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Articles

Lancet Neurol2010; 9: 46980

Published Online

March 12, 2010

DOI:10.1016/S1474-

4422(10)70066-1

See Reflection and Reaction

page 448

See CommentLancet2010;375: 86769

See ArticlesLancet2010;

375: 895905 and 90615

See ReviewLancet

2010; 375: 93848

Stroke Prevention Research

Unit, University Department of

Clinical Neurology, John

Radcliffe Hospital, Oxford, UK

(P M Rothwell FMedSci,

S C Howard DPhil); Stroke and

Hypertension Unit, Connolly

Hospital, Dublin 15, Ireland

(E Dolan MRCP); Conway

Institute of Biomolecular and

Biomedical Research,

University College Dublin,

Belfield, Dublin 4, Ireland

(E OBrien FRCP); International

Centre for Circulatory Health,

Imperial College London,

London, UK(J E Dobson MSc,

N R Poulter FMedSci,

P S Sever FRCP); and

Department of Medicine,

University of Gteborg,

Gteborg, Sweden

(B DahlfMD)

Correspondence to:

Peter M Rothwell, Stroke

Prevention Research Unit,

University Department of

Clinical Neurology, Level 6,

West Wing, John Radcliffe

Hospital, Headington,

Oxford OX3 9DU, UK

[email protected].

ac.uk

Effects of blockers and calcium-channel blockers on

within-individual variability in blood pressure and riskof stroke

Peter M Rothwell, Sally C Howard, Eamon Dolan, Eoin OBrien, Joanna E Dobson, Bjorn Dahlf, Neil R Poulter, Peter S Sever, on behalf of the

ASCOT-BPLA and MRC Trial Investigators

SummaryBackgroundAnalyses of some randomised trials show that calcium-channel blockers reduce the risk of stroke morethan expected on the basis of mean blood pressure alone and that blockers are less effective than expected. Weaimed to investigate whether the effects of these drugs on variability in blood pressure might explain these disparitiesin 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 vascularrisk factors and the Medical Research Council (MRC) trial compared atenolol-based and diuretic-based regimensversus placebo in 4396 hypertensive patients aged 6574 years. We expressed visit-to-visit variability of blood pressureduring follow-up in the two trials as standard deviation (SD) and as transformations uncorrelated with mean bloodpressure. For ASCOT-BPLA, we also studied within-visit variability and variability on 24 h ambulatory blood-pressuremonitoring (ABPM).

ResultsIn ASCOT-BPLA, group systolic blood pressure (SBP) SD was lower in the amlodipine group than in the atenololgroup at all follow-up visits (p


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calcium-channel blocker (amlodipine), reported that anamlodipine-based regimen was more effective thanexpected on the basis of changes in mean blood pressurein preventing stroke and coronary events than was anatenolol-based regimen.3,4 This effect was alsoindependent of changes in all other measured vascularrisk factors during follow-up.4 The Medical ResearchCouncil (MRC) trial investigated the effects of atenolol, adiuretic combination, or placebo in elderly patients withhypertension.26In both this trial and an associated trialin younger patients with hypertension,27treatment witha blocker had no effect on stroke risk for the first23 years of follow-up, although the early risk of strokewas reduced substantially in groups assigned to diuretics.Thereafter, the risk of stroke in the -blocker groups wasreduced. We suggest that this consistent time course in

treatment effect in the MRC trials was caused by aninitial increase in variability in blood pressure in the

-blocker groups, which was then reversed, probably bythe addition of other classes of second-line drugs, theuse of which was particularly high in the -blockergroups in both MRC trials.

We aimed to investigate whether effects of blockersand calcium-channel blockers on variability in bloodpressure in the ASCOT-BPLA and the MRC trial couldexplain the unexpected effects of treatment on stroke risk.

