How does hypertension cause stroke:
usual BP, variability in BP or both?
PM Rothwell
Professor of Clinical Neurology
University of Oxford
BHS; September 2011
CVS Reactivity
Ultrasound: Carotid + TCD
Cold Pressor Test
Mental Arithmetic
Pulse Wave Analysis
Analysis
Neurovascular
Physiology
Aortic BP
Aortic stiffness
Peripheral stiffness
IMT
MCA stiffness
Cerebral Autoregulation
Beat-to-Beat BP
Postural BP
Baroreceptor Gain
Induced Hypotension
Measures of variability / lability
250
Statistics
• SD
• CV
• VIM
• ASV
• RSD
• Peak size
• Trough size
200
150
100
0
1
2
3
4
5
Variability period
Minutes (e.g. within-visit)
Hours
(e.g. ABPM)
Days
(e.g. home monitoring)
Weeks
(e.g. visit-to-visit)
Variability in clinic or home BP
• Is small compared with variance in “true” mean BP
• Is “random” and “noise”
• Anyway:
– usual BP already explains all variance in risk
– benefit of antihypertensive drugs is already fully
explained by effects on mean BP
mean
“Clinic readings are a surrogate marker for a patient’s true BP (the
average level over prolonged periods of time), which is thought to be
the most important component of BP in determining its adverse
effects.”
AHA Guideline 2005
“In the absence of markedly raised BP, repeat readings should be
obtained over several months to define the patient’s usual BP as
accurately as possible”.
Joint European Guideline 2007
Patient A
175
Systolic
Diastolic
150
125
100
75
01JAN1998
01JAN2000
0101JAN- JUN2002 2002
15102626SEP- OCT- NOV- APR2003 2003 2003 2004
07JAN2005
112316FEB- MAY- DEC2005 2005 2005
1905JUL- OCT2006 2007
200
150
100
50
100
150
200
250
250
200
150
100
50
300 50
120
100
80
60
40
40
60
80
100
120
140
Baseline DBP (mm Hg)
Howard SC, Rothwell PM.
Second m easurem ent of DBP
(m m Hg)
140
100
150
200
250
Dutch TIA
300
250
200
150
100
50
300 50
160
140
120
100
80
60
40
160 40
60
80
100
120
Baseline DBP (mm Hg)
J Clin Epidemiol 2003; 56: 1084-91 &
140
100
150
200
250
300
Baseline SBP (m m Hg)
Baseline SBP (m m Hg)
Baseline SBP (m m Hg)
160
Second m easurem ent (m
250
UK-TIA
300
Second m easurem ent of DBP
(m m Hg)
Second measurement (m
Second measurement of SBP
Hg)
SBP (mm
(mm Hg)
ECST
300
50
Second
m easurem
ent of DBP
(mm Hg)
DBP
(m m Hg)
Second measurement of
Variation in BP – baseline vs first follow-up
160
140
120
100
160
80
60
40
40
60
80
100
120
Baseline DBP (mm Hg)
Stroke 2006; 37: 2776-83
140
160
Variability in clinic or home BP
• Is small compared with variance in “true” mean BP
• Is “random” and “noise”
• Anyway:
– usual BP already explains all variance in risk
– benefit of antihypertensive drugs is already fully
explained by effects on mean BP
Took over chair
Lecture 2
200
Lecture 1
SBP (mmHg)
Lecture 3
150
100
Gym Break Board meeting
fast
Lunch
3 Lectures
Time of day
Formal
Walk meeting Walk
+ dinner
Sleep
Comparison of visit-to-visit variability in
