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Salt Intake and CVD - BMJ

Salt Intake and CVD - BMJ

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RESEARCH
Salt intake, stroke, and cardiovascular disease: meta-analysis of prospective studies
Pasquale Strazzullo, professor of medicine,
1
Lanfranco D’Elia, clinical lecturer in medicine,
1
Ngianga-BakwinKandala, principal research fellow in medical statistics,
2
Francesco P Cappuccio, professor of cardiovascularmedicine and epidemiology
2
 ABSTRACT
Objective
To assess the relation between the level of habitual salt intake and stroke or total cardiovascular disease outcome.
Design
Systematic review and meta-analysis of prospective studies published 1966-2008.
Datasources
Medline(1966-2008),Embase(from1988),AMED (from 1985), CINAHL (from 1982), Psychinfo (from1985), and the Cochrane Library.
Review methods
For each study, relative risks and 95%confidence intervals were extracted and pooled with arandom effect model, weighting for the inverse of thevariance. Heterogeneity, publication bias, subgroup, andmeta-regression analyses were performed. Criteria for inclusion were prospective adult population study,assessment of salt intake as baseline exposure,assessment of either stroke or total cardiovascular disease as outcome, follow-up of at least three years,indicationofnumberofparticipantsexposedandnumber of events across different salt intake categories.
Results
There were 19 independent cohort samples from13 studies, with 177025 participants (follow-up 3.5-19 years) and over 11000 vascular events. Higher saltintake was associated with greater risk of stroke (pooledrelative risk 1.23, 95% confidence interval 1.06 to 1.43;P
=
0.007)andcardiovasculardisease(1.14,0.99to1.32;P
=
0.07), with no significantevidence of publication bias.For cardiovascular disease, sensitivity analysis showedthat the exclusion of a single study led to a pooledestimateof1.17(1.02to1.34;P
=
0.02).Theassociationsobservedwere greaterthelargerthedifferenceinsodiumintake and the longer the follow-up.
Conclusions
High salt intake is associated withsignificantly increased risk of stroke and totalcardiovascular disease. Because of imprecision inmeasurementofsaltintake,theseeffectsizesarelikelytobe underestimated. These results support the role of asubstantial population reduction in salt intake for theprevention of cardiovascular disease.
INTRODUCTION
During the past century, the evidence for the risksimposed on human health by excess salt consumptionhas become compelling. The causal relation betweenhabitual dietary salt intake and blood pressure hasbeenestablishedthroughexperimental,epidemiologi-cal, migration, and intervention studies. Most adult populations around the world have average daily salt intakeshigherthan6g,andformanyineasternEuropeandAsiahigherthan12g.Internationalrecommenda-tionssuggestthataveragepopulationsaltintakeshouldbe less than 5-6 g per day. Population based inter-vention studies and randomised controlled clinicaltrials have shown that it is possible to achieve signifi-cant reductions in blood pressure with reduced salt intake in people with and without hypertension.
1
Based on the effects of high salt intake on blood pres-sure and on the prominent role of high blood pressurein promoting cardiovascular diseases, it has been sug-gested that a population-wide reduction in salt intakecould substantially reduce the incidence of cardio-vascular disease.
2
On the basis of the results of a meta-analysis of randomised controlled trials of salt reduction,
3
itwasestimatedthatareductioninhabitualdietarysaltintakeof6gadaywouldbeassociatedwithreductions in systolic/diastolic blood pressure of 7/4 mm Hg in people with hypertension and 4/2 mmHg in those without hypertension. At the populationlevel these reductions in blood pressure could predict an average lower rate of 24% for stroke and 18% forcoronary heart disease.
