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How does hypertension cause stroke: usual BP, variability in BP or both?

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. IMT. Neurovascular Physiology. MCA stiffness.

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How does hypertension cause stroke: usual BP, variability in BP or both?

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  1. How does hypertension cause stroke:usual BP, variability in BP or both? PM Rothwell Professor of Clinical Neurology University of Oxford BHS; September 2011

  2. CVS Reactivity Ultrasound: Carotid + TCD Cold Pressor Test Mental Arithmetic IMT Neurovascular Physiology MCA stiffness Cerebral Autoregulation Pulse Wave Analysis Analysis Beat-to-Beat BP Postural BP Aortic BP Baroreceptor Gain Aortic stiffness Induced Hypotension Peripheral stiffness

  3. 250 200 150 100 0 1 2 3 4 5 Measures of variability / lability Statistics • SD • CV • VIM • ASV • RSD • Peak size • Trough size Variability period Minutes (e.g. within-visit) Hours (e.g. ABPM) Days (e.g. home monitoring) Weeks (e.g. visit-to-visit)

  4. 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

  5. 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

  6. Patient A Systolic 175 Diastolic 150 125 100 75 01- 01- 01- 01- 15- 10- 26- 26- 07- 11- 23- 16- 19- 05- JAN- JAN- JAN- JUN- SEP- OCT- NOV- APR- JAN- FEB- MAY- DEC- JUL- OCT- 1998 2000 2002 2002 2003 2003 2003 2004 2005 2005 2005 2005 2006 2007

  7. Variation in BP – baseline vs first follow-up ECST UK-TIA Dutch TIA Second measurement of DBP (mm Hg) SBP (mm Hg) Howard SC, Rothwell PM. J Clin Epidemiol 2003; 56: 1084-91 & Stroke 2006; 37: 2776-83

  8. 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

  9. Took over chair Lecture 2 200 Lecture 1 Lecture 3 150 SBP (mmHg) 100 Formal meeting + dinner Breakfast Sleep Board meeting Gym 3 Lectures Walk Walk Lunch 06:38 07:31 08:30 09:30 10:30 11:30 12:30 13:30 14:30 15:30 16:30 17:30 18:30 19:30 20:30 21:30 22:30 00:00 02:00 04:00 06:00 Time of day

  10. 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

  11. Comparison of day-to-day and week-to-week variability Week 1 Weeks 1 - 30 A B Unpublished data

  12. 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

  13. Relevant epidemiology of stroke Diurnal pattern of stroke incidence in Oxfordshire, UK • Age • Acute hypertension • Diurnal variation • Triggers • Personality • Sex • Race • Renal failure, diabetes • Vascular dementia Lancet 2010; 375: 938-48

  14. “Usual” value Measured value Count “Usual” value Value Risk Measured value Value Regression Dilution Bias Prospective Studies Collaboration Lancet 2002; 360: 1903-13

  15. Problems in interpretation of adjustment for RDB • 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. • 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

  16. 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

  17. 12 10 8 6 Hazard ratio (95% CI) Adjusted for mean SBP 4 2 0 1 2 3 4 5 6 7 8 9 10 Decile of SD SBP Variability in BP versus stroke risk in UK-TIA Trial Excluding cases with prior stroke or CT infarction Cuffe RL, Rothwell PM. Medium-term variability in systolic blood pressure is an independent predictor of stroke. Cerebrovasc Dis 2005; 19 (suppl 2): 51. Lancet 2010; 375: 895-905

  18. Predictive value of residual visit-to-visit variability in SBP in ASCOT-BPLA HR for SD SBP HR for VIM SBP 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 Decile of measure Decile of measure Lancet 2010; 375: 895-905

  19. SYST-EUR: Stroke (fatal or non-fatal) (n = 197) Unpublished data

  20. 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 7 measurements 10 measurements exceeds mean SBP by: 0 - 9% 1 1 10 - 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 fell below mean SBP by: 0-4% 1 1 5-9% 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) Lancet 2010; 375: 895-905

  21. 170 150 SBP (mm Hg) 130 110 Time

  22. 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 SBP • Individual 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 SBP • Stroke 9 (3.7%) 37 (6.2%) 36 (13.7%) 7 (4.5%) p=0.00003 • HR (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=0.12 • HR (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 ≤140mmHg • 2 At least one BP ≤140mmHg, at least one >140mmHg, but all <180mmHg • 3 At least one BP ≤140mmHg and at least one BP ≥180mmHg. • 4 All BPs >140mmHg Lancet 2010; 375: 895-905

  23. 40 Stroke risk P<0.001 35 30 25 Average postural change 20 15 10 5 0 PC 0 10 20 30 40 visit-to-visit SD SBP V-to-V Unpublished data Postural instability (lying – standing) vs visit-to-visit SD SBP (sitting)

  24. 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

  25. 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

  26. Group SD SBP in the MRC Trial in elderly hypertensive patients Lancet Neurol 2010; 9: 469-80

  27. 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 - 79 - 55 1 year 138.5 (14.9) 136.9 (15.8) 140.0 (18.5) 9 x 10 7 x 10 - 48 - 28 2 years 137.1 (15.0) 135.9 (15.9) 138.4 (17.9) 3 x 10 1 x 10 - 25 - 25 3 years 135.6 (15.2 ) 134.8 (15.4) 136.7 (17.3) 9 x 10 2 x 10 - 24 - 14 4 years 134.8 (15.0) 133.9 (15.7) 135.5 (17.2) 1 x 10 2 x 10 - 24 - 25 5 years 134.7 (14.9) 133.9 (15.2) 135.9 (17.9) 1 x 10 8 x 10 Lancet 2010; 375: 938-48

