NPC Archive Item: Variation in blood pressure is an independent risk factor for stroke, but does it affect drug choice in hypertension?

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19 March 2010

We know already that having raised blood pressure increases the risk of stroke. Recent studies suggest that variation in blood pressure is also an independent risk factor for stroke.[1, 2, 3] Some evidence suggests that diuretics and calcium channel blockers may offer advantages over ACE inhibitors/A2RAs and beta-blockers in treating those with variable blood pressure.

Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.

NICE guidance should continue to be followed for the management of hypertension. These studies should not change practice until the research has been considered by NICE and, if appropriate, alternative recommendations made for assessing blood pressure (including assessment of variation) and/or drug treatments. .

This research does not challenge the important role that reducing mean blood pressure has in reducing cardiovascular risk. Clinicians should be aware, however, that wide variation in blood pressure measurements from time to time or episodic high blood pressure measurements might increase the risk of stroke, and that certain drugs might be more advantageous in this respect than others. The studies suggest that diuretics and calcium channel blockers may be more effective than ACE inhibitors, angiotensin-2 receptor antagonists (A2RAs) or beta-blockers in terms of their relative effects on blood pressure variation, although the clinical significance of the differences over and above that achieved by blood pressure reduction per se is not known.

The NICE guideline recommendation that diuretics or calcium channel blockers should be used first-line for most people (those over the age of 55 or black) with uncomplicated hypertension remains appropriate. NICE currently recommends ACE inhibitors (or A2RAs where not tolerated) for first-line treatment of patients under the age of 55. Beta-blockers, unless otherwise indicated, are an inappropriate first- or second-line antihypertensive choice.

What is the background to this?
Blood pressure reduction is presently considered to be the most important factor in preventing cardiovascular events in people with hypertension. These new studies have investigated through analysis of data from previous clinical trials the following questions: (1) whether visit to visit variation in blood pressure and episodic high blood pressure impacts stroke risk; (2) how drug class affects interindividual variation in blood pressure; and (3) if there are differences between beta-blockers and calcium channel blockers in this respect.

What do the studies claim?
Using data from the UK-TIA and ASCOT–BPLA trials Rothwell et al [1] identified that visit-to-visit variation in systolic blood pressure (SBP) and maximum SBP are strong predictors of stroke, independent of mean SBP.

Webb et al [2] analysed baseline and follow up data from 398 randomised controlled trials (RCTs) of antihypertensive trials and found that interindividual SBP varied significantly between individual drug classes and this, together with differences in effects on mean SBP, accounted for most of the drug effects on stroke risk. Compared with other drugs, calcium channel blockers and non-loop diuretics were associated with reduced interindividual variation in SBP (ratio of variances [VRs] 0.81, 95%CI 0.76 to 0.86; and 0.87, 95%CI 0.79 to 0.96, respectively), whereas ACE inhibitors, A2RAs, and beta-blockers were associated with increased interindividual variation in SBP (VRs 1.08, 95%CI 1.02 to 1.15;1.16, 95%CI 1.07 to 1.25; and 1.17, 95%CI 1.07 to 1.28, respectively).

Rothwell et al [3] also analysed the visit-to-visit variation in blood pressure measurements in the ASCOT-BPLA (amlodipine vs. atenolol based regimens) and the MRC (atenolol vs. diuretic based regimens). Both amlodipine- and diuretic-based regimens were associated with statistically significant reduced visit-to-visit variation in SBP compared with the atenolol-based regimen in each of the studies, respectively.

How does this relate to other studies?
As pointed out in an accompanying commentary, other studies have previously indicated a relationship between blood-pressure variation and risk of stroke, although these were short-term studies with the use of 24-hour ambulatory or home blood pressure recording. The present studies, in contrast, considered long-term variation in blood pressure recorded in a standardised setting about which information is scarce.

So what?
The current NICE guideline for hypertension does not take into account the effect of variation in blood pressure on cardiovascular risk when identifying hypertension or recommending drug treatment. Hypertension is identified by persistent raised blood pressure above 140/90mmHg, i.e. confirmed by at least two subsequent clinic visits where blood pressure is assessed under the best conditions available.

An accompanying review article by Rothwell, considering the findings of all three studies, suggests that future diagnostic strategies for hypertension should take into account the effect of increased visit-to-visit variation in blood pressure and episodic hypertension on vascular risk. However, it is unclear how the variation and instability of these measurements would be assessed in routine clinical practice at present.

The present studies suggest that drugs that both decrease blood pressure and reduce variation might be preferable to other drugs for reducing the risk of stroke because of their effects in reducing the variation in blood pressure. In this regard diuretics and calcium channel blockers would seem preferable to ACE inhibitors/A2RAs or beta-blockers. This is consistent with current NICE hypertension guideline recommendations for first-line use of calcium channel blockers or diuretics for patients aged 55 years or older (or who are black) and for not using beta-blockers first-line (unless indicated for other reasons), although it may raise questions about the first-line use of ACE inhibitors/A2RAs in younger patients.

