treatment of hypertension in the 21 st century sir george pickering lecture peter sever...
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TREATMENT of HYPERTENSION in the 21st CenturySir George Pickering Lecture
Peter SeverInternational Centre for Circulatory Health
Imperial College London
Sir George Pickering
Professor of MedicineSt Mary’s Hospital Medical School 1939
Regius Professor of MedicineOxford 1956
Pickering: “High Blood Pressure” 1955Terminology
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
Platt’s hypothesis-Pickering’s data !
Platt’s hypothesis
Pickering’s data
If Pickering had had access to blood pressure responses to
different classes of antihypertensive drugs, the
unimodality hypothesis would have been much more persuasive
The frequency distribution of changes in diastolic blood pressure (DBP) produced by 3 drugs
0
4
8
12
16
DBP placebo – lisinopril, mmHg
Coun
t
0
4
8
12
16
Coun
t
0
4
8
12
16
Coun
t
20 10 0 -10 -20-30 -40
DBP placebo – atenolol, mmHg
20 10 0 -10 -20 -30 -40
DBP placebo – nifedipine, mmHg
20 10 0 -10 -20 -30 -40
Atwood et al J Hypertens 1994; 12:1053
Treatment of Hypertension
Does the magnitude of response to an antihypertensive drug inform on the mechanism(s) involved in blood pressure elevation ?
Two important observations :
Blood pressure responses to
Spironolactone and toRenal denervation
in subjects with resistant hypertension
Frequency distribution of change in SBP after spironolactone or renal denervation
Mean SBP: -21.87±21.27 mmHg
Decreased Increased
020
4060
8010
012
014
0Fr
eque
ncy
-100 -50 0 50-21.87Change in SBP (mmHg) after Spironolactone
Atenolol & Amlodipine (n=1411)
Mean SBP: -32±23 mmHg
ASCOT The Symplicity HTN 2 Trial
Decreased Increased
05
1015
2025
30Fr
eque
ncy
-100 -50 0 50-32Change in SBP (mmHg) from baseline
Renal Denervation (n=46)
Simulated FD curveBased on reported mean +/-SD in SBP
Chapman et al. Hypertension. 2007 ;49:839-45. Symplicity HTN-2 Investigators. Lancet 2010; 376:1903-09
Placebo corrected SBP response to monotherapy ( ) and dual therapy ( ) meta analysis of 42 trials
Wald DS et al. Am J Med 2009; 122:290-300
Frequency distribution of change in SBP from baseline among ASCOT monotherapy users (untreated at baseline)
Decreased Increased
010
020
030
040
0Fre
quen
cy
-100 -50 0 50-18.81Change in SBP (mmHg) from baseline
Atenolol & Amlodipine (n=3252)
Mean SBP: -18.81±16.93 mmHg
Decreased Increased
050
100
150
200
250
Fre
quen
cy
-100 -50 0 50-17.35Change in SBP (mmHg) from baseline
Atenolol group (n=1568)
Decreased Increased
-100 -50 0 50-20.16Change in SBP (mmHg) from baseline
Amlodipine group (n=1684)
Mean SBP: Atenolol: -17.35±18.36 mmHg; Amlodipine: -20.16±15.37 mmHg
Frequency distribution of change in SBP from baseline among ASCOT monotherapy users (untreated at baseline)
Decreased Increased
050
100
150
200
250
Fre
quen
cy
-100 -50 0 50-17.35Change in SBP (mmHg) from baseline
Atenolol group (n=1568)
Decreased Increased
-100 -50 0 50-20.16Change in SBP (mmHg) from baseline
Amlodipine group (n=1684)
Mean SBP: Atenolol: -17.35±18.36 mmHg; Amlodipine: -20.16±15.37 mmHg
NotePlacebo response from randomised controlled trials in hypertensive subjects estimated to be approx 10mmHg systolic pressure
Frequency distribution of change in SBP after second drug ( BFZ+K or Perindopril) therapy
Decreased Increased
020
4060
8010
012
014
0F
req
uenc
y
-100 -50 0 50-9.24Change in SBP (mmHg) after BFZ+K
Atenolol Arm(n=751)
Decreased Increased
-100 -50 0 50-6.29Change in SBP (mmHg) after Perindopril
Amlodipine Arm (n=815)
