1. TREATMENT of HYPERTENSION in the 21st Century
Sir George Pickering Lecture
Peter Sever
International Centre for Circulatory Health
Imperial College London

2. Sir George Pickering Professor of Medicine
St Mary’s Hospital Medical School 1939
Regius Professor of Medicine
Oxford 1956

4. Pickering: “High Blood Pressure” 1955 Terminology
Hypertension – not a well chosen word, a bastard of Greek and Latin parentage and signifying not high blood pressure but over-much stretching.
The use of the term has lead to the practice of distinguishing between normal pressure and hypertension, and thus by easy stages to the assumption that those subjects with hypertension differ qualitatively from the rest of mankind

5. Platt’s hypothesis-Pickering’s data !

6. GWP: Letter to the Lancet 1957
“My old chief, Sir Thomas Lewis, would not allow readings of blood pressure taken by nurses to appear in scientific publications . Although it had been claimed that digit preference could be excluded because the nurses had no incentive, in a survey of 67,976 people, 85% of systolic readings and 87% of diastolic readings taken by nurses ended in a 0. Diastolic readings showed bimodality attributed to a change in the team of nurses making the measurements.”

7. If Pickering had had access to blood pressure responses to different classes of antihypertensive drugs, the unimodality hypothesis would have been much more persuasive

8. DBP placebo – lisinopril, mmHg
The frequency distribution of changes in diastolic blood pressure (DBP) produced by 3 drugs
DBP placebo – lisinopril, mmHg
DBP placebo – atenolol, mmHg 16 16 12 12
Count 8
Count 8 4 4 20 10
-10
-20
-30
-40 16
DBP placebo – nifedipine, mmHg 12
Count 8 4
Atwood et al
J Hypertens 1994; 12:1053

9. Treatment of Hypertension

10. Does the magnitude of response to an antihypertensive drug inform on the mechanism(s) involved in blood pressure elevation ?

11. Two important observations : Blood pressure responses to Spironolactone and to Renal denervation in subjects with resistant hypertension

12. Frequency distribution of change in SBP after spironolactone or renal denervation
The Symplicity HTN 2 Trial
ASCOT
Simulated FD curve
Based on reported mean +/-SD in SBP
Mean  SBP: ±21.27 mmHg
Mean  SBP: -32±23 mmHg
Chapman et al. Hypertension ;49:
Symplicity HTN-2 Investigators. Lancet 2010; 376:

13. Placebo corrected SBP response to monotherapy ( ) and
dual therapy ( ) meta analysis of 42 trials
Wald DS et al. Am J Med 2009; 122:

14. Frequency distribution of change in SBP from baseline among ASCOT monotherapy users (untreated at baseline)
Mean  SBP: ±16.93 mmHg
Mean  SBP: Atenolol: ±18.36 mmHg;
Amlodipine: ±15.37 mmHg

15. Frequency distribution of change in SBP from baseline among ASCOT monotherapy users (untreated at baseline)
Note
Placebo response from randomised controlled trials in hypertensive subjects estimated to be approx 10mmHg systolic pressure
Mean  SBP: Atenolol: ±18.36 mmHg;
Amlodipine: ±15.37 mmHg

16. Frequency distribution of change in SBP after second drug ( BFZ+K or Perindopril) therapy
Mean  SBP: BFZ+K: mmHg; Perindopril: mmHg

17. Frequency distribution of change in SBP after third drug (doxazosin) therapy
Mean  SBP: ±18.81 mmHg
Mean  SBP: Atenolol group: ±19.89 mmHg;
Amlodipine group: -9.39±16.98 mmHg

18. Frequency distribution of change in SBP after spironolactone therapy
Mean  SBP: ±21.27 mmHg
Mean  SBP: Atenolol group: ±21.46 mmHg;
Amlodipine group: ±20.33 mmHg

19. Frequency distribution of change in SBP after spironolactone therapy
Note greater response
in the atenolol/thiazide
arm. Effect not influenced by concomitant diuretic use
Mean  SBP: atenolol group: mmHg; amlodipine group: mmHg

