B.Dahlof (Co-chair), P.Sever (Co-chair), N. Poulter (Secretary) H. Wedel (Statistician), G. Beevers, M. Caulfield, R. Collins S. Kjeldsen, A. Kristinsson,

B.Dahlof (Co-chair), P.Sever (Co-chair), N. Poulter (Secretary) H. Wedel (Statistician), G. Beevers, M. Caulfield, R. Collins

S. Kjeldsen, A. Kristinsson, J. Mehlsen, G. McInnes, M. Nieminen E. O’Brien, J. Östergren, on behalf of the ASCOT Investigators

A randomised controlled trial of the prevention of CHD and other vascular events by BP and

cholesterol lowering in a factorial study design

ASCOT- BPLA: Rationale

• Insufficient outcome data on newer types of BP-lowering agents, especially in specific combination treatment regimens

• Less-than-expected CHD prevention using standard therapy

ASCOT- BPLA

To compare the effect on non-fatal myocardial infarction (MI) and fatal

CHD of the standard antihypertensive regimen (-blocker ± diuretic) with a more

contemporary regimen (CCB ± ACE inhibitor)

Primary Objective

Additional objectives include:Secondary end points• Total stroke• All coronary events• Primary end point minus

silent MI• Total cardiovascular (CV)

events and procedures• CV mortality• All-cause mortality• Heart failure

Tertiary end points• Development of diabetes• Impairment of renal function• Pre-specified end points in

pre-specified subgroups• Life-threatening arrhythmias

Other objectives• Interaction between statins

and antihypertensive treatment

• Health economic analyses

Study design

atenolol ± bendroflumethiazide

amlodipine ± perindopril

19,257 hypertensive

patients

PROBE design

ASCOT-BPLA

Investigator-led, multinational randomised controlled trial

placeboatorvastatin 10 mg Double-blind

ASCOT-LLA10,305 patients

TC ≤ 6.5 mmol/L (250 mg/dL)

Treatment algorithm to BP targets < 140/90 mm Hg or < 130/80 mm Hg in patients with diabetes

amlodipine 5-10 mg atenolol 50-100 mg

perindopril 4-8 mgbendroflumethiazide-K

1.25-2.5 mg

doxazosin GITS 4-8 mg

add

add add

additional drugs, eg, moxonidine/spironolactone

add

Patient inclusion criteria

• Screening and baseline BP

160/100 mm Hg untreated

140/90 mm Hg following treatment with 1 or more drugs

• Age 40-79 years

• No previous MI or current clinical CHD

• 3 or more CV risk factors

Study power and recruitment (Feb 1998-May 2000)

15671567

2382238222262226

39843984

90989098

Relative additional benefit (ITT) 16%

Significance level 5%

Power 80%

Estimated sample size 18,000

Persons with events 1150

TOTAL RECRUITED 19,257

POWER: PRIMARY END POINT

Baseline characteristics amlodipine perindopril atenolol thiazide

Demographics and clinical characteristics n = 9639 n = 9618 Woman 2258 (23.4%) 2257 (23.5%) White 9187 (95.3%) 9170 (95.3%) Current smoker 3168 (32.9%) 3110 (32.3%) Age (years) 63.0 (8.5) 63.0 (8.5) SBP (mm Hg) 164.1 (18.1) 163.9 (18.0) DBP (mm Hg) 94.8 (10.4) 94.5 (10.4) Heart rate (bpm) 71.9 (12.7) 71.8 (12.6) BMI (kg/m2) 28.7 (4.6) 28.7 (4.5)

Drug therapy Previous antihypertensive treatments 0 1841 (19.1%) 1825 (19.0%) 1 4280 (44.4%) 4283 (44.5%) ≥ 2 3518 (36.5%) 3510 (36.5%) Lipid-lowering therapy 1046 (10.9%) 1004 (10.4%) Aspirin 1851 (19.2%) 1837 (19.1%)

Values are number of patients, (%) or mean (SD)

Data safety monitoring board (DSMB)

In October 2004 the DSMB recommended that the BP

arm of ASCOT should be stopped on account of

concerns that those patients receiving atenolol

thiazide would continue to be disadvantaged compared

with the comparator group

The Steering Committee endorsed the recommendation

of the DSMB, and trial closure began Dec, 2004 and

ended June 2005.