Mean SBP: BFZ+K: -9.24 mmHg; Perindopril: -6.29 mmHg
Frequency distribution of change in SBP after third drug (doxazosin) therapy
Decreased Increased
010
020
030
040
050
060
070
080
090
010
00Fr
eque
ncy
-100 -50 0 50-11.68
Change in SBP (mmHg) after doxazosin
Atenolon & Amlodipine (n=10069)
Mean SBP: -11.68±18.81 mmHg
Decreased Increased
010
020
030
040
050
060
0F
requ
ency
-100 -50 0 50-13.38Change in SBP (mmHg) after doxazosin
Atenolol group (n=5787)
Decreased Increased
-100 -50 0 50-9.39Change in SBP (mmHg) after doxazosin
Amlodipine group (n=4282)
Mean SBP: Atenolol group: -13.38±19.89 mmHg; Amlodipine group: -9.39±16.98 mmHg
Frequency distribution of change in SBP after spironolactone therapy
Mean SBP: -21.87±21.27 mmHg
Decreased Increased
020
4060
8010
012
014
0Fr
eque
ncy
-100 -50 0 50-21.87Change in SBP (mmHg) after Spironolactone
Atenolol & Amlodipine (n=1411)
Decreased Increased
020
4060
8010
012
014
0F
requ
ency
-100 -50 0 50-22.99Change in SBP (mmHg) after Spironolactone
Atenolol Arm(n=1061)
Decreased Increased
-100 -50 0 50-18.51Change in SBP (mmHg) after Spironolactone
Amlodipine Arm (n=350)
Mean SBP: Atenolol group: -22.99±21.46 mmHg; Amlodipine group: -18.51±20.33 mmHg
Frequency distribution of change in SBP after spironolactone therapy
Decreased Increased
020
4060
8010
012
014
0F
req
uenc
y
-100 -50 0 50-22.99Change in SBP (mmHg) after Spironolactone
Atenolol Arm(n=1061)
Decreased Increased
-100 -50 0 50-18.51Change in SBP (mmHg) after Spironolactone
Amlodipine Arm (n=350)
Mean SBP: atenolol group: -22.99 mmHg; amlodipine group: -18.51 mmHg
Note greater response in the atenolol/thiazide arm. Effect not influenced by concomitant diuretic use
Blood pressure response to renal denervation: The Symplicity HTN 2 Trial
Symplicity HTN-2 Investigators .Lancet 2010;376:1903-1909
SummaryBlocking 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 ?
Decreased Increased
020
4060
8010
012
014
0Fr
eque
ncy
-100 -50 0 50-21.87Change in SBP (mmHg) after Spironolactone
Atenolol & Amlodipine (n=1411)
Spiro
Denervation
Decreased Increased
05
1015
2025
30Fr
eque
ncy
-100 -50 0 50-32Change in SBP (mmHg) from baseline
Renal Denervation (n=46)
Denervation
,
Resistant hypertension : Haemodynamics
After Brown M. BHS Guideline on Resistant Hypertension ( unpublished)
,
Resistant hypertension :Key features
Muscle sympathetic nerve activityand increasing blood pressure
Grassi G et al. Exp Physiol 2010;95:581-586
normotensive
mild-moderatehypertensive
severeBlunted natriuresis
Increased extracellular volume
Activation of RAAS
Increased renal sympathetic nerve activity
Increased sodium reabsorption
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
Spironolactoneactions 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
Spironolactone
Renal denervation
• Blocks renal efferent sympathetic nerve activity
• Blocks renal afferent nerve activity
• Induces substantial sodium and water loss
Intrauterineprogramming
Mosaic 2011Environmental
eg Salt
Renal
Anatomical
Adaptive
NeuralEndocrine
Humoral
Haemodynamics
Genetic
BP
Modified from Page 1959
Implication of these observations in resistant hypertension to pathophysiology of “essential” hypertension
Linkage of dietary salt and the CNS to elevated blood pressure
Interaction hypothesis supported by:-Experimental models of hypertension
- SHR and salt loading Koepke et al.Hypertension 1985; 7: 357-363
- DOCA salt model and stress Koepke et al. Am J Physiol. 1986; 251: R289-294
- 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: 519-524.