20. Blood pressure response to renal denervation:
The Symplicity HTN 2 Trial
Symplicity HTN-2 Investigators .Lancet 2010;376:

21. Summary
Spiro
Blocking two apparently different physiological systems in patients with drug resistant hypertension leads to substantial reductions in blood pressure. These reductions in blood pressure far greater than expected from renal efferent sympathetic blockade or the action of aldosterone blockade on sodium and water homeostasis
Do these observations highlight two separate phenotypes with resistant hypertension - volume overload and excess vascular resistance ?
Denervation
Denervation

22. Resistant hypertension : Haemodynamics
After Brown M. BHS Guideline on Resistant Hypertension ( unpublished) ,

23. Resistant hypertension : Key features
Muscle sympathetic nerve activity
and increasing blood pressure
Blunted natriuresis
Increased extracellular volume
Activation of RAAS
Increased renal sympathetic nerve activity
Increased sodium reabsorption
severe
mild-moderate
hypertensive
normotensive
Grassi G et al. Exp Physiol 2010;95: ,

24. But…Don’t forget Pickering !
“Essential hypertension is a type of disease not hitherto recognised in medicine, in which the defect is quantitative not qualitative. It is difficult for doctors to understand because it is a departure from the ordinary process of binary thought to which they were brought up. Medicine in its present state can count up to 2 but not beyond.”
G W Pickering, 1968
George Pickering

25. Response to spironolactone and to denervation Or are these observations providing a clue to an important interaction between sodium homeostasis and CNS activation which may be relevant not only in the context of resistant hypertension but also perhaps , importantly, more generally in the context of raised blood pressure

26. Spironolactone actions include :-
Lowers sympathetic nervous system activity in older hypertensive subjects
( lowers plasma noradrenaline and reduces 3H –NA release rates - not seen with thiazides )
Binds to aldosterone sensitive mineralocorticoid receptors in the NTS, the anterior hypothalamus and other brain stem centres including the RVLM and PVN
(Geerling and Loewy 2009)
Enhances parasympathetic tone and may decrease sympathetic activity
Wray and Supiano 2010

27. Mineralocorticoids and dietary salt excess
Renal tubular sodium reabsorption.
Increased excitability of sympathetic regulatory neurons in brain stem nuclei
(RVLA,NTS).
Non-genomic effects on heart and vasculature.

28. Spironolactone

29. Renal denervation Blocks renal efferent sympathetic nerve activity
Blocks renal afferent nerve activity
Induces substantial sodium and water loss

30. Genetic
Environmental
eg Salt
Mosaic 2011
Haemodynamics
Renal BP
Humoral
Anatomical
Intrauterine
programming
Adaptive
Endocrine
Neural
Modified from Page 1959

31. Implication of these observations in resistant hypertension to pathophysiology of “essential” hypertension Linkage of dietary salt and the CNS to elevated blood pressure

32. Renal Afferents External Stimuli Higher Centres Insulin Aldosterone
High salt diet
Leptins
Baroreceptors
Renal Afferents
Angiotensin 2
Sympathetic outflow

33. Interaction hypothesis supported by:-
Experimental models of hypertension
- SHR and salt loading Koepke et al.Hypertension 1985; 7:
DOCA salt model and stress Koepke et al. Am J Physiol. 1986; 251: R
Dietary salt enhances excitability and increases the gain of sympathetic-regulatory neurons in RVLM in salt sensitive animal models.
Stocker et al. Physiol.Behav. 2010;100:
Stress, sodium retention and BP elevation in normotensive human subjects with family history of hypertension Light et al.Science 1983: 220:
Linked to genetic polymorphism of the alpha 2 adrenoceptor
Finlay et al. J. Appl Phys 2004; 96:
Longitudinal migration study Poulter et al. BMJ Apr 14;300:

34. Kenyan Luo Migration Study modified from Poulter et al. BMJ
Kenyan Luo Migration Study modified from Poulter et al. BMJ Apr 14;300: SBP levels at 0-24 months
130
migrants
120
mmHg
Mean pre-migration blood pressure
non-migrants
110
100 3 6 12 18
24 months
Males
DBP levels at 0-24 months 70
migrants
mmHg 60
Mean pre-migration blood pressure
non-migrants 50 3 6 12 18
24 months