Statistical methods

• Based on an intention-to-treat analysis

• Time to first primary event

• Log-rank procedure and Cox’s Proportional Hazards were used to calculate confidence intervals

• Cumulative incidence curves were generated using the Kaplan-Meier method

Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

All patients in ASCOT have hypertension plus ≥ 3 risk factors for CHD

Patients with risk factor (%)

0 10 20 30 40 50 60 70 80 90 100

Hypertension

Age ≥ 55 years

Male

Microalbuminuria/proteinuria

Smoker

Family history of CHD

Plasma TC:HDL-C ≥ 6

Type 2 diabetes

Certain ECG abnormalities

LVH

Previous cerebrovascular events

Peripheral vascular disease

84

77

61

30

27

24

24

14

13

11

6

ASCOT patient population risk factor profile

100

trial design19,342 randomised to

antihypertensive therapy

85 excluded before end of study due to irregularities

9,639 assigned and received amlodipine

perindopril

9,618 assigned and received atenolol

thiazide

121 with incomplete information• 81 alive at last visit• 24 withdrawn consent• 16 lost to follow-up

171 with incomplete information• 102 alive at last visit• 36 withdrawn consent• 33 lost to follow-up

• 9639 assessed for primary endpoint on intention-to-treat basis

• 9,518 with complete information (8,780 alive 738 dead)

• 9618 assessed for primary endpoint on an intention-to-treat basis

• 9,447 with complete information ( 8,627 alive 820 dead)

19,257 randomised

Systolic and diastolic blood pressure

mm

Hg

60

80

100

120

140

160

180

Time (years)

Baseline 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5

atenolol thiazide amlodipine perindopril

137.7

136.1

79.2

77.4

Mean difference 1.9

Last visit

Mean difference 2.7

SBP

DBP

163.9

164.1

94.8

94.5

Mean proportion of time on antihypertensive medication by treatment group

Year 1 All Study

Randomised to Amlodipine

Amlodipine 88.2 82.5

Perindopril 46.2 58.5

Amlodipine + perindopril 39.1 49.5

Randomised to atenolol

Atenolol 87.4 79.4

Bendroflumethiazide 56.6 65.7

Atenolol + bendroflumethiazide 49.1 54.9

Number at riskAmlodipine perindopril 9639 9475 9337 9168 8966 7863Atenolol thiazide 9618 9470 9290 9083 8858 7743

0.0 1.0 2.0 3.0 4.0 5.0Years0.0

1.0

2.0

3.0

4.0

5.0

HR = 0.90 (0.79 1.02)p = 0.1052

Atenolol thiazide(No. of events =474)

Amlodipine perindopril(No. of events = 429)

%

Primary end point: Non-fatal MI, fatal CHD

Endpoints: Non-fatal MI (excl silent) + fatal CHD


0.0 1.0 2.0 3.0 4.0 5.0Years0.0

1.0

2.0

3.0

4.0

5.0

HR = 0.87 (0.76 1.00)p = 0.0458

Atenolol thiazide(No. of events 444)

Amlodipine perindopril(No. of events 390)

%

Primary end point + coronaryrevascularisation procedures


%

0.0 1.0 2.0 3.0 4.0 5.0 Years0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

HR = 0.86 (0.77 0.96)p = 0.0058



8.0


Years0.0 1.0 2.0 3.0 4.0 5.0

0.0

2.0

4.0

6.0

8.0

10.0



HR = 0.87 (0.79 0.96)p = 0.0070

%

Total coronary end point

Fatal and non-fatal stroke


0.0 1.0 2.0 3.0 4.0 5.0 Years0.0

1.0

2.0

3.0

4.0

5.0



HR = 0.77 (0.66 0.89)p = 0.0003

%

Total CV events and procedures


0.0 1.0 2.0 3.0 4.0 5.0 Years

0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

16.0

18.0



HR = 0.84 (0.78 0.90)p < 0.0001

%

CV mortality


0.0 1.0 2.0 3.0 4.0 5.0 Years0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5



HR = 0.76 (0.65 0.90)p = 0.0010

%

All-cause mortality


0.0 1.0 2.0 3.0 4.0 5.0 Years0.0

2.0

4.0

6.0

8.0

10.0

HR = 0.89 (0.81 0.99)p = 0.0247

%



Fatal and non-fatal heart failure


0.0 1.0 2.0 3.0 4.0 5.00.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

HR = 0.84 (0.66 1.05)p = 0.1257



%

Years

1.8

Unstable angina


0.0 1.0 2.0 3.0 4.0 5.00.0

0.2

0.4

0.6

0.8

1.0

1.2

HR = 0.68 (0.51 0.92)p = 0.0115

%



Years

Chronic stable angina

0.0 1.0 2.0 3.0 4.0 5.0

0.0

0.5

1.0

1.5

2.0

2.5

HR = 0.98 (0.81 1.19)p = 0.8323

%

YearsNumber at riskAmlodipine perindopril 9639 9493 9350 9198 9017 7917Atenolol thiazide 9618 9482 9327 9135 8924 7817


Atenolol thiazide(No. of events = 208)

