2014 evidence_based guideline for the management of high blood pressure in adults

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Copyright 2013 American Medical Association. All rights reserved.

2014 Evidence-BasedGuideline for theManagement

ofHighBlood Pressure inAdults

Report From the Panel Members Appointed

to the Eighth Joint National Committee (JNC8)Paul A. James, MD;SuzanneOparil, MD;Barry L. Carter, PharmD; WilliamC. Cushman, MD;

Cheryl Dennison-Himmelfarb, RN, ANP, PhD;Joel Handler, MD; Daniel T. Lackland,DrPH;

Michael L. LeFevre, MD,MSPH; Thomas D. MacKenzie, MD,MSPH; Olugbenga Ogedegbe, MD,MPH, MS;

SidneyC. Smith Jr, MD;Laura P. Svetkey, MD, MHS; SandraJ. Taler, MD;RaymondR. Townsend, MD;

Jackson T. WrightJr,MD,PhD; AndrewS. Narva,MD; Eduardo Ortiz,MD, MPH

Hypertensionis themost commoncondition seen in primary care and leads to myocardial

infarction, stroke, renalfailure, and deathif not detected early and treated appropriately.

Patientswantto be assuredthat blood pressure (BP) treatmentwill reduce their disease

burden, while clinicians wantguidance on hypertension management usingthe best scientific

evidence. Thisreport takes a rigorous, evidence-based approach to recommend treatment

thresholds, goals, and medications in the management of hypertension in adults. Evidence

was drawn from randomized controlled trials, which representthe gold standardfor

determining efficacy and effectiveness. Evidence quality and recommendations were graded

based on their effect on important outcomes.

There is strong evidence to support treating hypertensivepersons aged 60 years or older to a

BPgoal oflessthan 150/90 mmHg and hypertensivepersons 30 through 59years ofage toa

diastolic goal of less than 90 mm Hg;however, there is insufficientevidencein hypertensive

persons younger than 60 years fora systolicgoal,or in those younger than 30 years fora

diastolic goal, so the panel recommends a BP of less than 140/90mm Hg for thosegroups

based on expert opinion. The same thresholds and goals arerecommended for hypertensive

adultswith diabetes or nondiabetic chronic kidneydisease (CKD)as forthe general

hypertensive population younger than60 years. There is moderate evidence to support

initiating drug treatment with an angiotensin-convertingenzyme inhibitor, angiotensinreceptor blocker, calcium channel blocker, or thiazide-type diuretic in the nonblack

hypertensive population, including those with diabetes. In the black hypertensive population,

including those with diabetes, a calcium channel blocker or thiazide-type diuretic is

recommended as initial therapy. There is moderate evidence to support initial or add-on

antihypertensive therapy with an angiotensin-convertingenzyme inhibitor or angiotensin

receptor blocker in persons with CKDto improve kidneyoutcomes.

Although this guideline provides evidence-based recommendations for the management of

high BP and shouldmeet theclinicalneeds of most patients,theserecommendations arenot

a substitute forclinicaljudgment, and decisionsaboutcare must carefullyconsider and

incorporate the clinical characteristics and circumstances of each individual patient.

JAMA. doi:10.1001/jama.2013.284427

Published onlineDecember 18, 2013.

Editorials

Author AudioInterview at

jama.com

Supplementalcontent at

jama.com

Author Affiliations: Author

affiliationsare listed atthe endof this

article.

Corresponding Author: Paul A.

James,MD,University of Iowa, 200

Hawkins Dr, 01286-D PFP, IowaCity,

IA 52242-1097 (paul-james@uiowa

.edu).

Clinical Review & Education

Special Communication

E1


wnloaded From: http://jama.jamanetwork.com/ on 12/18/2013




Hypertension remainsone of themostimportant prevent-

able contributors to disease and death. Abundant evi-

dencefromrandomizedcontrolled trials (RCTs)has shown

benefit of antihypertensive drug treatment in reducing important

health outcomes in persons with hypertension.1-3 Clinical guide-

linesare at theintersectionbetween researchevidenceand clinical

actions that canimprove patient outcomes.The Institute of Medi-

cineReportClinicalPracticeGuidelinesWeCanTrust outlineda path-way to guideline development and is the approach that this panel

aspired to in the creation of this report.4

The panel members appointed to the Eighth Joint National

Committee (JNC 8) used rigorous evidence-based methods,

developing Evidence Statements and recommendations for blood

pressure (BP) treatment based on a systematic review of the lit-

erature to meet user needs,

especially the needs of the

primary care clinician. This

report is an executive sum-

mary of the evidence and is

designed to provide clear

recommendations for all

cl inicians. Major differ-

ences from the previous

JNC report are summarized

in Table 1. The complete

ev i den ce s umma ry a n d

detailed description of the evidence review and methods are pro-

vided online (see Supplement).