MethodsCohortsThe methods of the ASCOT-BPLA were reportedpreviously.3,4 Patients aged 4079 years who hadhypertension and at least three other vascular risk factorsbut no coronary heart disease were randomly assigned, byuse of the PROBE (prospective randomised open, blinded

endpoint) design, to one of two antihypertensive regimensinstead of any existing treatment for hypertension:amlodipine adding perindopril as needed (amlodipine-based) versus atenolol adding bendroflumethiazide andpotassium as needed (atenolol-based). Treatment wastitrated to achieve a clinic blood pressure of less than140/90 mm Hg, or less than 130/80 mm Hg in patientswith diabetes. Patients with total cholesterol 65 mmol/Lor highercould also be randomly assigned to atorvastatin10 mg daily or to placebo.28

At every follow-up visit (baseline, 6 weeks, 3 months,6 months, and every 6 months thereafter) clinic bloodpressure was measured three times in the sitting positionafter 5 min rest by use of a validated, semi-automated

oscillometric device (Omron HEM-705CP; OmronHealthcare, Kyoto, Japan).29Participants at four centreshad yearly 24 h ambulatory blood-pressure monitoring(ABPM) (SpaceLabs 90207, SpaceLabs, Hertford, UK).3032No editing criteria were applied to individual readings.Mean time-weighted daytime (09002100 h), night-time(01000600 h) and 24 h, SBP, diastolic blood pressure(DBP), and pulse pressures were calculated.32

The methods of the MRC trial were reportedpreviously.26Patients with mean SBP of 160209 mm Hgand mean DBP of less than 115 mm Hg during an8-week run-in period were randomly assigned, single-blind, to 50 mg atenolol daily versus 25 mghydrochlorothiazide plus 25 mg amiloride daily

(diuretic group) versus daily placebo. At randomisationand at each follow-up visit (every 3 months to 24 monthsand then yearly) clinic blood pressure was measuredthree times in the sitting position using a random zerosphygmomanometer, and the mean of the second tworeadings was recorded. Treatment was titrated to achievea clinic blood pressure of less than 150 mm Hg if meanrun-in SBP was 160179 mm Hg, or less than 160 mm Hgif mean run-in SBP was 180 mm Hg or greater. Whenblood pressure was inadequately controlled in theatenolol group, the dose was increased to 100 mg. Iffurther control was necessary in the atenolol group,hydrochlorothiazide was added. When blood-pressure

Atenolol-based

regimen (n=9228)

Amlodipine-based

regimen (n=9302)

Difference (95% CI)

Systolic blood pressure

Mean 1418 (130) 1391 (111) 268 (258 to 278)

Maximum 1642 (189) 1574 (161) 680 (668 to 692)

Minimum 1226 (135) 1230 (118) 040 (050 to 030)

180 mm Hg* 1776 (19%) 851 (9%) 101% (91 to 111)

200 mm Hg* 438 (5%) 164 (2%) 30% (25 to 35)

Visit-to-visit variability

SD 1342 (577) 1099 (479) 243 (236 to 250)

CV 941 (378) 787 (323) 154 (149 to 159)

VIM 1313 (521) 1114 (452) 199 (193 to 205)ASV 1379 (650) 1128 (532) 251 (244 to 258)

RSD 1215 (513) 997 (432) 218 (212 to 224)

Within-visit variability

SD 591 (002) 542 (002) 049 (044 to 054)

Range 516 (004) 485 (004) 031 (020 to 042)

White coat effect 1121 (004) 1028 (004) 093 (083 to 103)

Diastolic blood pressure

Mean 821 (76) 802 (74) 198 (190 to 206)

Maximum 935 (96) 904 (90) 310 (300 to 320)

Minimum 718 (84) 708 (81) 100 (090 to 110)

100 mm Hg* 2257 (24%) 1326 (14%) 102% (91 to 113)

105 mm Hg* 1071 (12%) 568 (6%) 55% (47 to 63)

Visit-to-visit variability

SD 698 (272) 626 (242) 072 (067 to 077)

CV 854 (330) 786 (304) 068 (063 to 073)

VIM 695 (266) 630 (241) 065 (060 to 070)

ASV 712 (314) 624 (270) 088 (083 to 093)

RSD 620 (247) 547 (216) 073 (069 to 077)

Data are mean (SD) or number (%). Parameters were calculated using all measurements from 6 mo nths onwards.

p


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control was inadequate in the diuretic group, atenololwas added. Thereafter, up to 20 mg nifedipine dailycould be added in both groups.

