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

http://upload.wikimedia.org/wikipedia/commons/e/e1/St_Mary's_Hospital.jpg

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