The Process

The panel members appointed to JNC 8 were selected from more

than 400 nominees based on expertise in hypertension (n = 14),

primary care (n = 6), including geriatrics (n = 2), cardiology (n = 2),nephrology (n = 3), nursing (n = 1), pharmacology (n = 2), clinical

trials (n = 6), evidence-based medicine (n = 3), epidemiology

(n = 1), informatics (n = 4), and the development and implementa-

tion of clinical guidelines in systemsof care (n = 4).

The panel also included a seniorscientist from theNational In-

stitute ofDiabetesand Digestiveand KidneyDiseases (NIDDK), a se-

niormedical officer fromthe NationalHeart, Lung, andBlood Insti-

tute(NHLBI),anda seniorscientist from NHLBI,who withdrewfrom

authorship prior to publication. Two members left the panel early

inthe process beforetheevidencereviewbecauseof newjobcom-

mitmentsthatpreventedthemfromcontinuingtoserve.Panelmem-

bers disclosed any potential conflicts of interest including studies

evaluatedin thisreport andrelationshipswith industry. Those withconflicts were allowed to participate in discussions as long as they

declared their relationships, butthey recused themselves fromvot-

ingon evidencestatements andrecommendationsrelevantto their

relationshipsor conflicts.Four panelmembers (24%) had relation-

shipswith industry or potentialconflicts to discloseat theoutsetof

the process.

In January 2013, the guideline was submitted for external

peer review by NHLBI to 20 reviewers, all of whom had expertise

in hypertension, and to 16 federal agencies. Reviewers also had

expertise in cardiology, nephrology, primary care, pharmacology,

research (including clinical trials), biostatistics, and other impor-

tant related fields. Sixteen individual reviewers and 5 federal

agencies responded. Reviewers’ comments were collected, col-

lated, and anonymized. Comments were reviewed and discussed

by the panel from March through June 2013 and incorporated

into a revised document. (Reviewers’ comments and suggestions,

and responses and disposition by the panel are available on

request from the authors.)

Questions Guiding the Evidence Review

This evidence-based hypertension guideline focuses on the pan-

el’s3 highest-rankedquestions relatedto highBP managementiden-

tified through a modified Delphi technique.5 Nine recommenda-

tions aremade reflectingthesequestions.These questions address

thresholdsand goals for pharmacologictreatment of hypertension

andwhether particular antihypertensive drugs or drug classes im-

proveimportanthealthoutcomescomparedwithotherdrugclasses.

1. Inadults withhypertension,doesinitiatingantihypertensive phar-

macologic therapyat specific BP thresholdsimprove health out-

comes?

2. In adults withhypertension,does treatmentwith antihyperten-

sive pharmacologic therapy to a specified BP goal lead to im-

provements in health outcomes?

3. In adults with hypertension, do various antihypertensive drugs

or drugclassesdiffer in comparativebenefitsand harms on spe-

cific health outcomes?

The Evidence Review

The evidence reviewfocused on adultsaged 18 years or older with

hypertension and included studies withthe following prespecified

subgroups: diabetes,coronary artery disease,peripheral arterydis-ease, heart failure, previous stroke, chronic kidney disease (CKD),

proteinuria,olderadults, menand women,racialand ethnicgroups,

andsmokers. Studies with sample sizes smaller than 100 were ex-

cluded, as were studies with a follow-up period of less than 1 year,

because small studies ofbrief durationare unlikely toyieldenough

health-relatedoutcomeinformationto permitinterpretationof treat-

ment effects. Studies were included in theevidence review only if

theyreportedtheeffectsofthestudiedinterventionsonanyofthese

important health outcomes:

• Overall mortality, cardiovascular disease (CVD)–relatedmortality,

CKD-related mortality

• Myocardial infarction, heart failure, hospitalization for heart fail-

ure, stroke• Coronary revascularization (includes coronary artery bypass sur-

gery, coronary angioplasty and coronary stent placement), other

revascularization (includescarotid,renal, and lower extremityre-

vascularization)

• End-stage renal disease (ESRD) (ie, kidney failure resulting in di-

alysis or transplantation), doubling of creatinine level, halving of

glomerular filtration rate (GFR).