4
Validation of these predic-tions by a randomised controlled trial of the effects of long term reduction in dietary salt on morbidity andmortality from cardiovascular disease would providedefinite proof. At present, a study of this kind is not available and, in fact, it is extremely unlikely that it willeverbeperformedbecauseofpracticaldifficulties,the long duration required, and high costs. Neverthe-less, prospective cohort studies performed in the past three decades that measured the levels of dietary salt intakeatbaselineandrecordedtheincidenceofvascu-lar events have provided important indirect evidence.Most of these studies found evidence of such relation,althoughfewhadenoughpowertoattainstatisticalsig-nificance.We performed a systematic review and meta-analy-sis of the prospective studies of habitual dietary salt intakeandincidenceofstrokeandtotalcardiovascular
1
Department of Clinical andExperimental Medicine,
FedericoII
University of Naples MedicalSchool, Naples, Italy
2
University of Warwick, WHOCollaborating Centre for Nutrition,Warwick Medical School, ClinicalSciences Research Institute,Coventry CV2 2DX
Correspondence to: P Strazzullostrazzul@unina.it, FP Cappucciof.p.cappuccio@warwick.ac.uk
Cite this as:
BMJ 
2009;339:b4567
doi:10.1136/bmj.b4567BMJ |
ONLINE FIRST | bmj.com page 1 of 9
 
disease using strictly predetermined criteria for inclu-sionorexclusion.Weassessedwhetherornottheover-all evidence in prospective studies supports thepresence of a relation between levels of dietary salt intake and both stroke and cardiovascular outcomesand calculated an estimate of the risk.
METHODS
Data sources and searches
We performed a systematic search for publicationsusing Medline (1966-2008), Embase (from 1988),AMED(from1985),CINAHL(from1982),Psychinfo(from 1985), and the Cochrane Library. Search strate-gies used subject headings and key words with no lan-guage restrictions. Further information was retrievedthrough a manual search of references from recent reviews and relevant published original studies. Weexamined reference lists of the relevant reviews, iden-tified studies, and reviewed the cited literature.
5
Study selection
Two reviewers (LD and N-BK) independently extra-cted the data. Discrepancies about inclusion of studiesandinterpretationofdatawereresolvedbyarbitration(PS or FPC), and consensus was reached after discus-sion.Inthecaseofmissingdataforpotentiallysuitablestudies, we contacted authors and asked them to pro-vide the necessary information. To be included in themeta-analysis a published study had to be an originalarticle published from January 1966 to December2008, be a prospective population study, assess salt intake as baseline exposure, determine either strokeortotalcardiovasculardiseaseprospectivelyastheout-come, follow participants for at least three years,include an adult population, and indicate the numberof participants exposed and the rate or number of events in different categories of salt intake.Of the 3246 publications retrieved, we identified 15studiesthatmettheinclusioncriteria.Onewasadupli-cateanalysisofasinglecohortpreviouslydescribedbythe same authors
67
and another
8
referred to the samecohort (national health and nutrition examination sur-vey(NHANES)I)analysedbyotherauthorswithmorestringent criteria.
9
We therefore included 13 studies inthe meta-analysis that provided suitable data on 19population samples
610-21
(tables 1 and 2).
Data extraction
Fromthe identifiedstudiesandrespectivepopulationswe recorded publication reference, total number of participants, country, sex, age (mean, median, orrange), recruitment time, follow-up (years), outcomereported (stroke, cardiovascular disease) and methodof outcome assessment, number (rate) of events,method of assessing salt intake, and level of salt intakein different categories.Categorisation of salt intake differed among studies.Somereportedthenumberofsubjectsexposedandtherate (number) of events across the distribution of salt intake;othersreporteddifferencesintheeventratefora 100 mmol/day difference in sodium intake, as in thestudies by He et al
9
and Tuomilehto et al.
13
In the last two cases we used the relative risk or hazard ratioreported by the authors for the analysis. In all thecases in which categorisation of the study participantsby level of salt intake was available, we calculated therelative risk of higher versus lower salt intake by com-paringtheeventrateinthetwocategorieswithadiffer-ence in average salt intake closest to 100 mmol of sodium or about 6 g of salt a day.
Statistical analysis
We evaluated the quality of the studies included in themeta-analysis with the Downs and Black scoresystem.