SBP with other measures in ASCOT
Correlation
• Within-visit variability
– r=0.21, p<0.0001
• Daytime variability on ABPM
– r=0.35, p<0.0001
• Morning surge on ABPM
– r=0.15, p=0.008
Lancet 2010; 375: 895-905
% Predictive value
10%
50%
20%
Comparison of day-to-day and week-to-week variability
Weeks 1 - 30
180
180
160
160
140
120
100
140
120
100
80
80
60
60
0
1
2
3
4
5
6
25
0
7
5
10
180
180
160
160
BP (mm Hg)
BP (mm Hg)
20
25
30
Week
Day
B
15
140
120
100
0
1
2
3
4
Day
Unpublished data
5
6
7
15
10
5
0
5
10
15
120
Within-w eek SD SBP
100
60
60
20
0
140
80
80
Week-to-week SD SBP
BP (mm Hg)
A
BP (mm Hg)
Week 1
0
5
10
15
Week
20
25
30
20
25
Variability in clinic or home BP
• Is small compared with variance in “true” mean BP
• Is “random” and “noise”
• Anyway:
– usual BP already explains all variance in risk
– benefit of antihypertensive drugs is already fully
explained by effects on mean BP
Relevant epidemiology of stroke
•
•
•
•
•
•
•
•
•
Age
Acute hypertension
Diurnal variation
Triggers
Personality
Sex
Race
Renal failure, diabetes
Vascular dementia
Lancet 2010; 375: 938-48
Diurnal pattern of
stroke incidence in
Oxfordshire, UK
Regression Dilution Bias
Prospective Studies Collaboration
Count
“Usual” value
Measured
value
Value
Risk
“Usual” value
Measured
value
Lancet 2002; 360: 1903-13
Value
Problems in interpretation of adjustment for RDB
1. The more variable BP - the greater is the degree of adjustment
BUT - the more variable BP is the less credible it becomes to argue that the
underlying usual BP is likely to be pathologically relevant.
2. Adjustment is driven by patients with variable BP and assumes that the
predictive value of usual BP is independent of variability
BUT - this assumption has never been tested – and is false
3. Assumes that all of the prognostic value of a single baseline BP reading
is attributable to usual BP – variability being “random”
BUT - variability is of prognostic value and reproducible (not random);
AND - a single high BP reading is more related to variability than to
mean BP.
Lancet 2010; 375: 938-48
Relative contribution of mean vs SD
Relative strength of association of mean vs SD SBP (7 clinic
visits) with baseline systolic BP in the UK-TIA Trial
100
90
80
70
60
Mean
50
SD
40
30
20
10
0
1
2
4
5
Quintile of baseline SBP
Contributions from the Wald statistics from multinomial logistic regression
(outcome = probability of being in a particular quintile, relative to quintile 3).
Lancet 2010; 375: 938-48
Variability in BP versus stroke risk in UK-TIA Trial
Excluding cases with prior stroke or CT infarction
Hazard ratio (95% CI)
12
10
8
6
Adjusted for
mean SBP
4
2
0
1
2
3
4
5
6
7
8
9
10
Decile of SD SBP
Lancet 2010; 375: 895-905
Cuffe RL, Rothwell PM. Medium-term variability in systolic blood pressure is an
independent predictor of stroke. Cerebrovasc Dis 2005; 19 (suppl 2): 51.