Thepanel limited itsevidencereview to RCTs because theyare

lesssubjectto biasthan other study designs andrepresentthe gold

standard for determining efficacy and effectiveness.6 The studies

ACEI angiotensin-converting enzyme

inhibitor

ARB angiotensinreceptorblocker

BP blood pressure

CCB calciumchannel blocker

CKD chronic kidney disease

CVD cardiovascular disease

ESRD end-stage renaldisease

GFR glomerular filtration rate

HF heart failure

Clinical Review & Education SpecialCommunication 2014Guidelinefor Managementof HighBlood Pressure

E2 JAMA Published online December 18, 2013 jama.com






in the evidence review were from original publications of eligible

RCTs. These studies were used to createevidencetables andsum-

mary tablesthatwereusedby thepanel for theirdeliberations (see

Supplement). Because the panelconductedits own systematic re-

view using original studies, systematic reviews and meta-analyses

of RCTs conducted and published by other groups were not in-

cluded in the formalevidencereview.InitialsearchdatesfortheliteraturereviewwereJanuary1,1966,

through December 31, 2009. The search strategy and PRISMA dia-

gram foreach questionis in theonline Supplement. To ensurethat

nomajor relevantstudies publishedafterDecember31, 2009, were

excluded from consideration, 2 independent searches of PubMed

and CINAHL between December 2009and August 2013were con-

ductedwiththe same MeSH termsas theoriginal search. Threepanel

membersreviewed theresults.The panel limited theinclusion cri-

teriaof this secondsearch tothe following. (1)The studywas a ma-

jor studyin hypertension (eg, ACCORD-BP, SPS3; however, SPS3 did

not meet strict inclusioncriteria because it included nonhyperten-

sive participants. SPS3 would not have changed our conclusions/

recommendations because the only significant finding supportinga lowergoalfor BPoccurred inan infrequentsecondaryoutcome).7,8

(2)Thestudyhadatleast2000participants.(3)Thestudywasmul-

ticentered. (4) The study met all the other inclusion/exclusion cri-

teria. The relatively high threshold of 2000 participants was used

because of themarkedlylower event rates observedin recent RCTs

such as ACCORD, suggesting that larger study populations are

neededto obtain interpretable results.Additionally, allpanel mem-

bers were asked to identify newly published studies for consider-

ation if they metthe above criteria.No additional clinical trialsmet

the previously described inclusion criteria. Studies selected were

rated forqualityusing NHLBI’s standardizedqualityratingtool (see

Supplement) and were only included if rated as good or fair.

An external methodology team performed the literature re-

view, summarized data from selected papers intoevidence tables,

and provided a summary of the evidence. From this evidence re-

view, the panel crafted evidence statements and voted on agree-

ment or disagreement with each statement. For approved evi-dence statements, the panel then voted on the quality of the

evidence (Table 2). Once all evidence statements for each critical

question were identified, the panel reviewed the evidence state-

ments to craft the clinical recommendations, voting on each rec-

ommendation andon thestrengthof therecommendation(Table3).

For both evidence statements and recommendations, a record of

thevote count (for, against, or recusal) was made without attribu-

tion. The panel attempted to achieve 100% consensus whenever

possible, buta two-thirdsmajority wasconsideredacceptable, with

theexception ofrecommendationsbased onexpert opinion,which

required a 75% majority agreement to approve.

Results (Recommendations)

The following recommendations are based on the systematic evi-

dencereview described above (Box). Recommendations 1 through

5 address questions 1 and2 concerning thresholds and goalsfor BP

treatment. Recommendations 6, 7, and 8 address question 3 con-

cerning selection of antihypertensive drugs.Recommendation 9 is

asummaryofstrategiesbasedonexpertopinionforstartingandadd-

ingantihypertensivedrugs. Theevidencestatementssupporting the

recommendations are in the online Supplement.

Table 1. Comparison of Current Recommendations WithJNC 7 Guidelines

Topic JNC 7 2014 Hypertension Guideline

Methodology Nonsystematicliteraturereview by expertcommittee includingarange of study designsRecommendations based on consensus

Criticalquestions and review criteria defined by expert panel withinput frommethodologyteamInitial systematic review by methodologists restricted to RCTevidenceSubsequent review of RCT evidenceand recommendationsby thepanel according to a standardizedprotocol

D efini tio ns Defi ned hy pert ensio n and prehypertensi on Defi nit io ns o fh yperten sio n and preh ypertensi on n ot a ddressed,

but thresholds for pharmacologictreatment were defined

Treatmentgoals

Separatetreatment goals defined for “uncomplicated” hypertensionandfor subsets withvariouscomorbid conditions(diabetes andCKD)