Stress, sodium retention and BP elevation in normotensive human subjects with family history of hypertension Light et al.Science 1983: 220: 429-43
Linked to genetic polymorphism of the alpha 2 adrenoceptor
Finlay et al. J. Appl Phys 2004; 96: 2231-2239
Longitudinal migration study Poulter et al. BMJ. 1990 Apr 14;300: 967-72
Kenyan Luo Migration Study modified from Poulter et al. BMJ. 1990 Apr 14;300: 967-72
SBP levels at 0-24 months130
120
110
1000 3 6 12 18 24 months
Males
Mean pre-migration blood pressure
DBP levels at 0-24 months
70
60
500 3 6 12 18 24 months
Mean pre-migration blood pressure
migrants
non-migrants
migrants
non-migrants
mmHg
mmHg
Sever et alIn Concepts in hypertensionSpringer-Verlag1989 p 55-66
Body weight, pulse and urinary NaK ratios at 0-24 months
0 3 6 12 18 24 0 3 6 12 18 24 0 3 6 12 18 24
0 3 6 12 18 240 3 6 12 18 240 3 6 12 18 24
54.0
57.5
61.0 75
69
63 2.0
3.5
5.0
5.0
3.5
2.063
69
75
54.0
57.5
61.0
Migrants Controls
Males
Females
Body weight (kg) Pulse (bpm) Urinary NaK ratio
Body weight (kg) Pulse (bpm) Urinary NaK ratio
Poulter et al. BMJ. 1990 Apr 14;300: 967-72
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
Renal genotype(s)-influence tubular reabsorption of sodium and/or renal afferent nerve responses to sodium load
Neuronal genotype (s) -influences neuronal responses to plasma/CSF sodium
*Impaired if prevented by:
Angiotensin IIRenal sympathetic nerve activityAldosteroneReduced renal mass
Guyton hypothesis
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.
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.
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
Hypertension treatment
The ASCOT Legacy
Hypertension treatment
The ASCOT Legacy
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
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
ASCOT: Study design
atenolol ± bendroflumethiazide
amlodipine ± perindopril
19,257 hypertensive
patients
PROBE design
ASCOT-BPLA stopped after 5.5 yrs
Investigator-led, multinational randomised controlled trial
placeboatorvastatin 10 mg Double-blind
ASCOT-LLA stopped after 3.3 yrs
10,305 patientsTC ≤ 6.5 mmol/L (250 mg/dL)
Sever et al J. Hypertension. 2001;19:1139
Lipid-lowering armLipid-lowering arm
0
1
2
3
4
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Years
Cu
mu
lati
ve
Inc
ide
nc
e (
%)
36% reduction
ASCOT-LLA : Nonfatal MI and Fatal CHD
HR = 0.64 (0.50-0.83)
Atorvastatin 10 mg Number of events 100
Placebo Number of events 154
p=0.0005
Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
Relative risk reductions independent of baseline cholesterol
Censoring Time
Risk Reduction Event Rate
(%) Atorvastatin Placebo
83 2.4 14.2
67 5.5 16.6
48 7.5 14.3
45 6.6 12.0
38 5.9 9.5
36 6.0 9.4
Hazard Ratios (95% CI)
Atorvastatin better Placebo better
30 days
90 days
180 days
1 Year
2 Years
End of Study
ASCOT-LLA CHD events :early benefits
*
* Per 1000 patient years
Hazard Ratio
0.64 (0.50-0.83)
0.79 (0.69-0.90)0.71 (0.59-0.86)0.62 (0.47-0.81)0.87 (0.71-1.06)0.90 (0.66-1.23)0.73 (0.56-0.96)1.13 (0.73-1.78)
0.82 (0.40-1.66)0.87 (0.49-1.57)0.59 (0.38-0.90)1.02 (0.66-1.57)1.15 (0.91-1.44)1.29 (0.76-2.19)
ASCOT-LLASummary 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 PointsNonfatal MI (incl silent) + fatal CHD
Secondary End PointsTotal CV events and proceduresTotal coronary eventsNonfatal MI (excl silent) + fatal CHDAll-cause mortalityCardiovascular mortalityFatal and nonfatal strokeFatal and nonfatal heart failure
Tertiary End PointsSilent MIUnstable anginaChronic stable anginaPeripheral arterial diseaseDevelopment of diabetes mellitusDevelopment of renal impairment
Risk Ratio
Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
Blood Pressure-lowering armBlood Pressure-lowering arm
ASCOT BPLA Summary of all end points
The area of the blue square is proportional to the amount of statistical information
Amlodipine perindopril better Atenolol thiazide better0.50 0.70 1.00 1.45
Primary Non-fatal MI (incl silent) + fatal CHD
SecondaryNon-fatal MI (exc. Silent) +fatal CHDTotal coronary end pointTotal CV event and proceduresAll-cause mortalityCardiovascular mortalityFatal and non-fatal strokeFatal and non-fatal heart failure