35. Sever et al
In Concepts in
hypertension
Springer-Verlag
1989 p 55-66

36. Males Migrants Controls Females
Body weight, pulse and urinary NaK ratios at 0-24 months
Males
Body weight (kg)
Pulse (bpm)
Urinary NaK ratio
61.0 75
5.0
57.5 69
3.5
54.0 63
2.0 3 6 12 18 24 3 6 12 18 24 3 6 12 18 24
Migrants
Controls
Females
Body weight (kg)
Pulse (bpm)
Urinary NaK ratio
61.0 75
5.0
57.5 69
3.5
54.0 63
2.0 3 6 12 18 24 3 6 12 18 24 3 6 12 18 24
Poulter et al. BMJ Apr 14;300:

37. Hypothesis required to incorporate:-
Early blood pressure elevation
Rapid increase in body weight ( not explained by increase in dietary calorie intake)
Increase in dietary sodium
Increase in heart rate

40. Neuronal genotype (s) -
influences neuronal responses to plasma/CSF sodium
Renal genotype(s)-influence tubular reabsorption of sodium and/or renal afferent nerve responses to sodium load

41. Guyton hypothesis *Impaired if prevented by: Angiotensin II
Renal sympathetic nerve activity
Aldosterone
Reduced renal mass

42. The way forward :Integrative physiology
Further understanding of genetic and environmental factors, the basis of their interaction and their influence on the neuro/humoral/renal/vascular mechanisms that are likely to be involved in the multi-factorial, multi-genetic nature of hypertension.

43. Improved methods to understand the integration of biological systems
Requires more quantitative approaches and modelling of cardiovascular system dynamics
Requires advances in medical imaging technology to permit non-invasive studies of the brain, vasculature and kidney in the whole animal/human.
A fully integrative mathematical model is essential for the complete analysis of currently available data
Data needs to be acquired from long-term minimally invasive observations of cardiovascular variables in humans and animal models under a variety of behavioural and environmental conditions.

44. Challenges to the scientific community
Need for teams of researchers to design studies that draw upon expertise in the fields of genomics, proteomics, informatics, statistical genetics, cellular and integrative physiology, mathematics and computer science.
Systems biology is the delineation of the elements in a biological system and the analysis of their interactions after genetics or environmental perturbation.
The goal of systems biology is to explain the systems emergent properties (phenotypic transformation) that are absent when the elements of the system are studied in isolation, but are only present when multiple elements within a system interact
Systems biology should be hypothesis driven, quantitative, integrative and iterative.
Bioinformatics and computational biology is necessary to resolve the complex interrelationships between the multiple organs and systems involved not only in blood pressure regulation but also in the consequential impact of blood pressure and other risk factors on target organs

45. Hypertension treatment
The ASCOT Legacy

46. ASCOT History
1988/9 European Blood Pressure Group- discussion on unmet needs in hypertension research
1991 British Hypertension Society Working Party formed; produced initial trial design but no funding
1993 Furberg and the CCB controversy
1993 NHLBI agree to fund ALLHAT
1995 Joint discussions between UK, Sweden and Pfizer.
1996 ASCOT announcement and Steering Committee established

47. ASCOT: Rationale
Insufficient outcome data on newer types of blood pressure lowering agents
No data on the evaluation of specific combination treatment regimens
Shortfall of CHD prevention using standard therapy
Need to evaluate multiple risk factors in the prevention of CHD
No data on the benefits of lipid lowering among hypertensives

48. Investigator-led, multinational randomised controlled trial
ASCOT: Study design
19,257 hypertensive patients
ASCOT-BPLA stopped after 5.5 yrs
atenolol ± bendroflumethiazide
PROBE
design
amlodipine ± perindopril
Investigator-led, multinational randomised controlled trial
placebo
atorvastatin 10 mg
Double-blind
ASCOT-LLA stopped
after 3.3 yrs
10,305 patients
TC ≤ 6.5 mmol/L (250 mg/dL)
Sever et al J. Hypertension. 2001;19:1139

