pediatrics 2013- sreening para has

Screening for Hypertension in Children and Adolescentsto Prevent Cardiovascular Disease

abstractBACKGROUND AND OBJECTIVE: The prevalence of hypertension is in-creasing in children, and may persist into adulthood. This systematicreview was conducted for the US Preventive Services Task Force rec-ommendation on the effectiveness of screening asymptomatic childrenand adolescents for hypertension in order to prevent cardiovasculardisease.

METHODS: Eligible studies were identified from Medline and theCochrane Library (through July 2012). We included trials and controlledobservational studies in asymptomatic children and adolescents on theeffectiveness and harms of screening and treatment, as well as accu-racy of blood pressure measurement. One author extracted study char-acteristics and results, which were checked for accuracy by a secondauthor.

RESULTS: No studies evaluated the effects of screening for hyperten-sion on health outcomes. Two studies of screening tests for elevatedblood pressure reported moderate sensitivities (0.65, 0.72) and speci-ficities (0.75, 0.92). Sensitivities and specificities of child hypertensionfor the later presence of adult hypertension (7 studies) were wideranging (0–0.63 and 0.77–1.0, respectively), and associations betweenchild hypertension and carotid intima media thickening and protein-uria in young adults (3 studies) were inconsistent. Seven studiesreported that drug interventions effectively lowered blood pressurein adolescents over short follow-up periods. No serious treatment-related adverse effects were reported.

CONCLUSIONS: There is no direct evidence that screening for hyper-tension in children and adolescents reduces adverse cardiovascularoutcomes in adults. Additional studies are needed to improve diagnosisand risk stratification of children with elevated blood pressure and toquantify risks and benefits of interventions. Pediatrics 2013;131:490–525

AUTHORS: Matthew Thompson, MD, MPH, DPhil,a,b TracyDana, MLS,a Christina Bougatsos, MPH,a Ian Blazina, MPH,a

and Susan L. Norris, MD, MPH, MSca

aOregon Evidence-Based Practice Center, Oregon Health andScience University, Portland, Oregon; and bDepartment ofPrimary Care Health Sciences, Oxford University, Oxford, UnitedKingdom

KEY WORDShypertension, children, adolescents, screening, treatment, drug,lifestyle

ABBREVIATIONSADAPT—Dietary/Exercise Alteration Program TrialCI—confidence intervalDBP—diastolic blood pressureOR—odds ratioRCT—randomized controlled trialSBP—systolic blood pressureUSPSTF—US Preventive Services Task Force

Dr Thompson made substantial contributions to conception anddesign, acquisition of data, analysis and interpretation of data,drafted the article and revised it critically for importantintellectual content, and gave final approval of the version to bepublished. He is guarantor for this article. Ms Dana andBougatsos, Mr Blazina, and Dr Norris made substantialcontributions to conception and design, acquisition of data,analysis and interpretation of data, revised the article criticallyfor important intellectual content, and gave final approval of theversion to be published.

The staff at the Agency for Healthcare Research Quality andmembers of the US Preventive Services Task Force developedthe scope of the work and reviewed draft manuscripts. Approvalfrom the Agency for Healthcare Research Quality was requiredbefore the manuscript was submitted for publication, but theauthors are solely responsible for the content and the decisionto submit it for publication.

www.pediatrics.org/cgi/doi/10.1542/peds.2012-3523

doi:10.1542/peds.2012-3523

Accepted for publication Dec 19, 2012

Address correspondence to Matthew Thompson, MD, MPH, DPhil,Department of Primary Care Health Sciences, Oxford University,New Radcliffe House, Woodstock Road, Oxford OX2 6GG, UK. E-mail:[email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2013 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they haveno financial relationships relevant to this article to disclose.

FUNDING: This review was supported by the Agency forHealthcare Research Quality for the US Preventive Services TaskForce under contract 290-2007-10057-I to support the work ofthe US Preventive Services Task Force.

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mailto:[email protected]

http://pediatrics.aappublications.org/

Between 1% and 5% of children andadolescents have hypertension, and itsprevalence has risen in the UnitedStates by 1% to 2% over recent deca-des.1–4 Hypertension is usually asymp-tomatic, and a significant proportion ofchildren with hypertension are un-diagnosed.5,6 Screening children andadolescents for elevated blood pres-sure could identify hypertension at anearly stage where interventions couldbe initiated, potentially decreasing therate of progression of hypertensionfrom childhood to adulthood and re-ducing the clinical consequences ofhypertension in adulthood.7

The strongest risk factor for primaryhypertension in children of all ages andboth genders is elevated BMI8–14; chil-dren who are overweight or obese havea two- to threefold increased risk ofhypertension.8–10 This increased risk isparticularly concerning given that∼17% of children and adolescents inthe United States are now obese15 andhave higher risk of other cardiovascu-lar risk factors such as an adverselipid profile and insulin resistance.16

Other risk factors for primary hyper-tension include low birth weight, gen-der, ethnicity, and a positive familyhistory.2,3,9,10,17–19

Secondary hypertension is most com-monly related to underlying renal pa-renchymal or renovascular disease;less common causes include aorticcoarctation and endocrine disorders.20,21 Elevated blood pressure is usuallyonly 1 clinical manifestation of the un-derlying disorder, and treatment istypically directed at correcting theunderlying cause.

For the majority of children and ado-lescents, the rationale for identifyingelevated blood pressure lies in the po-tential to stratify risk of future cardio-vascular disease. There is convincingevidence that structural and functionalchanges in the cardiovascular system,which indicate early atherosclerosis,can be detected in adolescents andyoung adults. What is less clear are thenature and magnitude of the relation-ship between elevated blood pressureand other cardiovascular risk factors inchildren or adolescents and cardiovas-cular risk in adults. Cohort studies thathave followed children to young adult-hood suggest that adiposity, insulin re-sistance, and an adverse lipid profileprogress at an increased rate in pre-hypertensive and hypertensive childrenand adolescents compared with nor-motensive children.7,22,23

AIMS OF THIS REVIEW

Thepurpose of this systematic review isto provide the US Preventive ServicesTask Force (USPSTF) with evidence toupdate their 2003 recommendation onscreening for high blood pressure inchildren and adolescents.24 The largerreview is available at www.uspreventi-veservicestaskforce.org.25 With the in-put of members of the USPSTF, wedeveloped an analytic framework (Fig 1)and key questions to guide our litera-ture search and review.

1. Is screening for hypertension inchildren/adolescents effective indelaying the onset or reducing ad-verse health outcomes related tohypertension?

2. What is the diagnostic accuracy ofscreening tests for elevated bloodpressure in children/adolescents?

3. What is the association between hy-pertension in children/adolescentsand hypertension and other inter-mediate outcomes in adults?

4. What are the adverse effects ofscreening for hypertension in children/adolescents, including labeling andanxiety?

5. What is the effectiveness of drug, non-drug, and combination interventions

FIGURE 1Analytic framework and key questions. aThe assessment and treatment of secondary hypertension is beyond the scope of this review. bIncludes left ventricularhypertrophy, urinary albumin excretion (microalbuminuria), intima media thickness (measured at carotid and/or femoral arteries), and retinal vascularchanges. KQ, key question.

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for treating primary hypertensionin children/adolescents?

6. What is the effectiveness of drug,nondrug, and combination inter-ventions initiated for the treatmentof primary hypertension in children/adolescents for reducing blood pres-sure and other intermediate outcomesin adults?

7. What is the effectiveness of drug,nondrug, and combination inter-ventions initiated for the treatmentof primary hypertension in children/adolescents for reducing adversehealth outcomes in adults relatedto primary hypertension?

8. What are the adverse effects ofdrug, nondrug, and combinationinterventions for treating primaryhypertension in children/adoles-cents?

METHODS

ThisreviewwasdevelopedbytheOregonEvidence-Based Practice Center undercontract with the Agency for HealthcareResearch Quality (contract 290-2007-10057-I) and follows the systematic re-view methods of the USPSTF.26,27

Search Strategies

We searched the Cochrane CentralRegister of Controlled Trials and theCochrane Database of SystematicReviews (through July 2012) and Med-line (1946 to July 9, 2012) for relevantstudies and systematic reviews, andmanually reviewed reference lists forrelevant citations (Appendix 1).

Study Selection and Processes

Papers were selected for full review ifthey met predefined inclusion criteria(Appendix 2). Controlled studies ofscreening for hypertension in asymp-tomatic children and adolescents wereincluded. For studies of diagnostic ac-curacy, eligible studies included a refer-encestandardcomparisonandprovided

adequate data to reproduce contingencytables. Evidence from randomizedplacebo-controlled trials was used toassess the efficacy of treatments onmultiple outcomes, including bloodpressure, other intermediate healthoutcomes, and final health outcomes, inchildhood, adolescence, and adulthood.Studies with ,30 participants andstudies of interventions for the treat-ment of obesity and lipid disorders inchildren were excluded, because thesepopulations are considered in otherUSPSTF recommendations.28,29 To assessharms of treatment, studies withouta comparison or a placebo group wereincluded. Studies of secondary hyper-tension were excluded, although somestudies included proportions of partic-ipants with secondary hypertension.

All citations identified throughsearchesand other sources were independentlyreviewed by 2 authors for inclusion andexclusion. Discrepancies at the full-textlevelwere resolved through consensus.One author extracted data on the pa-tient population, study design, testingmethods, analysis, follow-up, and re-sults, andasecondauthorcheckeddataextraction for accuracy.

Quality Assessment and Synthesis

By using predefined criteria developedby the USPSTF,26 2 authors rated thequality of studies (good, fair, poor) andresolved discrepancies by consensus.Authors assessed the overall strengthof the body of evidence for each keyquestion as good, fair, or poor by usingmethods developed by the USPSTF onthe basis of the number, quality, andsample size of studies, as well as theconsistency of results among studiesand directness of the evidence.26 Thelimited number of studies and theheterogeneity of study designs, inter-ventions, and diagnostic tests pre-cluded meta-analyses; results aretherefore summarized qualitatively asmeans or as ranges, as appropriate.

RESULTS

Our literature search identified a totalof 6435 citations, of which we reviewed1059 full-text publications and included34 studies (Fig 2).

Key Question 1: Is Screening forHypertension in Children/Adolescents Effective in Delayingthe Onset or Reducing AdverseHealth Outcomes Related toHypertension?

No randomized trials compared healthoutcomes related to hypertension inscreened versus nonscreened child oradolescent populations.

Key Question 2: What Is theDiagnostic Accuracy of ScreeningTests for Elevated Blood Pressurein Children and Adolescents?

We identified 2 fair-quality studies thatprovided data on the diagnostic accu-racyof screening tests (Appendix 3).30,31

Compared with a reference standardof 24-hour ambulatory measurement,office-based blood pressure measure-ment (3 measurements at each of 2clinic visits) had a sensitivity of 0.65(95% confidence interval [CI], 0.45–0.80) and a specificity of 0.75 (95% CI,0.63–0.84).31 The positive predictivevalue was 0.37 (95% CI, 0.28–0.47) andthe negative predictive value was 0.63(95% CI, 0.53–0.72). All 105 participants(mean age, 13 years) had been re-ferred for evaluation at a specialtyclinic, so they may not have been rep-resentative of screened populations ofasymptomatic children. In addition,ambulatory measurement is not yetan internationally accepted referencestandard in children and adolescents.A second study examined a randomsample of 9017 eighth graders, ofwhom about 10% (900/9017) had bloodpressure .95th percentile on initialscreening, whereas the remainder(8117/9017) were normotensive.30 Atfollow-up in 10th grade, the sensitivity



and specificity of initial elevated bloodpressure for persistent elevation ofblood pressure were 0.72 (95% CI,0.65–0.78) and 0.92 (95% CI, 0.91–0.92),respectively; however, the positivepredictive value was low (0.17 [95% CI,0.15–0.20]). This study primarily fol-lowed only the sample of childrenwhose initial screening test was posi-tive rather than the entire population,which may have biased the diagnosticaccuracy in this study.

In addition, 12 studies compared $1measurement of blood pressure withsubsequent reference measurementsbut did not meet our inclusion criteriabecause either they failed to apply thereference tests to participants whoinitially screened negative or they didnot use an acceptable reference stan-dard.11,32–42 Positive predictive valuesamong these studies ranged from 0.04to 0.53. The reasons for this heteroge-neity were unclear but did not appear

to be related to varying prevalence ofhypertension, method or device usedfor testing, or thresholds used to de-fine positive tests.

Key Question 3: What Is theAssociation Between Hypertensionin Children/Adolescents andHypertension and OtherIntermediate Outcomes in Adults?

Ten longitudinal studies provided evi-dence on the association between ele-vated blood pressure or hypertensionin childhood and elevated blood pres-sure, hypertension, or intermediateoutcomes in adults (Appendix 4).7,43–51

These studies used different thresh-olds for defining elevated blood pres-sure and hypertension in childhoodand different definitions of hyperten-sion in adults. The sensitivities andspecificities of elevated blood pressureor hypertension in childhood for pre-dicting adult hypertension ranged from

0 to 0.63 and 0.77 to 1, respectively,depending on thresholds.45,47,51 Positivepredictive values (ie, the probability ofadult hypertension given the presenceof elevated blood pressure or hyper-tension in childhood) ranged from 0.19to 0.65.45,47 Five studies reported sig-nificant associations between elevatedblood pressure in childhood and hy-pertension in adults, with odds ratios(ORs) ranging from 1.1 to 4.57,47 andrelative risks ranging from 1.5 to 9.43,44,48

Two studies reported conflicting find-ings on the association between child-hood hypertension and carotid intimamedia thickness in young adults. Sys-tolic blood pressure (SBP) .80th per-centile in adolescence was mildlyassociated with carotid intima mediathickness in adulthood in 1 study (re-gression coefficient, 0.013; P, .001).50

A second study, however, found no in-creased risk of carotid intima mediathickness in adulthood related to

FIGURE 2Literature search flow diagram. aCochrane databases include the Cochrane Central Register of Controlled Trials and the Cochrane Database of SystematicReviews. bOther sources include reference lists, suggested by peer reviewers, etc. cSome articles are included for.1 key question. dTwelve of these studiesdid not provide enough data to recreate 2 3 2 tables or calculate sensitivity and specificity.