Statistical analysisWithin-individual visit-to-visit variability in SBP, DBP,and pulse pressure was expressed as the standarddeviation (SD) and coeffi cient of variation (SD/mean) ofreadings taken over multiple follow-up visits (mean ofthe second and third readings at each visit was used inASCOT-BPLA). If the coeffi cient of variation remainedcorrelated with mean blood pressure, a transformation,defined as variation independent of mean (VIM), was

derived as SD/mean, with x estimated from curve fitting.In ASCOT-BPLA, visit-to-visit heart-rate variability was

also calculated with measurements (mean of second andthird reading at each visit) from 6 months onwards.Because the SD and mean heart rate were correlated(r=034, p


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adjusted for each measure of variability separately (indeciles and as continuous variables) and in conjunctionwith mean blood pressure.

In the MRC trial, the time-course of stroke risk in theatenolol group compared with the placebo and diureticgroups was assessed by testing for time-dependent

variation in the treatment effect HRs. Differencesbetween treatment groups in within-individual variabilitywere assessed in the early phase of follow-up (nine visitsbefore 21 months) versus the later phase (seven visitsfrom 21 months onwards)the 21-month cut-point wasa compromise between a suffi cient length of follow-up inthe early phase and a suffi cient number of visits in thelater phase. Any time trends in group mean, SD, andcoeffi cient of variation of blood pressure were alsoassessed: within-individual visit-to-visit variability in SBPusually explains about 50% of the group variance in SBPat each follow-up visit.24 Within-individual variabilitychanged over time in the atenolol group and thereforeadjusted treatment effects could not be established.

Role of the funding source

ASCOT-BPLA and the MRC trial were investigator-designed and investigator-led studies. None of theagencies that funded ASCOT-BPLA or the MRC trial hadany input into the design, performance, analysis, orreporting of the analysis reported in this Article. Thereport was sent to the major sponsor of ASCOT-BPLA(Pfizer) for information before final acceptance forpublication. The contractual agreement between ImperialCollege, London, UK, and the sponsor allows the sponsorthe opportunity to see and comment upon any paper, butnot to exercise any right of veto. The correspondingauthor had full access to all data and had finalresponsibility for the decision to submit for publication.

ResultsOf 19 257 patients in ASCOT-BPLA, 18 530 (962%; 9228in the atenolol group and 9302 in the amlodipine group)had at least two scheduled follow-up visits (median 10,IQR 911) from 6 months onwards. Baselinecharacteristics were balanced (webappendix p 1). From6 months onwards, there were 350 strokes and704 coronary events in the atenolol group, and 279 strokesand 611 coronary events in the amlodipine group.11 019 patients met the criteria for the on-treatmentanalysis: 5195 in the atenolol group and 5824 in theamlodipine group. Results of analyses based on pulsepressure and SBP were similar (data not shown). Visit-to-visit SD SBP (r=037) and coeffi cient of variation SBP

(r=017) were correlated with mean SBP and so VIM SBP(proportional to SD/mean) was calculated. VIM DBPwas proportional to SD/mean.

Mean SBP from 6-month follow-up onwards was268 mm Hg higher in the atenolol versus the amlodipinegroup (p


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visit-to-visit SD for the atenolol versus the amlodipinegroup was 476 (413548, p


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randomisation, and differences in variability were greaterin the on-treatment group (webappendix p 2). Visit-to-visit SD and VIM SBP were also reduced in the grouprandomly assigned to atorvastatin treatment versusplacebo in the ASCOT substudy (difference in VIM033 mm Hg, 95% CI 013054; p=0001), with a non-significantly larger effect in the amlodipine groupcompared with that in the atenolol group.

The treatment effect HR for risk of stroke in theamlodipine group compared with the atenolol group

(078, 95% CI 067090; p=0001; table 2) diminishedless after adjustment for mean SBP during follow-up(084, 072098, p=0025) than after adjustment forvisit-to-visit SD SBP (094, 081110, p=047, table 2).The HR for stroke after 30 months changed from 083(95% CI 068102) to 097 (079120) after adjustingfor mean and SD SBP from 6 months to 30 months. Thetreatment HR for coronary events (085, 077094,p=0002) changed slightly after adjusting for mean SBP(088, 080098; p=0019; table 2) but was abolished byadjusting for SD SBP (100, 090111, p=096). For bothstroke and coronary events, adjustment for DBP variabilityhad less effect on the HR compared with adjustment forSBP(table 2). Results were similar irrespective of whether

blood-pressure parameters were entered into the modelsas deciles or as continuous variables.