49. Lipid-lowering arm

50. ASCOT-LLA : Nonfatal MI and Fatal CHD
Atorvastatin 10 mg Number of events 100
Placebo Number of events 154
36% reduction
The primary end point of nonfatal MI (including silent MI) and fatal CHD was significantly lower by 36% (hazard ratio 0.64, CI 0.5 – 0.83, p=0.005) in the atorvastatin group compared with the placebo group.
HR = 0.64 ( )
p=0.0005
Relative risk reductions independent of baseline cholesterol
Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

51. ASCOT-LLA CHD events :early benefits*
Risk Reduction Event Rate
(%) Atorvastatin Placebo
Censoring Time
Hazard Ratios (95% CI)
30 days
90 days
180 days
1 Year
2 Years
End of Study
* Per 1000 patient years
Atorvastatin better
Placebo better

52. ASCOT-LLA Summary of all end points
Area of squares is proportional to the amount of statistical information
0.5
1.0
1.5
Atorvastatin better
Placebo better
Primary End Points
Nonfatal MI (incl silent) + fatal CHD
Secondary End Points
Total CV events and procedures
Total coronary events
Nonfatal MI (excl silent) + fatal CHD
All-cause mortality
Cardiovascular mortality
Fatal and nonfatal stroke
Fatal and nonfatal heart failure
Tertiary End Points
Silent MI
Unstable angina
Chronic stable angina
Peripheral arterial disease
Development of diabetes mellitus
Development of renal impairment
Risk Ratio
Hazard Ratio
0.64 ( )
0.79 ( )
0.71 ( )
0.62 ( )
0.87 ( )
0.90 ( )
0.73 ( )
1.13 ( )
0.82 ( )
0.87 ( )
0.59 ( )
1.02 ( )
1.15 ( )
1.29 ( )
There was a significant reduction in the primary end point and also in four of the seven secondary end points, some of which were incorporated the primary end point.
Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

53. Blood Pressure-lowering arm

54. ASCOT BPLA Summary of all end points
Unadjusted Hazard ratio (95% CI)
0.90 ( )
0.87 ( )
0.87 ( )
0.84 ( )
0.89 ( )
0.76 ( )
0.77 ( )
0.84 ( )
1.27 ( )
0.68 ( )
0.98 ( )
0.65 ( )
1.07 ( )
0.70 ( )
0.85 ( )
0.86 ( )
0.84 ( )
Primary Non-fatal MI (incl silent) + fatal CHD
Secondary Non-fatal MI (exc. Silent) +fatal CHD
Total coronary end point Total CV event and procedures All-cause mortality Cardiovascular mortality Fatal and non-fatal stroke Fatal and non-fatal heart failure
Tertiary Silent MI
Unstable angina Chronic stable angina Peripheral arterial disease Life-threatening arrhythmias New-onset diabetes mellitus New-onset renal impairment
Post hoc
Primary end point + coronary revasc procs
CV death + MI + stroke
0.50
0.70
1.00
1.45
2.00
Amlodipine  perindopril better
Atenolol  thiazide better
The area of the blue square is proportional to the amount of statistical information

55. Synergy of atorvastatin and amlodipine based treatment arm

56. Benefits of atorvastatin according to BP lowering strategy
ASCOT-LLA 2x2 analyses
Benefits of atorvastatin according to BP lowering strategy
Primary endpoint: Non-fatal MI and fatal CHD
Amlodipine-based treatment
Atenolol-based treatment
4.0
4.0
Atorvastatin
Placebo
Atorvastatin
Placebo
3.0
3.0
16%
53%
Cumulative incidence (%)
Cumulative incidence (%)
2.0
2.0
1.0
1.0
HR=0.47 ( ) p<0.001
HR=0.84 ( ) p=0.30
0.0
0.0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Years
Years
P for interaction = 0.017
Sever, Poulter, Dahlof, Wedel. Europ.Heart Journal. 2006;27:2982

57. Combined benefits of lipid- and blood pressure- lowering
LLA and BPLA
Combined benefits of lipid- and blood pressure- lowering