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elevated systolic blood pressure inchildhood (highest quartile versuslower 3 quartiles: OR, 1; 95% CI, 0.80–1.25), although the level of SBP elevationis not defined in this study.49 Childhoodhypertension was significantly associ-ated with microalbuminuria in blackbut not white adults in a single study.46

We found no evidence for associationsbetween diagnosed hypertension inchildhood and other intermediate orfinal health outcomes.

Key Question 4: What Are theAdverse Effects of Screening forHypertension in Children andAdolescents, Including Labelingand Anxiety?

One small good-quality study compared85 children (10–18 years of age) withelevated blood pressure identified byscreening to children matched by ageand gender from the same commu-nity.52 The only outcome reported wasrates of school absenteeism, which didnot differ significantly between the 2groups.

Key Question 5: What Is theEffectiveness of Drug, Nondrug,and Combination Interventions forTreating Primary Hypertension inChildren and Adolescents?

Fourteen fair-quality randomized con-trolled trials (RCTs)33,53–66 (in 15 pub-lications) of treatment of hypertensionin children and adolescents met in-clusion criteria (Table 1; Appendix 5). Theproportion of children with primary hy-pertension ranged from 31%54 to 56%55;however, most studies did not report theproportion of participants with second-ary hypertension.53,57–60,62,64–66

Drug Interventions

All seven included trials of drug inter-ventions examined different drugs.53–59

Most compared active drug (in differ-ent doses) to placebo, with follow-up ofonly 4 weeks. The magnitude of effects

on SBP and diastolic blood pressure(DBP) varied and were not consis-tently different from changes inblood pressure in the placebo group(or these differences were not re-ported).

Five studies53,54,57–59 reported the per-centage of participants achieving tar-get blood pressure at the end of thefollow-up period, and all noted an in-crease in those who achieved targetlevels with the active drug (range 15–86% of subjects). However, 26% to 47%of children in the placebo groups alsoachieved normal blood pressure at theend of the study period.53–59 Moststudies reported significant reductionsinmean SBP (range, 1.9–10.2mm Hg) andDBP (range, 0.4–8.1 mm Hg). Eplerenone(50 mg/day) produced a small increasein mean SBP and no change in DBP.55

Most studies had limitations, most no-tably the failure to report the statisticalsignificance of differences between treat-ment groups in addition to within-grouptreatment differences. Also, comparisonamong studies was difficult because ofvarying drug dosages.

Drug Plus Lifestyle Interventions

The school-based A Dietary/ExerciseAlteration Program Trial (ADAPT) ex-amined the effectiveness of a multi-component, school-based intervention,including nutrition education for andpromotion of diet modification to chil-drenandparents; expandedcommunityavailability of low-sodium foods in gro-cery stores, restaurants, and schoollunches; a school-based exercise pro-gram; and propranolol and chlorthali-done compared with a no interventiongroup.60,61 This complex interventionresulted in a significant decrease inboth SBP and DBP at the 6-monthfollow-up (mean SBP change: 27.6mm Hg [P, .0001]; mean DBP change:26.9 mm Hg [P, .01]) compared withthe control group. At 30 months, how-ever, SBP increased from baseline in

both the intervention (1.4 mm Hg) andcontrol groups (3.5 mm Hg), althoughDBP remained below baseline levels(mean change: 24.2 mm Hg in the in-tervention group and 23.3 mm Hg inthe control group).

Lifestyle Interventions

Most of the six trials examining lifestyleinterventions included support relatedto the interventions (eg, regular check-ins) in addition to diet, exercise, ormeditation.33,62–66 Only 1 study demon-strated statistically significant reduc-tions in blood pressure comparedwith untreated controls.64 This small,school-based RCT compared the effectsof 5 versus 3 weekly physical educationclasses in hypertensive children andreported that blood pressure de-creased significantly more in partic-ipants receiving 5 weekly classes overthe 8-month follow-up period (meanbetween-group difference in SBP =24.9mm Hg and DBP =23.8 mm Hg; P, .05for both outcomes).64 In another trial,a low-sodium diet combined with per-sonalized support from a nutritionistand/or potassium chloride supplemen-tation was effective in reducing bloodpressure compared with usual careplus placebo at 36 months among girlsbut not among boys.66 Other studies ofmeditation,63 relaxation,33 and dietarychanges62,65 reported no significantdifferences between intervention andcontrol groups.

Key Question 6: What Is theEffectiveness of Drug, Nondrug,and Combination InterventionsInitiated for the Treatment ofPrimary Hypertension in Children/Adolescents for Reducing BloodPressure and Other IntermediateOutcomes in Adults?

No RCTs examined the effectiveness ofinterventions for hypertension in chil-dren or adolescents for reducing bloodpressure or other intermediate out-comes in adults.



TABLE 1 Effect of Interventions on Blood Pressure: Reported Mean Differences From Baseline and/or Placebo

Author, Year, Duration Interventions Baseline (mm Hg) Follow-up(mm Hg)

Mean Difference:Follow-up VersusBaseline (mm Hg)

MeanDifference atFollow-up:Intervention

VersusPlacebo(mm Hg)

SBP DBP SBP DBP SBP DBP SBP DBP

Drug interventionsBatisky et al 200776 (4 wk) Metoprolol 0.2 mg/kg 131.4 76.3 126.2 73.2 25.2 23.1 24.6 26.1

Metoprolol 1.0 mg/kg 135.0 81.0 127.3 76.1 27.7 24.9 23.5 23.2Metoprolol 2.0 mg/kg 130.60 76.7 124.3 69.2 26.3 27.5 20.2 210.1Placebo 132.7 81.4 130.8 79.3 21.9 22.1 — —

Flynn et al 200454 (4 wk) Amlodipine 2.5 mg 137.9a 74.2a Not reported 26.9 24.2 Not reportedAmlodipine 5 mg 28.7 24.4Placebo 23.6 20.4 — —

Li et al 201055 (4 wk) Eplerenone 25 mg 125.0 71.3 124.1 70.7 20.9 20.6 25.4 0.8Eplerenone 50 mg 125.7 70.9 126.2 70.9 0.5 0.0 23.3 1.0Eplerenone 100 mg 128.1 70.3 127.0 69.4 21.1 20.9 22.5 20.5Placebo (mean, all arms) 128.7 70.4 129.5 69.9 0.8 20.5 — —

Sorof et al 200256 (4 wk) Bisoprolol + hydrochlorothiazide(all doses)

133.8 83.0 124.0 76.0 29.8 27.0 24.5 23.5

Placebo 133.8 81.8 128.5 79.5 25.3 22.3 — —

Trachtman et al 200357 (3 wk) Felodipine 2.5 mg Not reported 20.7 22.1Felodipine 5 mg 20.1 24.6Felodipine 10 mg 21.1 1.3Placebo Not reported 83.1 Not reported 81.0 Not reported 22.1 — —

Trachtman et al 200858 (4 wk) Candesartan (all doses) Not reported 210.2 26.6 Not reportedPlacebo 23.7 21.8 — —

Wells et al 201059 (4 wk) Telmisartan, low-dose 132.0 79.0 123.0 71.3 29.7 28.1 23.6 24.2Telmisartan, high-dose 131.0 78.4 117.0 70.6 214 27.8 28.5 24.9Placebo 130.0 78.4 126.0 75.5 26 23.5 — —

Drug plus lifestyle interventionsBerenson et al 198360 (6 mo) ADAPT program 116.6 77.7 109.0 70.8 27.6 26.9 26.5 23.6

Control 118.5 78.3 115.5 74.4 23.0 23.9 — —

Berenson et al 199061 (30 mo)b ADAPT program 116.6 77.7 118.0 73.5 1.4 24.2 23.6 21.7Control 118.5 78.5 122.0 75.2 3.5 23.3 — —

Lifestyle interventionsCouch et al 200862 (6 mo) DASH diet 129.4 80.4 120.1 75.2 29.3 25.2 0.1 21.2

Routine care 124.3 81.7 120.0 76.4 24.3 25.3 — —

Ewart et al 198733 (9 mo) Relaxation training 127.0 79.1 118.6 72.9 28.4 26.2 22.3 23.1No intervention 126.5 80.4 120.9 76.0 25.6 24.4 — —

Gregoski et al 201163 (3 mo) Meditation 119.4 68.1 116.6 66.3 22.8 21.8 24.4 22.4LifeSkills training 119.6 68.0 119.8 68.2 0.2 0.2 21.2 20.5Regular health education 121.4 69.3 121.0 68.7 20.4 20.6 — —

Hansen et al 199164 (3 mo) Extra physical education classes Not reported 24.9 23.8No extra classes — —

Howe et al 199165 (4 wk) Low sodium diet 115.0a 60.1a 112.6 59.1 Not reported 21.2 20.9High sodium diet 113.8 60 — —

DASH, Dietary Approaches to Stop Hypertension; —, indicates that data is not available.a Values for total cohort; data not stratified according to treatment group.b Continuation of Berenson et al 1983 study.

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Key Question 7: What Is theEffectiveness of Drug, Nondrug,and Combination InterventionsInitiated for the Treatment ofPrimary Hypertension in Children/Adolescents for Reducing AdverseHealth Outcomes in Adults Relatedto Primary Hypertension?

No RCTs examined the effectiveness ofinterventions for hypertension in chil-dren or adolescents for reducing clin-ical outcomes in adults.

Key Question 8: What Are theAdverse Effects of Drug, Nondrug,and Combination Interventions forTreating Primary Hypertension inChildren and Adolescents?

Drug Interventions

Twelve trials reported adverse eventswith drug therapy (Appendix 6).53–59,67–71

One study was rated good quality67; theremainderwereof fairquality.53–55,57–59,68–71

Four of the studies included childrenwithprimary hypertension,53,57–59 whereas theremainder included children with pri-mary or secondary hypertension.54,55,67–71

The number of children enrolled in thestudies ranged from 76 to 304, the meanage ranged from 12 to 14 years, and theduration of follow-up for reporting ad-verse events ranged from 4 weeks to 1year.

Serious adverse events were rarelyreported, and there were no deaths inany of the studies. One study of meto-prolol reported 1 case each of pneu-monia andmetometrorrhagia.53 Anotherstudy reported a case of near syncopeand an elevated creatinine in a patientwho received an incorrect dose of tel-misartan. A third study reported 8 seri-ous adverse events among 304 patients,although none were considered to betreatment related.55

Adverse event data were often poorlyreported, and most studies reportednoncomparative data from open-labelextensions of RCTs. Five studies ofmonotherapy reported similar rates of

adverse events in the intervention(range, 27–77%) and placebo groups(range, 25–66%).55,57,59,67,68 Childrentaking a combination of bisoprolol plushydrochlorothiazide had lower overallrates of adverse events compared withplacebo (53–75%, P = .05) after 12weeks of follow-up.56 Withdrawalscaused by adverse events ranged from0% to 7% in children receiving activetreatments53,54,56–59,67–71 and 0% to6.2% in placebo groups.53,56,58,59,67,68

Headache was the most common spe-cific adverse event in most studies:rates ranged from 2% to 33% in childrenreceiving active treatments,53,56,57,59,68,71

but only 2 studies reported rates forthe placebo group. One study reportedthat no headaches occurred in theplacebo group compared with 11%of active treatment patients,59 where-as in a second study, headache wasreported in 31% versus 26% (pla-cebo versus combination treatment,significance not reported).56 Othercommonly reported adverse eventsassociated with active treatmentswere cough, upper respiratory in-fections, and gastrointestinal events,including nausea and diarrhea, al-though specific rates were not alwaysreported.53,54,56–59,68–71

Two studies pooled adverse event datafrom selected drug trials submittedto the Food and Drug Administrationover a 7-year period; however, neitherstudyusedstandardsystematic reviewmethods.72,73 Pooled patient-level datafrom 1707 children from 10 placebo-controlled RCTs of 10 different activeagents72 revealed similar rates of ad-verse events between active treat-ment (0.83 events per patient) andplacebo groups (0.76 per patient) af-ter 2 to 4 weeks of follow-up (between-group P = .37). Pooled data from 8 RCTsof hypertensive children revealed nodifference in the incidence of coughbetween active treatment and placebogroups (3% in both groups; P = .86).73

Other Interventions

The fair-quality ADAPT of a propranololand chlorthalidone/lifestyle interventiondescribed inkeyquestion54reportednoadverse events.60,61 No studies of life-style modification alone reported ad-verse events.

DISCUSSION

Direct evidence linking screening ofchildren and adolescents for hyper-tension and delaying the onset orreducing the risk cardiovascular out-comes in adults is not available, andindirect evidence is sparse and of vari-able quality. We did not identify evidencefor the effectiveness of interventionsused to treat primary hypertension inchildren on lowering blood pressurelevels or reducing adverse health out-comes in adults. A summary of the evi-dence is provided in Table 2.

High-quality data on the diagnostic ac-curacy of blood pressuremeasurementto detect hypertension were alsosparse and suggest moderate sensi-tivities (0.65 and 0.72), with somewhathigher specificities (0.75 and 0.92).These data suggest that many childrenwho have elevated blood pressure onscreening will not have hypertension.There are also some data to suggestthat hypertension in childhood is as-sociated with hypertension in youngadults (OR range, 1.1–4.5; relative riskrange, 1.5–9) or has low to moderatesensitivities (0 and 0.63) and specific-ities (0.77 and 1) for predicting adulthypertension. Moreover, the associa-tion between childhood hypertensionand carotid intima media thicknessand microalbuminura in young adultswas also inconclusive, and direct evi-dence on other intermediate or finalhealth outcomes was lacking.