Peripheral arterial disease

0.0 1.0 2.0 3.0 4.0 5.00.0

0.5

1.0

1.5

2.0

2.5

HR = 0.65 (0.52 0.81)p = 0.0001

Number at riskAmlodipine perindopril 9639 9523 9382 9237 9070 7958 Atenolol thiazide 9618 9495 9348 9163 8958 7828

%

Years



Life-threatening arrhythmias

0.0 1.0 2.0 3.0 4.0 5.0 Years0.0

0.1

0.2

0.3

HR = 1.07 (0.62 1.85)p = 0.8009




%

New-onset renal impairment


HR = 0.85 (0.75 0.97)p = 0.0187

0.0 1.0 2.0 3.0 4.0 5.0 Years0.0

1.0

3.0

4.0

5.0%

2.0



New-onset diabetes mellitus


0.0 1.0 2.0 3.0 4.0 5.0 Years0.0

2.0

4.0

6.0

8.0

10.0



HR = 0.70 (0.63 0.78)p < 0.0001

%

CV death + MI + stroke

0.0 1.0 2.0 3.0 4.0 5.0 Years0.00.0

2.0

4.0

6.0

8.0

10.0



HR = 0.840 (0.76 0.92)p < 0.0003


%

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)

Total CV events and procedures among subgroups

0.60 0.70 0.80 0.90 1.00 1.50

The area of the black square is proportional to the amount of statistical information

Amlodipine perindopril better Atenolol thiazide better

DiabetesNo diabetes

Current smokerNon-current smoker

ObeseNon-obese

Older (>60 years)Younger (≤60 years)

FemaleMale

LVH according to ECG or ECHONo LVH according to ECG or ECHO

Previous vascular diseaseNo previous vascular disease

Renal dysfunctionNo renal dysfunction

With metabolic syndromeWithout metabolic syndrome

All patients

Total CV events and procedures among subgroups

0.60 0.70 0.80 0.90 1.00 1.50

The area of the black square is proportional to the amount of statistical information

Amlodipine perindopril better Atenolol thiazide better

DiabetesNo diabetes

Current smokerNon-current smoker

ObeseNon-obese

Older (>60 years)Younger (≤60 years)

FemaleMale

LVH according to ECG or ECHONo LVH according to ECG or ECHO

Previous vascular diseaseNo previous vascular disease

Renal dysfunctionNo renal dysfunction

With metabolic syndromeWithout metabolic syndrome

All patients

p value

0.0283<0.0001

0.00010.0030

0.0162<0.0001

<0.00010.0227

0.00150.0001

0.0056<0.0001

0.00190.0001

<0.00010.0055

0.00150.0002

<0.0001

Heterogeneity p

0.5205

0.1138

0.6753

0.7816

0.2889

0.6364

0.4863

0.7130

0.9417

Adverse events leading to treatment discontinuation

Adverse eventAmlodipine perindopril

(%)

Atenolol thiazide(%)

Total 2358 (24.5) 2402 (25.0)

Serious 162 (1.7) 254 (2.6)*

* p<0.0001

Adverse events

Adverse event* Amlodipine perindopril

n (%)

Atenolol thiazide n

(%)p-value

Bradycardia 34 (0.4) 536 (6) <0.0001

Chest pain 740 (8) 849 (9) 0.0040

Cough 1859 (19) 782 (8) <0.0001

Diarrhoea 377 (4) 548 (6) <0.0001

Dizziness 1183 (12) 1555 (16) <0.0001

Dyspnoea 599 (6) 987 (10) <0.0001

Eczema 493 (5) 383 (4) 0.0002

Erectile dysfunction 556 (6) 707 (7) <0.0001

Fatigue 782 (8) 1556 (16) <0.0001

Joint swelling 1371 (14) 308 (3) <0.0001

Lethargy 202 (2) 525 (6) <0.0001

Oedema peripheral 2188 (23) 588 (6) <0.0001

Peripheral coldness 81 (1) 579 (6) <0.0001

Vertigo 642 (7) 745 (8) 0.0039

* Adverse events with incidence >5% and difference of more than 1%

ASCOT CommitteesExecutive and Writing CommitteeB Dahlöf, Co-Chairman, Gothenburg, P Sever, Co-Chairman, London, N Poulter, Secretary, London, H Wedel, Statistician, Gothenburg.

Steering CommitteeA Adderkin, London, DG Beevers, Birmingham, J Buch, New York (non-voting), M Caulfield, London, R Collins, Oxford, B Dahlöf, Gothenburg, A Jarl, Stockholm (non-voting), SE Kjeldsen, Oslo, A Kristinsson, Reykjavik, J Mehlsen, Copenhagen, G McInnes, Glasgow, M Nieminen, Helsinki, N Poulter, London, E O'Brien, Dublin, P Sever, London, H Wedel, Gothenburg, J Östergren, Stockholm, Servier representative, Paris (non-voting).

