PS Sever, PM Rothwell, SC Howard, JE Dobson, B Dahlöf, 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 London and 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 19,257 hypertensive patients ASCOT-BPLA Stopped after 5.5 yrs atenolol ± bendroflumethiazide PROBE design amlodipine ± perindopril 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 add add bendroflumethiazide-K 1.25-2.5 mg perindopril 4-8 mg add doxazosin GITS 4-8 mg add additional drugs, eg, moxonidine/spironolactone Median follow up was for 5.5 years 3

Baseline characteristics Amlodipine ± perindopril n = 9639 Atenolol ± 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) 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) Drug therapy Previous antihypertensive treatments 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)

Systolic and diastolic blood pressure amlodipine  perindopril atenolol  bendroflumethiazide 180 164.1 SBP 160 163.9 Mean difference 2.7 137.7 140 136.1 Blood pressure (mmHg) 120 DBP 100 94.8 Mean difference 1.9 94.5 79.2 80 77.4 60 Baseline 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 Last visit Follow-up (years)

ASCOT-BPLA: summary of all endpoints 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) Primary Non-fatal MI (incl. silent) + fatal CHD Secondary Non-fatal MI (excl. silent) + fatal CHD Total coronary endpoint Total CV events and procedures All-cause mortality Cardiovascular mortality Fatal and non-fatal stroke Fatal and non-fatal heart failure Tertiary Silent MI Unstable angina Chronic stable angina Peripheral arterial disease Life-threatening arrhythmias New-onset diabetes mellitus New-onset renal impairment Post hoc Primary endpoint + coronary revasc procs CV death + MI + stroke 0.50 0.70 1.00 1.45 2.00 Amlodipine  perindopril better Atenolol  thiazide better The area of the blue square is proportional to the amount of statistical information

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

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 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 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 DBP 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 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

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

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

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

Number of patients in each decile of within-visit SD SBP Stroke risk and coronary risk expressed by decile of within-visit SBP variability Number of patients in each decile 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

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

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

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