The effectiveness of antihypertensivemedications in children and adoles-cents has been examined in 7 trials, allof which were small and of short du-ration, and each examined a different



TABLE 2 Summary of Evidence

Number of Studies(Overall Quality)

Limitations Consistency Applicability toPrimary Care

Summary of Findings

Key question 1: Is screening for hypertension in children/adolescents effective in delaying the onset or reducing adverse health outcomes related to hypertension?No studies NA NA NA NA

Key question 2: What is the diagnostic accuracy of screening tests for elevated blood pressure in children/adolescents?2 trials (poor) Studies were flawed or not directly applicable

to an asymptomatic US population. Only 1included a comparisonwith a gold standardof ambulatory monitoring.

Consistent Low Sensitivity and specificity of office-basedscreening for hypertension was 0.65 and0.75 (positive predictive value, 0.37)compared with ambulatory screening in 1study of a referred population.

A second, school-based study comparing aninitial positive screen to subsequentdiagnosis of hypertension had sensitivity(0.72) and specificity (0.92), but the positivepredictive value was lower (0.17).

Key question 3: What is the association between hypertension in children/adolescents and hypertension and other intermediate outcomes in adults?10 cohort studies (poor) Studies used different thresholds for defining

elevated blood pressure and hypertensionin children and different definitions ofhypertension in adults. Studies hadmethodologic shortcomings.

Inconsistent Moderate Sensitivities and specificities of elevated bloodpressure or hypertension from childhood toadult hypertension ranged from0 to 0.66 andspecificities of 0.77 to 1. PPVs ranged from0.19 to 0.65. Five studies reported significantassociations between elevated bloodpressure in childhood and hypertension inadults, with ORs ranging from 1.1 to 4.5 andRRs of 1.5 to 9. Two studies reportedassociations between childhoodhypertension and carotid intima mediathickness in young adults, with conflictingfindings. One study reported a significantassociation between childhood hypertensionand microalbuminuria only in blackindividuals.

Key question 4: What are the adverse effects of screening for hypertension in children/adolescents, including labeling and anxiety?1 study (poor) Evidence limited to results from1, good-quality

studyNA (1 study) High Children labeled as hypertensive did not miss

more days of school in the year afterdiagnosis compared with prelabeling orcompared with nonhypertensive children.Other harms associated with screeningwere not reported.

Key question 5: What is the effectiveness of drug, nondrug, and combination therapies for treating primary hypertension in children/adolescents?14 RCTs (poor) Longest drug study duration was only 4 wk Consistent Moderate Children achieving normotensive status (on the

basis of varyingdefinitions) ranged from15%to86%inpatients takingdrugtreatmentsand11% to 48% in patients taking placebo.

For many studies, the proportion of childrenwith secondary hypertension was unclear

There were significant reductions ofmean SBP(range 2–10 mm Hg), and mean DBP (range0.4–8 mm Hg) with some drugs anddosages. The difference betweenintervention and placebo groups rangedfrom 0 to 9mm Hg for SBPand 0.5 to 10mmHg for DBP. However, reductions were oftenonly at higher doses of active treatments,and studies only lasted for 4 wk.

One school-based study of a drug plus lifestyleintervention reported a significant,sustained reduction in blood pressure in thecombination group versus the control group.

Studies of nondrug therapies were limited, andonly 1 study examining the effect ofadditional physical education classes inschool reported a sustainedmean reductionin blood pressure in for both boys and girls.

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agent. Most importantly, their antihy-pertensive effects varied in magnitude,were not consistently present fora given agent for both SBP and DBP, andwere not consistently different fromplacebo or from baseline. Blood pres-sures inplacebogroupsoften improvedalong with those of the interventiongroup, suggesting regression to themean. From the limited data we iden-tified, medications appeared to be welltolerated, with no serious adverseeffects.

Interventions for treating elevatedblood pressure that involve lifestyleinterventions alone or in combinationwith an antihypertensive medicationfound inconsistent results. Of the 3studies that had positive results, in-creased physical education at schoolwas effective at reducing blood pres-sure in 1 study,64 whereas in a secondlonger-term school-based study, the

effects of an antihypertensive com-bined with a complex lifestyle program(the ADAPT program) were not sus-tained,60,61 and finally, a low sodiumdiet combined with personalized sup-port was only effective in girls.66

Themost important potential limitationof this review was the absence of anyevidence to address several of the keyquestions and the limited quantity andquality of evidence for others. This lackof evidence inevitably limits the con-clusions that can be drawn from thisreview. Second, our search strategy,although rigorous, may have failed toidentify relevant studies. We used ci-tation searching of included articlesand reviewed all articles identified bythe expert reviewers to augment oursearch strategy. We limited our searchto English language publications, whichcould have limited eligible studies.We cannot exclude the possibility of

publication and selective reportingbiases, but we were not able to formallytest for this. In addition, by includingonly studies where the interventionswere directed against treatment of hy-pertension (eg, rather than obesity),indirect evidence was excluded. Finally,identified studies had multiple defi-ciencies in reporting and methodology,which limited the data available foranalysis and interpretation. Limitationsincluded the lack of studies that exam-ined 1 intervention in .1 trial or obvi-ous clinical heterogeneity, precludingthe use of meta-analyses.

Future research in this area needs toaddress the followingmajor gaps in thecurrent state of evidence.

� Diagnostic accuracy of blood pres-sure measurement in primarycare and community settings forscreening children of varying agesand characteristics. This includes

TABLE 2 Continued

Number of Studies(Overall Quality)

Limitations Consistency Applicability toPrimary Care

Summary of Findings

Key question 6: What is the effectiveness of drug, nondrug, and combination therapies initiated for the treatment of primary hypertension in children/adolescents forreducing blood pressure and other intermediate outcomes in adults?No studies NA NA NA NA

Key question 7: What is the effectiveness of drug, nondrug, and combination therapies initiated for the treatment of primary hypertension in children/adolescents forreducing adverse health outcomes in adults related to primary hypertension?No studies NA NA NA NA

Key question 8: What are the adverse effects of drug, nondrug, and combination therapies for treating primary hypertension in children/adolescents?15 studies (13 RCTs, 2 FDA

analyses) (fair)Numerous trials from key question 5 did notreport comparative events rates betweenactive treatment and placebo arms, andadverse event rates overall ere not well-reported in most studies.

Consistent Moderate Studies of antihypertensive drugs in childrenand adolescents generally reported nosignificant difference between activetreatments and placebo in adverse eventrates or in withdrawals due to adverseevents. In one study, a combination ofbisoprolol and hydrochlorothiazide wasassociated with lower adverse event ratesthan placebo.

Four studies reported serious adverse events,although with the exception of 1 case ofsyncope due to a dosing error, seriousadverse events were generally not deemedtreatment related. Analysis of FDA datarevealed no significant difference betweendrug treatments and placebo in theincidence of specific adverse events,including headache (the most commonlyreported adverse event), cardiac events,gastrointestinal events, and cough.

No studies reported on harms associated withnondrug treatments.

FDA, Food and Drug Administration; NA, not applicable; PPV, positive predictive value; RR, relative risk.



identifying the number, frequency,and timing of readings neededto confirm or rule out hyperten-sion.74

� Adverse effects of screening, in-cluding health care utilization, bur-den on the family, and discomfortand anxiety for the child and fam-ily.

� Epidemiologic studies to describethe natural history of elevatedblood pressure and hypertensionin children and adolescents, id-entifying factors that predictpersistence into adulthood, andregression to normal based onbaseline characteristics such asage, BMI, and pattern of bloodpressure. Such studies need touse current definitions of hyper-tension and be of sufficient dura-tion to draw clinically usefulconclusions.74,75

� Epidemiologic studies to better de-fine thresholds used to definehypertension in children and ado-lescents and their association withboth structural (eg, carotid intimamedia thickening, left ventricularmass) and functional (eg, arterialstiffening) markers of target endorgan damage related to hyperten-sion.

� Longer-term trials of benefits andrisks of all antihypertensive agents(as monotherapy and in combina-tion) and evidence for both short-and long-term safety. Given theexpected duration of antihyperten-sive therapy, the absence of long-term safety data is a significantlimitation.

� Large, controlled, good-quality trialsof feasible nondrug interventionsfor children and adolescents usingmore sophisticated approaches tocomplex interventions to identifycomponents that provide the great-est benefit over prolonged periods.

CONCLUSIONS

The prevalence of hypertension inchildren and adolescents is increasingin the United States, largely driven byincreased BMI. Screening children forelevated blood pressure or hyperten-sion has the potential to shift themanagement of hypertension to youn-ger age groups and potentially reducefuture cardiovascular disease risk inadults. However, at present, the evi-denceneeded tosupport thesepracticesis limited. Although it would be logisti-cally (and ethically) very challengingto demonstrate the effects of inter-ventions in children and adolescents

with elevated blood pressure on car-diovascular outcomes occurring manydecades later in adults, there areclearly a number of outstanding re-search gaps that can be addressed byfeasible research designs in a muchshorter time frame. Increasingly, bloodpressure is being viewed within a par-adigm of overall cardiovascular riskstratification, along with other riskfactors, such as lipid profiles, insulinresistance, and BMI.16 We anticipatethat addressing these current gaps inthe evidence for blood pressure will becritical to add to clinicians’ ability toidentify children and adolescents withincreased cardiovascular risk and alsoto offer a balanced assessment of theoverall benefit of interventions to re-duce this risk and prevent future car-diovascular disease.

ACKNOWLEDGMENTSThe authors thank the responsibleMed-ical Officer at the Agency of HealthcareResearch and Quality, Iris Mabry-Hernandez, MD,MPH, and US PreventiveServices Task Force members KirstenBibbins-Domingo, PhD, MD, DavidGrossman, MD, MPH, BernadetteMelnyk, PhD, RN, CPNP/NPP, andWandaNicholson, MD, MPH. We also thankMatthew Gillman, MD, for providingclinical expertise.

REFERENCES

1. Lurbe E, Álvarez J, Redon J. Diagnosis andtreatment of hypertension in children. CurrHypertens Rep. 2010;12(6):480–486

2. Obarzanek E, Wu CO, Cutler JA, Kavey RE,Pearson GD, Daniels SR. Prevalence andincidence of hypertension in adolescentgirls. J Pediatr. 2010;157(3):461–467, 467,e1–e5

3. Din-Dzietham R, Liu Y, Bielo M-V, Shamsa F.High blood pressure trends in children andadolescents in national surveys, 1963 to2002. Circulation. 2007;116(13):1488–1496

4. Flynn JT, Falkner BE. The importance ofblood pressure screening in children.

J Pediatr. 2009;155(2):299–300, author re-ply 299–300

5. Brady TM, Solomon BS, Neu AM, Siberry GK,Parekh RS. Patient-, provider-, and clinic-level predictors of unrecognized elevatedblood pressure in children. Pediatrics.2010;125(6). Available at: www.pediatrics.org/cgi/content/full/125/6/e1286

6. Hansen ML, Gunn PW, Kaelber DC. Under-diagnosis of hypertension in children andadolescents. JAMA. 2007;298(8):874–879

7. Sun SS, Grave GD, Siervogel RM, Pickoff AA,Arslanian SS, Daniels SR. Systolic bloodpressure in childhood predicts hyperten-

sion and metabolic syndrome later in life.Pediatrics. 2007;119(2):237–246

8. Rosner B, Cook N, Portman R, Daniels S,Falkner B. Blood pressure differences byethnic group among United States childrenand adolescents. Hypertension. 2009;54(3):502–508

9. Falkner B, Gidding SS, Ramirez-Garnica G,Wiltrout SA, West D, Rappaport EB. The re-lationship of body mass index and bloodpressure in primary care pediatricpatients. J Pediatr. 2006;148(2):195–200

10. Sorof JM, Lai D, Turner J, Poffenbarger T,Portman RJ. Overweight, ethnicity, and the

REVIEW ARTICLE



prevalence of hypertension in school-agedchildren. Pediatrics. 2004;113(3 pt 1):475–482

11. Moore WE, Eichner JE, Cohn EM, ThompsonDM, Kobza CE, Abbott KE. Blood pressurescreening of school children in a multira-cial school district: the Healthy Kids Pro-ject. Am J Hypertens. 2009;22(4):351–356

12. Chiolero A, Cachat F, Burnier M, Paccaud F,Bovet P. Prevalence of hypertension inschoolchildren based on repeated meas-urements and association with overweight.J Hypertens. 2007;25(11):2209–2217

13. Liao CC, Su TC, Chien KL, et al. Elevatedblood pressure, obesity, and hyperlipid-emia. J Pediatr. 2009;155(1):79–83, 83, e1

14. Jago R, Harrell JS, McMurray RG, EdelsteinS, El Ghormli L, Bassin S. Prevalence ofabnormal lipid and blood pressure valuesamong an ethnically diverse population ofeighth-grade adolescents and screeningimplications. Pediatrics. 2006;117(6):2065–2073

15. Centers for Disease Control and Pre-vention. Overweight and obesity: data andstatistics. Available at: www.cdc.gov/obe-sity/childhood/data.html. Accessed Decem-ber 3, 2012

16. Friedemann C, Heneghan C, Mahtani K,Thompson M, Perera R, Ward AM. Cardio-vascular disease risk in healthy childrenand its association with body mass index:systematic review and meta-analysis. BMJ.2012;345:e4759

17. Muntner P, He J, Cutler JA, Wildman RP,Whelton PK. Trends in blood pressureamong children and adolescents. JAMA.2004;291(17):2107–2113

18. Jung FF, Ingelfinger JR. Hypertension inchildhood and adolescence. Pediatr Rev.1993;14(5):169–179

19. Hohn AR, Dwyer KM, Dwyer JH. Bloodpressure in youth from four ethnic groups:the Pasadena Prevention Project. J Pediatr.1994;125(3):368–373