Working GroupA Adderkin, London, J Buch, New York, S Cavanaugh (up to 2003), New York, R Chamberlain, New York, B Dahlöf, Gothenburg, S Gee, London, A Holmner, Gothenburg, A Jarl, Stockholm, N Poulter, London, P Sever, London, H Wedel, Gothenburg.

Data Safety Monitoring BoardJ Cohn, Minneapolis, L Erhardt, Malmö, K Fox, London, A Oden, Gothenburg, S Pocock, London, J Tuomilehto, Helsinki. Endpoint CommitteeU Dahlström, Linköping, F Fyhrquist, Helsinki, H Hemingway, London, K Midtbo, Oslo.

Substudy CommitteeM Caulfield, London, B Dahlöf, Gothenburg, T Kahan, Stockholm, J Mehlsen, Copenhagen, M Nieminen, Helsinki, E O'Brien, Dublin, I Os, Oslo, N Poulter, London, P Sever, London, S Thom, London.

Possible explanations for the observed differences in outcomes

• Better BP lowering with amlodipine perindopril

• Non-BP-lowering benefits of amlodipine perindopril

• Non-BP-related disadvantages of atenolol thiazide

• Adverse interaction between atenolol thiazide and statin

• Beneficial interaction between amlodipine perindopril and statin

Variables which differed significantly (baseline - final visit) between treatment regimens

Mean differences (Amlodipine

perindopril - Atenolol thiazide)

Changes baseline to final visit

p-valueSystolic BP (mm Hg) -1.78 <0.0001Diastolic BP (mm Hg) -2.05 <0.0001Heart rate (bpm) 11.12 <0.0001Weight (kg) -0.79 <0.0001HDL-cholesterol (mmol/L) 0.11 <0.0001Triglycerides (mmol/L) -0.23 <0.0001Glucose (mmol/L) -0.20 <0.0001Creatinine (µmol/L) -5.06 <0.0001Potassium (mmol/L) 0.05 <0.0001

Endpoints evaluated

1. Primary endpoint + coronary revascularisation (coronary events)

2. Non-fatal and fatal stroke

Rationale

• Significantly different rates

• Potentially different mechanisms

• Sufficient power

The role of BP differences?Methods

• Temporal association

• Serial mean matching

• Updated Cox regression adjustment

Which BP measure?

• SBP

• DBP

• MBP - [(SBP + DBP) / 2]

• Pulse pressure

When?

• Latest

• One year recurrent average

• Accumulated mean

Differences in coronary event rates and in BP over time

Time interval Accumulated differences (mmHg) Atenolol thiazide - Amlodipine perindopril

SBP DBP

0-6 months 4.95 1.72

0.5 - 1 year 4.03 1.99

1 - 2 years 2.62 1.89

2 - 3 years 2.02 1.76

3 - 4 years 1.85 1.88

4 - 5 years 1.62 1.88

> 5 years 1.55 1.78

All study 2.76 1.91

0.500.25 0.70 1.00 1.45 2.00 2.85Hazard ratio

Amlodipine perindopril better

Atenolol thiazide better


SBP DBP

0-6 months 4.95 1.72

0 - 1 year 4.51 1.86

0 - 2 years 3.67 1.89

0 - 3 years 3.24 1.87

0 - 4 years 3.01 1.89

0 - 5 years 2.85 1.91

All study 2.76 1.91

0.500.25 0.70 1.00 1.45 2.00 2.85



Hazard ratio

Differences in stroke event rates and in BP over time


SBP DBP

0-6 months 4.95 1.72

0.5 - 1 year 4.03 1.99

1 - 2 years 2.62 1.89

2 - 3 years 2.02 1.76

3 - 4 years 1.85 1.88

4 - 5 years 1.62 1.88

> 5 years 1.55 1.77

All study 2.76 1.91

Time intervalAccumulated differences (mmHg)

Atenolol thiazide - Amlodipine perindopril

SBP DBP

0-6 months 4.95 1.72

0 - 1 year 4.51 1.86

0 - 2 years 3.67 1.89

0 - 3 years 3.24 1.87

0 - 4 years 3.01 1.89

0 - 5 years 2.85 1.91

All study 2.76 1.91

0.500.25 0.70 1.00 1.45 2.00 2.85



Hazard ratio

0.500.25 0.70 1.00 1.45 2.00 2.85Hazard ratio



Serial mean matching: Methods

SBP

%

• Take Amlodipine ± perindopril cohort at each of five time points plus baseline

Amlodipine ± perindopril (all patients)

