ArticlesEffects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis
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)
- et al.
Global burden of blood-pressure-related disease, 2001
Lancet
(2008) - et al.
Blood pressure, stroke, and coronary heart disease: part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context
Lancet
(1990) - et al.
Should β blockers remain first choice in the treatment of primary hypertension? A meta-analysis
Lancet
(2005) Limitations of the usual blood-pressure hypothesis and importance of variability, instability, and episodic hypertension
Lancet
(2010)- et al.
Blood pressure, stroke, and coronary heart disease: part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias
Lancet
(1990) - et al.
Regression dilution of systolic and diastolic blood pressure in patients with established cerebrovascular disease
J Clin Epidemiol
(2003) - et al.
Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension
Lancet
(2010) - et al.
Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol
Lancet
(2002) - et al.
Randomised trial of effects of calcium antagonists compared with diuretics and ? blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study
Lancet
(2000) - et al.
Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial
Lancet
(2004)
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
Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension)
Lancet
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
Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial
Lancet
Systolic blood pressure, diabetes and the risk of cardiovascular diseases in the Asia-Pacific region
J Hypertens
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
Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis
JAMA
Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials
Lancet
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
Angiotensin-converting enzyme inhibitors and calcium channel blockers for coronary heart disease and stroke prevention
Hypertension
Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. PREVENT Investigators
Circulation
Carotid intima-media thickness and antihypertensive treatment: a meta-analysis of randomized controlled trials
Stroke
Effects of β blockers and calcium-channel blockers on within-individual variability in blood pressure and risk of stroke
Lancet Neurol
Which resources should be used to identify RCT/CCTs for systematic reviews: a systematic review
BMC Med Res Methodol
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration
BMJ
Caution on the use of variance ratios: a comment
Rev Educ Res
Cited by (639)
Short-term blood pressure variability and brain functional network connectivity in older adults
2024, Neuroimage: ReportsSafety and efficacy of candesartan versus valsartan combined with amlodipine on peripheral and central blood pressure
2024, Hipertension y Riesgo VascularClinical trials in vascular cognitive impairment following SPRINT-MIND: An international perspective
2023, Cell Reports Medicine