20. Flynn JT. Evaluation and management ofhypertension in childhood. Prog PediatrCardiol. 2001;12(2):177–188

21. Viera AJ, Neutze DM. Diagnosis of sec-ondary hypertension: an age-based ap-proach. Am Fam Physician. 2010;82(12):1471–1478

22. Srinivasan SR, Myers L, Berenson GS.Changes in metabolic syndrome variablessince childhood in prehypertensive andhypertensive subjects: the Bogalusa HeartStudy. Hypertension. 2006;48(1):33–39

23. Rademacher ER, Jacobs DR Jr, Moran A,Steinberger J, Prineas RJ, Sinaiko A. Re-lation of blood pressure and body massindex during childhood to cardiovascular

risk factor levels in young adults. JHypertens. 2009;27(9):1766–1774

24. US Preventive Services Task Force. Guide toClinical Preventive Services: PeriodicUpdates. 3rd ed. Rockville, MD: Agency forHealthcare Research and Quality; 2003

25. Thompson M, Bougatsos C, Dana T, BlazinaI, Norris S. Screening for Hypertension inChildren and Adolescents to Prevent Car-diovascular Disease: Systematic Review forthe U.S. Preventive Services Task Force.Rockville, MD: Agency for Healthcare Re-search and Quality

26. Harris RP, Helfand M, Woolf SH, et al;Methods Work Group, Third US PreventiveServices Task Force. Current methods ofthe US Preventive Services Task Force:a review of the process. Am J Prev Med.2001;20(3 suppl):21–35

27. US Preventive Services Task Force. Proceduremanual: section 4 evidence report development.Available at: www.uspreventiveservicestaskforce.org/uspstf08/methods/procmanual4.htm.Accessed December 3, 2012

28. Whitlock EP, O’Connor EA, Williams SB, BeilTL, Lutz KW. Effectiveness of weight man-agement interventions in children: a tar-geted systematic review for the USPSTF.Pediatrics. 2010;125(2). Available at: www.pediatrics.org/cgi/content/full/125/2/e396

29. Haney EM, Huffman LH, Bougatsos C, FreemanM, Steiner RD, Nelson HD. Screening andtreatment for lipid disorders in childrenand adolescents: systematic evidence re-view for the US Preventive Services TaskForce. Pediatrics. 2007;120(1). Available at:www.pediatrics.org/cgi/content/full/120/1/e189

30. Fixler DE, Laird WP. Validity of mass bloodpressure screening in children. Pediatrics.1983;72(4):459–463

31. Stergiou GS, Nasothimiou E, Giovas P,Kapoyiannis A, Vazeou A. Diagnosis of hy-pertension in children and adolescentsbased on home versus ambulatory bloodpressure monitoring. J Hypertens. 2008;26(8):1556–1562

32. Berenson GS, Dalferes E Jr, Savage D,Webber LS, Bao W. Ambulatory bloodpressure measurements in children andyoung adults selected by high and lowcasual blood pressure levels and parentalhistory of hypertension: the BogalusaHeart Study. Am J Med Sci. 1993;305(6):374–382

33. Ewart CK, Harris WL, Iwata MM, Coates TJ,Bullock R, Simon B. Feasibility and effec-tiveness of school-based relaxation in low-ering blood pressure. Health Psychol. 1987;6(5):399–416

34. Fixler DE, Laird WP, Fitzgerald V, Stead S,Adams R. Hypertension screening inschools: results of the Dallas study. Pedi-atrics. 1979;63(1):32–36

35. Kelsall JE, Watson AR. Should school nursesmeasure blood pressure? Public Health.1990;104(3):191–194

36. Michaud PA. Adolescent hypertension:a follow-up study in the community. RevEpidemiol Sante Publique. 1989;37(1):23–28

37. Miller FS III, Record NB Jr. Hypertensioncontrol in rural Maine. Franklin County highblood pressure program. J Maine MedAssoc. 1976;67(9):280–283

38. Rames LK, Clarke WR, Connor WE, ReiterMA, Lauer RM. Normal blood pressure andthe evaluation of sustained blood pressureelevation in childhood: the Muscatine study.Pediatrics. 1978;61(2):245–251

39. Reichman LB, Cooper BM, Blumenthal S,et al. Hypertension testing among highschool students. I. Surveillance proceduresand results. J Chronic Dis. 1975;28(3):161–171

40. Sailors EL. Project “hypertension alert”.J Sch Health. 1983;53(6):374–376

41. Sinaiko AR, Gomez-Marin O, Prineas RJ.“Significant” diastolic hypertension in pre-high school black and white children. Thechildren and adolescent blood pressureprogram. Am J Hypertens. 1988;1(2):178–180

42. Stern B, Heyden S, Miller D, Latham G, Kli-mas A, Pilkington K. Intervention study inhigh school students with elevated bloodpressures. Dietary experiment with poly-unsaturated fatty acids. Nutr Metab. 1980;24(3):137–147

43. Bao W, Threefoot SA, Srinivasan SR,Berenson GS. Essential hypertension pre-dicted by tracking of elevated blood pres-sure from childhood to adulthood: theBogalusa Heart Study. Am J Hypertens.1995;8(7):657–665

44. Beckett LA, Rosner B, Roche AF, Guo S. Se-rial changes in blood pressure from ado-lescence into adulthood. Am J Epidemiol.1992;135(10):1166–1177

45. Gillman MW, Cook NR, Rosner B, et al.Identifying children at high risk for thedevelopment of essential hypertension. JPediatr. 1993;122(6):837–846

46. Hoq S, Chen W, Srinivasan SR, Berenson GS.Childhood blood pressure predicts adultmicroalbuminuria in African Americans,but not in whites: the Bogalusa Heart Study.Am J Hypertens. 2002;15(12):1036–1041

47. Juhola J, Magnussen CG, Viikari JSA, et al.Tracking of serum lipid levels, blood pres-sure, and body mass index from childhoodto adulthood: the Cardiovascular Risk in


http://www.cdc.gov/obesity/childhood/data.html

http://www.cdc.gov/obesity/childhood/data.html

http://www.uspreventiveservicestaskforce.org/uspstf08/methods/procmanual4.htm

http://www.uspreventiveservicestaskforce.org/uspstf08/methods/procmanual4.htm


Young Finns Study. J Pediatr. 2011;159(4):584–590

48. Lauer RM, Clarke WR, Mahoney LT, Witt J.Childhood predictors for high adult bloodpressure. The Muscatine Study. Pediatr ClinNorth Am. 1993;40(1):23–40

49. Li S, Chen W, Srinivasan SR, et al. Child-hood cardiovascular risk factors andcarotid vascular changes in adulthood:the Bogalusa Heart Study. JAMA. 2003;290(17):2271–2276

50. Raitakari OT, Juonala M, Kähönen M, et al.Cardiovascular risk factors in childhoodand carotid artery intima-media thicknessin adulthood: the Cardiovascular Risk inYoung Finns Study. JAMA. 2003;290(17):2277–2283

51. Shear CL, Burke GL, Freedman DS, WebberLS, Berenson GS. Designation of childrenwith high blood pressure—considerationson percentile cut points and subsequenthigh blood pressure: the Bogalusa HeartStudy. Am J Epidemiol. 1987;125(1):73–84

52. Stenn PG, Noce A, Buck C. A study of thelabelling phenomenon in school childrenwith elevated blood pressure. Clin InvestMed. 1981;4(3–4):179–181

53. Batisky DL, Sorof JM, Sugg J, et al; Toprol-XLPediatric Hypertension Investigators. Effi-cacy and safety of extended release meto-prolol succinate in hypertensive children 6to 16 years of age: a clinical trial experience.J Pediatr. 2007;150(2):134–139, 139, e1

54. Flynn JT, Newburger JW, Daniels SR, et al;PATH-1 Investigators. A randomized, placebo-controlled trial of amlodipine in childrenwith hypertension. J Pediatr. 2004;145(3):353–359

55. Li JS, Flynn JT, Portman R, et al. The efficacyand safety of the novel aldosterone antag-onist eplerenone in children with hyper-tension: a randomized, double-blind, dose-response study. J Pediatr. 2010;157(2):282–287

56. Sorof JM, Cargo P, Graepel J, et al. Beta-blocker/thiazide combination for treatmentof hypertensive children: a randomizeddouble-blind, placebo-controlled trial.Pediatr Nephrol. 2002;17(5):345–350

57. Trachtman H, Frank R, Mahan JD, et al.Clinical trial of extended-release felodipinein pediatric essential hypertension. PediatrNephrol. 2003;18(6):548–553

58. Trachtman H, Hainer JW, Sugg J, Teng R,Sorof JM, Radcliffe J; Candesartan inChildren with Hypertension (CINCH)Investigators. Efficacy, safety, and phar-

macokinetics of candesartan cilexetil inhypertensive children aged 6 to 17 years.J Clin Hypertens (Greenwich). 2008;10(10):743–750

59. Wells TG, Portman R, Norman P, HaertterS, Davidai G, Fei Wang . Safety, efficacy,and pharmacokinetics of telmisartan inpediatric patients with hypertension.Clin Pediatr (Phila). 2010;49(10):938–946

60. Berenson GS, Voors AW, Webber LS, et al. Amodel of intervention for prevention ofearly essential hypertension in the 1980s.Hypertension. 1983;5(1):41–54

61. Berenson GS, Shear CL, Chiang YK, WebberLS, Voors AW. Combined low-dose medica-tion and primary intervention over a 30-month period for sustained high bloodpressure in childhood. Am J Med Sci. 1990;299(2):79–86

62. Couch SC, Saelens BE, Levin L, Dart K, Fal-ciglia G, Daniels SR. The efficacy of a clinic-based behavioral nutrition interventionemphasizing a DASH-type diet for adoles-cents with elevated blood pressure.J Pediatr. 2008;152(4):494–501

63. Gregoski MJ, Barnes VA, Tingen MS,Harshfield GA, Treiber FA. Breathingawareness meditation and LifeSkills Train-ing programs influence upon ambulatoryblood pressure and sodium excretionamong African American adolescents.J Adolesc Health. 2011;48(1):59–64

64. Hansen HS, Froberg K, Hyldebrandt N,Nielsen JR. A controlled study of eightmonths of physical training and reductionof blood pressure in children: the Odenseschoolchild study. BMJ. 1991;303(6804):682–685

65. Howe PR, Cobiac L, Smith RM. Lack of effectof short-term changes in sodium intake onblood pressure in adolescent school-children. J Hypertens. 1991;9(2):181–186

66. Sinaiko AR, Gomez-Marin O, Prineas RJ.Effect of low sodium diet or potassiumsupplementation on adolescent blood pres-sure. Hypertension. 1993;21(6 pt 2):989–994

67. Hazan L, Hernández Rodriguez OA, BhoratAE, Miyazaki K, Tao B, Heyrman R; Assess-ment of Efficacy and Safety of Olmesartanin Pediatric Hypertension Study Group. Adouble-blind, dose-response study of theefficacy and safety of olmesartan medox-omil in children and adolescents with hy-pertension. Hypertension. 2010;55(6):1323–1330

68. Li JS, Berezny K, Kilaru R, et al. Is the ex-trapolated adult dose of fosinopril safe andeffective in treating hypertensive children?Hypertension. 2004;44(3):289–293

69. Shahinfar S, Cano F, Soffer BA, et al. Adouble-blind, dose-response study of los-artan in hypertensive children. Am JHypertens. 2005;18(2 pt 1):183–190

70. Soffer B, Zhang Z, Miller K, Vogt BA, Sha-hinfar S. A double-blind, placebo-controlled,dose-response study of the effectivenessand safety of lisinopril for children withhypertension. Am J Hypertens. 2003;16(10):795–800

71. Wells T, Frame V, Soffer B, et al; EnalaprilPediatric Hypertension Collaborative StudyGroup. A double-blind, placebo-controlled,dose-response study of the effectivenessand safety of enalapril for children withhypertension. J Clin Pharmacol. 2002;42(8):870–880

72. Smith PB, Li JS, Murphy MD, Califf RM,Benjamin DK Jr. Safety of placebo controlsin pediatric hypertension trials. Hyperten-sion. 2008;51(4):829–833

73. Baker-Smith CM, Benjamin DK Jr, Califf RM,Murphy MD, Li JS, Smith PB. Cough in pe-diatric patients receiving angiotensin-converting enzyme inhibitor therapy orangiotensin receptor blocker therapy inrandomized controlled trials. Clin Phar-macol Ther. 2010;87(6):668–671

74. Chen X, Wang Y, Appel LJ, Mi J. Impacts ofmeasurement protocols on blood pressuretracking from childhood into adulthood:a metaregression analysis. Hypertension.2008;51(3):642–649

75. Tirosh A, Afek A, Rudich A, et al. Pro-gression of normotensive adolescents tohypertensive adults: a study of 26,980teenagers. Hypertension. 2010;56(2):203–209

76. Batisky DL. Obesity and the role of lifestyleand dietary intervention in the manage-ment of pediatric hypertension. J MedLiban. 2010;58(3):171–174

77. Juonala M, Viikari JSA, Hutri-Kähönen N,et al. The 21-year follow-up of the Cardio-vascular Risk in Young Finns Study: riskfactor levels, secular trends and east-westdifference. J Intern Med. 2004;255(4):457–468

78. Frank GC, Farris RP, Ditmarsen P, Voors AW,Berenson GS. An approach to primarypreventive treatment for children with highblood pressure in a total community. J AmColl Nutr. 1982;1(4):357–374

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APPENDIX 1 Search Strategies

Screening

Database: Ovid Medline(R) and Ovid OLDMEDLINE(R)1 Hypertension or hypertension.mp.2 prehypertension.mp.3 pre-hypertension.mp.4 2 or 35 high blood pressure.mp.6 or/1–57 Mass screening8 6 and 79 Limit 8 to (English language and humans)10 Limit 9 to “all child (0 to 18 years)”11 9 and (child$ or pediatri$ or adolescen$ or school-age).mp.12 10 or 11

Database: EBM Reviews: Cochrane Central Register of Controlled Trials1 Hypertension/ or hypertension.mp.2 prehypertension.mp.3 pre-hypertension.mp.4 2 or 35 high blood pressure.mp.6 or/1–57 Mass screening/8 6 and 79 8 and (child$ or pediatri$ or school or adolescen$ or teen$).mp.