• Select “atenolol ± thiazide” person closest to mean after randomisation

Mean

• Add others sequentially to maintain group SBP matching

Atenolol ± thiazide matched subsetNB: n> 7500 (86%)

• Maximum mean SBP group difference = 0.02 mm Hg

• 9% of coronary events and 14% of stroke events excluded

• Multiple Cox regression - adjusted HR in 6 periods

• Further adjustment for age and number of risk factors

Serial mean matching: Results

Hazard ratio unadjusted

Pooled hazard ratio SMM adjusted

p-value

for adjusted HR

Primary endpoint + Coronary revascularisation

0.86 (0.77 - 0.96) 0.87 (0.78 - 0.98) 0.0177


0.77 (0.66 - 0.89) 0.83 (0.71 - 0.96) 0.0147

Hazard ratios for treatment effect on coronary events adjusted for accumulated mean levels of

variables that differed

Coronary eventsHR p-value

Unadjusted 0.86 0.0058Systolic BP 0.88 0.0258Diastolic BP 0.86 0.0065Mean BP* 0.88 0.0205Pulse pressure 0.87 0.0170Heart rate 0.85 0.0201Glucose 0.85 0.0041HDL cholesterol 0.90 0.0610Triglycerides 0.85 0.0043Creatinine 0.86 0.0091Potassium 0.85 0.0045Weight 0.86 0.0053

* Mean BP = (SBP/DBP)/2

Hazard ratios for treatment effect on stroke events adjusted for accumulated mean levels of

variables that differed

Fatal and non-fatal strokeHR p-value

Unadjusted 0.77 0.0003Systolic BP 0.83 0.0144Diastolic BP 0.80 0.0033Mean BP* 0.84 0.0170Pulse pressure 0.80 0.0026Heart rate 0.74 0.0007Glucose 0.78 0.0007HDL cholesterol 0.76 0.0002Triglycerides 0.78 0.0008Creatinine 0.79 0.0014Potassium 0.76 0.0002Weight 0.76 0.0002

* Mean BP = (SBP/DBP)/2

Impact on the treatment effect on coronary events after adjustment for BP

and all variables that differed

Hazard ratio

95% CI

Unadjusted 0.86 0.77 - 0.96

SBP 0.88 0.79 - 0.98

SBP + covariates 0.93 0.81 - 1.07

SBP + DBP + covariates 0.92 0.80 - 1.06

MBP** + covariates 0.94 0.81 - 1.08

PP + covariates 0.91 0.79 - 1.04

Hazard ratio

95% CI

Unadjusted 0.86 0.77 - 0.96

SBP 0.88 0.79 - 0.98

SBP + covariates 0.93 0.81 - 1.07


MBP** + covariates 0.94 0.81 - 1.08

PP + covariates 0.91 0.79 - 1.04

p-value

0.0058

0.0258

0.3276

0.2744

0.3519

0.1791

0.50 0.70 1.00 1.45



** MBP = (SBP+DBP)/2

Hazard ratio

Hazard ratio

95% CI

Unadjusted 0.86 0.77 - 0.96

SBP 0.88 0.79 - 0.98

SBP + covariates 0.93 0.81 - 1.07


MBP** + covariates 0.94 0.81 - 1.08

PP + covariates 0.91 0.79 - 1.04

Impact on the treatment effect on stroke events after adjustment for BP and all

variables that differedHazard ratio

95% CI

Unadjusted 0.77 0.66 - 0.89

Mean BP 0.84 0.72 - 0.97

SBP + covariates 0.85 0.71 - 1.02


MBP** + covariates 0.87 0.73 - 1.05

PP + covariates 0.80 0.67 - 0.96

Hazard ratio

95% CI

Unadjusted 0.77 0.66 - 0.89

Mean BP 0.84 0.72 - 0.97

SBP + covariates 0.85 0.71 - 1.02


MBP** + covariates 0.87 0.73 - 1.05

PP + covariates 0.80 0.67 - 0.96

p-value

0.0003

0.0170

0.0836

0.1386

0.1380

0.0164

0.50 0.70 1.00 1.45



** MBP = (SBP+DBP)/2

Hazard ratio

Hazard ratio

95% CI

Unadjusted 0.77 0.66 - 0.89

Mean BP 0.84 0.72 - 0.97

SBP + covariates 0.85 0.71 - 1.02


MBP** + covariates 0.87 0.73 - 1.05

PP + covariates 0.80 0.67 - 0.96

Summary• Several potentially important variables including BP differed post-

randomisation between 2 treatment groups

• No temporal association between BP differences and event rate differences

• SMM for SBP and updated Cox regression analyses suggested BP accounted for about 15% of coronary differences and 30% of stroke differences

• Full multivariate adjustment accounted for about 50% of coronary differences (mainly HDL-C differences) and 40% of strokes

