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How does hypertension cause stroke:usual BP, variability in BP or both?
PM RothwellProfessor of Clinical Neurology
University of Oxford
BHS; September 2011
Pulse Wave Analysis Analysis Beat-to-Beat BP
Ultrasound: Carotid + TCDCold Pressor TestMental Arithmetic
IMTMCA stiffness
Cerebral Autoregulation
Aortic BP
Peripheral stiffnessAortic stiffness
Postural BPBaroreceptor Gain
Induced Hypotension
CVS Reactivity
Neurovascular Physiology
Measures of variability / lability
Statistics• SD• CV• VIM• ASV• RSD• Peak size• Trough size
100
150
200
250
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
“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
mean
05-OCT-2007
19-JUL-2006
16-DEC-2005
23-MAY-2005
11-FEB-2005
07-JAN-2005
26-APR-2004
26-NOV-2003
10-OCT-2003
15-SEP-2003
01-JUN-2002
01-JAN-2002
01-JAN-2000
01-JAN-1998
175
150
125
100
75
DiastolicSystolic
Patient A
Variation in BP – baseline vs first follow-up
ECST UK-TIA Dutch TIA
50
100
150
200
250
300
50 100 150 200 250 300
Baseline SBP (mm Hg)
Se
co
nd
me
as
ure
me
nt
(m
50
100
150
200
250
300
50 100 150 200 250 300
Baseline SBP (mm Hg)
Se
co
nd
me
as
ure
me
nt
(m
40
60
80
100
120
140
160
40 60 80 100 120 140 160
Baseline DBP (mm Hg)
Se
con
d m
eas
ure
me
nt
of
DB
P
(mm
Hg
)
40
60
80
100
120
140
160
40 60 80 100 120 140 160
Baseline DBP (mm Hg)
Seco
nd m
easu
rem
ent o
f DBP
(m
m H
g)
50
100
150
200
250
300
50 100 150 200 250 300
Baseline SBP (mm Hg)
Se
co
nd
me
as
ure
me
nt
of
SB
P
(mm
Hg
)
40
60
80
100
120
140
160
40 60 80 100 120 140 160
Baseline DBP (mm Hg)
Seco
nd m
easu
rem
ent o
f DBP
(m
m H
g)
Sec
on
d m
easu
rem
en
t o
f
DB
P (
mm
Hg
)
S
BP
(m
m H
g)
Howard SC, Rothwell PM. J Clin Epidemiol 2003; 56: 1084-91 & Stroke 2006; 37: 2776-83
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
100
150
200
06:3
807
:31
08:3
009
:30
10:3
011
:30
12:3
013
:30
14:3
015
:30
16:3
017
:30
18:3
019
:30
20:3
021
:30
22:3
000
:00
02:0
004
:00
06:0
0
Board meeting 3 LecturesFormal
meeting + dinner
Took over chairLecture 2
Lecture 3Lecture 1
Lunch WalkBreakfast
Gym Walk Sleep
SB
P (
mm
Hg
)
Time of day
Comparison of visit-to-visit variability in SBP with other measures in ASCOT
Correlation % Predictive value
• Within-visit variability – r=0.21, p<0.0001 10%
• Daytime variability on ABPM– r=0.35, p<0.0001 50%
• Morning surge on ABPM– r=0.15, p=0.008 20%
Lancet 2010; 375: 895-905
60
80
100
120
140
160
180
0 1 2 3 4 5 6 7
Day
BP (m
m H
g)
60
80
100
120
140
160
180
0 5 10 15 20 25 30
Week
BP (m
m H
g)
60
80
100
120
140
160
180
0 5 10 15 20 25 30
Week
BP (m
m H
g)
60
80
100
120
140
160
180
0 1 2 3 4 5 6 7
Day
BP
(mm
Hg)
Comparison of day-to-day and week-to-week variability
Week 1 Weeks 1 - 30
Unpublished data
0
5
10
15
20
25
0 5 10 15 20 25
Within-week SD SBP
Wee
k-to
-wee
k S
D S
BP
A
B
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
Diurnal pattern of stroke incidence in Oxfordshire, UK
Lancet 2010; 375: 938-48
Prospective Studies Collaboration
Lancet 2002; 360: 1903-13
Regression Dilution Bias
Value
Co
un
t
“Usual” value
Measuredvalue
Value
Ris
k
“Usual” value
Measured value
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.
