Elsevier

The Lancet Neurology

Volume 9, Issue 5, May 2010, Pages 469-480
The Lancet Neurology

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Effects of β blockers and calcium-channel blockers on within-individual variability in blood pressure and risk of stroke

https://doi.org/10.1016/S1474-4422(10)70066-1Get rights and content

Summary

Background

Analyses of some randomised trials show that calcium-channel blockers reduce the risk of stroke more than expected on the basis of mean blood pressure alone and that β blockers are less effective than expected. We aimed to investigate whether the effects of these drugs on variability in blood pressure might explain these disparities in effect on stroke risk.

Methods

The Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm (ASCOT-BPLA) compared amlodipine-based regimens with atenolol-based regimens in 19 257 patients with hypertension and other vascular risk factors and the Medical Research Council (MRC) trial compared atenolol-based and diuretic-based regimens versus placebo in 4396 hypertensive patients aged 65–74 years. We expressed visit-to-visit variability of blood pressure during follow-up in the two trials as standard deviation (SD) and as transformations uncorrelated with mean blood pressure. For ASCOT-BPLA, we also studied within-visit variability and variability on 24 h ambulatory blood-pressure monitoring (ABPM).

Results

In ASCOT-BPLA, group systolic blood pressure (SBP) SD was lower in the amlodipine group than in the atenolol group at all follow-up visits (p<0·0001), mainly because of lower within-individual visit-to-visit variability. Within-visit and ABPM variability in SBP were also lower in the amlodipine group than in the atenolol group (all p<0·0001). Analysis of changes from baseline showed that variability decreased over time in the amlodipine group and increased in the atenolol group. The lower risk of stroke in the amlodipine group (hazard ratio 0·78, 95% CI 0·67–0·90) was partly attenuated by adjusting for mean SBP during follow-up (0·84, 0·72–0·98), but was abolished by also adjusting for within-individual SD of clinic SBP (0·99, 0·85–1·16). Findings were similar for coronary events. In the ABPM substudy, reduced variability in daytime SBP in the amlodipine group (p<0·0001) partly accounted for the reduced risk of vascular events, but reduced visit-to-visit variability in clinic SBP had a greater effect. In the MRC trial, group SD SBP and all measures of within-individual visit-to-visit variability in SBP were increased in the atenolol group compared with both the placebo group and the diuretic group during initial follow-up (all p<0·0001). Subsequent temporal trends in variability in blood pressure during follow-up in the atenolol group correlated with trends in stroke risk.

Interpretation

The opposite effects of calcium-channel blockers and β blockers on variability of blood pressure account for the disparity in observed effects on risk of stroke and expected effects based on mean blood pressure. To prevent stroke most effectively, blood-pressure-lowering drugs should reduce mean blood pressure without increasing variability; ideally they should reduce both.

Funding

None.

Introduction

Hypertension is the most prevalent treatable risk factor for stroke.1, 2 Randomised controlled trials have shown that blood-pressure lowering is effective in the prevention of stroke, but recent meta-analyses have suggested that there are important drug-class effects, with calcium-channel blockers reducing stroke risk to a greater extent, and β blockers to a lesser extent, than expected by their observed effects on mean blood pressure.3, 4, 5, 6, 7, 8, 9, 10 Although it is widely believed that underlying usual blood pressure is of most importance in the aetiology of vascular disease,11, 12 and hence in the diagnosis and treatment of hypertension,13, 14, 15 and this idea now underpins all major clinical guidelines,16, 17, 18, 19 it is possible that the differences between drug classes in their effects on stroke risk are caused by effects on some other parameter of blood pressure. Visit-to-visit variability in systolic blood pressure (SBP) is increased in cohorts at high risk of stroke,20, 21 is reproducible over time,22 and is a powerful predictor of stroke independently of mean SBP.23, 24 Other evidence that instability and variability in SBP are important in causing end-organ damage is detailed in the accompanying Review,25 but more evidence of a causal link is needed.

The Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm (ASCOT-BPLA), a large randomised trial of a treatment regimen involving a β blocker (atenolol) compared with one that involved a calcium-channel blocker (amlodipine), reported that an amlodipine-based regimen was more effective than expected on the basis of changes in mean blood pressure in preventing stroke and coronary events than was an atenolol-based regimen.3, 4 This effect was also independent of changes in all other measured vascular risk factors during follow-up.4 The Medical Research Council (MRC) trial investigated the effects of atenolol, a diuretic combination, or placebo in elderly patients with hypertension.26 In both this trial and an associated trial in younger patients with hypertension,27 treatment with a β blocker had no effect on stroke risk for the first 2–3 years of follow-up, although the early risk of stroke was reduced substantially in groups assigned to diuretics. Thereafter, the risk of stroke in the β-blocker groups was reduced. We suggest that this consistent time course in treatment effect in the MRC trials was caused by an initial increase in variability in blood pressure in the β-blocker groups, which was then reversed, probably by the addition of other classes of second-line drugs, the use of which was particularly high in the β-blocker groups in both MRC trials.

We aimed to investigate whether effects of β blockers and calcium-channel blockers on variability in blood pressure in the ASCOT-BPLA and the MRC trial could explain the unexpected effects of treatment on stroke risk.

Section snippets

Cohorts

The methods of the ASCOT-BPLA were reported previously.3, 4 Patients aged 40–79 years who had hypertension and at least three other vascular risk factors but no coronary heart disease were randomly assigned, by use of the PROBE (prospective randomised open, blinded endpoint) design, to one of two antihypertensive regimens instead of any existing treatment for hypertension: amlodipine adding perindopril as needed (amlodipine-based) versus atenolol adding bendroflumethiazide and potassium as

Results

Of 19 257 patients in ASCOT-BPLA, 18 530 (96·2%; 9228 in the atenolol group and 9302 in the amlodipine group) had at least two scheduled follow-up visits (median 10, IQR 9–11) from 6 months onwards. Baseline characteristics were balanced (webappendix p 1). From 6 months onwards, there were 350 strokes and 704 coronary events in the atenolol group, and 279 strokes and 611 coronary events in the amlodipine group. 11 019 patients met the criteria for the on-treatment analysis: 5195 in the atenolol

Discussion

In the accompanying Article on the prognostic implications of blood-pressure variability,24 increased visit-to-visit variability in blood pressure was a strong predictor of the long-term risk of stroke after TIA, and patients with good control of mean blood pressure but a high residual variability in SBP had a five times higher risk of stroke than did those with low residual SBP variability in ASCOT-BPLA. In this paper, we have added to the evidence that the link between variability in blood

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