Diagnostic accuracyDatabase: Ovid Medline(R) and Ovid OLDMEDLINE(R)1 Hypertension/2 prehypertension.mp. or Prehypertension/3 1 or 24 Blood pressure determination/5 sensitivity.mp.6 specificity.mp.7 5 and 68 “Sensitivity and specificity”/9 7 or 810 3 and 911 4 and 912 10 or 1113 Limit 12 to “all child (0 to 18 years)”

Database: EBM Reviews: Cochrane Central Register of Controlled Trials1 Hypertension/2 prehypertension.mp. or Prehypertension/3 1 or 24 Blood pressure determination/5 sensitivity.mp.6 specificity.mp.7 5 and 68 “Sensitivity and specificity”/9 7 or 810 3 and 911 4 and 912 10 or 1113 12 and (child$ or pediatr$ or school or adolescen$ or teen$).mp.

TrackingDatabase: Ovid Medline(R) and Ovid OLDMEDLINE1 “cardiovascular risk in young finns”.mp.2 “bogalusa heart”.mp.3 muscatine.mp.4 (“childhood determinants of adult health” or cdah).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol

supplementary concept, rare disease supplementary concept, unique identifier]5 or/1–46 5 and (child$ or pediatric$ or adolescen$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary

concept, rare disease supplementary concept, unique identifier]



APPENDIX 1 Continued

Screening

7 blood pressure.mp. or Blood Pressure/8 Hypertension/ or hypertension.mp.9 7 or 810 9 and (child$ or pediatric$ or adolescen$).mp.11 10 and adult$.mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease

supplementary concept, unique identifier]12 Longitudinal studies/13 11 and 1214 6 or 1315 “Amsterdam Growth and Health Longitudinal Study”.mp.16 15 and (child$ or pediatric$ or adolescen$).mp.17 14 or 1618 17 not pregnancy.mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease

supplementary concept, unique identifier]19 17 not infan$.mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease

supplementary concept, unique identifier]20 18 or 1921 Limit 20 to (English language and humans)22 Atherosclerosis/23 Vascular diseases/24 Albuminuria/25 Cerebrovascular disorders/26 Hypertrophy, Left ventricular/27 Hypertension/28 or/22–2729 21 and 28

InterventionsDatabase: Ovid Medline(R) and Ovid OLDMEDLINE(R)1 Hypertension/dh, de, dt, pc, rt, rh, su, th [Diet Therapy, Drug Effects, Drug Therapy, Prevention & Control, Radiotherapy, Rehabilitation, Surgery, Therapy]2 Wt Loss/3 Exercise/4 dietary modification.mp. or Food Habits/5 Diet, sodium-restricted/6 Angiotensin-Converting Enzyme Inhibitors/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]7 Angiotensin II Type 1 Receptor Blockers/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]8 Labetalol/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]9 Adrenergic b-Antagonists/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]10 Atenolol/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]11 Bisoprolol/ad, ae, tu [Administration & Dosage, Adverse Effects, Therapeutic Use]12 Metoprolol/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]13 Propranolol/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]14 Calcium Channel Blockers/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]15 Amlodipine/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]16 Felodipine/ad, ae, tu, to [Administration & Dosage, Adverse Effects, Therapeutic Use, Toxicity]17 Isradipine/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]18 Nifedipine/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]19 Clonidine/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]20 Diuretics/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]21 Hydrochlorothiazide/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]22 Chlorthalidone/ad, ae, tu, to [Administration & Dosage, Adverse Effects, Therapeutic Use, Toxicity]23 Furosemide/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]24 Spironolactone/ad, ae, tu, to [Administration & Dosage, Adverse Effects, Therapeutic Use, Toxicity]25 Triamterene/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity] (26 Amiloride/ad, ae, tu, to [Administration & Dosage, Adverse Effects, Therapeutic Use, Toxicity]27 Adrenergic a-Antagonists/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]28 Doxazosin/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]29 Prazosin/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]30 Vasodilator Agents/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]31 Hydralazine/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]32 Minoxidil/ad, ae, po, tu [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use]33 Captopril/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]34 Enalapril/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]

REVIEW ARTICLE



APPENDIX 1 Continued

Screening

35 Fosinopril/ad, ae, tu, to [Administration & Dosage, Adverse Effects, Therapeutic Use, Toxicity]36 Lisinopril/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]37 Losartan/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]38 (benazepril or quinapril or irbesartan or terazosin).mp.39 or/2–3840 Hypertension/41 39 and 4042 1 or 4143 Limit 42 to (English language and humans)44 Limit 43 to “all child (0 to 18 years)”

Database: EBM Reviews: Cochrane Central Register of Controlled Trials1 Wt Loss/2 Exercise/3 dietary modification.mp. or Food Habits/4 Diet, Sodium-Restricted/5 Angiotensin-Converting Enzyme Inhibitors/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]6 Angiotensin II Type 1 Receptor Blockers/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]7 Labetalol/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]8 Adrenergic b-Antagonists/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]9 Atenolol/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]10 Bisoprolol/ad, ae, tu [Administration & Dosage, Adverse Effects, Therapeutic Use]11 Metoprolol/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]12 Propranolol/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]13 Calcium Channel Blockers/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]14 Amlodipine/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]15 Felodipine/ad, ae, tu, to [Administration & Dosage, Adverse Effects, Therapeutic Use, Toxicity]16 Isradipine/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]17 Nifedipine/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]18 Clonidine/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]19 Diuretics/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]20 Hydrochlorothiazide/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]21 Chlorthalidone/ad, ae, tu, to [Administration & Dosage, Adverse Effects, Therapeutic Use, Toxicity]22 Furosemide/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]23 Spironolactone/ad, ae, tu, to [Administration & Dosage, Adverse Effects, Therapeutic Use, Toxicity]24 Triamterene/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]25 Amiloride/ad, ae, tu, to [Administration & Dosage, Adverse Effects, Therapeutic Use, Toxicity]26 Adrenergic a-Antagonists/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]27 Doxazosin/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]28 Prazosin/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]29 Vasodilator Agents/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]30 Hydralazine/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]31 Minoxidil/ad, ae, po, tu [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use]32 Captopril/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]33 Enalapril/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]34 Fosinopril/ad, ae, tu, to [Administration & Dosage, Adverse Effects, Therapeutic Use, Toxicity]35 Lisinopril/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]36 Losartan/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]37 (benazepril or quinapril or irbesartan or terazosin).mp.38 or/1–3739 Blood Pressure/40 38 and 39

Systematic reviewsDatabase: EBM Reviews: Cochrane Database of Systematic Reviews1 hypertension.ti.2 blood pressure.ti.3 1 or 24 3 and (child$ or pediatri$ or school or adolescen$ or teen$).mp.5 4 not (neonat$ or newborn or infan$).ti.6 5 not (pregnan$ or postpartum).ti.



APPENDIX 2 Inclusion and Exclusion Criteria

Key Questions Inclusion Criteria Exclusion Criteria

Settings All Primary care clinics, well-child/adolescent visits, school orcommunity-based screening

Pediatric specialty/subspecialty clinics, inpatient, or long-termcare settings, emergency or urgent care facilities

Populations 1, 2, and 4 Asymptomatic, otherwise healthy children and adolescents, 0–18y of age, with no known diagnosis of hypertension

Pregnant adolescents

3 and 5–8: Primary hypertension defined as average blood pressurebetween 95th percentile and 5 mm Hg above the 99thpercentile

Majority of study population included secondary hypertension

Interventions 1–4: Blood pressure measurements using auscultatory oroscillometric devices that can be performed in a primary careclinic

24-h, ambulatory, or home-based blood pressuremeasurements.Diagnostic tests or investigations used to identify or confirmpossible causes of secondary hypertension

5–8: Drug: Antihypertensive medications which are currently FDA-approved for use in children/adolescents

Interventions for treatment of secondary hypertension

Lifestyle: Diet, exercise, etc. Interventions where reduction in blood pressure was nota primary objective of the study (eg, weight loss studies)

Outcomes 4, 5, and 6: Blood pressure Measures of cognitive functionLeft ventricular hypertrophy (defined using left ventricular mass

index and/or measures of left ventricular geometry)Bloodpressurevariability, suchasdiurnalvariationsornocturnalblood pressure dipping

Urinary albumin excretion (microalbuminuria) Arterialwall dysfunction, includingmeasuresofarterial stiffness,pulse wave velocity, or augmentation index

Intima-medial thickness (measured at carotid and/or femoralarteries)

Metabolicmeasures, eg,measuresof impairedglucose tolerance,levels of insulin, lipid profiles, homocysteine levels

Retinal vascular changes uric acid levelsInflammatory markers including C-reactive proteinBody changes in weight or BMI

1 and 7: Severe visual impairment Studies reporting intermediate outcomesStage IV or V chronic kidney diseaseCardiovascular events, including ischemic heart disease, heart

failureCerebrovascular events, including hemorrhagic and thrombotic

stroke, Hypertensive encephalopathyMortality (all-cause and disease-specific)

2 Measures of predictive validity of screening tests (eg, predictivevalue, likelihood ratios, sensitivity, specificity)

Studies that do not provide enough data to recreate 23 2 tablesor calculate sensitivity and specificity

Studies that do not use a true reference standard forcomparison

3 Measures of association (eg, odds ratio; risk ratio, sensitivity,specificity, correlation or regression coefficients)

Studies not reporting measures of association

8 Side effects of hypertension treatments or interventions —

Study designs 1 Randomized controlled trials, controlled clinical trials,observational studies with a comparison group (eg,comparative cohort and case-control studies), and systematicreviews

Study designs other than those specified

2 Studies of predictive validity that compare with a referencestandard (eg, ambulatory monitoring)


3 Longitudinal cohort and epidemiology studies Study designs other than those specified4 and 8 Randomized controlled trials, controlled clinical trials,

observational studies with a comparison group (eg, largecohort and case-control studies), and systematic reviews. Ifnone were identified, uncontrolled before-after studies wereexamined.


5–7 Randomized controlled trials, controlled clinical trials,observational studies with a comparison group (eg, largecohort and case-control studies), and systematic reviews


REVIEW ARTICLE



APPENDIX

3DiagnosticAccuracy

ofScreeningforElevated

BloodPressure

inChildrenandAdolescents

Study,

Year

Screening

Test

ReferenceStandard

DefinitionofaPositive

ScreeningExam

ination

Population

Sensitivity

Specificity

PositivePredictive

Value

NegativePredictive

Value

Quality

Rating

Fixler and

Laird

1983

30

Threemeasureswith

mercury

manom

eter

measuredatleast4

wkapart

Initialscreeningresults

comparedwith

subsequent

measures

SBPor

DBP$95th

percentilebasedon

norm

ativelevelsfor

thestudy

population

n=9017;eighth

graderswith

follow-

upat10th

grade;

meanagenot

reported;allwerein

eighthgradeattim

eofinitialscreening:

53%male,44%

black,42%white,

14%Hispanic

Initialpositivescreen

versus

subsequent

screens:0.72

(95%

CI,0.65–0.78)


versus

subsequent

positivescreening

test:0.92(95%

CI,

0.91–0.92)


versus

subsequent

positivescreening

test:0.17(95%

CI,

0.15–0.2)


versus

subsequent

positivescreening

test:0.993

(95%

CI,

0.991–0.994)

Fair

Stergiou

etal

2008

31

Threeaveraged

measurementswith

mercury

sphygm

omanom

eter,

measuredin

nondom

inant

arminsittingposition

after

5minat

rest

24-ham

bulatory

bloodpressure

measurements

SBPor

DBP$95th

percentilebasedon

USnorm

ativeblood

pressure

tables

N=102;100%

referred

forscreening;mean

age13

y(SD,3;

range,6–18);63%

male;race

not

reported

Positiveam

bulatory

resultversus

positiveclinicresult:

0.65

(95%

CI,0.45–

0.80)

Positiveam

bulatory

resultversus


0.75

(95%

CI,0.63–

0.84)

Positiveam

bulatory

resultversus


0.37

(95%

CI,0.28–

0.47)

Positiveam

bulatory

resultversus


0.63

(95%

CI,0.53–

0.72)

Fair



APPENDIX

4StudiesTracking

Hypertension

From

Childhood

toAdulthood

Author,Year,andStudyName

(Follow-up)

DefinitionofHTNin

Childhood

DefinitionofHTNin

Adulthood

Outcom

esQuality

Considerations

Recruitm

ent

Attrition:%

with

completedata,%

oforiginalNat

follow-up

Measurement

MethodStated

for

Both

TimePeriods?