Tertiary Silent MIUnstable anginaChronic stable anginaPeripheral arterial diseaseLife-threatening arrhythmiasNew-onset diabetes mellitusNew-onset renal impairment
Post hoc Primary end point + coronary revasc procsCV death + MI + stroke
2.00
Unadjusted Hazard ratio (95% CI)
0.90 (0.79-1.02)
0.87 (0.76-1.00)0.87 (0.79-0.96)0.84 (0.78-0.90)0.89 (0.81-0.99)0.76 (0.65-0.90)0.77 (0.66-0.89)0.84 (0.66-1.05)
1.27 (0.80-2.00)0.68 (0.51-0.92)0.98 (0.81-1.19)0.65 (0.52-0.81)1.07 (0.62-1.85)0.70 (0.63-.078)0.85 (0.75-0.97)
0.86 (0.77-0.96)0.84 (0.76-0.92)
Synergy of atorvastatin and amlodipine based treatment arm
Synergy of atorvastatin and amlodipine based treatment arm
ASCOT-LLA 2x2 analyses
Benefits of atorvastatin according to BP lowering strategy
Primary endpoint: Non-fatal MI and fatal CHD
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.50.0
1.0
2.0
3.0
4.0
Years
Cum
ula
tive
inci
denc
e (%
)
Atorvastatin
Placebo53%
Amlodipine-based treatment
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.50.0
1.0
2.0
3.0
4.0
Years
Cum
ula
tive
inci
denc
e (%
)
Atorvastatin
Placebo 16%
Atenolol-based treatment
HR=0.84 (0.60 - 1.17) p=0.30
HR=0.47 (0.32 - 0.69) p<0.001
P for interaction = 0.017
Sever, Poulter, Dahlof, Wedel. Europ.Heart Journal. 2006;27:2982
LLA and BPLA
Combined benefits of lipid- and blood pressure- lowering
LLA and BPLA
Combined benefits of lipid- and blood pressure- 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%
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.2009. Feb 18, epub ahead of print
A molecular mechanism for synergy A molecular mechanism for synergy
Clunn GF, Sever,P, Hughes A. Int J Cardiol 2009 Jun 10 [Epub ahead of print]Clunn GF, Sever,P, Hughes A. Int J Cardiol 2009 Jun 10 [Epub ahead of print]
Macrophage
Cytokine release
Foam cells
SMC dedifferentiationto synthetic phenotype
SMCmigration
andproliferation
SMC = smooth muscle cell
Destructionof intercellular
matrix
Apoptosis
Lipid-ladenmacrophage
MMPs
MMP = matrix metalloproteinase
Plaque rupture
SMC DEDIFFERENTIATION
Contractile phenotype Synthetic phenotype
L-type VOC
• CCBs effective
Loss offunctionality
of L-type VOC
• CCBs ineffective
Presence of statins leads to growth arrest
and re-expressionof functioningL-type VOCs
Ca2+CCB
Clunn GF, Sever P, Hughes A. Int J Cardiol 2009 Jun 10 [Epub ahead of print]
CCB = calcium channel blocker
VOC = voltage-operated Ca2+ channel
An additional mechanism?
SMC: reversion to a more differentiated phenotype
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
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
Effect of atorvastatin on carotid systolic pressure in those assigned amlodipine- or atenolol- based treatment in ASCOTAplanation 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 atorvastatinManisty C, Mayet J, Tapp R, Sever P et al. Hypertension 2009:54; e-pub online Aug 31
Lipid-lowering arm
The relationship Between statin therapy andthe progression of renal damage
Lipid-lowering arm
The relationship Between statin therapy andthe progression of renal damage
www.ascotstudy.org
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 ?
www.ascotstudy.org
Mean eGFR During Follow-up in the ASCOT-LLA, Stratified by Allocated Treatment
6870
7274
Mea
n eG
FR
(95
% C
I),
mL/
min
/1.7
3 m
2
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 69.5Aten-based & Atorvastatin: 68.9 67.9 68.0 68.8 70.0Amlo-based & Placebo: 69.9 70.8 71.1 72.2 73.2Amlo-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
Blood Pressure-lowering arm
Substudies
Blood Pressure-lowering arm
Substudies
CAFÉ Study: Methods
• Radial artery waveforms measured via noninvasive applanation tonometry
• Augmentation index (AIx) defined as ratio of augmentation to central pulse pressure: Alx = (∆ P/PP) × 100
CAFE Investigators. Circulation. 2006;113: epublished Feb 13, 2006.ED = ejection duration
Pressure(mm Hg)
∆ PSPP1
DPIncisura
Time (msec)ED
CAFE: Lower central aortic BP with newer vs older antihypertensive regimen despite similar
brachial BP
Amlodipine ± perindoprilAtenolol ± bendroflumethiazide
140
135
130
125
120
1150 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 AUC
Time (years)
mm Hg
Brachial SBP
Central aortic SBP
CAFE Investigators. Circulation. 2006;113: epublished Feb 13, 2006.