Problems in interpretation of adjustment for RDB
Lancet 2010; 375: 938-48
0
10
20
30
40
50
60
70
80
90
100
1 2 4 5
Quintile of baseline SBP
Rel
ativ
e co
ntr
ibu
tio
n o
f m
ean
vs
SD
Mean
SD
Relative strength of association of mean vs SD SBP (7 clinic visits) with baseline systolic BP in the UK-TIA Trial
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
Adjusted for mean SBP
0
2
4
6
8
10
12
1 2 3 4 5 6 7 8 9 10
Decile of SD SBP
Haz
ard
ratio
(95
% C
I)
Lancet 2010; 375: 895-905Cuffe RL, Rothwell PM. Medium-term variability in systolic blood pressure is an independent predictor of stroke. Cerebrovasc Dis 2005; 19 (suppl 2): 51.
Predictive value of residual visit-to-visit variability in SBP in ASCOT-BPLA
0
1
2
3
4
5
6
0 1 2 3 4 5 6 7 8 9 10
0
1
2
3
4
5
6
0 1 2 3 4 5 6 7 8 9 10
Decile of measureDecile of measure1 2 3 4 5 6 7 8 9 10
1 2 3 4 5 6 7 8 9 10
HR
for
SD
SB
P
HR
for
VIM
SB
P
Lancet 2010; 375: 895-905
0
1
2
3
4
5
6
7
1 2 3 4 5 6 7 8 9 10
Decile of mean SBP
Ha
zard
rat
io (
95%
CI)
0
2
4
6
8
10
12
1 2 3 4 5 6 7 8 9 10
Decile of CV SBP
Haz
ard
rat
io (
95%
CI)
SYST-EUR: Stroke (fatal or non-fatal) (n = 197)
Unpublished data
Maximum SBP 7 measurements 10 measurementsexceeds meanSBP by:
0 - 9% 1 110 - 19% 1.21 (0.69 – 2.14) 2.24 (0.67 – 7.46)20 – 29% 1.84 (1.01 – 3.35) 4.10 (1.22 – 13.8)30 - 39% 3.24 (1.54 – 6.78) 6.16 (1.70 – 22.4)≥40% 6.21 (2.29 – 16.9) 9.31 (2.07 – 41.8)
Minimum SBP fellbelow mean SBP by:
0-4% 1 15-9% 0.98 (0.43-2.25) 1.19 (0.40-3.52)10-14% 0.90 (0.39-2.06) 1.02 (0.35-2.95)15-19% 1.72 (0.75-3.95) 2.17 (0.76-6.17)≥20% 1.64 (0.66-4.07) 2.59 (0.91-7.36)
Hazard ratios (95% CI) for the risk of subsequent stroke in relation to maximum SBP and minimum SBP in the UK-TIA trial
Lancet 2010; 375: 895-905
Perfusion pressure
Cer
ebra
l blo
od fl
ow
Perfusion pressure
Cer
ebra
l blo
od fl
owArteriolar calibrer
Arteriolar calibrer:
Perfusion pressure
Cer
ebra
l blo
od fl
ow
Perfusion pressure
Cer
ebra
l blo
od fl
ow
Perfusion pressure
Cer
ebra
l blo
od fl
ow
Perfusion pressure
Cer
ebra
l blo
od fl
owArteriolar calibrer
Arteriolar calibrer:
110
130
150
170
SB
P (
mm
Hg
)
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 Episodic severe Stable Heterogeneity normotension hypertension2 hypertension3 hypertension4
Cases 241 601 263 154