58. Blood Pressure Lowering Combined BP & Lipid Lowering
Estimated benefits of combined blood pressure and lipid lowering from meta-analyses of placebo controlled trials
Blood Pressure Lowering
(15/10mmHg)
Lipid Lowering
(1mmol/L)
Combined BP & Lipid Lowering
CHD
30%
25-35%
About 50%
Stroke
45%
15-20%
About 55%

59. Reduction in risk of non-fatal MI and fatal CHD using Framingham model for baseline estimates **
Framingham risk estimate from baseline data ( n=10,305)
Final risk in those assigned amlodipine/perindopril and atorvastatin
Relative risk reduction
22.8*
4.8*
79%
*per 1000 patient years
**Variables include SBP, smoking status, total and HDL-cholesterol, presence or absence of LVH,
age, gender, presence or absence of diabetes. No correction for on- treatment blood pressure
Sever et al. Int. J. Cardiol Feb 18, epub ahead of print

60. A molecular mechanism for synergy
Clunn GF, Sever,P, Hughes A. Int J Cardiol 2009 Jun 10 [Epub ahead of print]

61. SMC migration and proliferation
SMC dedifferentiation
to synthetic phenotype
Macrophage
Foam cells
Cytokine release
SMC
migration
and
proliferation
SMC = smooth muscle cell

62. Apoptosis MMPs Destruction of intercellular matrix Lipid-laden
macrophage
MMP = matrix metalloproteinase

63. Plaque rupture

64. SMC DEDIFFERENTIATION Contractile phenotype Synthetic phenotype
Loss of
functionality
of L-type VOC
• CCBs ineffective
CCB
Ca2+
Presence of statins leads to growth arrest and re-expression of functioning L-type VOCs
L-type VOC
• CCBs effective
CCB = calcium channel blocker
VOC = voltage-operated Ca2+ channel
Clunn GF, Sever P, Hughes A. Int J Cardiol 2009 Jun 10 [Epub ahead of print]

65. An additional mechanism?

66. SMC: reversion to a more differentiated phenotype

67. Atorvastatin and carotid artery pressure
Lipid-lowering arm
Atorvastatin and carotid artery pressure
Atorvastatin lowers carotid artery pressure but not brachial
artery pressure, with evidence of an enhanced
effect in those assigned amlodipine-based treatment

68. Effect of atorvastatin on carotid systolic pressure in those assigned amlodipine- or atenolol- based treatment in ASCOT
Aplanation tonometry performed on the right carotid artery .Carotid artery flow velocity measured by pulsed wave Doppler ultrasound, and wave intensity analysis also performed
Augmentation pressure and augmentation index were lower in those assigned atorvastatin
Manisty C, Mayet J, Tapp R, Sever P et al. Hypertension 2009:54; e-pub online Aug 31

69. The relationship Between statin therapy and
Lipid-lowering arm
The relationship Between statin therapy and
the progression of renal damage

70. Final copy
Background
Uncertainty whether the use of statin therapy is effective in retarding the progression of renal damage among high-risk patients in a primary prevention setting.
Would the use of statin therapy in combination with antihypertensive medication, be additive in reducing the age-related decline in renal function ?
notes to be added

71. Mean eGFR (95% CI), mL/min/1.73 m2
Final copy
Mean eGFR During Follow-up in the ASCOT-LLA, Stratified by Allocated Treatment 68 70 72 74
Mean eGFR (95% CI), mL/min/1.73 m2
Baseline
6 Month
Year 1
Year 2
Year 3
Aten-based & Placebo
Aten-based & Atorvastatin
Amlo-based & Placebo
Amlo-based & Atorvastatin
Aten-based & Placebo:
69.0
67.7
67.8
68.4
69.5
Aten-based & Atorvastatin:
68.9
67.9
68.0
68.8
70.0
Amlo-based & Placebo:
69.9
70.8
71.1
72.2
73.2
Amlo-based & Atorvastatin:
70.3
71.4
71.6
72.5
73.7
eGFR: estimated glomerular filtration rate; CI: confidence interval; Aten-based: Atenolol ± thiazide ; Amlo-based: Amlodipine ± Perindopril
notes to be added

72. Blood Pressure-lowering arm
Substudies

73. CAFÉ Study: Methods SP
∆ P P1
Radial artery waveforms measured via noninvasive applanation tonometry
Augmentation index (AIx) defined as ratio of augmentation to central pulse pressure: Alx = (∆ P/PP) × 100
Pressure (mm Hg) DP
Incisura ED
Time (msec)
ED = ejection duration
CAFE Investigators. Circulation. 2006;113: epublished Feb 13, 2006.