Similartreatment goals defined for all hypertensive populationsexcept whenevidence review supports differentgoals for a particu-lar subpopulation

Lifestylerecommendations

Recommendedlifestyle modificationsbased on literaturereview andexpert opinion

Lifestyle modifications recommended by endorsing the evidence-based Recommendations of the LifestyleWork Group

Drugtherapy Recommended 5 classes tobe consideredas initial therapy but rec-ommended thiazide-typediuretics as initial therapy for mostpa-tients without compelling indication for another classSpecifiedparticular antihypertensivemedication classes for patientswithcompelling indications, ie, diabetes, CKD, heartfailure,myocar-dialinfarction,stroke,and highCVD riskIncluded a comprehensive table of oralantihypertensive drugsin-cluding names and usual doseranges

Recommendedselection among 4 specificmedication classes (ACEIor ARB, CCB or diuretics) and dosesbasedon RCTevidenceRecommendedspecificmedication classes based on evidencereviewfor racial, CKD, and diabeticsubgroupsPanel created a tableof drugs anddosesused inthe outcome trials

Scope of topics Addressed multiple issues(bloodpressuremeasurement methods,patient evaluationcomponents, secondary hypertension,adherenceto regimens,resistant hypertension,and hypertension in specialpopulations) based on literature review and expert opinion

Evidence review of RCTs addressed a limitednumber of questions,those judgedby the panel to be of highestpriority.

Review processprior topublication

Reviewedby the NationalHigh Blood Pressure Education ProgramCoordinatingCommittee, a coalitionof 39 major professional, pub-lic,and voluntaryorganizations and7 federal agencies

Reviewedby experts including those affiliated withprofessionalandpublic organizations andfederalagencies; no official sponsorship byanyorganizationshouldbe inferred

Abbreviations: ACEI,angiotensin-converting enzyme inhibitor;ARB,

angiotensinreceptorblocker; CCB, calciumchannelblocker;CKD, chronic

kidney disease; CVD, cardiovasculardisease;JNC, JointNational Committee;

RCT, randomizedcontrolledtrial

2014Guidelinefor Management of HighBlood Pressure Special Communication ClinicalReview & Education

jama.com JAMA Published onlineDecember 18,2013 E3






Recommendation 1

In the general population aged 60 years or older, initiate pharma-

cologic treatmentto lower BPat systolicbloodpressure (SBP) of150

mm Hgor higheror diastolicblood pressure (DBP)of 90 mm Hgor

higherand treat toa goalSBPlower than150mm Hgandgoal DBP

lower than90 mmHg.

Strong Recommendation– GradeA

Corollary RecommendationIn the general population aged 60 years or older, if pharmacologic

treatment for high BP results in lower achieved SBP (for example,

<140 mm Hg)and treatmentis not associated with adverse effects

onhealth orqualityof life,treatment does not need tobe adjusted.

ExpertOpinion – GradeE

Recommendation 1 is basedon evidence statements 1 through

3 from question 2 in which there is moderate- to high-quality evi-

dence from RCTs that in the general population aged 60 years or

older, treating high BP to a goal of lower than 150/90 mm Hg re-

duces stroke,heartfailure, andcoronary heart disease(CHD).There

is alsoevidence(albeitlow quality) fromevidencestatement 6,ques-

tion 2 that setting a goal SBP of lower than 140 mm Hg in this age

group provides no additional benefit compared with a higher goal

SBP of140to160mm Hgor 140 to149 mmHg.9,10

To answerquestion2 about goal BP, thepanelreviewed allRCTs

thatmettheeligibilitycriteriaandthateithercomparedtreatmentwith

a particular goal vs no treatment or placeboor compared treatment

with one BP goal with treatment to another BP goal. The trials on

whichtheseevidencestatementsandthisrecommendationarebased

includeHYVET,Syst-Eur, SHEP, JATOS,VALISH, andCARDIO-SIS.1-3,9-11

Strengths,limitations,andotherconsiderationsrelatedtothisevidence

review arepresentedin theevidencestatementnarrativesandclearly

support the benefitof treating toa BPlower than150mm Hg.

Thecorollaryto recommendation1 reflectsthat there aremany

treated hypertensivepatients aged 60 years or olderin whom SBP

iscurrentlylowerthan140mmHg,basedonimplementationofpre-

vious guideline recommendations.12 The panel’s opinion is that in

these patients,it is not necessary to adjustmedication to allow BP

Table 3. Strengthof Recommendation

Grade Strength of Recommendation

A S trong Rec omm en da ti onThere is high certainty based on evidence that the net benefita is substantial.