The group distributions of SBP at baseline and atfollow-up are shown in webappendix p 6. Group SD SBPdecreased after randomisation in the amlodipine group(figure 2), with a smaller change in coeffi cient of variation,whereas both SD and coeffi cient of variation increased inthe atenolol group, and remained higher than in theamlodipine group for the duration of follow-up(p


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(table 3). Daytime minimum SBP was lower in theatenolol group but there was no difference in maximumblood pressure. The morning surge was similar in bothgroups (eg, mean first ABPM after 6 months 281 mm Hg[95% CI 269293] in the amlodipine group vs275 mm Hg [262288] in the atenolol group), and wasweakly correlated with visit-to-visit variability in clinicSBP (r=002 for SD SBP).

Intra-ABPM variability in SBP (SD of daytime SBP)correlated with mean daytime SBP (r=026, p


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at baseline, but there were significant differences duringthe initial follow-up phase (024 months, figure 5). Boththe SD and the coeffi cient of variation were initiallyincreased in the atenolol group (p55 0515 1525 2535 3545 4555

Time from randomisation (years)

>55

0

79

83

87

91

95

Meanintra-A

BPM

daytimeCVSBP


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time the difference in mean blood pressure remainedlarge, but variability no longer differed. In the comparisonof atenolol with diuretic, the risk of stroke was again highin the first 2 years (183, 098342) and low at follow-upafter 2 years (093, 056156).

DiscussionIn the accompanying Article on the prognosticimplications of blood-pressure variability,24 increasedvisit-to-visit variability in blood pressure was a strongpredictor of the long-term risk of stroke after TIA, andpatients with good control of mean blood pressure but ahigh residual variability in SBP had a five times higherrisk of stroke than did those with low residual SBPvariability in ASCOT-BPLA.In this paper, we have addedto the evidence that the link between variability in blood

pressure and risk of stroke is likely to be causal. First,atenolol-based treatment and amlodipine-based treatmenthad opposite effects on within-individual variability inblood pressure (within-visit, visit-to-visit, and ABPM),independently of their effects on mean blood pressure.Second, the reduced event rates in the amlodipine groupin ASCOT-BPLA, which could not be fully accounted forby changes in mean blood pressure or in other riskfactors,4 can be explained by effects on visit-to-visitvariability in SBP. Third, in the MRC trial, atenololincreased visit-to-visit variability in SBP compared withplacebo, whereas the diuretic combination did not, andtemporal trends in variability in the atenolol group(probably caused by add-on use of thiazides and

nifedipine) were associated with stroke risk.We cannot conclude that the effects of the specificdrugs used in the ASCOT-BPLA and MRC trials onvariability are necessarily class effects. However, theaccompanying meta-analysis33 of all published data ongroup SD in SBP in all trials of blood-pressure-loweringdrugs shows consistent drug-class effects, with reducedgroup SD on calcium-channel blockers and increasedgroup SD on blockers. The mechanisms underlyingthese effects on variability in blood pressure areuncertain,25but changes in peripheral vascular resistanceare perhaps the most likely explanation: atenolol reducingarterial compliance by vasoconstriction and amlodipineincreasing it by vasodilatation. Structural remodelling of

the vasculature might also be responsible,25

but the earlyeffects of treatment on variability in ASCOT-BPLA andthe MRC trial, and the immediate reduction in blood-pressure variability on home blood-pressure-monitoringafter starting calcium-channel blockers25show that short-term mechanisms are mainly responsible. Reduction inheart rate is also a possible explanation for the effect ofatenolol, but heart rate and blood-pressure variabilitywere not correlated in ASCOT-BPLA or the MRC trial.

