Elsevier

The Lancet

Volume 375, Issue 9718, 13–19 March 2010, Pages 906-915
The Lancet

Articles
Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis

https://doi.org/10.1016/S0140-6736(10)60235-8Get rights and content

Summary

Background

Unexplained differences between classes of antihypertensive drugs in their effectiveness in preventing stroke might be due to class effects on intraindividual variability in blood pressure. We did a systematic review to assess any such effects in randomised controlled trials.

Methods

Baseline and follow-up data for mean (SD) of systolic blood pressure (SBP) were extracted from trial reports. Effect of treatment on interindividual variance (SD2) in blood pressure (a surrogate for within-individual variability), expressed as the ratio of the variances (VR), was related to effects on clinical outcomes. Pooled estimates were derived by use of random-effects meta-analysis.

Findings

Mean (SD) SBP at follow-up was reported in 389 (28%) of 1372 eligible trials. There was substantial heterogeneity between trials in VR (p<1×10−40), 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 0·76–0·86, p<0·0001) and non-loop diuretic drugs (0·87, 0·79–0·96, p=0·007), and increased by angiotensin-converting enzyme (ACE) inhibitors (1·08, 1·02–1·15, p=0·008), angiotensin-receptor blockers (1·16, 1·07–1·25, p=0·0002), and β blockers (1·17, 1·07–1·28, p=0·0007). Compared with placebo only, interindividual variation in SBP was reduced the most by calcium-channel blockers (0·76, 0·67–0·85, p<0·0001). Effects were consistent in parallel group and crossover design trials, and in analyses of dose-response. Across all trials, effects of treatment on VR of SBP (r2=0·372, p=0·0006) and on mean SBP (r2=0·328, p=0·0015) accounted for effects on stroke risk (eg, odds ratio 0·79, 0·71–0·87, p<0·0001, for VR≤0·80), and both remained significant in a combined model.

Interpretation

Drug-class effects on interindividual variation in blood pressure can account for differences in effects of antihypertensive drugs on risk of stroke independently of effects on mean SBP.

Funding

None.

Introduction

Blood pressure is a powerful predictor of cardiovascular events, with systolic blood pressure (SBP) greater than 115 mm Hg accounting for up to 60% of the population-attributable risk of stroke,1, 2 and an increment of 20 mm Hg SBP doubling the risk of stroke in individuals aged 40–69 years.3 Reduction in mean blood pressure reduced the risk of cardiovascular events in randomised controlled trials (RCTs).4, 5, 6, 7 Clinical benefits were shown for all classes of antihypertensive drugs, with reduction in risk of stroke and coronary events correlated with a reduction in group mean SBP.4, 5, 6, 7 However, class-specific effects seem to exist, with calcium-channel blockers reducing the risk of stroke to a greater extent than expected from reduction in mean SBP alone, and β blockers reducing risk to a smaller extent than expected.7, 8, 9 The mechanism(s) of these differences in effects are not known, although several mechanisms that are not related to blood pressure have been postulated.10, 11 One potential blood-pressure-related explanation for these class effects is differences between drug classes in their effects on within-individual visit-to-visit variability in blood pressure.12 The consensus about the importance of mean blood pressure in relation to risk of vascular events and the benefits of antihypertensive drugs1, 2, 3, 4, 5, 6, 7 does not take into account the within-individual variability in blood pressure, except in the adjustment for regression-dilution bias.13, 14 In the accompanying reports, we show that within-individual visit-to-visit variability in SBP is a powerful predictor of stroke independently of mean SBP in several cohorts,12, 15, 16 and that effects on within-individual variability in SBP account for the previously unexplained effects of treatment on risk of stroke in two RCTs of antihypertensive drugs.16 Here, we address two issues: whether evidence of similar differences between treatment groups in variability in blood pressure is present in other trials of antihypertensive drugs; and whether these differences account for residual differences in effects of randomised treatment on the risk of stroke in all trials after accounting for mean SBP.

Section snippets

Methods

With the availability of many meta-analyses of RCTs of antihypertensive drugs, and the limitations of de-novo searches of bibliographic databases for identification of all eligible studies,17 we identified RCTs from published systematic reviews. We searched Medline and Cochrane databases (1950 to first week of July, 2009) using combinations of the search terms “meta(-)analysis” and “antihypertensive agents OR blood-pressure lowering”.18 There were no language restrictions. We subsequently

Results

We identified 255 systematic reviews and meta-analyses (webappendix p 3), of which 68 were duplicate publications or reviewed trials in excluded patient groups. The remaining 187 meta-analyses generated 1858 citations to independent trials, of which 102 (5%) were not obtainable after extensive searches by citation, author, and title on Medline; hand searches of the relevant journals available in the libraries at the University of Oxford; or on request from the British National Library. These

Discussion

Reporting of interindividual variation in blood pressure in RCTs of antihypertensive drugs is poor, but we have nevertheless been able to show highly consistent and significant drug-class effects on interindividual variability in blood pressure during follow-up. Compared with other drug classes, calcium-channel blockers and non-loop diuretic drugs reduced interindividual variation in SBP, whereas ACE inhibitors, angiotensin-2-receptor blockers, and β blockers increased it, with calcium-channel

References (52)

  • B Dahlöf et al.

    Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial

    Lancet

    (2005)
  • B Dahlöf et al.

    Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension)

    Lancet

    (1991)
  • L Hansson et al.

    Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial

    Lancet

    (1998)
  • A Amery et al.

    Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial

    Lancet

    (1985)
  • AP Kengne et al.

    Systolic blood pressure, diabetes and the risk of cardiovascular diseases in the Asia-Pacific region

    J Hypertens

    (2007)
  • Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies

    Lancet

    (2002)
  • BM Psaty et al.

    Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis

    JAMA

    (2003)
  • Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials

    Lancet

    (2003)
  • MR Law et al.

    Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-anlaysis of 147 randomised trials in the context of expectations from prospective epidemiological studies

    BMJ

    (2009)
  • P Verdecchia et al.

    Angiotensin-converting enzyme inhibitors and calcium channel blockers for coronary heart disease and stroke prevention

    Hypertension

    (2005)
  • B Pitt et al.

    Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. PREVENT Investigators

    Circulation

    (2000)
  • JG Wang et al.

    Carotid intima-media thickness and antihypertensive treatment: a meta-analysis of randomized controlled trials

    Stroke

    (2006)
  • PM Rothwell et al.

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

    Lancet Neurol

    (2010)
  • ET Crumley et al.

    Which resources should be used to identify RCT/CCTs for systematic reviews: a systematic review

    BMC Med Res Methodol

    (2005)
  • A Liberati et al.

    The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration

    BMJ

    (2009)
  • JP Shaffer

    Caution on the use of variance ratios: a comment

    Rev Educ Res

    (1992)
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