The Anglo-Scandinavian Cardiac Outcomes Trial –Blood Pressure Lowering Arm (ASCOT-BPLA)

Blood Pressure Variability and Cardiovascular Outcomes

PS Sever, PM Rothwell, SC Howard, JE Dobson, B Dahlöf,

H Wedel, NR Poulter, for the ASCOT Investigators

International Centre for Circulatory Health, Imperial College Londonand

Stroke Prevention Research Unit, University of Oxford

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

cholesterol lowering in a factorial study design

Study design

atenolol ± bendroflumethiazide

amlodipine ± perindopril

19,257 hypertensive

patients

PROBE design

ASCOT-BPLAStopped after 5.5 yrs

Investigator-led, multinational randomised controlled trial conducted in hypertensive patients, 40 -79 yrs, with no prior history of CHD, but with 3 additional cardiovascular risk factors (male sex, > 55 yrs, smoking etc )

Treatment algorithm to BP targets < 140/90 mmHg or < 130/80 mmHg 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

Median follow up was for 5.5 years

Baseline characteristicsAmlodipine ± perindopril

n = 9639Atenolol ± thiazide

n = 9618

Demographic and clinical characteristics

Male 7381 (76.6%) 7361 (76.5%)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 (mmHg) 164.1 (18.1) 163.9 (18.0)DBP (mmHg) 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)Diabetes 2567 (27%) 2578 (27%)Other vascular disease 2169 (23%) 2162 (22%)Total cholesterol (mmol/L) 5.9 (1.1) 5.9 (1.1)

Drug therapy

Previous antihypertensive treatments 1841 (19.1%) 1825 (19.0%)01 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)

Systolic and diastolic blood pressureB

lood

pre

ssur

e (m

mH

g)

60

80

100

120

140

160

180

Follow-up (years)

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

amlodipine perindopril atenolol bendroflumethiazide

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

ASCOT-BPLA: summary of all endpoints

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 (excl. silent) + fatal CHDTotal coronary endpointTotal CV events 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 endpoint + 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 (0.63-0.78)0.85 (0.75-0.97)

0.86 (0.77-0.96)0.84 (0.76-0.92)

Conclusions• Amlodipine perindopril-based therapy

conferred an advantage over atenolol thiazide-based therapy on all major CV endpoints, all-cause mortality and new-onset diabetes

• Additional statistical analyses demonstrated that adjusting for blood pressure differences between treatment groups early on in the trial, did not account for the observed differences in cardiovascular outcomes

ASCOT-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

• From 6 months onwards there were 350 strokes and 704 coronary events (non-fatal MI, fatal CHD, new onset angina, non-fatal and fatal heart failure) in the atenolol-based group and 279 and 611 respectively in the amlodipine-based group

Blood pressure variability: methods• Visit-to-visit variability of SBP and DBP during

follow-up, from 6 months after randomisation to the end of the trial, were expressed as the standard deviation (SD), coefficient of variation (CV), and a transformation of SD uncorrelated with mean BP (variability independent of mean – VIM)

• Within-visit variability was expressed as the SD of the three measurements taken at each visit averaged across all follow-up visits

• Among 1905 patients, mean BP and variability were also determined with annual 24 hour ambulatory monitoring (ABPM)

• Cox models were used to determine associations with risks of vascular events during follow-up, and whether an effect on variability in BP could account for the reduction in events in the amlodipine group

Amlodipine-based regimen n = 9302

Atenolol-based regimen n = 9228

Difference (95% CI)

Parameter Mean (SD) Mean (SD)

Mean SBP 139.1 (11.1) 141.8 (13.0) 2.68 (2.58–2.78)

Maximum SBP 157.4 (16.1) 164.2 (18.9) 6.80 (6.68–6.92)

Any SBP ≥180 mmHg 9.1% (851) 19.2% (1776) 10.1% (9.1–11.1)

Any SBP ≥200 mmHg 1.8% (164) 4.7% (438) 3.0% (2.5–3.5)

Visit-to-visit variability

SD SBP 10.99 (4.79) 13.42 (5.77) 2.43 (2.36–2.50)

CV SBP 7.87 (3.23) 9.41 (3.78) 1.54 (1.49–1.59)

VIM SBP 11.14 (4.52) 13.13 (5.21) 1.99 (1.93–2.05)

Within-visit variability

SD SBP 5.42 (0.02) 5.91 (0.02) 0.49 (0.44–0.54)

SD, standard deviation; CV, coefficient of variation; VIM, variability independent of mean

Means and measures of variability of clinic SBP by treatment group

Parameters calculated using all measurements from 6 months onwards

Amlodipine-based regimen n = 9302

Atenolol-based regimen n = 9228

Difference (95% CI)

Parameter Mean (SD) Mean (SD)

Mean DBP 80.2 (7.4) 82.1 (7.6) 1.98 (1.90–2.06)

Maximum DBP 90.4 (9.0) 93.5 (9.6) 3.10 (3.00–3.20)

Any DBP ≥100 mmHg 14.3% (1326) 24.5% (2257) 10.2% (9.1–11.3)

Any DBP ≥105 mmHg 6.1% 568) 11.6% (1071) 5.5% (4.7–6.3)

Visit-to-visit variability

SD DBP 6.26 (2.42) 6.98 (2.72) 0.72 (0.67–0.77)

CV DBP 7.86 (3.04) 8.54 (3.30) 0.68 (0.63–0.73)

VIM DBP 6.30 (2.41) 6.95 (2.66) 0.65 (0.60–0.70)

SD, standard deviation; CV, coefficient of variation; VIM, variability independent of mean

Means and measures of variability of clinic DBP by treatment group

Parameters calculated using all measurements from 6 months onwards

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 risk and coronary risk expressed by decile of within-visit SBP variability

Number of patients in eachdecile of within-visit SD SBP

Stroke risk(HR, 95% CI)

Coronary risk(HR, 95% CI)

Average within-visit CV in the two treatment groups during follow-up

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

Ambulatory blood pressure monitoring

• 1905 patients had an average of 3.25 recordings from 6 months onwards

• Daytime SBP slightly higher but night-time SBP slightly lower on amlodipine-based treatment

• Morning surge similar on both treatments and only weakly correlated with BP visit-to-visit variability

• Intra ABPM coefficient of variation of SBP correlated with visit-to-visit variability in clinic SBP

– atenolol group, r = 0.38

– amlodipine group, r = 0.29, p < 0.0001 for both groups

• Intra ABPM variability in daytime SBP predicted both stroke and coronary events (but less so than visit-to-visit variability)

Summary• Mean BP in trial has minimal effect on stroke outcome and no effect on CHD

outcome

• Various measures of visit-to-visit BP variability (SD, coefficient of variation and variation independent of mean BP) are powerful predictors of both stroke and CHD outcomes

• Other measures of variability (within-visit variability and variability assessed by ABPM) also predict cardiovascular outcomes but less than visit-to-visit variability

• Amlodipine reduces variability compared with atenolol

• Variability increased with age, diabetes, smoking, and in those with established vascular disease

• Adjusting for BP variability completely explains differences in stroke and CHD outcomes between amlodipine-based and atenolol-based treatment in ASCOT