B M od erat e Rec omm en da ti onThere is moderate certainty based on evidence that the net benefit is moderate to substantial or there is highcertainty that the net benefit is moderate.

C Weak Re commendatio nThere is at least moderate certainty based on evidence that there is a small net benefit.

D Rec om mend at io n a ga in stThere is at least moderate certainty based on evidence that it has no net benefit or that risks/harms outweighbenefits.

E Expert Opinion (“There is insufficient evidence or evidence is unclear or conflicting, but this is what thecommittee recommends.”)Net benefit is unclear. Balance of benefits and harms cannot be determined because of no evidence, insuffi-cient evidence, unclear evidence, or conflicting evidence, but the committee thought it was important to

provide clinical guidance and make a recommendation. Further research is recommended in this area.

N No Recommendation for or against (“There is insufficient evidence or evidence is unclear or conflicting.”)Net benefit is unclear. Balance of benefits and harms cannot be determined because of no evidence, insuffi-cient evidence, unclear evidence, or conflicting evidence, and the committee thought no recommendationshould be made. Further research is recommended in this area.

Thestrengthof recommendation

grading system used in thisguideline

wasdeveloped bythe National Heart,

Lung,and Blood Institute’s (NHLBI’s)

Evidence-BasedMethodologyLead

(withinput from NHLBIstaff,external

methodologyteam, and guideline

panelsand workgroups)for useby all

theNHLBI CVDguideline panelsand

workgroups duringthisproject.

Additional details regarding the

strength of recommendation grading

systemare available inthe onlineSupplement.

aNetbenefitis definedas benefits

minus therisks/harmsof the

service/intervention.

Table 2. Evidence Quality Rating

Type of Evidence Quality Ratinga

Well-designed, well-executed RCTs that adequately represent populations to which the results are applied and directlyassess effects on health outcomesWell-conducted meta-analyses of such studiesHighly certain about the estimate of effect; further research is unlikely to change our confidence in the estimate of effect

High

RCTs with minor limitations affecting confidence in, or applicability of, the resultsWell-designed, well-executed non–randomized controlled studies and well-designed, well-executed observational studiesWell-conducted meta-analyses of such studies

Moderately certain about the estimate of effect; further research may have an impact on our confidence in the estimateof effect and may change the estimate

Moderate

RCTs with major limitationsNon–randomized controlled studies and observational studies with major limitations affecting confidence in,or applicability of, the resultsUncontrolled clinical observations without an appropriate comparison group (eg, case series, case reports)Physiological studies in humansMeta-analyses of such studiesLow certainty about the estimate of effect; further research is likely to have an impact on our confidence in the estimateof effect and is likely to change the estimate.

Low

Abbreviations: RCT, randomizedcontrolledtrial

aTheevidence quality ratingsystem used in this guidelinewas developedby the

National Heart,Lung, and Blood Institute’s (NHLBI’s)Evidence-Based

MethodologyLead (withinput from NHLBIstaff,externalmethodology team,

andguideline panelsand work groups)for useby allthe NHLBI CVDguideline

panelsand work groupsduringthisproject.As a result, it includesthe evidence

quality ratingfor many types of studies, includingstudies that were notusedin

thisguideline.Additionaldetails regarding the evidence quality rating system

are available in theonline Supplement.








toincrease.In2ofthetrialsthatprovideevidencesupportinganSBP

goallowerthan150mmHg,theaveragetreatedSBPwas143to144

mmHg.2,3Many participants inthosestudies achieved anSBP lower

than 140 mm Hg with treatmentthat was generally well tolerated.

Two other trials9,10suggest therewasno benefitforanSBP goal lower

than 140mm Hg,butthe confidenceintervalsaround theeffectsizes

were wide and did not exclude the possibility of a clinically impor-

tant benefit. Therefore, thepanel included a corollary recommen-dationbasedonexpertopinionthattreatmentforhypertensiondoes

notneed to be adjusted if treatmentresults in SBPlower than 140

mmHg and isnotassociatedwithadverse effects onhealthor qual-

ityof life.