1.44 (0.58 – 3.57)
10 readings
13.04 (1.66 – 102.6)
0.43
0.015
Predictive value of residual visit-to-visit variability in
SBP in ASCOT-BPLA
HR for top quintile of mean SBP
HR for VIM SBP
5
2.82 (1.67 – 4.76)
4
4 readings
3
6
<0.0001
HR for SD SBP
2.67 (1.74 – 4.11)
6
2 readings
3.07 (1.62 – 5.83)
0.001
1
8 readings
2.68 (1.29 – 5.56)
0.008
66 7
10
7 88 99 10
2.26
(0.98
– 5.17)
Decile of measure
0.055
0
10 readings0
11 22 33 44 55
1.09 (0.73 – 1.62)
0.67
1.50 (0.90 – 2.48)
0.12
1.98 (1.05 – 3.77)
0.036
5.00 (1.75 – 14.30)
0.003
5
4
<0.0001
6 readings
2
HR for top quintile of CV SBP
3
2
1
0
0 1 1 22 33 4 4 5 5 6 6 7 7 8 8 9 910 10
HR for top quintile of mean SBP
13.05 (1.74 – 97.66)
Decile of measure
0.012
HR for top quintile of VIM SBP
2 readings
2.86 (1.88 – 4.36)
<0.0001
1.25 (0.86 – 1.82)
0.25
4 readings
3.18 (1.90 – 5.33)
<0.0001
1.59 (1.00 – 2.54)
0.053
6 readings
3.70 (1.97 – 6.94)
<0.0001
2.31 (1.26 – 4.23)
0.007
8 readings
3.70 (1.81 – 7.56)
<0.0001
6.04 (2.14 – 17.03)
0.001
10 readings
3.31 (1.46 – 7.47)
0.004
15.35 (2.08 – 113.1)
0.007
Lancet 2010; 375: 895-905
SYST-EUR: Stroke (fatal or non-fatal) (n = 197)
12
Hazard ratio (95% CI)
Ha z a rd ratio (9 5% C I)
7
6
5
4
3
2
1
0
10
8
6
4
2
0
1
2
3
4
5
6
7
8
D e c il e of m e a n S B P
Unpublished data
9
10
1
2
3
4
5
6
7
8
Decile of CV SBP
9 10
Hazard ratios (95% CI) for the risk of subsequent stroke in relation to
maximum SBP and minimum SBP in the UK-TIA trial
Maximum SBP
exceeds mean
SBP by:
7 measurements
10 measurements
0 - 9%
10 - 19%
20 – 29%
30 - 39%
≥40%
1
1.21 (0.69 – 2.14)
1.84 (1.01 – 3.35)
3.24 (1.54 – 6.78)
6.21 (2.29 – 16.9)
1
2.24 (0.67 – 7.46)
4.10 (1.22 – 13.8)
6.16 (1.70 – 22.4)
9.31 (2.07 – 41.8)
1
0.98 (0.43-2.25)
0.90 (0.39-2.06)
1.72 (0.75-3.95)
1.64 (0.66-4.07)
1
1.19 (0.40-3.52)
1.02 (0.35-2.95)
2.17 (0.76-6.17)
2.59 (0.91-7.36)
Minimum SBP fell
below mean SBP by:
0-4%
5-9%
10-14%
15-19%
≥20%
Lancet 2010; 375: 895-905
C e re b ra l b lo o d flo w
A rte rio la r c a lib re r
C e re b ra l b lo o d flo w
P e rfusio n pressure
A rte rio la r c a lib re r:
SBP (mm Hg)
170
150
130
110
P e rfusio n pressure
Time
Blood pressure parameters and their predictive values (hazard ratios and 95% CI for risk of events relative to the stable
normotension group) in the four groups of patients from the UK-TIA Trial cohort based on the patterns of their blood pressure over
the first seven clinic visits. Patients with mean usual SBP ≥180mmHg are excluded
Stable1
Episodic moderate
normotension
hypertension2
Cases
241
Mean (SD) of measures 1-7 of SBP
Individual mean
123.5 (7.6)
Individual SD
8.5 (3.3)
Individual CV
6.9 (2.8)
Individual VIM
11.5 (4.9)
Individual maximum
134.3 (7.6)
Individual minimum
112.0 (9.9)
601
141.1 (8.6)
12.8 (4.1)
9.1 (3.1)
13.9 (5.0)
159.4 (8.5)
124.2 (10.6)
Episodic severe
hypertension3
263
Stable
hypertension4
Heterogeneity
154
157.9 (8.7)
21.4 (5.7)
13.6 (3.6)
19.1 (5.2)
190.2 (12.3)
130.2 (9.5)
167.3 (7.2)
13.4 (5.8)
7.9 (3.2)
10.6 (4.1)
187.8 (16.2)
151.7 (4.9)
Events after 7th measure of SBP
Stroke
9 (3.7%)
HR (95% CI)
1.00
37 (6.2%)
1.68 (0.81-3.47)
36 (13.7%)
4.18 (2.01-8.68)
7 (4.5%)
1.22 (0.45-3.27)
p=0.00003
Coronary event
HR (95% CI)
22 (9.1%)
1.00
66 (11.0%)
1.40 (0.86-2.28)
39 (14.8%)
1.72 (1.02-2.91)
13 (8.4%)
0.84 (0.42-1.70)
p=0.12
All vascular events
31 (12.9%)
103 (17.1%)
75 (28.5%)
20 (13.0%)
1
2
3
4
p=0.000007
All values ≤140mmHg
At least one BP ≤140mmHg, at least one >140mmHg, but all <180mmHg
At least one BP ≤140mmHg and at least one BP ≥180mmHg.
