
Carotid artery IMT / Atherosclerosis
CA / ACEI
Arteriolar remodelling
ACEI / ARB / CA
Urinary protein excretion
ACEI / ARB
Endothelial dysfunction
CA / ACEI (?) / ARB (?)
Arterial stiffening
?
Mild renal damage
CA
CA coronary content
CA
JNC7 vs ESH-ESC GLs
Major Differences
• Total CV risk assesment
• Term “pre-hypertension” avoided / no therapeutic reccomendations
if risk not high
• Drug administration in grade I hypertension more flexible
• 5 drug classes (not only D) for T initiation / maintenance
• Intermediate end-points considered for risk assessment / treatment
goals
• All trial (not only ALLHAT) considered
• Combination T as first choice
• Mention of -blockers / central agents
• Wider disclosure of conflict of interest
Definitions and classification of blood
pressure levels
Category
Systolic
(mmHg)
Diastolic
(mmHg)
Optimal
<120
<80
Normal
120-129
80-84
High normal
130-139
85-89
Grade 1 hypertension (mild)
140-159
90-99
Grade 2 hypertension (moderate)
160-179
100-109
Grade 3 hypertension (severe)
 180
 110
Isolated systolic hypertension
 140
<90
ESH/ESC 2003
2003 European Society of Hypertension–European Society
of Cardiology guidelines for the management of arterial
hypertension
“Due to the importance of target organ damage in determining the overall
cardiovascular risk of the hypertensive patient, evidence of organ
involvement should be sought carefully…”
“…the importance of organ damage, not only in diagnosing cardiovascular
risk but also in the follow-up of patients, as well as in using additional
enpoints for assessing treatment outcomes…”
Journal of Hypertension 2003
Unplanned Cross-Over Treatment in ALLHAT
C
A
L
Addition of
comparison drug(s)*
13.2%
16.6%
15.7%
Only taking
comparison drug(s)*
9.0%
6.9%
8.5%
22.2%
23.5%
24.2%
Total
* drug(s) classes
4856
RR of New Onset Diabetes in NCAS (vs CAS) Patients in INVEST
HCTZ
2
No
Yes
(25)
Trandolapril
Yes
(50)
No
Yes
(2)
Yes
(4)
RR
1.28
1.11
1.00
1
0
7543 M
1.00
0.99
0.98
In ALPINE study risk of developing
metabolic syndrome 13 times greater
with HCTZ (and BB) than with ARB
(and CA)
7479 M
Lindholm et al., J Hypertension 2003; 21: 1563
BP Range Termed Hypertension is Clinically Heterogeneous
7390 M
Very high CV risk
Drug treatment
High CV risk
Drug treatment if BP “high normal”
Moderate CV risk
Life style changes advisable
Low CV risk
No intervention necessary
(particularly if BP “normal”)
10 Year Risk of Fatal CVD in High Risk Regions of Europe
by Gender, Age, SBP, Total Cholesterol and Smoking Status
6614 M
Are JNC-7 Recommendations Less Costly than ESH/ESC Recommendations?
JNC-7
ESH/ESC
Diagnostic
Procedures
Very simple, with poor characterization
of TOD
More liberal recommendations, but those
patients in whom careful search has excluded
TOD more likely to have deferred treatment
Life-style
Measures
In all individuals with BP 120-139 or
80-89 mmHg independently of
other risk factors and TOD
In individuals with BP 120-139 or
80-89 mmHg only if other risk factors or TOD
are present
Initiation of
Drug
Treatment
In all individuals with BP > 140 or 90
mmHg
In individuals with BP > 140 or 90 mmHg
and no additional risk factor only after up
to 1 year of lifestyle measures, and only if
preferred by the patients and resources
available
Drugs
Thiazide diuretics for all individuals
with BP > 140 or 90 mmHg without
compelling indications
All major classes of agents, but many patients
with grade I hypertension and low additional
risk will not necessarily receive drug treatment
7622 M
Death is in all living creatures’ future
Should they be called “predeath”?
7391 M
Relationship of CV Events and Organ Damage
Events do not take place on the background
of a healthy cardiovascular system but
on the top of subclinical organ damage
2936
High / Very High Risk Patients
BP > 180/110 mmHg
BP > 130/ 85 mmHg if:
- Risk factors > 3
- Diabetes
- Associated CVD
- TOD
LVH
CA thickening
Microalbuminuria
Mild renal damage
6707 M
Arterial remodelling?
Endothelial dysfunction?
Arterial stiffening?
Calcium deposition?
Arguments Opposing Diuretics (D) as Sole 1st Choice in HT
No evidence that D more protective than other drug classes
No evidence from trials on D at low dose
BP lowering effect limited with D at low doses
Diabetogenic / dismetabolic effects of D substantial
Hypokalemic effect of D substantial
6447 M
CA vs D or BB (n = 11685)
CVD
20
CV
death
Stroke
15
CHD
CHF
°
+12%
+14%
Total
mortality
10
5
+4%
+1%
+1%
 RR 0
-5
-10
-15
-14%
*
-20
n events
7775 M
* statistically significant
° borderline significant
1078
409
454
561
274
776
Coll Group, Lancet 2003
ESH/ESC Guidelines: Stratification of Risk to Quantify Prognosis
Blood Pressure (mmHg)
Normal
High Normal
Grade 1
Grade 2
Grade 3
Other Risk Factors
and Disease History
SBP 120-129
or DBP 80-84
SBP 130-139
or DBP 85-89
SBP 140-159
or DBP 90-99
SBP 160-179
or DBP 100-109
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
ACC: associated clinical conditions; TOD: target organ damage; SBP: systolic blood pressure; DBP: diastolic blood pressure
6252 M