While allpanelmembers agreed that the evidence supporting

recommendation1isverystrong,thepanelwasunabletoreachuna-

nimityon therecommendation ofa goal SBPof lower than150 mm

Hg. Some members recommended continuing the JNC 7 SBP goal

oflowerthan140 mmHg for individuals older than 60 years based

on expert opinion.12 These members concluded that the evidence

wasinsufficienttoraisetheSBPtargetfromlowerthan140tolower

than 150 mm Hg in high-risk groups, such as black persons, those

withCVD includingstroke, andthose withmultiplerisk factors.The

panel agreed that moreresearch is needed toidentifyoptimal goals

of SBPfor patients with high BP.

Recommendation 2

In the general population younger than 60 years, initiate pharma-

cologic treatment to lower BP at DBP of 90 mm Hg or higher and

treat toa goalDBP oflower than90 mmHg.

For ages 30through 59years, StrongRecommendation – GradeA

For ages 18 through 29 years, ExpertOpinion – GradeE

Recommendation 2 is based on high-quality evidence from 5

DBPtrials (HDFP, Hypertension-StrokeCooperative, MRC,ANBP,and

VA Cooperative) that demonstrate improvements in health out-

comesamongadultsaged30 through 69yearswithelevated BP.13-18

Initiation of antihypertensive treatment at a DBP threshold of 90

mmHgorhigherandtreatmenttoaDBPgoaloflowerthan90mm

Hg reduces cerebrovascular events, heart failure, and overall mor-

tality (question 1, evidence statements 10, 11, 13; question 2, evi-

dencestatement10).InfurthersupportforaDBPgoaloflowerthan

90mmHg,thepanelfoundevidencethatthereisnobenefitintreat-

ing patientsto a goalofeither 80mm Hgor lower or85 mmHg or

lowercomparedwith90mmHgorlowerbasedontheHOTtrial,in

which patients were randomized to these 3 goals without statisti-

cally significant differences between treatment groups in the pri-

maryor secondaryoutcomes(question2, evidencestatement14).19

In adults younger than 30 years, there are no good- or fair-

quality RCTs thatassessed thebenefitsof treatingelevated DBPon

health outcomes (question 1, evidence statement 14). In the ab-

senceof suchevidence,it isthe panel’s opinion that inadults younger

than 30years, theDBPthreshold and goal shouldbe thesameas in

adults30 through 59 years of age.

Recommendation 3

In the general population younger than 60 years, initiate pharma-

cologic treatment to lower BP at SBP of 140 mm Hg or higher and

treat toa goalSBP oflower than140 mmHg.


Box. Recommendations for Management of Hypertension

Recommendation1

In the general population aged 60 years, initiate pharmacologic treat-

ment to lower blood pressure (BP) at systolic blood pressure (SBP)150

mmHg or diastolicbloodpressure(DBP)90mmHgandtreattoa goal

SBP <150 mm Hg and goal DBP <90 mm Hg. (Strong Recommendation –

Grade A)

Corollary Recommendation

Inthe general populationaged60years, if pharmacologictreatmentfor

high BP results in lower achieved SBP(eg,<140 mmHg) andtreatment is

welltoleratedandwithoutadverseeffectsonhealthorqualityoflife,treat-

ment does notneedto be adjusted. (ExpertOpinion– Grade E)

Recommendation2

In the general population <60 years, initiate pharmacologic treatment to

lowerBPatDBP90mmHgandtreattoagoalDBP<90mmHg.(Forages

30-59 years, Strong Recommendation – Grade A; For ages 18-29 years,

ExpertOpinion – Grade E)

Recommendation3

In the general population <60 years, initiate pharmacologic treatment to

lowerBPatSBP140mmHgandtreattoagoalSBP<140mmHg.(Expert

Opinion – Grade E)

Recommendation4

In the population aged 18 years with chronic kidney disease (CKD), ini-

tiatepharmacologictreatmenttolowerBPatSBP 140mmHgorDBP90

mmHgandtreattogoalSBP<140mmHgandgoalDBP<90mmHg.(Expert

Opinion – Grade E)

Recommendation5

Inthepopulationaged18years withdiabetes,initiatepharmacologictreat-

menttolowerBPatSBP140mmHgorDBP90mmHgandtreattoagoal

SBP<140 mmHg and goalDBP<90 mmHg.(Expert Opinion – GradeE)

Recommendation6

In the general nonblack population, including those with diabetes, initial

antihypertensive treatment should include a thiazide-type diuretic, cal-

cium channel blocker (CCB), angiotensin-converting enzyme inhibitor

(ACEI), or angiotensin receptor blocker (ARB). (Moderate Recommenda-

tion– Grade B)