Amlodipine also reduced central blood pressure inASCOT-BPLA,34 but this did not explain the treatmenteffect, and has since been accounted for by differences inheart rate,35which were not correlated with variability in

blood pressure and did not account for the effect of treat-ment on risk of vascular events in our analyses. Benefitfrom the amlodipine-based regimen in ASCOT-BPLAwas also independent of baseline pulse rate.36The longerhalf-life of amlodipine could affect variability, but mostclinics took place at similar times of day, patients usuallytook medication in the morning, and the extent of themorning-surge was much the same in both treatmentgroups. Moreover, the effect of calcium-channel blockerson variability in the accompanying systematic review ofother trials was independent of drug half-life.33Differencesin compliance with study drugs are also unlikely to beconfounding given that the difference between treatment

groups in visit-to-visit variability was most notable in thestringently-defined on-treatment cohort and that within-visit and ABPM variability were both also reduced in theamlodipine group. The smaller benefit from amlodipinefor coronary events than for stroke might be because oftheir opposite effects on heart rate, although neithermean heart rate nor variability had prognostic value,24andneither accounted for the treatment effect in ASCOT-BPLA. Alternatively, mean SBP is a stronger risk factorfor stroke than for coronary heart disease and so thismight also be the case for variability.

Both within-visit variability in sitting SBP and daytimevariability in SBP on ABPM were lower in the amlodipine

Diuretic p Atenolol p Placebo

On the basis of nine visits from 2 weeks until 18 months*

Mean 1512 (121)


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group than in the atenolol group in the ASCOT-BPLAbut were weaker predictors of vascular events than wasvisit-to-visit variability24 and accounted less well for thereduced event rate in the amlodipine group, suggestingthat the larger variations in blood pressure that are seenfrom visit to visit better reflect the factor or factors thatare causally related to the risk of vascular events. Indeed,in the analysis of ASCOT-BPLA ABPM data, ASV SBPdid not predict stroke,24and accounted less well for theclinical benefit of amlodipine versus atenolol than didSD or coeffi cient of variation SBP. ASV measures short-term changes between adjacent blood-pressure readings,whereas SD or coeffi cient of variation are influenced bychanges over hours, give more weight to extreme values,and are therefore more sensitive to instability in bloodpressure related to specific stressors. Of note, maximum

SBP reached was more predictive of stroke than wasmean SBP in ASCOT-BPLA, on the basis of either clinicor ABPM measures, and in the UK-TIA trial.24Atenololwas associated with lower minimum daytime SBP andDBP, possibly because of a higher frequency of posturalfalls, which in the case of DBP might reduce coronaryperfusion. Further research is needed to establishwhether variability in DBP might be more closelyassociated with risk of coronary events than with stroke.

Our analyses of ASCOT-BPLA had some limitations.First, the treatment group comparison was not onlybetween atenolol and amlodipine. The trial protocolrequired that high blood pressure at any follow-up shouldtrigger either an increase in medication or an additional

clinic visit,3,4

and increased variability and high maximumblood pressure were therefore associated with use ofadditional drugs in both treatment groups.24 The timecourse of within-visit and ABPM variability in SBP duringfollow-up suggests that addition of bendroflumethiazideand other add-on drugs in the atenolol group reduced thehigh initial variability of SBP. Second, interpretation ofapparent correlates with treatment effects in randomisedtrials on the basis of data collected after randomisation isnot straightforward and is potentially subject to bias.However, our approach is not new in this respect. Manyprevious investigators have attempted to relate changesin mean blood pressure on follow-up to randomisedtreatment in similar trials, which will be subject to the

same potential biases. Moreover, all of our main analyseswere done on an intention-to-treat basis, which reducesthe risk of bias, and there were no differences betweenthe treatment groups in loss to follow-up. There werealso no differences in the number of missing follow-upvisits (37% overall), and so any bias in estimation ofvisit-to-visit variability is unlikely.

Third, our findings are not proof of a causal link betweenvariability in blood pressure and vascular risk. However,the fact that visit-to-visit variability accounts for thepreviously unexplained treatment effects in ASCOT-BPLAand other trials,25,33and can explain the greater reductionin stroke risk with calcium-channel blockers than expected

on the basis of changes in mean blood pressure and theless than expected reduction with blockers, supports acausal link. The accompanying Review provides othersupporting evidence.25 A collaboration to study within-individual variability in blood pressure in all availabletrials will assess the generalisability of our findings in theASCOT-BPLA and MRC trial (further informationavailable from corresponding author). However, assumingthat our findings are generalisable, absolute proof of acausal association would require a trial of an interventionthat only affected variability in blood pressure and had noeffects on mean blood pressure or other known and as yetunknown vascular risk factors. Such an intervention isunlikely to exist, although in stroke-prone spontaneouslyhypertensive rats, increased short-term variability in bloodpressure causes ischaemic stroke and other end-organ

damage,37

and experimental sinoaortic denervation (whichsubstantially increases variability in blood pressurewithout changing mean blood pressure) also causes end-organ damage,38even at normal mean blood pressure.38,39