There are many limitations to this analysis. It is important to remember that finding an association between variation in blood pressure and stroke does not by itself prove a causal relationship between them. As stated in the commentary, further studies are required to better characterise the effects of different classes of drugs, and lifestyle factors, on long-term blood pressure variability. Furthermore, the variation in blood pressure measurement with calcium channel blockers is considered to be small on average in the Rothwell review; the clinical significance of any benefits that might accrue has yet to be established in prospective trials.

Although the articles raise many questions for research, the current studies in isolation should not change practice from the current NICE guidance. A review of NICE hypertension guidelines is currently underway and the findings from these studies should be taken into account together with other available evidence. In the meantime, clinicians should be aware that wide variation in blood pressure measurements from time to time or episodic high blood pressure measurements appear to increase the risk of stroke, and this is a factor to consider when evaluating the cardiovascular risk of an individual patient and when considering which drug treatment to provide.

Study details

1) Rothwell PM, et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet 2010;375:895–905

Design: Retrospective cohort study

Patients: Patients with previous transient ischaemic attack (TIA) (UK-TIA trial [n=2,006] and three validation cohorts [n=7,661]) and in patients with treated hypertension (ASCOT-BPLA [n=18,530]).

Comparisons: Risk of stroke in relation to visit-to-visit variability in blood pressure (expressed as standard deviation (SD) and parameters independent of mean blood pressure) and maximum blood pressure..

Results: In each TIA cohort, visit-to-visit variability in SBP was a strong predictor of subsequent stroke (e.g. top-decile hazard ratio [HR] for SD SBP over seven visits in UK-TIA trial: 6·22, 95%CI 4·16 to 9·29, P<0·0001), independent of mean SBP, but dependent on precision of measurement (top-decile HR over ten visits: 12·08, 95%CI 7·40 to19·72, P<0·0001). Maximum SBP reached was also a strong predictor of stroke (HR for top-decile over seven visits: 15·01, 95%CI 6·56 to 34·38, P<0·0001, after adjustment for mean SBP). In ASCOT-BPLA, residual visit-to-visit variability in SBP on treatment was also a strong predictor of stroke and coronary events (e.g. top-decile HR for stroke: 3·25, 2·32 to 4·54, P<0·0001), independent of mean SBP in clinic or on ambulatory blood pressure measurement (ABPM)

2) Webb AJS, et al. Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis. Lancet 2010; 375:906–15.

Design: Systematic review and meta-analysis.

Patients: as included in 389 RCTs of antihypertensive drugs.

Comparisons: The relationship between interindividual variance in blood pressure (a surrogate for within-individual variability), expressed as VR (a ratio of the variances), for each treatment and clinical outcomes. Pooled estimates were derived by use of random-effects meta-analysis.

Results: There was substantial heterogeneity between trials in VR (P<0.0001), 68% of which was attributable to allocated drug class. Compared with other drugs, interindividual variation in SBP was reduced by calcium-channel blockers (VR 0·81, 95%CI 0·76 to 0·86, P<0·0001) and non-loop diuretic drugs (VR 0·87, 95%CI 0·79 to 0·96, P=0·007), and increased by ACE inhibitors (VR 1·08, 95%CI 1·02 to 1·15, P=0·008), A2RAs (VR 1·16, 95%CI 1·07 to 1·25, P=0·0002), and beta-blockers (VR 1·17, 95%CI 1·07 to 1·28, P=0·0007). Compared with placebo only, interindividual variation in SBP was reduced the most by calcium-channel blockers (VR 0·76, 95%CI 0·67 to 0·85, P<0·0001). Effects were consistent in parallel group and crossover design trials, and in analyses of dose-response.

3) Rothwell PM, et al. Effects of β blockers and calcium-channel blockers on within-individual variability in blood pressure and risk of stroke. Lancet Neurol 2010; Early Online Publication, 12 March 2010doi:10.1016/S1474-4422(10)70066-1

Design: Retrospective cohort study (two hypertension studies)

Patients: Patients included in the ASCOT-BPLA study (compared amlodipine-based regimens with atenolol-based regimens in 19,257 patients with hypertension and other vascular risk factors) and the MRC trial (compared atenolol-based and diuretic-based regimens versus placebo in 4,396 hypertensive patients aged 65–74 years).

Comparisons: Visit-to-visit variability of blood pressure during follow-up in the two trials (as SD and as transformations uncorrelated with mean blood pressure) was correlated with the risk of stroke.

Results: In ASCOT-BPLA, group 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 (HR 0·78, 95%CI 0·67 to 0·90) was partly attenuated by adjusting for mean SBP during follow-up (HR 0·84, 95%CI 0·72 to 0·98), but was abolished by also adjusting for within-individual SD of clinic SBP (HR 0·99, 95%CI 0·85 to 1·16). Findings were similar for coronary events. In an 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).

Sponsorship: The studies were not commercially funded.

More information on hypertension can be found on the hypertension section of NPC.

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