Recommendation7

In the general blackpopulation, includingthose withdiabetes,initial anti-

hypertensivetreatmentshouldincludea thiazide-typediureticor CCB.(For

generalblack population:ModerateRecommendation– GradeB; forblack

patients with diabetes: WeakRecommendation– GradeC)

Recommendation8

In thepopulation aged18 years with CKD, initial(or add-on) antihyper-

tensive treatment should include an ACEI or ARB to improve kidney out-

comes.Thisapplies toall CKDpatientswith hypertensionregardlessofrace

or diabetes status.(ModerateRecommendation – GradeB)

Recommendation9

Themainobjectiveof hypertensiontreatmentis toattainand maintaingoal

BP.IfgoalBPisnotreachedwithinamonthoftreatment,increasethedose

of the initial drug or add a second drug from one of the classes in recom-mendation6(thiazide-typediuretic,CCB,ACEI,orARB).Theclinicianshould

continue to assess BP and adjust the treatment regimen until goal BP is

reached.If goal BP cannotbe reached with2 drugs,add andtitratea third

drug fromthe list provided.Donot useanACEIand anARBtogetherin the

same patient.If goal BP cannotbe reached usingonlythe drugs inrecom-

mendation6 becauseofa contraindication ortheneedto usemorethan 3

drugs to reach goal BP, antihypertensive drugs from other classes canbe

used.Referral to a hypertension specialistmay be indicatedfor patients in

whomgoalBP cannotbeattainedusingtheabovestrategyor fortheman-

agement of complicated patients for whom additional clinical consulta-

tion is needed. (ExpertOpinion– Grade E)








Recommendation3 is based on expert opinion. While there is

high-qualityevidenceto support a specific SBPthreshold andgoal

forpersonsaged60yearsorolder(Seerecommendation1),thepanel

found insufficient evidence from good- or fair-quality RCTs to sup-

port a specific SBP threshold or goal for persons younger than 60

years. In the absence of such evidence, the panel recommends an

SBPtreatmentthreshold of140 mmHg orhigher andan SBPtreat-

ment goal of lower than 140mm Hg based on several factors.First,intheabsenceofanyRCTsthatcomparedthecurrentSBP

standard of140 mmHg withanotherhigher orlowerstandard inthis

age group, there was no compelling reason to change current rec-

ommendations.Second,intheDBPtrialsthatdemonstratedtheben-

efitoftreatingDBPtolowerthan90mmHg,manyofthestudypar-

ticipantswhoachievedDBPoflowerthan90mmHgwerealsolikely

tohave achievedSBPsof lower than 140mm Hgwith treatment. It

isnotpossibletodeterminewhethertheoutcomebenefitsinthese

trialswere due to lowering DBP, SBP, or both. Third, given the rec-

ommended SBP goal of lower than 140 mm Hg in adults with dia-

betesor CKD(recommendations 4 and5),a similar SBPgoal forthe

general population younger than 60 years may facilitate guideline

implementation.

Recommendation 4

In thepopulation aged 18 years or older with CKD, initiate pharma-

cologictreatmenttolower BPat SBPof140mm Hgor higherorDBP

of90 mmHg orhigher and treat togoal SBP oflowerthan 140 mm

Hgand goalDBP lower than90 mmHg.


Based on the inclusion criteria used in the RCTs reviewed by

the panel, this recommendation applies to individuals younger

than 70 years with an estimated GFR or measured GFR less than

60 mL/min/1.73 m2 and in people of any age with albuminuria

defined as greater than 30 mg of albumin/g of creatinine at any

level of GFR.Recommendation 4 isbasedon evidencestatements15-17from

question2. In adults younger than70 years withCKD, theevidence

is insufficient to determine if there is a benefit in mortality, or car-

diovascular or cerebrovascular healthoutcomes with antihyperten-

sive drug therapyto a lowerBP goal(forexample, <130/80mm Hg)

comparedwithagoaloflowerthan140/90mmHg(question2,evi-

dence statement 15). There is evidence of moderate quality dem-

onstrating no benefitin slowing the progression of kidney disease

from treatment with antihypertensive drug therapy to a lower BP

goal (for example, <130/80 mmHg) compared with a goal oflower

than 140/90mm Hg (question 2, evidence statement16).

Three trials that met our criteria for review addressed the

effect of antihypertensive drug therapy on change in GFR or time

to development of ESRD, but only one trial addressed cardiovas-

cular disease end points. Blood pressure goals differed across the

trials, with 2 trials (AASK and MDRD) using mean arterial pressure

and different targets by age, and 1 trial (REIN-2) using only DBP

goals.20-22 None of the trialsshowed that treatment to a lower BP

goal (for example, <130/80 mm Hg) significantly lowered kidney

or cardiovascular disease end points compared with a goal of

lower than 140/90 mm Hg.