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 <0.001
Tissue Doppler Systolic velocity (S), cm/s′ 8.2 ± 1.75 9.5 ± 2.21 <0.001
Early diastolic velocity (E ), cm/s′ 7.91 ± 1.84 8.76 ± 2.04 <0.001
Late diastolic velocity (A ), cm/s′ 10.76 ± 2.15 12.34 ± 2.31 <0.001
*Mean E/E ratio′ 8.14 ± 2.38 7.76 ± 2.05 0.013 *BNP, pg/ml 37 (20–56) 19 (10–34) <0.001
ASCOT Study of LV diastolic function : Treatment effects at I year
Tapp et al J Am Coll Cardiol. 2010 Apr 27;55(17):1875-81
* Both independent predictors of cardiac events
Early diastolic velocity (E`)( measure of diastolic relaxation) lower on atenolol, and left ventricular filling pressure (E/E`) and BNP higher on atenolol
Blood Pressure VariabilityBlood Pressure Variability
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.
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
164/96159/92150/92
164/90168/94158/94
156/88148/86159/86
170/92166/88174/88
Within visit variability
Between visit or visit-visit variability
173/90169/89174/96
Stroke risk Coronary riskMean SBP
Visit-to-visit mean systolic blood pressure expressed in deciles, hazard ratios (95% CI) and number of stroke and
coronary events in each decile
Variation independent of mean SBP
Coefficient of variation of SBP
Stroke and coronary risk expressed by decile of measure of visit-to-visit SBP variability
Standard deviation of SBP
Atenolol
Amlodipine
Stroke Risk Coronary Risk
Decile of measure Decile of measure
Group distribution (SD and CV) of measures of SBP at baseline and at each follow-up visit in the
two treatment groups
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 0.96 (0.82–1.12) 0.58
Within-visit and visit-to-visit BP variability
Rx + within-visit SD 0.84 (0.72–0.98) 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
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
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 1.00 (0.90–1.11) 0.99
Rx + mean + VIM 1.00 (0.90–1.10) 0.99
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
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
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
Biomarkers and cardiovascular risk predictionBiomarkers and cardiovascular risk prediction
Biomarkers
Inflammation
CRP,IL6,LpPLA2,neopterin
Lipids
ApoA,ApoB1,Lp(a)
Metabolic
proinsulin,insulin,adiponectin,
fructosamine
Thrombosis
aPAF, aPC
Current hot biomarkers
NT-proBNP, cystatin C
Others
cortisol, urate, renin, aldo, CFH,GDF 15
Vascular
ADMA, t-PA, ICAM-1
ASCOT Biomarker Programme: Although both these biomarkers independently predict risk of future cardiovascular events in the ASCOT Trial of 19342 hypertensive subjects, Nt-proBNP is the only one which has predictive ability beyond classical risk factors (Net reclassification improvement 11.8%)
Per 1 SD increase log Nt-BNP 451 1265 1.30 <0.0001
Tertile 1 :<57 128 441 1 (ref) <0.0006 Tertile 2 :58-141 141 438 1.17 0.30
Tertile 3: >141 182 338 1.70 0.0007
Baseline CRP and Risk of CV Events
Per 1 SD increase log CRP 452 1269 1.19 0.006
Tertile 1 CRP: <1.74mg/L 131 448 1 (ref) 0.05
Tertile 2 CRP: 1.74-4.09mg/L 153 417 1.25 0.14
Tertile 3 CRP: >4.09mg/L 168 404 1.35 0.05
1 1.5 2
Baseline Nt-BNP and Risk of CV Events
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
Odds ratio and 95% CI (log scale)
Odds ratio 95% CI
0.5 1.0 1.5 2.0
Sever et al Europ Heart J 2011 epub July 28
Lipid-lowering arm
The LLA Extension
Lipid-lowering arm
The LLA Extension
Changes in total cholesterol over time
0.0 1.0 2.0 3.0 4.0 5.0 FinalVisitYears
4.0
4.2
4.4
4.6
4.8
5.0
5.2
5.4
5.6mmol/L
160
170
180
190
200
210
mg/Dl
AtorvastatinPlacebo