All BPs >140mmHg
Lancet 2010; 375: 895-905
Postural instability (lying – standing) vs
visit-to-visit SD SBP (sitting)
40
10
Average postural change
35
Stroke risk
P<0.001
9
30
8
25
7
20
6
Stroke risk (%)
15
5
4
3
10
5
0
0
10
20
30
visit-to-visit SD SBP
Unpublished data
40
2
1
0
3
2
1
1
2
V-to-V SD
Tertile of visit-to-visit
3
PCTe
Variability in clinic or home BP
• Is small compared with variance in “true” mean BP
• Is “random” and “noise”
• Anyway:
– usual BP already explains all variance in risk
– benefit of antihypertensive drugs is already fully
explained by effects on mean BP
The relationships between change in SBP and the
effect on vascular risk in RCTs of BP lowering
JA Staessen et al. Lancet 2001; 358: 1305-15
Inter-individual SD SBP (mmHg)
Group SD SBP in the MRC Trial in
elderly hypertensive patients
20
19
18
17
Placebo
16
beta-blocker
diuretic
15
0
5
10
15
Months
Lancet Neurol 2010; 9: 469-80
20
25
Mean (SD) SBP (mmHg) at baseline and during follow-up
stratified by randomised treatment in the ALLHAT trial
Follow-up
visit
Treatment group
Significance (p) of difference in SD
Amlodipine (A) Chlorthalidone (C) Lisinopril (L)
A vs L
C vs L
0.5
Baseline
146.2 (15.7)
146.2 (15.7)
146.4 (15.7)
0.5
1 year
138.5 (14.9)
136.9 (15.8)
140.0 (18.5)
9 x 10
2 years
137.1 (15.0)
135.9 (15.9)
138.4 (17.9)
3 x 10
3 years
135.6 (15.2)
134.8 (15.4)
136.7 (17.3)
9 x 10
4 years
134.8 (15.0)
133.9 (15.7)
135.5 (17.2)
1 x 10
5 years
134.7 (14.9)
133.9 (15.2)
135.9 (17.9)
1 x 10
Lancet 2010; 375: 938-48
-79
7 x 10
-55
-48
1 x 10
-25
2 x 10
-24
2 x 10
-24
8 x 10
-28
-25
-14
-25
Distributions of SBP at the one year follow-up visit in ASCOTBPLA stratified by randomised treatment group
Am lo d ip in e g ro u p
Ate n o lo l g ro u p
3000
N u m b e r o f s u b je c ts
2500
S D = 1 5 .8
S D = 1 9 .2
2000
1500
1000
500
0
270
250
230
S B P (m m H g )
210
190
170
150
130
110
90
70
50
270
250
230
Lancet Neurol 2010; 9: 469-80
210
190
170
150
130
110
90
70
50
S B P (m m H g )
All large RCTs of CCBs vs beta-blockers or ACE-inhibitors in which the mean
(SD) SBP during follow-up has been reported by treatment group
Stroke risk
Events/Patients
CCB
Drug B
Odds
Ratio
159 / 5410
196 / 5471
0.81
Mean SBP
95% CI
95% CI
0.66-1.01
3.70
3.07, 4.33
-2.36, -1.44
Difference
Trial
NORDIL (vs BB/D)98
ASCOT (vs
BB)64
327 / 9639
422 / 9618
0.77
0.66-0.89
-1.90
VALUE (vs
ARB)99
281 / 7596
322 / 7649
0.87
0.74-1.03
-1.80
-4.92, 1.32
176 / 11267
201 / 11309
0.88
0.72-1.08
0.00
-0.27, 0.27
377 / 9048
457 / 9054
0.82
0.71-0.94