• Residual differences are large for stroke but non-significant for coronary and stroke events

Conclusions

• These analyses are compatible with the possibility that CV event differences were explained by the variables considered

• BP differences unlikely single explanation

• Residual differences, albeit non-significant, are large especially for stroke

• ASCOT provides implications for optimal CV prevention independent of these analyses

ASCOT: BPLA and LLA combined: Insight into optimal CV prevention (2)

EndpointAmlodipine

perindopril + statin

Atenolol thiazide + placebo

Relative risk reduction

Fatal MI and non-fatal CHD 4.8 9.2 48%

Fatal and non-fatal stroke 4.6 8.2 44%

Rates / 1000 patient years

Final conclusions

• Amlodipine perindopril based therapy confers an advantage over atenolol thiazide based therapy on all major CV end points, all-cause mortality and new-onset diabetes

• Irrespective of the reasons for benefit, the standard regimen of beta-blocker thiazide should not be preferred to the amlodipine perindopril regimen for most patients

• Compared with standard antihypertensive therapy without statin therapy, the amlodipine perindopril regimen plus atorvastatin reduced coronary and stroke events by almost 50%

AHA 2006Results CAFE study, a substudy of ASCOT

Central vs brachial bloodpressure

•Are antihypertensive drugs equal in lowering central bloodpressure?

• What determines central bloodpressure ?

• What are the consequences of lower central bloodpressure?

CAFE study: Rationale

• Brachial blood pressure is a strong predictor of clinical outcomes in people with hypertension

• It is assumed that brachial blood pressure accurately reflects pressures in the central aorta and thus left ventricular load

• This assumption may not be valid in all circumstances because different classes of blood pressure-lowering drugs may differentially influence central aortic blood pressures

• In clinical trials comparing different blood pressure lowering-drugs, clinical outcomes could be influenced by drug effects on central aortic pressures, despite similar effects on brachial blood pressure

CAFE : Background (1)

• In clinical trials comparing different blood pressure lowering-drugs, clinical outcomes could be influenced by drug effects on central aortic pressures, despite similar effects on brachial blood pressure

• This hypothesis required testing in a prospective clinical outcomes trial evaluating 2 different blood pressure-lowering treatment regimens

• The Conduit Artery Functional Evaluation (CAFE) study was designed to test this hypothesis as a major substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

CAFE : Background (2)

CAFE Hypothesis

Primary Objective• The different blood pressure-lowering regimens in

ASCOT (atenolol ± thiazide versus amlodipine ± perindopril) would produce different effects on central aortic pressures and hemodynamics despite similar effects on brachial blood pressure

Secondary Objective• Central aortic pressures would be an important

determinant of clinical outcomes in ASCOT

Williams B. et al. J Hum Hypertens. 2001; 15 (suppl 1): S69-S73

Methods

• Seated brachial blood pressure measured using Omron 705CP

• Pulse wave analysis 10 second sampling of radial artery pulse waves were recorded by tonometry

• The radial pulse wave was calibrated to brachial blood pressure and transformed to derive a central aortic pressure wave using the Sphygmocor© apparatus (v7)

CAFE study Profile2199 subjects recruited from 5

UK ASCOT centers

2073 evaluable for tonometry

1042 receivedAmlodipine-based regimen

1031 received atenolol-based regime

4 subjects incomplete information, 1 alive at last visit, 2 withdrawn consent, 1 lost to

follow-up

1042 assessed on an intention-to-treat basis 1038 complete

information(997 alive, 41 dead)

1 subject incomplete information, withdrawn

consent

1031 assessed on an intention-to-treat basis 1030 complete

information(989 alive, 41 dead)

126 excluded due to heart rate irregularity/poor waveforms

Baseline Demographics (1)

Atenolol-basedn=1031

Amlodipine-basedn=1042



Women 189 (18.3%) 208 (20%) 2257 (23.5%) 2258 (23.4%)

Age (years) 62.6 (8.3) 62.9 (8.2) 63.0 (8.5) 63.0 (8.5)

White 886 (85.9%) 892 (85.6%) 9170 (95.3%) 9187 (95.3%)

Current smoker 251 (24.3%) 267 (25.6%) 3109 (32.3%) 3168 (32.9%)

SBP mm Hg 159.9 (16.6) 161 (18.4) 163.9 (18) 164.1 (18.1)

DBP (mm Hg) 92.4 (9.6) 92.6 (9.8) 94.5 (10.4) 94.8 (10.4)

Heart rate (bpm) 71.8 (12.3) 71.2 (12.4) 71.8 (12.6) 71.9 (12.7)

BMI (kg/m2) 29 (4.5) 29.1 (4.7) 28.7 (4.5) 28.7 (4.6)

