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. 2024 Apr 1;45(13):1159-1169.
doi: 10.1093/eurheartj/ehad814.

Legacy benefits of blood pressure treatment on cardiovascular events are primarily mediated by improved blood pressure variability: the ASCOT trial

Ajay Gupta  1   2 , William N Whiteley  3 , Thomas Godec  1 , Somayeh Rostamian  2 , Cono Ariti  2 , Judith Mackay  2 , Andrew Whitehouse  2 , Leila Janani  4 , Neil R Poulter  5 , Peter S Sever  2 ; ASCOT-10 Investigators
Collaborators, Affiliations

Legacy benefits of blood pressure treatment on cardiovascular events are primarily mediated by improved blood pressure variability: the ASCOT trial

Ajay Gupta et al. Eur Heart J. .

Abstract

Background and aims: Visit-to-visit systolic blood pressure variability (BPV) is an important predictor of cardiovascular (CV) outcomes. The long-term effect of a period of blood pressure (BP) control, but with differential BPV, is uncertain. Morbidity and mortality follow-up of UK participants in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure-Lowering Arm has been extended for up to 21 years to determine the CV impact of mean systolic blood pressure (SBP) control and BPV during the trial, and amongst those allocated to amlodipine- and atenolol-based treatment.

Methods: Eight thousand five hundred and eighty hypertensive participants (4305 assigned to amlodipine ± perindopril-based and 4275 to atenolol ± diuretic-based treatment during the in-trial period (median 5.5 years) were followed for up to 21 years (median 17.4 years), using linked hospital and mortality records. A subgroup of participants (n = 2156) was followed up 6 years after the trial closure with a self-administered questionnaire and a clinic visit. In-trial mean SBP and standard deviation of visit-to-visit SBP as a measure of BPV, were measured using >100 000 BP measurements. Cox proportional hazard models were used to estimate the risk [hazard ratios (HRs)], associated with (i) mean with SBP and BPV during the in-trial period, for the CV endpoints occurring after the end of the trial and (ii) randomly assigned treatment to events following randomization, for the first occurrence of pre-specified CV outcomes.

Results: Using BP data from the in-trial period, in the post-trial period, although mean SBP was a predictor of CV outcomes {HR per 10 mmHg, 1.14 [95% confidence interval (CI) 1.10-1.17], P < .001}, systolic BPV independent of mean SBP was a strong predictor of CV events [HR per 5 mmHg 1.22 (95% CI 1.18-1.26), P < .001] and predicted events even in participants with well-controlled BP. During 21-year follow-up, those on amlodipine-based compared with atenolol-based in-trial treatment had significantly reduced risk of stroke [HR 0.82 (95% CI 0.72-0.93), P = .003], total CV events [HR 0.93 (95% CI 0.88-0.98), P = .008], total coronary events [HR 0.92 (95% CI 0.86-0.99), P = .024], and atrial fibrillation [HR 0.91 (95% CI 0.83-0.99), P = .030], with weaker evidence of a difference in CV mortality [HR 0.91 (95% CI 0.82-1.01), P = .073]. There was no significant difference in the incidence of non-fatal myocardial infarction and fatal coronary heart disease, heart failure, and all-cause mortality.

Conclusions: Systolic BPV is a strong predictor of CV outcome, even in those with controlled SBP. The long-term benefits of amlodipine-based treatment compared with atenolol-based treatment in reducing CV events appear to be primarily mediated by an effect on systolic BPV during the trial period.

Keywords: ASCOT; Blood pressure variability; Cardiovascular events.

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Figures

Structured Graphical Abstract
Structured Graphical Abstract
Blood pressure variability and blood pressure control in the 20-year follow-up of the ASCOT Legacy Study. BPV, blood pressure variability; SBP, systolic blood pressure; CHD, coronary heart disease; CV, cardiovascular; HF, heart failure; MI, myocardial infarction; SD, standard deviation.
Figure 1
Figure 1
Diagram of BPLA of the ASCOT Legacy Cohort. *Subjects with prior atrial fibrillation at baseline were excluded from the analyses. Therefore, the denominators for the atrial fibrillation groups are different (amlodipine group: 4215 patients and atenolol group: 4245 patients were included)
Figure 2
Figure 2
Risk of total cardiovascular events and procedures according to the mean systolic blood pressure and blood pressure variability in thirds. Association between thirds of mean systolic blood pressure and visit-to-visit systolic blood pressure variability (standard deviation of systolic blood pressure) with total cardiovascular events and procedures in the landmark analysis population. Range of mean systolic blood pressure: Third 1: 107.5–132.5 mmHg; Third 2: 132.5–139.9 mmHg; Third 3: 140.0–216.0 mmHg. Range of standard deviation for systolic blood pressure variability: Third 1: 1.15–9.30 mmHg; Third 2: 9.31–12.99 mmHg; Third 3: 13.00–50.06 mmHg
Figure 3
Figure 3
Kaplan–Meier curves showing the cumulative incidence of cardiovascular and coronary heart disease events amongst those allocated to amlodipine- and atenolol-based treatment in the ASCOT Legacy population. Kaplan–Meier curves show the association of amlodipine vs. atenolol allocation with (A) fatal and non-fatal stroke, (B) non-fatal myocardial infarction and fatal coronary heart disease, (C) total coronary events, (D) fatal and non-fatal heart failure, (E) total cardiovascular events and procedures, (F) new-onset of atrial fibrillation, (G) cardiovascular mortality, and (H) all-cause mortality in ASCOT Legacy population
See this image and copyright information in PMC

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