  28. Distributions of SBP at the one year follow-up visit in ASCOT-BPLA stratified by randomised treatment group Lancet Neurol 2010; 9: 469-80

  29. Stroke risk Events/Patients Odds 95% CI Ratio CCB Drug B Trial Trial NORDIL (vs BB/D)98 NORDIL (vs BB/D)98 159 / 5410 196 / 5471 0.81 0.66-1.01 ASCOT (vs BB)64 ASCOT (vs BB)64 327 / 9639 422 / 9618 0.77 0.66-0.89 VALUE (vs ARB)99 VALUE (vs ARB)99 281 / 7596 322 / 7649 0.87 0.74-1.03 INVEST (vs BB)97 INVEST (vs BB)97 176 / 11267 201 / 11309 0.88 0.72-1.08 ALLHAT (vs ACE)95 ALLHAT (vs ACE)95 377 / 9048 457 / 9054 0.82 0.71-0.94 CAMELOT (vs ACE)63 CAMELOT (vs ACE)63 6 / 663 8 / 673 0.76 0.26-2.20 TOTAL TOTAL 1326 / 43623 1606 / 43774 0.82 0.76-0.88 0.5 1.5 SBP at follow-up Odds Ratio (95%CI) Mean SBP Mean SBP Mean (sd) Variance 95% CI 95% CI 95% CI Difference Difference Ratio CCB Drug B 3.70 3.70 3.07, 4.33 3.07, 4.33 155.2 (16.3) 151.5 (17.4) 0.88 0.83-0.93 -1.90 -1.90 -2.36, -1.44 -2.36, -1.44 138.4 (14.8) 140.3 (17.8) 0.69 0.67-0.72 -1.80 -1.80 -4.92, 1.32 -4.92, 1.32 138.2 (13.8) 140.0 (16.2) 0.73 0.68-0.77 0.00 0.00 -0.27, 0.27 -0.27, 0.27 131.0 (11.0) 131.0 (13.0) 0.83 0.80-0.86 -1.30 -1.30 -1.78, -0.82 -1.78, -0.82 137.1 (15.0) 138.4 (17.9) 0.70 0.67-0.73 0.60 0.60 -1.20, 2.40 -1.20, 2.40 124.2 (15.5) 123.6 (18.0) 0.74 0.64-0.86 -0.21 -0.21 -0.41, -0.01 -0.41, -0.01 0.76 0.74-0.77 0.5 1.5 Variance Ratio (95%CI) 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 Lancet 2010; 375: 938-48

  30. Effect of treatment of group versus individual variability in SBP Blood Pressure Lowering Trialists’ Collaboration G-VR 2.0 G-VR 2.0 R2 = 0.87, p<0.0001 I-VR 0.5 2.0 0.5 2.0 Unpublished data 0.5 0.5

  31. 4.5 Atenolol Amlodipine 4.3 4.1 3.9 Average within-visit CV SBP 3.7 3.5 1 year 3 year 2 year 4 year 5 year Baseline 3 months Follow-up Effect of treatment on group SD SBP in ASCOT-BPLA Within-visit individual SD Group SD ABPM daytime SD Lancet Neurol 2010; 9: 469-80

  32. Atenolol 1400 1200 Amlodipine 1000 800 600 No. of patients 400 200 0 1 2 3 4 5 6 7 8 9 10 Decile of CV SBP Effect of treatment allocation on within- individual variability in SBP in ASCOT Lancet 2010; 375: 895-905

  33. Effect of treatment on risk of stroke in ASCOT-BPLAAdjustment for mean BP and variability in BP Lancet Neurol 2010; 9: 469-80

  34. 1372 Eligible Reports 910 phase 2 trials excluded due to inadequate reporting 377 Phase 2 Trials with follow-up SD (9 reports included 2 trials) 94 Phase 3 Trials (>100 patients per group for >1 year) + 21 phase 3 trials 361 comparisons in 150663 patients VR or %CV on different agents 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 Systematic review of all RCTs of BP-lowering drugs Lancet 2010; 375: 906-15

  35. Pooled estimates of variance ratio between drug classes in crossover trials Lancet 2010; 375: 906-15

  36. OXVASC Bluetooth Home BP monitoring • COMMIT Study • 310 patients • 1284 drug changes • 92% uptake Lancet 2010; 375: 938-48

  37. Pooled estimates of VR in parallel group trials compared with drug-class effects on stroke risk Lancet 2010; 375: 906-15

  38. 1.4 1.4 HOT<85 1.2 ALLHAT II ALLHAT 1.2 UKPDS 39 MOSES 11 10 1 1 ALLHAT II 25 IPPPSH 2 5 24 HOT<80 23 12 VALUE 11 INVEST 21 13 NORDIL 1 23 3 HAPPHY 0.8 4 18 22 0.8 6 NICS 14 LIFE SCOPE ASCOT 20 OR (EXP/REF) PATS 1 15 7 CAMELOT 9 SHEP FEVER 19 16 0.6 0.6 ECOST EWPHE 17 STOP I CAMELOT UKPDS 38 8 0.4 0.4 SCAT USPHS 0.2 0.2 PREVEND IT 0 0 0.6 0.8 1 1.2 1.4 1.6 0.6 0.8 1 1.2 1.4 1.6 Variance Ratio (REF/EXP) 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 Lancet 2010; 375: 906-15

  39. Pooled estimates of VR in parallel group trials in BPLTC: Intra-individual versus inter-individual variability Unpublished data

  40. Drug vs control Drug A vs Drug B Reduction in SBP (mmHg) Reduction in SBP (mmHg) - VR Change in I Unpublished data

  41. 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

  42. 250 200 150 100 Systolic BP (mmHg) 250 200 150 100 0 1 2 3 4 5 Months 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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