Height (cm) 170.7 (8.7) 170.2 (9.4) NA NA

Total cholesterol (mg/dL)

224.3 (38.7) 224.3 (42.5) 228.2 (42.5) 228.2 (42.5)

LDL-cholesterol (mg/dL) 143.1 (34.8) 143.1 (34.8) 146.9 (38.7) 146.9 (38.7)

HDL-cholesterol (mg/dL)

50.3 (15.5) 50.3 (15.5) 50.3 (15.5) 50.3 (15.5)

Triglycerides (mg/dL) 159.4 (88.6) 159.4 (8.6) 168.3 (88.6) 159.4 (88.6)

Glucose (mg/dL) 110 (38) 110 (38) 112 (38) 112 (38)

Creatinine (mg/dL) 1.08 (0.18) 1.09 (0.19) 1.09 (0.19) 1.09 (0.18)

CAFE ASCOT

Baseline Demographics (2)





Medical history

Prior stroke/TIA 76 (7.4%) 62.9 (8.2) 63.0 (8.5) 63.0 (8.5)

Diabetes 252 (24.4%) 892 (85.6%) 9170 (95.3%) 9187 (95.3%)

LVH (echo or ECG) 237 (23%) 267 (25.6%) 3109 (32.3%) 3168 (32.9%)

Peripheral vascular disease

61 (5.9%) 59 (5.7%) 613 (6.4%) 586 (6.1%)

Other relevant CV disease

22 (2.1%) 27 (2.6%) 486 (5.1%) 533 (5.5)

Mean (SD) # risk factors 3.7 (0.9) 3.7 (0.9) 3.7 (0.9) 3.7 (0.9)

Drug therapy

BP treatment naive 109 (10.6%) 100 (9.6%) 1825 (19%) 1841 (19.1%)

Lipid-lowering therapy 120 (11.6%) 120 (11.5%) 1004 (10.4%) 1046 (10.9%)

Aspirin use 244 (23.7%) 274 (26.3%) 1837 (19.1%) 1851 (19.2%)

CAFE ASCOT

Mean Proportion of Time (%) on BPLowering Medication by Treatment Group*

Year 1 All study

Randomized to Amlodipine

Amlodipine 90.0 80.7

Perindopril 56.0 66.7

Amlodipine + perindopril 47.8 55.5

Randomized to Atenolol

Atenolol 88.1 73.5

Bendroflumethiazide 69.8 74.2

Atenolol + bendroflumethiazide 60.2 59.6

* From time of randomization into ASCOT

CAFE Study: Different waveforms demonstrate lower central BP in CCB/ACEI arm

Peripheral waveform Central aortic waveform

amlodipine ± perindopril atenolol ± bendroflumethiazide

Williams B. Circulation 2006.

Central aortic SBP difference: 4.3 mm Hg (P < 0.0001)

Central aortic PP difference: 3.0 mm Hg (P < 0.0001)

Williams B. Circulation 2006.

BP lowering drugs have different effects on central bloodpressure

Results summary (1)

• Atenolol±thiazide was associated with higher central aortic systolic pressure and higher central aortic pulse pressure, despite similar brachial pressures, when compared with amlodipine±perindopril

• Central aortic outgoing pressure wave (P1 height) was lower with atenolol±thiazide vs amlodipine±perindopril

• Pulse wave augmentation and the percentage of the central aortic pressure wave attributable to wave reflection was increased by atenolol±thiazide compared with amlodipine±perindopril




• What are the consequences of lower central bloodpressure?

• If there was no wave reflection (ie. the aorta was an open-ended tube providing a simple resistance to flow), then:

• the pressure wave in the aortic root would be the same as the flow wave (see graph).

Figure 1

Pressure Wave Reflection at the Heart What is it?

Menu

Figure 1

• Now if we connect up the network of arteries with all its bifurcations and vascular beds, then:

• as this primary wave travels along the arteries it will generate reflected waves from each bifurcation and from the peripheral vascular beds.

• all these small reflected waves return to the heart, summing to create a reflected wave as shown, starting even before the end of systole.

Menu

Figure 2

Pressure Wave Reflection at the Heart What is it?

• So the pressure in the aortic root is the sum of the outgoing and reflected wave (the green wave).

• Note importantly how the reflected wave boosts the coronary artery perfusion pressure – the aortic root pressure – during diastole when over 95% of perfusion of the sub-endocardium takes place.

Figure 3

Pressure aorta is sum of wave reflections at the Heart

Menu

Figure 3

• The speed at which the outgoing and reflected waves travel is dependent on the stiffness of the arteries along which they are travelling.

• So if a person has stiffer arteries, the waves will travel out and back quicker, arriving earlier back at the heart (see graph).