21
We extracted relative risks or hazard ratiosfrom the selected publications and calculated theirstandard errors from the respective confidence inter-vals.Thevaluefromeachstudyandthecorrespondinstandard error were transformed into their naturallogarithms to stabilise the variances and to normalisetheir distribution. The pooled relative risk (and 95%confidence interval) was estimated with a randomeffect model, weighting for the inverse of thevariance.
22
The heterogeneity among studies wastestedbyQstatisticandquantifiedbyHstatisticandI
2
statistic.
23
The influence of individual studies, fromwhich the meta-analysis estimates are derived, wasexamined by omitting one study at a time to see theextent to which inferences depend on a particularstudy or group of studies (sensitivity analysis). Sub-group or meta-regression analyses were used to iden-tify associations between risk of stroke orcardiovascular disease and relevant study characteris-tics (age and sex of participants, year of publication,durationoffollow-up,methodofassessmentofsodiumintake, difference in sodium level, control for baselineblood pressure) as possible sources of heterogeneity.We used funnel plot asymmetry to detect publicationbiasandappliedEgger
sregressiontesttomeasureanyasymmetry.
2425
All statisticalanalyseswereperformedwithMIXsoftwareversion1.7
26
andStatasoftwareformeta-regression analysis.
RESULTS
Characteristics of the study cohorts
We included in the meta-analysis 13 studies reporting on 19 independent cohorts (table 1). There were177025 participants from six different countries (sixstudies from the United States, two each from Finlandand Japan, one each from the Netherlands, Scotland,and Taiwan). Eleven studies recruited both male andfemale participants, while two studies included onlymen. Follow-up ranged from 3.5 to 19 years. Four stu-diesreportedonlystrokeevents(eithertotalstrokerateor stroke deaths), three only cardiovascular disease(totalcardiovasculardiseaserateorcardiovasculardis-ease deaths), and six reported both. Salt intake wasassessed by 24 hour dietary recall (n
=
4), food fre-quency questionnaire (n
=
4), 24 hour urine excretion(n
=
4), and questionnaire (n
=
1). In total there were5346 strokes reported and 5161 total cardiovasculardisease events. Of the 11 studies that included both
RESEARCH
page 2 of 9
BMJ |
ONLINE FIRST | bmj.com
 
men and women, five reported outcomesseparately.
6913-15
TheTOHPstudyincludedtwodiffer-ent cohorts (I and II)
17
and the study by He and cow-orkersprovidedseparatefindingsformenandwomenor, alternatively, for normal weight and overweight participants.
9
Overall, data on the relation betweensalt consumption and stroke were available from 14cohorts and on the relation between salt intake andcardiovascular disease from 14 cohorts.The overall study quality, evaluated by the DownsandBlackscore,averaged15.5(range12-18)onascaleof 19 (table 1).
Salt intake and risk of stroke
Table 2 provides data on the relation between salt intake and risk of stroke in each of the 14 cohortsincluded in our study. Figure 1 shows the results of the pooled analysis. In the pooled analysis, higher salt intake was associated with greater risk of stroke (rela-tive risk 1.23, 95% confidence interval 1.06 to 1.43;
=
0.007).Therewassignificantheterogeneitybetweenstudies(P 
=
0.04;I
2
=
61%).Thefunnelplotdidnotshow asymmetry, thus excluding publication bias (Egger
stest P 
=
0.26; see appendix on bmj.com). As shown infigure 1 for the individual cohorts included in the ana-lysis, we found a trend towards a direct associationbetween salt intake and risk of stroke in nine cohorts,which was significant in four. We observed a non-sig-nificant inverse trend in three cohorts.Sensitivity analysis showed that the pooled estimateof the effect of salt intake on risk of stroke did not varysubstantially with the exclusion of any one study; inparticular, the exclusion of the study by Umesawa et al,
19
which accounted for about 40% of all participantsin the meta-analysis and nearly 20% of all strokes,resulted in a pooled relative risk of 1.19 (1.03 to 1.39),
=
0.022.