Source data: Listing 5.3 Date of Reporting Dataset Creation: 06FEB2003 Date of Figure Generation: 27APR2006 (15:31)
Program: LLAXFig53I.sas
Figure 5.3.2AML NY 96 008: Anglo Scandinavian Cardiac Outcomes trial (ASCOT)
Change in Total Cholesterol Over Time(All LLA Subjects Followed to Final Visit)
0.0 1.0 2.0 3.0 4.0 5.0 FinalVisitYears
4.0
4.2
4.4
4.6
4.8
5.0
5.2
5.4
5.6mmol/L
160
170
180
190
200
210
mg/Dl
AtorvastatinPlacebo
Source data: Listing 5.3 Date of Reporting Dataset Creation: 06FEB2003 Date of Figure Generation: 27APR2006 (15:31)
Program: LLAXFig53I.sas
Figure 5.3.2AML NY 96 008: Anglo Scandinavian Cardiac Outcomes trial (ASCOT)
Change in Total Cholesterol Over Time(All LLA Subjects Followed to Final Visit)
0.0 1.0 2.0 3.0 4.0 5.0 FinalVisitYears
4.0
4.2
4.4
4.6
4.8
5.0
5.2
5.4
5.6mmol/L
160
170
180
190
200
210
mg/Dl
AtorvastatinPlacebo
Source data: Listing 5.3 Date of Reporting Dataset Creation: 06FEB2003 Date of Figure Generation: 27APR2006 (15:31)Program: LLAXFig53I.sas
Figure 5.3.2AML NY 96 008: Anglo Scandinavian Cardiac Outcomes trial (ASCOT)
Change in Total Cholesterol Over Time(All LLA Subjects Followed to Final Visit)
mmol/L
AtorvastatinPlacebo
mg/DlEnd of LLA
60% + of patients in both arms now on statins
End ofBPLA
Sever PS, et al. Eur Heart J 2008;29:499–508
ASCOT-LLA endpoints
Area of each square is proportional to the amount of statistical information
Primary endpointsNon-fatal MI (incl silent) + fatal
CHDSecondary endpoints
Total CV events and proceduresTotal coronary eventsNon-fatal MI (excl silent) + fatal CHDAll-cause mortalityCardiovascular mortalityFatal and non-fatal strokeFatal and non-fatal heart failureTertiary endpointsSilent
MIUnstable anginaChronic stable anginaPeripheral arterial diseaseDevelopment of diabetes mellitusDevelopment of renal impairment Atorvastatin better Placebo better
1.0 1.50.5
5.5 yrs2
Risk ratio
0.5 1.0 1.5
3.3 yrs1 Risk ratio
Atorvastatin better Placebo better
1. Sever PS, et al. Lancet 2003;361:1149–58; 2. Sever PS, et al. Eur Heart J 2008;29:499–508
ASCOT-ON and ASCOT-10
Mortality and morbidity follow up of UK ASCOT patients
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
Cumulative Incidence by Cause of Death ‒ 1
Number at risk
PlaceboAtorvastatin
22882317
21912228
20522091
12081226
22882317
21912228
20522091
12081226
22882317
21912228
20522091
12081226
22882317
21912228
20522091
12081226
All-cause mortality Non-cardiovascular mortality Cardiovascular mortality Cancer mortality
Cumulative Incidence by Cause of Death ‒ 2Mortality due to
infection Mortality due to
respiratory illnessMortality due to infection
and respiratory illness
Number at risk
PlaceboAtorvastatin
22882317
21912228
20522091
12081226
22882317
21912228
20522091
12081226
22882317
21912228
20522091
12081226
www.ascotstudy.org96
Hypertension treatment in the 21st century
ASCOT Legacy
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
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
2
Younger (e.g.<55yr)and Non-Black
Older (e.g.55yr) or Black
Step 1
Step 2
Step 3
Step 4Resistant Hypertension
Add: either -blocker or spironolactone or other diuretic
A: ACE Inhibitor or angiotensin receptor blocker B: b - blockerC: Calcium Channel Blocker D: Diuretic (thiazide)
A (or B*)
A (or B*)
A (or B*) C or D
C or D +
+ +C D
Adapted from: ‘Better blood pressure control: how to combine drugs’ Journal of Human Hypertension (2003) 17, 8186
* Combination therapy involving B and D may induce more new onset diabetes compared with other combination therapies
2003
X
X
X
X
X
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