Figure 4

What determines wave reflection at the heart?

Menu

Figure 4

• Now when the outgoing and reflected waves are added there is a very different aortic root pressure waveform.

• There are three important clinical implications.

Figure 5

Pressure Wave Reflection at the Heart

Menu

Figure 5




•Clinical consequences of lower central bloodpressure and

possible explanations?

PP

• First, the central systolic pressure and central pulse pressure is increased.

• An increase in the central pulse pressure that drives cerebral blood flow increases stroke risk.

• NOTE: this change in central systolic pressure can occur without any changes occurring in peripheral cuff systolic pressure.

Pressure Wave Reflection at the Heart Consequences

Increased CentralPulse Pressure

Menu

Figure 6



0.0 1.0 2.0 3.0 4.0 5.0 Years0.0

1.0

2.0

3.0

4.0

5.0



HR = 0.77 (0.66 0.89)p = 0.0003

%

• Second, there is an increase in left ventricular load (LV load).

• Increase in LV load accelerates increase in LV mass and increases risk of LV hypertrophy.

• The area under the pressure-time curve during systole is by definition LV load.

• This increase in LV Load (late systolic “afterload”) is shown by the black arrowed region.

Figure 7


LVLIncreased LV Load

Menu

• Third, the pressure that is perfusing the coronary arteries during the critical diastole period is reduced, increasing the risk of myocardial ischemias.

• Conclusion: Increasing arterial stiffness independently increases the risk of all three major cardiovascular outcomes.

Figure 8


Decreased Coronary ArteryPerfusion Pressure in

Diastole

Menu


Years0.0 1.0 2.0 3.0 4.0 5.0

0.0

2.0

4.0

6.0

8.0

10.0



HR = 0.87 (0.79 0.96)p = 0.0070

%

Total coronary end point

CV mortality


0.0 1.0 2.0 3.0 4.0 5.0 Years0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5



HR = 0.76 (0.65 0.90)p = 0.0010

%

-5

-10

-15

-20

-25

SBP DBP SBP PP2,3Brachial BP Central BP (aorta)

Dec

reas

e in

BP

(m

mH

g)

Adjusted difference

between group

(mmHg)

-6,02p<0,001

-0,32P= 0,715

-12,52p< 0,001

-10,34p< 0,01

Perindopril / indapamide (2 / 0,625 mg)

Atenolol (50 mg)

Asmar R et al. Hypertension. 2001;38:922-926.

BP lowering drugs have different effects on central bloodpressure

-4

-3

-2

-1

0

1

2

-3.1

Ao-AI (%)

+1.8

Perindopril-indapamide

Atenolol

P=0.002P=0.112

REASON study / AI decrease REASON study / AI decrease

P<0.001

Asmar R et al. Hypertens. 2001;38:922-926.

Thybo NK, et al. Hypertension 1995; 25: 474-481

vs before *P <0.05. **P <0.01 - vs atenolol iiP < 0.01

Mean BP (mmHg)

Lumen ø (µm)

90 122 101** 126 98**

237 208 247*ii 222 208

P < 0.01 P < 0.05

NS

Normotensive Before BeforeAfter After

Arterialmedia-to-lumen

ratio (%)

8

6

4 5.82

7.94

5.96

7.14

6.79

Perindopriln=13

Atenololn=12

Normotensiven=25

BP lowering drugs have different effects on structure small arteries

HCTZ 25 mg + amiloride 2,5 mg

Perindopril 4 mg

carotid artery elasticity(% improvement)

0

5

10

15

20

1

16*

p < 0.05

*p<0.05 versus baseline

Double-blind randomized study

41 hypertensive patients (DBP : 95 - 110 mmHg)

Perindopril : n = 20 - Diuretic : n = 21)

6-week placebo run-in

6-month study

BP lowering drugs have different effects on structure large arteries

Kool M.J. Van Bortel L.M. et al. J Hypertens 1995 ; 13 :839 - 848

CAFE Study Conclusions

• Brachial blood pressure overestimated the hemodynamic benefit of atenolol ± thiazide-based treatment and underestimated the benefit of amlodipine ± perindopril-based treatment on central aortic pressures and hemodynamics

• Central aortic pressure may be an important independent determinant of clinical outcomes

• Results of the CAFE study suggest that the “central aortic blood pressure hypothesis” is a plausible mechanism to explain the better clinical outcomes for hypertensive patients treated with amlodipine ± perindopril-based therapy in ASCOT

Documents

B.Dahlof (Co-chair), P.Sever (Co-chair), N. Poulter (Secretary) H. Wedel (Statistician), G. Beevers, M. Caulfield, R. Collins S. Kjeldsen, A. Kristinsson,