-1.30
-1.78, -0.82
-1.20, 2.40
-0.41, -0.01
INVEST (vs BB)97
ALLHAT (vs
ACE)95
CAMELOT (vs
ACE)63
TOTAL
6 / 663
8 / 673
0.76
0.26-2.20
0.60
1326 / 43623
1606 / 43774
0.82
0.76-0.88
-0.21
0.5
Odds Ratio (95%CI)
1.5
SBP at follow-up
Mean (sd)
CCB
Drug B
Variance
Ratio
155.2 (16.3)
151.5 (17.4)
0.88
Mean SBP
95% CI
95% CI
0.83-0.93
3.70
3.07, 4.33
-2.36, -1.44
Difference
Trial
NORDIL (vs BB/D)98
138.4 (14.8)
140.3 (17.8)
0.69
0.67-0.72
-1.90
138.2 (13.8)
140.0 (16.2)
0.73
0.68-0.77
-1.80
-4.92, 1.32
INVEST (vs BB)97
131.0 (11.0)
131.0 (13.0)
0.83
0.80-0.86
0.00
-0.27, 0.27
ALLHAT (vs ACE)95
137.1 (15.0)
138.4 (17.9)
0.70
0.67-0.73
-1.30
-1.78, -0.82
0.74
0.64-0.86
0.60
-1.20, 2.40
0.76
0.74-0.77
-0.21
-0.41, -0.01
ASCOT (vs BB)64
VALUE (vs
ARB)99
CAMELOT (vs ACE)63
TOTAL
Lancet 2010; 375: 938-48
124.2 (15.5)
123.6 (18.0)
0.5
Variance Ratio (95%CI)
1.5
Effect of treatment of group versus individual variability in SBP
Blood Pressure Lowering Trialists’ Collaboration
G-VR 2.0
2.0
G-VR
R2 = 0.87, p<0.0001
I-VR
0.5
2.0
0.5
Unpublished data
2.0
0.5
0.5
4.5
Atenolol
Amlodipine
Effect of treatment on group
SD SBP in ASCOT-BPLA
4.1
3.9
3.7
Within-visit individual SD
3.5
Atenolol
22
Amlodipine
20
Follow-up
18
16
14
Ba
se
l in
e
3
m
on
th
s
1
ye
ar
2
ye
ar
3
ye
ar
4
ye
ar
5
ye
ar
6
ye
ar
12
Follow -up
Lancet Neurol 2010; 9: 469-80
Average intra-ABPM daytime SD SBP
Inter-individual SD SBP
24
Group SD
Average within-visit CV SBP
4.3
ABPM daytime SD
12.5
12
11.5
11
Atenolol
10.5
Amlodipine
10
0.5 1.5yr
1.5 2.5yr
2.5 3.5yr
3.5 4.5yr
4.5 5.5yr
Tim e from random isation
> 5.5yr
No. of patients
Effect of treatment allocation on withinindividual variability in SBP in ASCOT
1400
Atenolol
1200
Amlodipine
1000
800
600
400
200
0
1
Lancet 2010; 375: 895-905
2
3 4 5 6 7
Decile of CV SBP
8
9
10
Effect of treatment on risk of stroke in ASCOT-BPLA
Adjustment for mean BP and variability in BP
Model
SBP
HR (95% CI)
p
Treatment
0.78 (0.67 – 0.90)
0.001
Treatment + mean
0.84 (0.72 – 0.98)
0.025
Treatment + SD
0.94 (0.81 – 1.10)
0.47
Treatment + CV
0.94 (0.79 – 1.07)
0.27
Treatment + VIM
0.93 (0.77 – 1.04)
0.16
Treatment + mean + SD
0.98 (0.82 – 1.12)
0.59
Treatment + mean + CV
0.97 (0.82 – 1.11)
0.55
Treatment + mean + VIM
0.98 (0.82 – 1.12)
0.58
Lancet Neurol 2010; 9: 469-80
Systematic review of all RCTs of BP-lowering drugs
1372 Eligible Reports
910 phase 2 trials
excluded due to
inadequate reporting
94 Phase 3 Trials
377 Phase 2 Trials with follow-up SD
(>100 patients per group for >1 year)