Mean (SD) of measures 1-7 of SBPIndividual mean 123.5 (7.6) 141.1 (8.6) 157.9 (8.7) 167.3 (7.2)Individual SD 8.5 (3.3) 12.8 (4.1) 21.4 (5.7) 13.4 (5.8)Individual CV 6.9 (2.8) 9.1 (3.1) 13.6 (3.6) 7.9 (3.2)Individual VIM 11.5 (4.9) 13.9 (5.0) 19.1 (5.2) 10.6 (4.1)Individual maximum 134.3 (7.6) 159.4 (8.5) 190.2 (12.3) 187.8 (16.2)Individual minimum 112.0 (9.9) 124.2 (10.6) 130.2 (9.5) 151.7 (4.9)
Events after 7th measure of SBPStroke 9 (3.7%) 37 (6.2%) 36 (13.7%) 7 (4.5%) p=0.00003HR (95% CI) 1.00 1.68 (0.81-3.47) 4.18 (2.01-8.68) 1.22 (0.45-3.27)
Coronary event 22 (9.1%) 66 (11.0%) 39 (14.8%) 13 (8.4%) p=0.12HR (95% CI) 1.00 1.40 (0.86-2.28) 1.72 (1.02-2.91) 0.84 (0.42-1.70)
All vascular events 31 (12.9%) 103 (17.1%) 75 (28.5%) 20 (13.0%) p=0.000007
1 All values ≤140mmHg2 At least one BP ≤140mmHg, at least one >140mmHg, but all <180mmHg3 At least one BP ≤140mmHg and at least one BP ≥180mmHg.4 All BPs >140mmHg Lancet 2010; 375: 895-905
Postural instability (lying – standing) vs
visit-to-visit SD SBP (sitting)
12
3
1
2
3
0
1
2
3
4
5
6
7
8
9
10
Tertile of visit-to-visit SD
Tertile of APD SBP
0
5
10
15
20
25
30
35
40
0 10 20 30 40
visit-to-visit SD SBP
Ave
rag
e
po
stu
ral
chan
ge
Unpublished dataV-to-V
PC
Stroke riskP<0.001
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
JA Staessen et al. Lancet 2001; 358: 1305-15
The relationships between change in SBP and the effect on vascular risk in RCTs of BP lowering
15
16
17
18
19
20
0 5 10 15 20 25
Months
Inte
r-in
div
idu
al S
D S
BP
(m
mH
g)
Placebo
beta-blocker
diuretic
Group SD SBP in the MRC Trial in elderly hypertensive patients
Lancet Neurol 2010; 9: 469-80
Mean (SD) SBP (mmHg) at baseline and during follow-up stratified by randomised treatment in the ALLHAT trial
Follow-up Treatment group Significance (p) of difference in SD
visit Amlodipine (A) Chlorthalidone (C) Lisinopril (L) A vs L C vs L
Baseline 146.2 (15.7) 146.2 (15.7) 146.4 (15.7) 0.5 0.5
1 year 138.5 (14.9) 136.9 (15.8) 140.0 (18.5) 9 x 10-79 7 x 10-55
2 years 137.1 (15.0) 135.9 (15.9) 138.4 (17.9) 3 x 10-48 1 x 10-28
3 years 135.6 (15.2) 134.8 (15.4) 136.7 (17.3) 9 x 10-25 2 x 10-25
4 years 134.8 (15.0) 133.9 (15.7) 135.5 (17.2) 1 x 10-24 2 x 10-14
5 years 134.7 (14.9) 133.9 (15.2) 135.9 (17.9) 1 x 10-24 8 x 10-25
Lancet 2010; 375: 938-48
50 70
90 110
130
150
170
190
210
230
250
270
50 70 90 110
130
150
170
190
210
230
250
270
Amlodipine group Atenolol group
Num
ber
of s
ubje
cts
SBP (mmHg) SBP (mmHg)
SD=15.8 SD=19.2
0
2500
3000
1500
500
1000
2000
50 70
90 110
130
150
170
190
210
230
250
270
50 70 90 110
130
150
170
190
210
230
250
270