Salt intake and risk of cardiovascular disease
Table 2 provides data on the association between salt intake and the risk of cardiovascular disease in 14cohorts. In the pooled analysis, there was an associa-tion between higher salt intake and risk of cardio-vascular disease (1.14, 0.99 to 1.32; P 
=
0.07) (fig 2).The heterogeneity between studies was significan(P<0.01; I
2
=
80%), but the funnel plot did not show asymmetry, thus excluding publication bias (Egger
stest:
=
0.39; see appendix on bmj.com). The
Table 1
|
Characteristics of prospective studies included in meta-analysis of studies on salt intake and stroke and cardiovascular disease (CVD)
Study Age (years) Sex No of people Outcome(s) Outcome assessmentSodium intakeassessmentStudy qualityscore
Kagan,1985, US(Hawaii)
10
45-68 Men 7895 Total stroke Physicalexamination for residual ofstroke atbaseline,2 and 6 yearfollow-up; surveillance of hospitaldischargesand death certificates reviewedbyneurologist24h dietary recall 14Hu, 1992, Taiwan
11
36 Menand women 8562 Total stroke Casefindingthroughlocalhospitalreferralsandstudynurses. Certificationby computedtomographyHousehold surveyquestionnaire12Alderman, 1995, US,occupational
6
52; 54 Men; women 1900; 1037 Total CVD,totalstrokeReview ofhospitalchartsand death certificates (ICD-9): CVD I410,I430-I434, I436-I438; stroke asabovewithoutI41024h urinecollection12Tunstall-Pedoe,1997, Scotland
12
40-59 Men; women 5754; 5875 Total CVD Case notes requested for all hospital episodes of myocardialinfarctionandotheremergencyadmissionfor coronary heart disease,then extracted and codedaccordingto MONICA project criteria24h urinecollection15He, 1999, US,NHANESI
9
25-74 Men;women;non-overweight;overweight3686;5799;6797; 2688CVD death,totalstroke,stroke deathMortality basedondeath certificatereports.Incidentstroke based on death certificatereports inwhichunderlyingcause ofdeath was recorded withICD-9code(430-434.9,436or437.0-437.1)oroneormorehospitalstayswithdischarges withone ofthesecodes24h dietary recall 17Tuomilehto,2001,Finland
13
25-64 Men; women 1173; 1263 CVD death.totalstrokeNationalhospital discharge register ICD-8 and ICD-9,430-438, and 390-44824h urinecollection18Nagata, 2004, Japan
14
35 Men; women 13355; 15724 Stroke death Nationalvitalstatistics ICD-9 430-448 FFQ 18Cohen,2006, US,NHANESII
15
30-74 Menand women 7154 CVD death,stroke deathMortality basedondeath certificatereports ICD-9430-43824h dietary recall 18Geleijnse, 2007,Netherlands
16
55 Menand women 1448 CVD death,totalstrokeGPs registries (ICD-10): I20-I25,I46,I49,I50,I60-I67,I70-I74 and R96;I60-I67FFQ and overnighturine sodium15Cook, 2007, US,TOHPI,USA,TOHPII
17
30-54; 30-54 Menand women;men and women542;1873 Total CVD Notification ofnon-fataloutcomes inpost-trialsurveillance,reviewbyphysicianplusNationalDeathIndex24h urinecollection12Larsson, 2008,Finland
18
50-69 Men(smokers) 26,556 Total stroke Dischargediagnosesand deathcertificates (ICD-8,9,and 10)FFQ 15Umesawa, 2008, Japan
19
40-79 Men; women 23119; 35611 CVD death,stroke deathNationalVital Statistics ICD-9 FFQ 4
×
3 daydietary records18Cohen,2008, US,NHANESIII
20
30 Menand women 8699 Total CVD Vital statusand cause ofdeath (ICD-9 and ICD-10) 24h dietary recall 18
FFQ 
=
food frequency questionnaire.
RESEARCH
BMJ |
ONLINE FIRST | bmj.com page 3 of 9

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