74. CAFE: Lower central aortic BP with newer vs older antihypertensive regimen despite similar brachial BP
140
Brachial SBP
135
130
mm Hg
Central aortic SBP
125
120
115
0.5 1
1.5 2
2.5 3
3.5 4
4.5 5
5.5 6
AUC
Time (years)
Amlodipine ± perindopril Atenolol ± bendroflumethiazide
CAFE Investigators. Circulation. 2006;113: epublished Feb 13, 2006.

75. ASCOT Study of LV diastolic function : Treatment effects at I year
Atenolol-Based Regimen (n = 411)
Amlodipine-Based Regimen (n = 413)
p Value
 Transmitral Doppler
  E wave, cm/s
60.08 ± 14.87
63.41 ± 15.01
0.001
  A wave, cm/s
68.25 ± 14.63
75.08 ± 15.76
<0.001
  E/A ratio
0.91 ± 0.29
0.86 ± 0.22
0.004
  E-wave deceleration time, ms
0.20 ± 0.05
0.18 ± 0.05
 Tissue Doppler
  Systolic velocity (S′), cm/s
8.2 ± 1.75
9.5 ± 2.21
  Early diastolic velocity (E′), cm/s
7.91 ± 1.84
8.76 ± 2.04
  Late diastolic velocity (A′), cm/s
10.76 ± 2.15
12.34 ± 2.31
  *Mean E/E′ ratio
8.14 ± 2.38
7.76 ± 2.05
0.013
  *BNP, pg/ml
37 (20–56)
19 (10–34)
Early diastolic velocity (E`)( measure of diastolic relaxation) lower on atenolol, and left ventricular filling pressure (E/E`) and BNP higher on atenolol
* Both independent predictors of cardiac events
Tapp et al J Am Coll Cardiol Apr 27;55(17):

76. Blood Pressure Variability

77. Blood Pressure variability Background
Blood pressure variability is increased in cohorts at high risk of stroke and predicts stroke independent of mean blood pressure Rothwell 2005.

78. Blood pressure variability: methods (based on over 1 million BP readings)
Of 19,257 patients, 18,530 had ≥ 2 follow-up visits (median = 10) from 6 months onwards until the end of the trial
3 blood pressure measurements were recorded at each visit, using standardised techniques, at 6 monthly intervals for a median follow up of 5.5 years

79. Within visit variability
164/96
159/92
150/92
156/88
148/86
159/86
170/92
166/88
174/88
173/90
169/89
174/96
164/90
168/94
158/94
Between visit or visit-visit variability

80. Visit-to-visit mean systolic blood pressure expressed in deciles, hazard ratios (95% CI) and number of stroke and coronary events in each decile
Mean SBP
Stroke risk
Coronary risk

81. Stroke and coronary risk expressed by decile of measure of visit-to-visit SBP variability
Stroke Risk
Coronary Risk
Standard deviation of SBP
Atenolol
Amlodipine
Coefficient of variation of SBP
Variation independent of mean SBP
Decile of measure
Decile of measure

82. Group distribution (SD and CV) of measures of SBP at baseline and at each follow-up visit in the two treatment groups

83. Systolic blood pressure
Hazard ratios (95% CI) for the effect of treatment (amlodipine versus atenolol) on risk of stroke
Parameters calculated using all BP measurements from 6 months onwards. Mean, SD, CV, and VIM are entered into the model as deciles
Stroke
Systolic blood pressure
Variables in model
HR (95% CI)
p value
Treatment (Rx)
0.78 (0.67–0.90)
0.001
Usual BP
Rx + mean
0.84 (0.72–0.98)
0.025
Visit-to-visit BP variability
Rx + mean + SD
0.96 (0.82–1.12)
0.59
Rx + mean + CV
0.95 (0.82–1.11)
0.55
Rx + mean + VIM
0.58
Within-visit and visit-to-visit BP variability
Rx + within-visit SD
0.024
Rx + mean + VIM + WVSD
0.99 (0.85–1.16)
0.89
SD, standard deviation; CV, coefficient of variation; VIM, variability independent of mean; WVSD, within-visit standard deviation