Amlodipine group Atenolol group
Num
ber
of s
ubje
cts
SBP (mmHg) SBP (mmHg)
SD=15.8 SD=19.2
0
2500
3000
1500
500
1000
2000
Distributions of SBP at the one year follow-up visit in ASCOT-BPLA stratified by randomised treatment group
Lancet Neurol 2010; 9: 469-80
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
CCB Drug B
NORDIL (vs BB/D)98 159 / 5410 196 / 5471 0.81 0.66-1.01
ASCOT (vs BB)64 327 / 9639 422 / 9618 0.77 0.66-0.89
VALUE (vs ARB)99 281 / 7596 322 / 7649 0.87 0.74-1.03
INVEST (vs BB)97 176 / 11267 201 / 11309 0.88 0.72-1.08
ALLHAT (vs ACE)95 377 / 9048 457 / 9054 0.82 0.71-0.94
CAMELOT (vs ACE)63 6 / 663 8 / 673 0.76 0.26-2.20
TOTAL 1326 / 43623 1606 / 43774 0.82 0.76-0.88
Events/Patients Odds
Ratio95% CI
0.5 1.5 Odds Ratio (95%CI)
Stroke risk
Trial
3.70 3.07, 4.33
-1.90 -2.36, -1.44
-1.80 -4.92, 1.32
0.00 -0.27, 0.27
-1.30 -1.78, -0.82
0.60 -1.20, 2.40
-0.21 -0.41, -0.01
Mean SBP
Difference95% CI
CCB Drug B
155.2 (16.3) 151.5 (17.4) 0.88 0.83-0.93
138.4 (14.8) 140.3 (17.8) 0.69 0.67-0.72
138.2 (13.8) 140.0 (16.2) 0.73 0.68-0.77
131.0 (11.0) 131.0 (13.0) 0.83 0.80-0.86
137.1 (15.0) 138.4 (17.9) 0.70 0.67-0.73
124.2 (15.5) 123.6 (18.0) 0.74 0.64-0.86
0.76 0.74-0.77
Mean (sd) Variance
Ratio95% CI
0.5 1.5 Variance Ratio (95%CI)
SBP at follow-up
NORDIL (vs BB/D)98
ASCOT (vs BB)64
VALUE (vs ARB)99
INVEST (vs BB)97
ALLHAT (vs ACE)95
CAMELOT (vs ACE)63
TOTAL
Trial
3.70 3.07, 4.33
-1.90 -2.36, -1.44
-1.80 -4.92, 1.32
0.00 -0.27, 0.27
-1.30 -1.78, -0.82
0.60 -1.20, 2.40
-0.21 -0.41, -0.01
Mean SBP
Difference95% CI
Lancet 2010; 375: 938-48
I-VR
2.0
2.0
0.5
0.5
G-VR
0.5
0.5
2.0
2.0
G-VR
Effect of treatment of group versus individual variability in SBPBlood Pressure Lowering Trialists’ Collaboration
Unpublished data
R2 = 0.87, p<0.0001
12
14
16
18
20
22
24
Follow-up
Inte
r-in
div
idu
al S
D S
BP Atenolol
Amlodipine
Effect of treatment on group SD SBP in ASCOT-BPLA
Lancet Neurol 2010; 9: 469-80
3.5
3.7
3.9
4.1
4.3
4.5
Baseli
ne
3 m
onth
s
1 ye
ar
2 ye
ar
3 ye
ar
4 ye
ar
5 ye
ar
Follow-up
Ave
rag
e w
ith
in-v
isit
CV
SB
P
Atenolol
Amlodipine
10
10.5
11
11.5
12
12.5
0.5 -1.5yr
1.5 -2.5yr
2.5 -3.5yr
3.5 -4.5yr
4.5 -5.5yr
> 5.5yr
Time from randomisation
Avera
ge in
tra-A
BP
M d
ayti
me S
D S
BP
Atenolol
Amlodipine
ABPM daytime SD
Group SDWithin-visit individual SD
Effect of treatment allocation on within- individual variability in SBP in ASCOT
0
200
400
600
800
1000
1200
1400
1 2 3 4 5 6 7 8 9 10
Decile of CV SBP
No.