Our analyses of the MRC trial also had limitations.Most importantly, we did not have data for individualpatients on add-on treatment with other drugs, and so wecannot be certain that the parallel reductions in groupSD SBP and within-individual variability after the initialfollow-up period in the atenolol group were due to theinitiation of treatment with other drug classes. However,use of other drugs was particularly high in the atenololgroup compared with the diuretic group (52% vs38% at5 years),26and the add-on drugs specified in the protocol

(particularly nifedipine) would have reduced variability.Irrespective of the explanation, the temporal associationbetween the reductions in variability and in stroke risk inthe atenolol group is consistent with the primaryhypothesis,25 and the initial increase in variability onatenolol versus placebo confirms the suggestion fromASCOT-BPLA that atenolol increases variability.

The effect of the diuretic combination versus placeboon variability in blood pressure in the MRC trial is lessclear. Absolute within-individual variability in SBP (ie, SDand ASV) was lower in patients receiving the diureticcombination than in those on placebo, but there was nodifference in variability relative to the lower mean SBP(ie, coeffi cient of variation). Analysis of group coeffi cient

of variation SBP in other trials suggests that thiazide andthiazide-like diuretics might reduce variability,36but to alesser extent than calcium-channel blockers.

Although more work is needed to fully understand thenature and consequences of variability in blood pressure,our findings have implications for the routinemanagement of hypertension, choice of medication,design and reporting of trials, and drug development.We have shown that effects of specific agents on within-individual variability of blood pressure can explaindifferences in clinical effi cacy, consistent with thefindings in the accompanying systematic review of allpublished data on group distributions of blood pressure


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during follow-up in trials of blood-pressure-loweringdrugs.33Data on blood pressure during follow-up shouldbe reported in more detail in future trials, andstabilisation of blood pressure is a potentially importanttarget for drug development and combination therapy.New drugs or combinations of drugs that reducevariability even more effectively than calcium-channelblockers could have a great effect on risk of stroke.Analysis of treatment effects in relation to variability inblood pressure assessed in a pre-randomisation run-inperiod might also be informative.

Contributors

PMR derived the hypothesis, planned and supervised the analyses, andwrote the paper. SCH and JED did the analyses. ED and EOB wereinvestigators in the ASCOT ABPM study, advised on analyses of theABPM data, and commented on drafts of the manuscript. NRP and PSSadvised on analyses of the main ASCOT-BPLA cohort, designed theASCOT-BPLA, along with BD, and commented on successive drafts ofthe manuscript.

ASCOT-BPLA ABPM collaborators

Ireland Molecular and Cellular Therapeutics and RCSI ResearchInstitute, Royal College of Surgeons in Ireland, Dublin (Alice V Stanton).UK National Heart and Lung Institute at St Marys Hospital, ImperialCollege London (Simon Thom), St Bartholomews Hospital, London(Mark Caulfield, David Collier), University of Glasgow, Glasgow(Gordon McInnes).

Conflicts of interest

PMR, NRP, and PSS are recipients of National Institute for HealthResearch (NIHR) Senior Investigator Awards. SCH was funded by theUK Medical Research Council and by the Oxford Partnership NIHRBiomedical Research Centre. NRP and PSS were supported by aBiomedical Research Centre Award to Imperial College National HealthService Health Care Trust and are in receipt of a British HeartFoundation Centre for Excellence Award. Pfizer was the major funding

source of the main ASCOT trial with additional support provided byServier Research Group, Paris, France. The MRC trial was funded by theUK Medical Research Council.

Acknowledgments

We thank Tom W Meade for allowing access to the MRC trial data. Wethank the investigators who worked on the ASCOT-BPLA and MRCtrials and the ASCOT-BPLA substudies committee for commenting onand authorising the initial protocol.

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