StatisticalAnalysisand

Adjusted

Variables

Bloodpressure

outcom

esBaoetal1995

43;Bogalusa

HeartS

tudy

(15y)

.80th

percentile

SBP.140mmHg

orDB

P.90

mmHg

orever

treatedfor

hypertension

Hypertension

atfollow-up,

baselinehighestS

BPquintileversus

otherSBP

quintiles:

Unclear;datafrom

1505

subjectswho

completed

baseline

andfollow-upsurveys

(of3865atbaseline)

Noloss

(Cohortselected

basedon

availability

ofdata;39%

oforiginal

cohortcompleted

both

surveys)

Yes

Logisticregression;age,

race,sex,SBP,DBP,

BMI,change

inBM

I

18%(54/301)

vs.5%(60/

1204);risk

ratio

3.6;95%

CI,2.5–5.1

Hypertension

atfollow-up,

baselinehighestD

BPquintileversus

otherDB

Pquintiles:

15%(45/301)

vs.6%(72/

1204);risk

ratio

2.5;95%

CI,1.8–3.6

Beckettetal19924

4 ;Fels

Longitudinal

Study(20y)

SBPnotd

efined

DBP.90

mmHg

DBP80

vs.60mmHg

atage

15andpresence

ofhypertension

atage35:

Unclear;datafrom

523

subjectswho

completed

baseline

andfollow-upsurveys

(of976

atbaseline)

Noloss

(Cohortselected

basedon

availability

ofdata;54%

oforiginal

cohortcompleted

both

surveys)

Nonotapplicable

Males:riskratio

3.0;females:

risk

ratio

4.5

DBP85

vs.60mmHg

atage

15andpresence

ofhypertension

atage35:

Males:riskratio

3.9;

females:riskratio

6.6

DBP90

vs.60mmHg

atage

15andpresence

ofhypertension

atage35:

Males:riskratio

4.9;

females:riskratio

9.0

REVIEW ARTICLE



APPENDIX

4Continued


(Follow-up)

DefinitionofHTNin

Childhood

DefinitionofHTNin

Adulthood

Outcom

esQuality

Considerations

Recruitm

ent

Attrition:%

with

completedata,%

oforiginalNatfollow-up

Measurement

MethodStated

for

Both

TimePeriods?


Adjusted

Variables

Gillm

anetal1993

45;Study

not

named

(12y)

.90th

percentile(SBP:

113mmHg,w

ithin

study)

.90th

percentile(SBP:

139mmHg,w

ithin

study)

Positivepredictivevalue,

sensitivity,and

specificity

ofBP

atage10

predicting

BP.

90th

percentileat

age20:

Childrenfrom

asingle

schoolinEastBoston,

MA;samplingmethod

unclear

6%(20/337)

attrition

Yes

notapplicable

SBP,males:

.75th

percentile(108

mmHg):0.26,0.59,0.80

.90th

percentile(113

mmHg):0.35,0.33,0.93

.95th

percentile(117

mmHg):0.44,0.17,0.97

.99thpercentile(123

mmHg):0.58,0.04,.0.99

SBP,females:

.75th

percentile(108

mmHg):0.27,0.66,0.79

.90th

percentile(114

mmHg):0.39,0.36,0.94

.95th

percentile(118

mmHg):0.48,0.20,0.98

.99thpercentile(125

mmHg):0.65,0.04,.0.99

DBP,males:

.75th

percentile(68

mmHg):0.21,0.34,0.82

.90th

percentile(71

mmHg):0.24,0.16,0.93

.95th

percentile(73

mmHg):0.27,0.08,0.97

.99thpercentile(77

mmHg):0.34,0.01,.0.99

DBP,females:

.75th

percentile(67

mmHg):0.19,0.49,0.77

.90th

percentile(71

mmHg):0.24,0.23,0.92

.95th

percentile(74

mmHg):0.30,0.10,0.98

.99thpercentile(78

mmHg):0.38,0.02,.0.99



APPENDIX

4Continued


(Follow-up)

DefinitionofHTNin

Childhood

DefinitionofHTNin

Adulthood

Outcom

esQuality

Considerations

Recruitm

ent

Attrition:%

with

completedata,%


Measurement

MethodStated

for

Both

TimePeriods?


Adjusted

Variables

Juholaetal2011

47;Cardio-

vascular

Risk

inYoungFinnsStudy(27y)

$95th

percentile

Unclear

Prehypertensionor

hypertension

inadulthoodandBP

$95th

percentileinchildhood:

Finnishchildrenand

adolescentsaged

3,6,

9,12,and

15y

random

lysampled

from

5cities

38.7%(1392/3596)lostto

follow-upat27

yYes


sex,race,study

year

Female,ages

6and9:OR

2.4

(95%

CI,1.1–5.2)

Female,ages

12,15,and18:

OR2.3(95%

CI,1.6–3.5)

Otherpublication:Juonalaetal

2004

77Males,ages6and9:OR

2.8

(95%

CI,1.5–5.1)

Males,ages12,15,and18:

OR2.1(95%

CI,1.5–3.1)

PPV,sensitivity,specificityof

BP.95%percentilein

childhood

and

hypertension

inadulthood

Allages6–18:0.44;0.1;0.97

Laueretal1993

48;M

uscatine

Study(unclear)

Unclear;results

reported

for.90th

percentile

SBPor

DBP.90th

percentile(cohort

specific)

24%ofchildrenwith

BP.90th

percentilehadBP

.90th

percentilein

adulthood;risk

ratio

2.4

(P,

.001)

Unclear;datafrom

2445

subjectswho

completed

baseline

andfollow-upsurveys

(num

beratbaseline

notreported)

Noloss

(Cohortselected

basedon

availability

ofdata)

Yes

notapplicable

39%ofchildrenwith

SBP

.90th

percentilehad

SBP.80th

percentilein

adulthood;risk

ratio

1.9

(P,

.001)

17%ofchildrenwith

DBP

.90th

percentilehad

DBP.90th

percentilein

adulthood;risk

ratio

1.7

(P,

.001)

32%ofchildrenwith

DBP

.90th

percentilehad

DBP.80th

percentilein

adulthood;risk

ratio

1.5

(P,

.001)

REVIEW ARTICLE



APPENDIX

4Continued


(Follow-up)

DefinitionofHTNin

Childhood

DefinitionofHTNin

Adulthood

Outcom

esQuality

Considerations

Recruitm

ent

Attrition:%

with

completedata,%


Measurement

MethodStated

for

Both

TimePeriods?


Adjusted

Variables

Shearetal1987

51;Bogalusa

HeartS

tudy

(8y)

Notreported

$140/90

mmHg

SBP$80th

percentileat

years1,4,and6and

hypertensive

atfollow-

up:

Datafrom

1501

subjects

who

completed

baselineandfollow-up

surveys(of4238

subjectsatbaseline)

Noloss

(cohortselected

basedon

availability

ofdata;35%

oforiginal

subjectscompleted

both

surveys)

Yes

notapplicable

Sensitivity:0.27;Specificity:

0.95

DBP$80th

percentileat

years1,4,and6and

hypertensive

atfollow-

up:


0.96

SBP$90th

percentileat

years1,4,and6and

hypertensive

atfollow-

up:


0.99

DBP$90th

percentileat

years1,4,and6and

hypertensive

atfollow-

up:


0.99

SBP$95th

percentileat

years1,4,and6and

hypertensive

atfollow-

up:


1.0

DBP$95th

percentileat

years1,4,and6and

hypertensive

atfollow-

up:


1.0



APPENDIX

4Continued


(Follow-up)

DefinitionofHTNin

Childhood

DefinitionofHTNin

Adulthood

Outcom

esQuality

Considerations

Recruitm

ent

Attrition:%

with

completedata,%

oforiginalNat

follow-up

Measurement

MethodStated

for

Both

TimePeriods?


Adjusted

Variables

Sunetal2007

7 ;Fels

LongitudinalStudy

(unclear)

Least-squares

means

determ

ined

according

toageandgender

(absolutevalues

not

reported)

SBP.130mmHg

and/

orDB

P.85

mmHg

Odds

ofhypertension

at.30

yofagegivenSBP

exceedingcriterion

values

atsingle

exam

inationin

childhood:

Unclear;datafrom

493

subjectswho

completed

baseline

andfollow-upsurveys

(of976

atbaseline)

8%loss

tofollow-upin

FelsLongitudinal

Studyoverall;data

from

51%oforiginal

subjects

Yes

notapplicable

Males

5–7yoldmales:3.8(95%

CI,

1.5–9.7)

8–13

yoldmales:3.5(95%

CI,1.5–8.3)

14–18

yoldmales:1.1(95%

CI,0.5–2.4)

Females

5–7yoldfemales:4.5(95%

CI,1.1–17.7)

8–13

yoldfemales:2.7(95%

CI,1.0–7.1)

14–18

yoldfemales:3.8

(95%

CI,1.2–12.7)

Otheroutcom

es

REVIEW ARTICLE



APPENDIX

4Continued


(Follow-up)

DefinitionofHTNin

Childhood

DefinitionofHTNin

Adulthood

Outcom

esQuality

Considerations

Recruitm

ent

Attrition:%

with

completedata,%


Measurement

MethodStated

for

Both

TimePeriods?


Adjusted

Variables

Hoqetal2002

46;Bogalusa

HeartS

tudy

(16y)

$90th

percentilefor

age,ethnicity,and

gender

$90th

percentilefor

age,ethnicity,and

gender

Annualchange

inBP

onadulthoodurinary

albumin/creatinineratio

byethnicity:

Unclear;datafrom

2122

subjectswho

completed

baseline

andfollow-upsurveys

(of3865atbaseline)

Noloss

(cohortselected

basedon

availability

ofdata;datafrom

55%

oforiginalsubjects)

Yes

Logisticregression;sex,

childhood

age,BM

I,BP,

annualchange

inBP

Childhood

SBPby

ethnicity:

Blacks:regression

coefficient0.016

(P=.05)

Whites:regression

coefficient2

0.002(P

=.78)

Annualchange

inSBPfrom

childhood

toadulthood

byethnicity:

Blacks:regression

coefficient0.315

(P=

.002)

Whites:regression

coefficient2

0.045(P

=.55)

Childhood

DBPby

ethnicity:

Blacks:regression

coefficient0.026

(P=

.012)

Whites:regression

coefficient2

0.002(P

=.761)

Annualchange

inDB

Pfrom

childhood

toadulthood

byethnicity:

Blacks:regression

coefficient0.292

(P=

.016)

Whites:regression

coefficient0.063

(P=.5)

Lietal2003

49;BogalusaHeart

Study(22y)

Notreported

Notreported

Odds

ofcarotid

intim

amedia

thicknessinupper

quartilegivenSBPrisk

factor

(notdefined):

childhood

(14–17

y):1.00

(95%

CI,0.80–1.25)

Unclear;datafrom

486

subjectswho

completed

baseline

andfollow-upsurveys

andcarotid

artery

ultrasound

(of3865at

baseline)

NR(94%

[486/516]had

dataavailable);data

from

13%oforiginal

subjects)

Yes


race,sex



APPENDIX

4Continued


(Follow-up)

DefinitionofHTNin

Childhood

DefinitionofHTNin

Adulthood

Outcom

esQuality

Considerations

Recruitm

ent

Attrition:%

with

completedata,%


Measurement

MethodStated

for

Both

TimePeriods?


Adjusted

Variables

Raitakarietal2003

50;

Cardiovascular

Risk

inYoungFinnsStudy(21y)

$80th

percentile

$80th

percentile

RelationshipbetweenSBP

.80th

percentileatage

12–18

(meanage14.9y)

andcarotid

intim

amedia

thickness21

ylater:

regression

coefficient

0.013(SE0.003);P

,.001

Finnishchildrenand

adolescentsaged

3,6,

9,12,and

15y

random

lysampled

from

5cities

38%(1367/3596)lostto

follow-upat21

yYes


sex

BMI,body

massindex;BP,blood

pressure;DBP,diastolicbloodpressure;NR,notreported;PPV,positive

predictivevalue;SBP,systolicbloodpressure.

REVIEW ARTICLE



APPENDIX

5Interventions

forHypertension

inChildrenandAdolescents

Author,Year(Quality

Rating)

StudyDesign

and

SettingDuration

NDemographicCharacteristics

Intervention

ProportionofPatientsAchieving

#95th

PercentileofBloodPressure

forAge,Gender,and

Height

BloodPressure

(mmHg)

Drug

interventions

Batisky

etal2007

53

(fair)

RCT

140

Meanage13

(SD2.8)

yGroupA:MetoprololER0.2mg/kg

Groups

A–Cpooled:46%

(95%

CI,37–

55)

Meanchange

from

baseline,SBP:

28sites

70%male

GroupB:MetoprololER1.0mg/kg

GroupB:26%(95%

CI,8–44)

GroupA:25.2(95%

CI,2

7.7to22.6)

UnitedStates

26%black

GroupC:MetoprololER2.0mg/kg

GroupB:27.7(95%

CI,2

11.3to24.0)

4wk

MeanSBP:132mmHg

GroupD:Placebo

GroupC:26.3(95%

CI,2

8.7to23.8)

MeanDB

P:78

mmHg

GroupD:21.9(95%

CI,2

5.5to

1.8)

74%BM

I$95%percentile

Meanchange

from

baseline,DB

P:GroupA:23.1(95%

CI,2

5.7to20.5)

GroupB:24.9(95%

CI,2

8.6to21.3)

GroupC:27.5(95%

CI,2

10.0to25.0)

GroupD:22.1(95%

CI,2

5.7to

1.5)

Flynnetal2004

54

(fair)

RCTcrossover

268

Meanage12

(SD3.3)

yStudyPhase2(includedplacebo

comparison)

SBP

Phase2results

49sitesinNorthandSouthAm

erica

MeanSBP:137.9(SD12.7)

mmHg

GroupA:Am

lodipine

2.5mg/day

GroupA:40%

Meanchange

from

baseline,SBP:

4wk

MeanDB

P:74.2(SD11.6)

mmHg

GroupB:Am

lodipine

5.0mg/day

GroupB:35%

GroupA:26.96

12.5(P=NS)(P=.05

versus

placebo)

31.3%(84/268)

primary

hypertension

GroupC:Placebo

GroupC:30%

GroupB:28.76

13.3(P

=NS)(2

3.6

612.7,P

=.01versus

placebo)

DBP

GroupC:23.66

12.7(P

=NS)

GroupA:42%

Meanchange

from

baseline,DB

P:GroupB:75%

GroupA:24.26

10.7(P

=NS)

GroupC:48%

GroupB:24.46

10.2(P

=NS)

GroupC:20.46

11.0(P

=NS)

