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

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Minutes (e.g. within-visit)

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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

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Variation in BP – baseline vs first follow-up

ECST UK-TIA Dutch TIA

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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

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Board meeting 3 LecturesFormal

meeting + dinner

Took over chairLecture 2

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Lunch WalkBreakfast

Gym Walk Sleep

SB

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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

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Comparison of day-to-day and week-to-week variability

Week 1 Weeks 1 - 30

Unpublished data

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Within-week SD SBP

Wee

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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

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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

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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

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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

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Lancet 2010; 375: 895-905

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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

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Arteriolar calibrer:

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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)

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Tertile of APD SBP

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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

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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

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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

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Effect of treatment of group versus individual variability in SBPBlood Pressure Lowering Trialists’ Collaboration

Unpublished data

R2 = 0.87, p<0.0001

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Effect of treatment on group SD SBP in ASCOT-BPLA

Lancet Neurol 2010; 9: 469-80

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Effect of treatment allocation on within- individual variability in SBP in ASCOT

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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

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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

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OR

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/RE

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ALLHAT II

CAMELOT

STOP ICAMELOT

FEVER

SCOPE

NORDIL

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UKPDS 39

ASCOT

SHEP

NICS

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LIFEPATS

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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

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A) B)

OR

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R (

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Reduction in SBP (mmHg) Change in I-VR

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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?

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