84. Systolic blood pressure
Hazard ratios (95% CI) for the effect of treatment (amlodipine versus atenolol) on risk of coronary events
Parameters calculated using all BP measurements from 6 months onwards. Mean, SD, CV, and VIM are entered into the model as deciles
Coronary Events
Systolic blood pressure
Variables in model
HR (95% CI)
p value
Treatment (Rx)
0.85 (0.77–0.94)
0.002
Usual BP
Rx + mean
0.88 (0.80–0.98)
0.019
Visit-to-visit BP variability
Rx + mean + SD
1.00 (0.90–1.11)
0.98
Rx + mean + CV
0.99
Rx + mean + VIM
1.00 (0.90–1.10)
Within-visit and visit-to-visit BP variability
Rx + within-visit SD
0.88 (0.79–0.97)
0.013
Rx + mean + VIM + WVSD
1.01 (0.91–1.12)
0.88
SD, standard deviation; CV, coefficient of variation; VIM, variability independent of mean; WVSD, within-visit standard deviation

85. Conclusions
Blood pressure variability is a major predictor of stroke and coronary events
In individual trials average (mean) blood pressures poorly predict outcome
Increased blood pressure variability is associated with smoking, increasing age, diabetes, presence of vascular disease
There are major differences in the effects of different drug regimens on blood pressure variability

86. Biomarkers and cardiovascular risk prediction

87. Biomarkers Current hot biomarkers Inflammation NT-proBNP, cystatin C
Others
cortisol, urate, renin, aldo, CFH,GDF 15
Vascular
ADMA, t-PA, ICAM-1
Inflammation
CRP,IL6,LpPLA2,neopterin
Lipids
ApoA,ApoB1,Lp(a)
Metabolic
proinsulin,insulin,adiponectin,
fructosamine
Thrombosis
aPAF, aPC

88. Baseline Nt-BNP and Risk of CV Events
ASCOT Biomarker Programme: Although both these biomarkers independently predict risk of future cardiovascular events in the ASCOT Trial of hypertensive subjects, Nt-proBNP is the only one which has predictive ability beyond classical risk factors (Net reclassification improvement 11.8%)
Baseline Nt-BNP and Risk of CV Events
Per 1 SD increase log Nt-BNP <0.0001
Tertile 1 :< (ref) <0.0006
Tertile 2 :
Tertile 3: >
Baseline CRP and Risk of CV Events
Per 1 SD increase log CRP
Tertile 1 CRP: <1.74mg/L (ref) 0.05
Tertile 2 CRP: mg/L
Tertile 3 CRP: >4.09mg/L 1
1.5 2
Odds ratio and 95% CI (log scale)
0.5
1.0
1.5
2.0
Odds ratio 95% CI
Sever et al Europ Heart J 2011 epub July 28
Multivariable adjustment. Adjusted for current smoking status, diabetes mellitus, randomized BP treatment (atenolol/amlodipine), randomized atorvastatin/placebo/not in LLA, left ventricular hypertrophy, baseline SBP, total cholesterol and HDL-C BMI, loge-glucose, family history of CHD, creatinine and educational attainment

89. Lipid-lowering arm
The LLA Extension

90. Changes in total cholesterol over time
60% + of patients in
both arms now on statins
mmol/L
mg/Dl
End of LLA
Atorvastatin
Placebo
End of
BPLA
Sever PS, et al. Eur Heart J 2008;29:499–508