Lietal2010

55(fair)

RCT

304

Meanagenotreported(53%

,12

y)StudyPhaseB(includedplacebo

comparison)

NRPhaseBresults

43sitesintheUS,India,South

Africa,

Russia,and

Dominican

Republic

63%male

GroupA:Eplerenone

25mgonce

daily

Least-squares

meanchange

from

baseline,SBP:

4wk

35%black

GroupB:Eplerenone

25mgtwicedaily

GroupA:P=NS

57%white

GroupC:Eplerenone

25mgbidfor2

wk

followed

by50

mgbidfor4wk

GroupB:2.76

(95%

CI,2

5.5to0;P=

.048

versus

placebo)

11%Hispanic

GroupD:Placebo

GroupC:P=NS

8%Asian

Least-squares

meanchange

from

baseline(any

group),DBP:P

=NS

56%primaryhypertension



APPENDIX

5Continued

Author,Year(Quality

Rating)

StudyDesign

and

SettingDuration


Intervention


#95th


forAge,Gender,and

Height

BloodPressure

(mmHg)

Sorofetal20025

6

(fair)

RCT

94Meanage14

yGroupA:Bisoprololfumarate2.5+

hydrochlorothiazide6.25

NRLeastsquares

meanchange

from

baseline,SBP:

Clinicaltrialfrom22

sitesinUnited

States

andBrazil

57%male

GroupB:Bisoprolol5mg+


mg

Groups

A–Cpooled:2

9.3(P

,.05

versus

placebo)

4wk

43%white

GroupC::Bisoprololfum

arate10

mg+


mg

GroupD:24.9

41%black

GroupD:Placebo

Least-squares

meanchange

from

baseline,DB

P:14%Hispanic

Groups

A–Cpooled:2

7.2(P

,.05

versus

placebo)

1%Asian

GroupD:22.7

1%multiracial

MeanBM

I=28

Trachtman

etal

2003

57(fair)

RCT

133

Meanage12

y(SD3)

GroupA:2.5mgfelodipine

ERBP

#90th

percentile

MeandifferenceSBPat

follow-up

versus

placebo(95%

CI):

Clinicaltrialat30sitesintheUnited

States

60%male

GroupB:5mgfelodipine

ERGroupA:15%

GroupA:20.71

(24.8to3.38;P

=NS)

3wk

39%black

GroupC:10mgfelodipine

ER,titrated

totargetdose

GroupB:18%

GroupB:20.06

(24.6to3.3;P=NS)

GroupD:Placebo

GroupC:19%

GroupC:21.73

(26.58

to3.13;P

=NS)

GroupD:11%

MeandifferenceDB

Patfollow-up

versus

placebo(95%

CI):

GroupA:22.07

(26.82

to2.69;P

=NS)

GroupB:24.64

(29.18

to0.09;P

,.05)

GroupC:1.31

(23.56

to6.11;P

=NS)

Trachtman

etal

2008

58(fair)

RCT

240

Meanagenotreported(29%

,12

y;71%.12

y)GroupA:Candesartan2/4mg

GroupA:54%

Least-squares

meanchange

from

baseline,SBP:

Clinicaltrialat42sitesinUnited

States

andEurope

71%male

GroupB:62%

Groups

A–C:-10.22

(P,

.0001versus

placebo)

4wk

69%BM

I$95th

percentile

GroupB:Candesartan8/16

mg

GroupC:65%

GroupD:23.66

47%black

GroupC:Candesartan16/32mg

GroupD:31%

Leastsquares

meanchange

from

baseline,DB

P:45%white

GroupD:Placebo

Groups

A–C:26.56

(P=.0029versus

placebo)

GroupD:21.8

REVIEW ARTICLE



APPENDIX

5Continued

Author,Year(Quality

Rating)

StudyDesign

and

SettingDuration


Intervention


#95th


forAge,Gender,and

Height

BloodPressure

(mmHg)

Wellsetal2010

59

(fair)

RCT

77Meanage:14

y(SD3y)

GroupA:Telmisartan1mg/kg/day

(low

-dosegroup)

GroupA:50%(6–,12

y);68%

(12–,18

y)Adjusted

meandifferenceSBPat

follow-upversus

placebo(95%

CI):


States,Brazil,andMexico

57%male

GroupB:Telmisartan1mg/kg/day,

titratedup

to2mg/k/dayafter1wk

(high-dose

group)

GroupB:86%(6–,12

y);79%

(12–,18

y)GroupA:23.6(2

9.2to1.9,P=NS)

4wk

51%white

GroupC:Placebo

GroupC:33%(6–,12

y);27%

(12–,18

y)GroupB28.5(2

14to23.0,P=.0027)

37%black

Adjusted

meandifferenceDB

Pat

follow-upversus

placebo:

GroupA:24.5(2

9.5to0.4,P=NS)

GroupB:24.8(2

9.7to0,P=.051)

Drug

plus

lifestyleinterventions

Berenson

etal1983

60

(fair)

RCT

150

NRADAPTProgram

NRMeanchange

from

baseline,SBP:

School-based

inUnitedSates

GroupA:Propranolol20–40

mg+

chlorthalidone6.25–12.5mg+

nutrition

educationandprom

otion

ofdietarymodification

GroupA:27.6

Otherpublication:

Franketal1982

786mo

GroupB:Hypertensive

controlgroup

with

notreatm

ent

GroupB:23.0

Meanchange

from

baseline,DB

P:GroupA:26.9

GroupB:23.9

Berenson

etal1990

61

(fair)

RCT

150

Meanage12

ySameas

above

NRAdjusted

meandifference,SBP:

School-based

inUnitedStates

55%male

GroupAversus

GroupB:23.6(SD1.12;

P,

.01)

Continuationof

Berenson

etal

1983

60

30mo

47%white

Adjusted

meandifferenceDB

P:MeanSBP117.7mmHg

GroupAversus

GroupB:21.7(SD0.82;

P,

.05)

MeanDB

P78.1mmHg

Lifestyleinterventions

Diet Co

uchetal2008

62

(fair)

RCT

57Meanage14

yGroupA:DASH-type

dietmodified

for

adolescentpopulation+counseling

NRMeandifferenceatfollow-up,SBP:

CincinnatiChildren’sHospitalM

edical

Center,UnitedStates

63%male

GroupB:Counselingalone

GroupAversus

GroupB:0.1

6mo

MeanSBP128.7mmHg

Meandifferenceatfollow-up,DB

P:MeanDB

P80.5mmHg

GroupAversus

GroupB:21.2

Proportionachievingnorm

otensive

status:

GroupA61%versus

GroupB44%;P

=NS

Howeetal1991

65

(fair)

RCTcrossover

103

Meanage13y(range11–14y)

GroupA:Low-sodiumdiet(,

75mmol/

day)+counseling

NRNo

significant

differences

inSBPor

DBPbetweendiets;baselinevalues

notreported

School-based

MeanSBP115.0mmHg

GroupB:High-sodiumdiet(.

150

mmol/day)diet+counseling

Adelaide,Australia

MeanDB

P60.1mmHg

2phases

of4wkeach



APPENDIX

5Continued

Author,Year(Quality

Rating)

StudyDesign

and

SettingDuration


Intervention


#95th


forAge,Gender,and

Height

BloodPressure

(mmHg)

Sinaikoetal

1993

66(fair)

RCT

210

Meanage13

yGroupA:Lowsodium

diet(,

70mmol/

day)

NRChangesinSBP:

St.Pauland

Minneapolispublic

schools,UnitedStates

50%male

GroupB:Potassiumchloride

supplementation

Boys:Nosignificant

differences

inratesofincrease

inSBPbetween

lowsodium

,potassium

supplement,andplacebogroups.

3y

MeanSBP113.8mmHg

GroupC:Participant’s

usualdiet+

placebo

Girls:Significant

differenceinSBP

betweenlowsodium

group(slight

overalldecrease)

andtheplacebo

group(significant

increase

from

baseline).Nootherdifferences

betweengroups.

MeanDB

P65.1mmHg

ChangesinDB

P:Boys:Nosignificant

differences

inratesofincrease

inBP

betweenlow

sodium

,potassium

supplement,

andplacebogroups

Girls:Thelowsodium

groupwas

the

onlygroupthathadratesof

increase

inDB

Pcomparedwith

placebothatweresignificantly

greaterthan

zero

Exercise

Hansen

etal

1991

64(fair)

RCT

137

Agerange9–11

yGroupA:3extralessonsperw

eekofan

ordinaryschoolphysicaleducation

program

NRMeandifferenceatfollow-up,SBP:

Odense,Denmark

Otherdemographic

characteristics:NR

GroupB:No

extraphysicaleducation

lessons

GroupAversus

GroupB:24.9;P,

.05

School-based

Meandifferenceatfollow-up,DB

P:8mo

GroupAversus

GroupB:23.8;P,.05;

Meditation

REVIEW ARTICLE



APPENDIX

5Continued

Author,Year(Quality

Rating)

StudyDesign

and

SettingDuration


Intervention


#95th


forAge,Gender,and

Height

BloodPressure

(mmHg)

Gregoskietal

2011

63(fair)

RCT

166

Meanage15

yGroupA:Breathingaw

areness

meditation

NRMean24-hSBPat3-mofollow-up:

School-based

inUnitedStates

59%female

GroupB:LifeSkillstraining

(weekly50-

minsessions

focusing

ontraining

inproblem-solving

skills,reflective

listening,conflictresolution,anger

managem

enttoenhancesocial

skillsandassertiveness)

GroupAversus

GroupBversus

GroupC:

3mo

100%

black

GroupC:Health

educationcontrol

116.6vs

119.8vs

121.0

MeanSBP118.9mmHg

GroupAversus

GroupB:P=NS

MeanDB

P63.6mmHg

GroupAversus

GroupC:P=.05

Mean24-hDB

Pat3-mofollow-up:

GroupAversus

GroupBversus

GroupC:

66.3vs

68.2vs

68.7;P

=NS

forall

comparisons

Progressivemusclerelaxation

Ewartetal19873

3

(fair)

RCT

159

BMIrange:19.0–31.2

GroupA:Progressivemuscle

relaxation(12wk,15–20

min,4

d/wk)

provided

inschool

NRNo

significant

differences

between

SBPandDB

Pbetweentreatm

ent

andcontrolgroups

2largeUS

BaltimoreCitypublichigh

schools

Meanage15y(range13–17y)

9mo

60%male

55%black

BP,blood

pressure;DASH,DietaryApproaches

toStop

Hypertension;ER,extended

release;NR

,not

reported;NS,notsignificant.



APPENDIX

6Harm

sof

Interventions

forHypertension

inChildrenandAdolecents

Author,Year(Quality

Rating)

Relevance

Type

ofStudySettingand

Duration

MeanAge

(SD)

(y)

NumberRandom

ized

orAnalyzed

Intervention

AEs

Drug

interventions

Batisky

etal

2007

53(fair)

Allparticipantshadprimary

hypertension

RCT

12.5(2.8)

144random

ized

indosing

study

100analyzed

insafetystudy

4-wkdose

rangingstudy:

4-wkdose-ranging

study:

28centers

ERmetoprololsuccinate0.2–2.0

mg/kg

1withdraw

alduetoAEs

UnitesStates

Placebo

Heartratedecreasedby

6.5bpm

in1.0mg/kg

group(com

pared

with

increase

of5.4bpmin

placebogroup),

4-wkdose-ranging

study

52-wkopen-labelstudy:

Fatigue

notedby

1patienteach

inthe0.2,1.0,and2.0mg/kg

groups

52-wksafetystudy

25mgor

12.5mgonce

daily

atinvestigator

discretion;

increase

every2wkuntil

maximum

of200mgonce

daily

52-wksafetystudy:

5withdraw

alsduetoAEs(1each

offatigue,nightmares,

anxiety,dizziness,asthma)

SeriousAEs:2/100(2%;1

pneumoniaand1

menom

etrorrhagia)

OtherAEs:

Headache:30%

Upperrespiratorytract

infection:20%

Cough:19%

Nasopharyngitis:13%

Pharyngolaryngealpain:12%

Fatigue:9%

Diarrhea:7%

Dizziness:6%

Flynnetal2004

54

(fair)

31%with

primary

hypertension

RCTcrossover

12.1(3.3)

268random

ized;84with

primary

hypertension

Amlodipine

2.5–5.0mg/day

Withdraw

alsduetoAEs:

Clinicaltrialfrom49

centersin

NorthandSouthAm

erica

Placebo

12/268

(??%

),ofwhich

6considered

bystudy

investigatorstobe

studydrug

related(3

worsening

hypertension,1facialedem

a,1

finger

edem

aandrash,1

prem

atureventricular

contractions)

24-wkphases

SeriousAEs:

5/268(2%;1

each:urinary

tract

infection,gastroenteritis

and

hypovolemia,pulmonary

edem

a,pneumonia,

pancreatitis)

REVIEW ARTICLE



APPENDIX

6Continued

Author,Year(Quality

Rating)

Relevance

Type

ofStudySettingand

Duration

MeanAge

(SD)

(y)

NumberRandom

ized

orAnalyzed

Intervention

AEs

Hazanetal

2010

67(good)

Primaryhypertension

75%(225/

302);Patientswith

clinically

significant

medicalcondition

orchronicdisease,malignant

orsevere

hypertension

excluded

RCT

12.2(2.97)

422screened

302random

ized

Olmesartanmedoxom

ilAnyadverseevent:olmesartan

33/93(36%

)versus

placebo

27/89(30)

Clinicaltrialat61sites;2cohorts

stratified

byrace

IncidenceofspecificAEsnot

reported;headachemost

common

2-wkwashout

period

Phase1:3-wkdosing

study

Phase2:2-wkwithdraw

alstudy

Lietal2004

68

(fair)