(9 reports included 2 trials)
+ 21 phase 3 trials
93 trials of
578456 patients
Meta-analyses
of OR between
drugs
Lancet 2010; 375: 906-15
28 comparisons
in 188564
patients
685 drug groups
of 157505
patients
Metaregressions
of VR vs OR
Change in VR or
%CV
361 comparisons
in 150663 patients
VR or %CV on
different agents
Pooled estimates of variance ratio between drug classes
in crossover trials
Lancet 2010; 375: 906-15
220
200
B lo o d p re s su re (m m H g )
OXVASC
Bluetooth
Home BP
monitoring
F e lo d ip in e 2 .5 m g
F e lo d ip in e
sto p p e d
F e lo d ip in e 5 m g
180
160
140
120
100
80
60
40
1
2
3
4
5
6
7
8
9
10
11
12
W eeks
A m lodipine 5m g
220
A m lodipine 10m g
B lo o d p re s s u re (m m H g )
200
COMMIT Study
180
160
- 310 patients
140
120
- 1284 drug changes
100
80
- 92% uptake
60
40
1
2
3
4
5
W eeks
6
7
8
Lancet 2010; 375: 938-48
Pooled estimates of VR in parallel group trials compared
with drug-class effects on stroke risk
Lancet 2010; 375: 906-15
Meta-regressions relating effect of treatment on group
variability in SBP to effect of treatment on risk of stroke
1.4
1.4
1.2
ALLHAT II
ALLHAT
Adjusted for difference in
mean SBP
HOT<85
1.2
UKPDS 39
MOSES
11
OR (EXP/REF)
1
10
ALLHAT II
IPPPSH
1
HOT<80
HAPPHY
LIFE
0.8
INVEST
NORDIL
SCOPE
CAMELOT
NICS
PATS
ECOST
STOP I
CAMELOT
23
0.8
ASCOT
11
3
22
6
12
21 13
4 18
20
EWPHE
14
1
15
7
9
FEVER SHEP
0.6
23
1
25
2
5
24
VALUE
16
0.6
19
17
UKPDS 38
8
0.4
0.4
USPHS
0.2
SCAT
0.2
PREVEND IT
0
0
0.6
0.8
1
1.2
1.4
1.6
0.6
Variance Ratio (REF/EXP)
Lancet 2010; 375: 906-15
0.8
1
1.2
1.4
1.6
Pooled estimates of VR in parallel group trials in BPLTC:
Intra-individual versus inter-individual variability
Unpublished data
Drug vs control
Drug A vs Drug B
OR (all stroke)
A)
B)
1.5
1.5
1.0
1.0
0.5
-4
0.5
0
16
1.5
OR (all stroke)
Reduction in SBP (mmHg)
1.5
1.0
1.0
Unpublished data
0.5
Reduction in SBP (mmHg)
1.5
0.5
-4
1.0
0.5
0
16
Change
in I- VR
Reduction
in SBP (mmHg)
1.5
1.0
0.5
Change in I-VR
Variability in clinic or home BP
• Is small compared with variance in “true” mean BP
• Is “random” and “noise”
• Anyway:
– usual BP already explains all variance in risk
– benefit of antihypertensive drugs is already fully
explained by effects on mean BP
Implications
• Diagnosis of “hypertension”
• Decision to treat
•
•
•
•
•
•
Risk prediction
Choice of agent
Combinations of agents
Monitoring of BP on Rx
Development of new agents
Aetiology of stroke?
200
Systolic BP (mmHg)
– Not currently treating
the right patients
250
150
100
250
200
150
100
0
1
2
3
Months
4
5