91. ASCOT-LLA endpoints Primary endpoints
0.5
1.0
1.5
3.3 yrs1
Risk ratio
Atorvastatin better
Placebo better
Atorvastatin better
Placebo better
1.0
1.5
0.5
5.5 yrs2
Risk ratio
Primary endpoints
Non-fatal MI (incl silent) + fatal CHD
Secondary endpoints
Total CV events and procedures
Total coronary events
Non-fatal MI (excl silent) + fatal CHD
All-cause mortality
Cardiovascular mortality
Fatal and non-fatal stroke
Fatal and non-fatal heart failure
Tertiary endpoints
Silent MI
Unstable angina
Chronic stable angina
Peripheral arterial disease
Development of diabetes mellitus
Development of renal impairment
Area of each square is proportional to the amount of statistical information
1. Sever PS, et al. Lancet 2003;361:1149–58; 2. Sever PS, et al. Eur Heart J 2008;29:499–508

92. Mortality and morbidity follow up of
ASCOT-ON and ASCOT-10
Mortality and morbidity follow up of
UK ASCOT patients

93. ASCOT-10 Objectives
 To establish the effect of study interventions on long term mortality and morbidity outcomes for coronary, stroke and other vascular diseases in patients from the ASCOT study, five years after completion of the study.
To ascertain the number of cases of new onset diabetes amongst the study population.
To ascertain, in patients who developed new onset diabetes during the main ASCOT study, whether this is associated with greater vascular morbidity and mortality.
To ascertain whether blood pressure variability during the main ASCOT trial follow up is a predictor of subsequent cardiovascular morbidity and mortality
Primary endpoint CV death + non-fatal MI + non-fatal stroke

94. Cumulative Incidence by Cause of Death ‒ 1
Number at risk
Placebo
Atorvastatin
2288
2317
2191
2228
2052
2091
1208
1226
All-cause mortality
Non-cardiovascular mortality
Cardiovascular mortality
Cancer mortality

95. Cumulative Incidence by Cause of Death ‒ 2
Mortality due to infection
Mortality due to respiratory illness
Mortality due to infection and respiratory illness
Number at risk
Placebo
Atorvastatin
2288
2317
2191
2228
2052
2091
1208
1226

96. Hypertension treatment in the 21st century
ASCOT Legacy

97. Guidelines influenced by ASCOT-LLA
BHS IV and JBS 2
Taskforce of ESH and ESC 2007 and 2009.
Advocate lipid-lowering in primary prevention based on absolute risk assessment
ATP III Update 2004

98. Influence on Blood Pressure Guidelines
The demise of the beta-blocker
ASCOT BPLA
Less protection against stroke
More new onset diabetes
(Higher central aortic blood pressures)
( Increase in BP variability )
(Less effect on LV dysfunction)
Pre-eminence of CCB over thiazide in treatment
strategies
Importance of CCB/ACEI combination

99. 2003 X X X X X 2 Younger (e.g.<55yr) and Non-Black
Older (e.g.55yr) or Black
Step 1 X
A (or B*)
C or D X
Step 2
A (or B*) X +
C or D X
Step 3
A (or B*) X + C + D
Step 4 Resistant Hypertension
Add: either -blocker or spironolactone or other diuretic
A: ACE Inhibitor or angiotensin receptor blocker B: b - blocker C: Calcium Channel Blocker D: Diuretic (thiazide)
* Combination therapy involving B and D may induce more new onset diabetes compared with other combination therapies
Adapted from: ‘Better blood pressure control: how to combine drugs’ Journal of Human Hypertension (2003) 17, 8186

100. Acknowledgment Colleagues Collaborators
Neil Poulter
Simon Thom
Alun Hughes
Neil Chapman
Jamil Mayet
Ajay Gupta
Limmie Chang
Andrew Whitehouse
Judy Mackay
Mike Schachter
Alison Adderkin
and many others
Jill Bunker
Wendy Callister
Nursing team at St Marys
Graham MacGregor
Mark Caulfield
Bryan Williams
Eoin O’Brien
Alice Stanton
Gareth Beevers
Gordon McInnes
David Collier
Naveed Sattar
Peter Rothwell
Nordic ASCOT Investigators
Bjorn Dahlof, Hans Wedel, Jan Ostergren, Marku Niemenen, Sverre Kjeldsen, Arni Kristensson, Jesper Mehlsen
Pfizer Jan Buch, Rachel Laskey, Mogens Westergard