Hypertensive

(20.9%

with

renal

etiology,otherwisenot

reported),or

high-normal

bloodpressure

inthe

presenceofassociated

clinical

condition

such

asdiabetes

mellitus

Dose-ranging

RCT;78

clinical

centersinUnitedStates,

Russia,Israel

12.1(2.6)

376screened

Fosinopril

Overallstudy

withdraw

alsacross

all4phasesofstudydue

toAEs:

5/253(2%)

PhaseA:10-day

run-in

255eligible

PhaseC:IncidenceofAEssimilar

betweenplacebo(33.9%

)and

combinedfosinopril

treatm

entgroups(34.3%

)PhaseB:4-wkdose-ranging

253random

ized

PhaseD:SpecificAEs:

PhaseC:2-wkwithdraw

alversus

placebo

Headache:51/253(20%

)

PhaseD:1-yopen-labelsafety

phase

Nasopharyngitis:24/253(10%

)Cough:23/253

(9%)

Pharyngitis:22/253(9%)

Abdominalpain:16/253(6%)



APPENDIX

6Continued

Author,Year(Quality

Rating)

Relevance

Type

ofStudySettingand

Duration

MeanAge

(SD)

(y)

NumberRandom

ized

orAnalyzed

Intervention

AEs

Lietal2010

55

(fair)

56%primaryhypertension

RCT

Age,12

y:52.6%

304random

ized

Eplerenone

25mgonce

daily,25

mgtwicedaily,or25

mgtwice

daily

for2wkthen

50mgtwice

daily

for4wk

PhaseA:

22%obesity-related

hypertension

Clinicaltrialin43

centersinthe

UnitedStates,India,South

Africa,Russia,andDominican

Republic

Placebo

AnyAE:low

dose

38%versus

middledose

31%versus

high

dose

40%

17%renal-related

hypertension

PhaseA:6-wkdosing

study(no

placebo)

274reportsofmild

AEs,mainly

headache

andupper

respiratorytractinfections

PhaseB:4-wkplacebo-controlled

study

106reportsofmoderateAEs

18reportsofsevere

AEs(4

possiblyor

definitelyrelated

totreatm

ent:migraine,

fatigue,bronchitis,headache)

4perm

anentd

iscontinuations,3

ofwhich

wereconsidered

treatm

ent-related:

hypotension,hypertension,

fatigue

PhaseB:

Nosignificant

differences

inAE

frequenciesbetweenactive

therapyandplacebo;8

patientshadworsening

hypertension

during

this

phase,including2inthehigh

dose

groupthatwere

withdraw

nfrom

thestudy

Shahinfaretal

2005

69(fair)

Hypertension;“morethan

50%

hadunderlying

kidney

disease”

(secondary

hypertension)butn

oadditionaldetailsreported

Dose-ranging

RCT:phase1

random

ized

to3different

doses,phase2random

ized

washout;43clinicalcentersin

NorthandSouthAm

erica

(including

UnitedStates),

Europe,Africa,36

days

12(3.1)

175random

ized

Losartan

Withdraw

alsduetoAEs:1/175

(,1%

)Drug-related

AEs:14/175

(8%),of

which

headache

(5)was

most

common

event

ComparisonofAE

inPhase2

betweenactivedrug

and

controlnot

reported

REVIEW ARTICLE



APPENDIX

6Continued

Author,Year(Quality

Rating)

Relevance

Type

ofStudySettingand

Duration

MeanAge

(SD)

(y)

NumberRandom

ized

orAnalyzed

Intervention

AEs

Sofferetal

2003

70(fair)

Hypertension;unclear

severityof

underlying

kidney

disease

(study

entryrequired

glom

eruralfiltrationrate$30

mL/min/1.73m2 )

Dose-ranging

RCT

Meannotreported47%

,6–12

y,53%13–16

y

115random

ized

Lisinopril

Withdraw

alsduetoAEs:1/115

(,1%

)Phase1random

ized

to3

different

doses,phase2

random

ized

washout

Drug-related

AEs:14/115

(12%

)

Multisite

(num

berandlocation

notreported);29days

Headache:4/115

(4%)

Gastrointestinal(abdom

inal

pain,diarrhea,nausea

and/or

vomiting):2/115(2%)

Dizziness:2/115(2%)

Cough:1/115(,

1%)

Sorofetal20025

6

(fair)

Excluded

severe

hypertension

andcorrectablesecondary

hypertension

RCT

13.8(3.1)

94random

ized

(62treatm

ent+

32placebo)

B/HT

(n=62):

B/HT

grouphadfeweroverallAEs

than

placebogroup,33/62

(53%

)vs24/32(75%

)(P=.047)

andfewer

seriousAEs,1/62

(2%)vs

5/32

(16%

)(P

=.016)

Clinicaltrialfrom22

centersin

UnitedStates

andBrazil

B/HT

group:

2-wkrun-in,8-wktitration

period,-wkdose

maintenance

period,2-wktapering

period

B2.5mg/HT

6.25

mg

Mostcom

mon

AEwas

headache

(26%

)B5mg/HT

6.25

mg

1patient

hadsevere

hypertension,and

discontinuedthestudy.

B10

mg/HT

6.25

mg

Placebogroup:

Mostcom

mon

AEwas

headache

(31%

)Placebo(n

=32)

2patientshadsevere

hypertension,and

discontinuedthestudy

Trachtman

etal

2003

57(fair)

Excluded

secondary

hypertension

RCT

12.1(2.7)

133random

ized

ERfelodipine

1withdraw

aldueto

“heart

racing”;heartratewas

96bpmandECGnorm

al;and

1withdraw

alduetovomiting

thefirstdose

(5mg)

Clinicaltrialat30sitesinthe

UnitedStates

2.5mg(n

=33),5mg(n=340,or

10mg(n

=31),titratedto

targetdose

over

2–3wk,

dependingon

dosage

%reportingAEs:placebo66%and

64%,56%

,and

77%inthe

felodine

ER2.5mg,5.0mg,and

10mggroups,respectively

1-to3-wkscreeningperiod,2-to

3-wkdose

titrationperiod,3-

wkmaintenance

study

Placebo(n

=35)

Mostcom

mon

AEswere

headaches(33%

),respiratory

infections

(12%

),andnausea

(10%

)Pedaledemawas

notedin2(2%)

ofpatients



APPENDIX

6Continued

Author,Year(Quality

Rating)

Relevance

Type

ofStudySettingand

Duration

MeanAge

(SD)

(y)

NumberRandom

ized

orAnalyzed

Intervention

AEs

Trachtman

etal

2008

58(fair)

Excluded

secondary

hypertension

RCT

%Age.12

y:70.8%

240random

ized

4wktrial:

3/240patientsinthe4wktrial

and5/233patientsinthe52

wk

studydiscontinuedduetoAEs,

specifically

hypotension,arm

fracture,dizziness,headache,

lowwhitebloodcellcount,and

progressionofunderlying

renaldisease

(2patients)

Otherhypertensives,except

for

otherangiotension

receptor

blockers,w

ereperm

itted


States

andEurope

Candesartandoses2,8,and16

mg/dayforthose,50

kg,and

4,16,and

32mg/dayforthose

$50

kg

Mostcom

mon

AEs:headache,

upperrespiratoryinfection,

dizziness,cough,andsore

throat

4-wktrialand

1-yopen-label

study

Placebo

Open

labelstudy:

Candesartanat4or

8mg/dayto

start,butlater

adjusted

tocontrolBP

Wellsetal2002

71

(fair)

Severe

orsymptom

atic

hypertension

excluded

Dose-ranging

RCT

Median12

y110enrolled

Enalapril

Drug-related

AEs:12/110

(11%

)2-wkdose

rangingphaseand2-

wkplacebocontrolled

washout

phase

Dizziness:4/110(4%)

Headache:2/110

(2%)

Cough:3/110(3%)

Noincidenceofrenalfailure,

angioedemaor

hyperkalem

ia5laboratory

AEspossibly,

probablyor

definitelyrelated

tostudydrug

REVIEW ARTICLE



APPENDIX

6Continued

Author,Year(Quality

Rating)

Relevance

Type

ofStudySettingand

Duration

MeanAge

(SD)

(y)

NumberRandom

ized

orAnalyzed

Intervention

AEs

Wellsetal2010

59

(fair)

Excluded

secondary

hypertension

RCT

14(2.5)

115enrolled

Telmisartanlowdose

(1mg/kg/

day)(n

=30)and

high

dose

(1mg/kg/daytitratedup

to2mg/

k/dayafter1wk)

(n=31)

AnyAE:

Clinicaltrialat16

centersin

UnitedStates,Brazil,and

Mexico

77random

ized

Placebo(n

=16)

High-dosepatients:41.9%

4wk,after2-wkwashout

period

Lowdose

patients:41.7%

Placebopatients:31.3%

Significancenotreported

2patientsdiscontinueddueto

AEs,both

inthehigh

dose

group:1patient

who

experiencedaseriousAE

(nearsyncopeandmoderate

increase

inbloodurea

nitrogen

andserum

creatinine)

who

received

anexcessivedose

inerror;and1

patient

duetomoderate-

intensity

dizziness,weakness,

andheadache

Drug

plus

lifestyleinterventions

Berenson

etal

1983

60(fair)

BP.90th

percentileforheight,

controlgroup

with

blood

pressure

,80th

percentiles

andthe50–60thpercentilefor

comparison(based

oncentilesderivedfrom

study)

“Close

toclinicaltrial”

12150(50high

bloodpressure

treatm

entgroup,50high

blood

pressure

comparisongroup,

50mediumbloodpressure

comparisongroup)

GroupA:

AEsreported

asvery

low

incidencewith

nomajor

complications

Excluded

childrenwith

evidence

ofsecondaryhypertension

School-based

Propranolol

1temporary

withdraw

alfrom

activetreatm

entd

ueto

nightm

ares

6mo

20mg/dayforchildren,

40kg,

40mg/dayforthose.40

kg+

chlorthalidone

6.25

mgperdayforchildren

,40kg,12.5mg/dayforthose

.40

kg+nutrition

education

andprom

otionofdietary

modificationtochildrenand

parents

GroupB(highBP

elevationat

baseline):

Notreatm

ent

GroupC(m

ediumBP

elevationat

baseline):

Notreatm

ent



APPENDIX

6Continued

Author,Year(Quality

Rating)

Relevance

Type

ofStudySettingand

Duration

MeanAge

(SD)

(y)

NumberRandom

ized

orAnalyzed

Intervention

AEs

Otherclinicalstudies(FDA

analyses)

Baker-Sm

ithetal

2010

73(not

rated)

Mild

tomoderatehypertension

Nonsystematicreview

andmeta-

analysisofdatafrom

8trials

subm

itted

toFDAbetween

1998

and2005

(original

studiesnotcited)

131299

analyzed

(42%

placebo+

58%activedrug)

ACEs

(6datasets)andARBs

(2datasets),includingbenazepril

(n=85),enalapril(n=101),

fosinopril(n

=222),lisinopril

(n=104),quinapril(n

=112),

ramipril(n=217),irbesartan

(n=293),losartan(n

=165)

Subjectswho

reported

coughin

thecohortreceivingactive

drugs(21/748,2.8%

)vs

placebo(14/551,2.5%

),P=.86

2wk(m

edian)

Dosagesnotreported

Subjectswho

reported

coughin

theACEgroup:(17/524,3.2%

);ARBgroup(4/224,1.8%),P=.34

Smith

etal2008

72

(notrated)

Unclear;severe

hypertension

andsignificant

renaldisease

excluded

Nonsystematicreview

andmeta-

analysisofdatafrom

10RCTs

subm

itted

toFDAbetween

1998

and2005

(original

studiesnotcited)

12.1

1707

analyzed

(685

placebo,1022

activetreatm

ents)

Activetreatm

ents(n

=1022;

meandosesnotreported):

amlodipine

(n=258),

benazepril(n

=85),enalapril

(n=101),felodipine(n

=133),

fosinopril(n

=235),

irbesartan

(n=295),lisinopril

(n=104),losartan(n

=165),

quinapril(n=112),ram

ilpril

(n=219)placebo(n

=685)

Placeboversus

activetreatm

ent:

2to4wk(variedby

trial)

Nosignificantdifferencebetween

groups

foranyAEs

AnyAE:235/685

(34%

)vs

382/

1022

(37%

)Hypertension:3/685

(4%)vs

1/1022

(.1%

)Hypotension:0/235(0%)vs

3/1022

(.1%

)Cardiac:8/685(1%)vs

16/1022

(2%)

Neuropsychological:13/685(2%)

vs26/1022(3%)

Headache:113/685

(17%

)vs179/

1022

(18%

)Syncope:15/685

(2%)vs

31/1022

(3%)

Gastrointestinal:54/685(8%)vs

90/1022(9%)

Asthma:11/685

(2%)vs

12/1022

(1%)

Elevated

LFT:7/685(1%)vs

7/1022

(.1%

)Muscleaches:11/685

(2%)vs17/

1022

(2%)

ACE,angiotensin-convertingenzymeinhibitors;AE,adverseevent;ARB,

angiotensinreceptor

blockers;bpm,beatsperminute;B/HT,bisoprolol

fumarate/hydrochlorothiazide;ECG,

electrocardiograph;ER,extended

release;FDA,

Food

andDrug

Administration;LFT,liver

functiontest.

REVIEW ARTICLE



DOI: 10.1542/peds.2012-3523; originally published online February 25, 2013; 2013;131;490Pediatrics

NorrisMatthew Thompson, Tracy Dana, Christina Bougatsos, Ian Blazina and Susan L.

Cardiovascular DiseaseScreening for Hypertension in Children and Adolescents to Prevent

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DOI: 10.1542/peds.2012-3523; originally published online February 25, 2013; 2013;131;490Pediatrics

NorrisMatthew Thompson, Tracy Dana, Christina Bougatsos, Ian Blazina and Susan L.

Cardiovascular DiseaseScreening for Hypertension in Children and Adolescents to Prevent


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