of
patie
nts
Atenolol
Amlodipine
Lancet 2010; 375: 895-905
Effect of treatment on risk of stroke in ASCOT-BPLAAdjustment 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
377 Phase 2 Trials with follow-up SD (9 reports included 2 trials)
94 Phase 3 Trials (>100 patients per group for >1 year)
1372 Eligible Reports
93 trials of 578456 patients
Meta-analyses of OR between
drugs
28 comparisons in 188564 patients
Metaregressions of VR vs OR
685 drug groups of 157505 patients
Change in VR or %CV
361 comparisons in 150663 patients
VR or %CV on different agents
910 phase 2 trials excluded due to inadequate reporting
+ 21 phase 3 trials+ 21 phase 3 trials
Systematic review of all RCTs of BP-lowering drugs
Lancet 2010; 375: 906-15
Pooled estimates of variance ratio between drug classes in crossover trials
Lancet 2010; 375: 906-15
40
60
80
100
120
140
160
180
200
220Amlodipine 5mg
Amlodipine 10mg
1 2 3 4 5 6 7 8Weeks
Blo
od p
ress
ure
(mm
Hg)
40
60
80
100
120
140
160
180
200
220Amlodipine 5mg
Amlodipine 10mgAmlodipine 10mg
1 2 3 4 5 6 7 8Weeks
Blo
od p
ress
ure
(mm
Hg)
40
100
120
140
160
180
200
220
Felodipine 2.5mg Felodipine 5mg Felodipinestopped
60
80
1 2 3 4 5 6 7 8 9 10 11 12
Weeks
Blo
od p
ress
ure
(mm
Hg)
40
100
120
140
160
180
200
220
Felodipine 2.5mg Felodipine 5mg Felodipinestopped
60
80
1 2 3 4 5 6 7 8 9 10 11 12
Weeks
Blo
od p
ress
ure
(mm
Hg)
OXVASC Bluetooth Home BP monitoring
COMMIT Study
- 310 patients
- 1284 drug changes
- 92% uptake
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
Lancet 2010; 375: 906-15
0
0.2
0.4
0.6
0.8
1
1.2
1.4
0.6 0.8 1 1.2 1.4 1.6
Variance Ratio (REF/EXP)
OR
(E
XP
/RE
F)
ALLHAT II
CAMELOT
STOP ICAMELOT
FEVER
SCOPE
NORDIL
ALLHAT II
UKPDS 39
ASCOT
SHEP
NICS
EWPHE
ALLHAT
VALUE
MOSES
LIFEPATS
HAPPHY
USPHS
HOT<80
HOT<85
SCAT
IPPPSH
ECOST
INVEST
PREVEND IT
UKPDS 388
15
14
19
71
16
18
13
20
4
21
17
12
6
25
11
2
322
23
23
5
9
24
1
10
11
0
0.2
0.4
0.6
0.8
1
1.2
1.4
0.6 0.8 1 1.2 1.4 1.6
Meta-regressions relating effect of treatment on group variability in SBP to effect of treatment on risk of stroke
Adjusted for difference in mean SBP
Pooled estimates of VR in parallel group trials in BPLTC:Intra-individual versus inter-individual variability
Unpublished data
0.5
1.0
1.5
A) B)
OR
(a
ll s
tro
ke
) O
R (
all
str
oke
)
Reduction in SBP (mmHg) Change in I-VR
0.5
1.0
1.5
0.5
1.0
1.5
0.5
1.0
1.5
-4 0 16
-4 0 16 1.5 1.0 0.5
1.5 1.0 0.5
Drug vs control Drug A vs Drug B
Unpublished data
Reduction in SBP (mmHg)Reduction in SBP (mmHg)
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
– Not currently treating the right patients
• Risk prediction• Choice of agent• Combinations of agents• Monitoring of BP on Rx• Development of new agents• Aetiology of stroke?
Sys
toli
c B
P (
mm
Hg
)
100
150
200
250
0 1 2 3 4 5
100
150
200
250
Months
Recommended