For patients with proteinuria (>3 g/24 hours), post hoc analy-

sis from only 1 study (MDRD) indicated benefit from treatment to

a lower BP goal (<130/80 mm Hg), and this related to kidney out-

comes only.22 Although post hoc observational analyses of data

from this trial andothers suggested benefit from thelower goal at

lower levels of proteinuria, this result was not seen in the primary

analyses or in AASK or REIN-2 (question 2, evidence statement

17).20,21

Based on available evidence the panel cannot make a recom-

mendation for a BP goal for people aged 70 years or older withGFR less than 60 mL/min/1.73m2. The commonly used estimating

equations for GFR were not developed in populations with signifi-

cant numbers of people older than 70 years and have not been

validated in older adults. No outcome trials reviewed by the panel

included large numbers of adults older than 70 years with CKD.

Further, the diagnostic criteria for CKD do not consider age-related

decline in kidney function as reflected in estimated GFR. Thus,

when weighing the risks and benefits of a lower BP goal forpeople

aged 70 years or older with estimated GFR less than 60 mL/min/

1.73m2, antihypertensive treatment should be individualized, tak-

ing into consideration factors such as frailty, comorbidities, and

albuminuria.

Recommendation 5

Inthepopulationaged18yearsorolderwithdiabetes,initiatephar-

macologictreatmentto lower BP atSBP of140 mmHg orhigher or

DBP of 90 mm Hg or higher and treat to a goal SBP of lower than

140 mmHg and goalDBP lower than90 mmHg.


Recommendation 5 is basedon evidencestatements 18-21from

question2, whichaddress BP goals inadultswith bothdiabetes and

hypertension.Thereismoderate-qualityevidence from3 trials (SHEP,

Syst-Eur, and UKPDS) that treatment to an SBP goal of lower than

150mmHg improves cardiovascularandcerebrovascularhealth out-

comesand lowersmortality(see question 2,evidence statement18)

in adults with diabetes and hypertension.23-25

No RCTs addressedwhether treatment to anSBP goal of lower than 140 mm Hgcom-

paredwithahighergoal(forexample,<150mmHg)improveshealth

outcomesin adults withdiabetesand hypertension.In theabsence

ofsuchevidence, the panelrecommendsan SBPgoalof lower than

140mmHgandaDBPgoallowerthan90mmHginthispopulation

based on expert opinion, consistent with the BP goals in recom-

mendation 3 forthe generalpopulationyounger than60 years with

hypertension. Useof a consistent BP goalin thegeneralpopulation

younger than 60 years and in adultswithdiabetes ofany age may

facilitate guidelineimplementation.ThisrecommendationforanSBP

goal of lower than 140mm Hgin patientswith diabetes is also sup-

ported by theACCORD-BPtrial, in which thecontrol group usedthis

goal and hadsimilar outcomes compared with a lower goal.7

The panel recognizes that the ADVANCE trial tested the ef-

fects of treatmentto lower BP on major macrovascular andmicro-

vascular eventsin adults with diabetes who were at increased risk

ofCVD,but thestudy didnot meet thepanel’sinclusioncriteriabe-

causeparticipantswereeligibleirrespectiveofbaselineBP,andthere

were no randomized BP treatmentthresholds or goals.26

The panel also recognizes that an SBP goal of lower than 130

mmHg iscommonly recommendedfor adultswith diabetesand hy-

pertension. However, this lower SBP goal is not supported by any

RCT that randomized participants into 2 or more groups in which








treatment was initiated at a lower SBP threshold than 140 mm Hg

or into treatmentgroups in whichthe SBPgoalwas lower than 140

mmHgandthatassessedtheeffectsofalowerSBPthresholdorgoal

onimportanthealthoutcomes.The onlyRCTthat comparedan SBP

treatment goalof lower than 140mm Hgwitha lower SBPgoaland

assessed theeffects on importanthealthoutcomes is ACCORD-BP,

which compared an SBP treatment goal of lower than 120 mm Hg

witha goallowerthan 140 mmHg.

7

Therewas no difference in theprimary outcome, a composite of cardiovascular death, nonfatal

myocardial infarction, and nonfatalstroke. There were also no dif-

ferences in any of the secondary outcomes except for a reduction

in stroke. However, theincidence of stroke in the group treated to

lower than140 mm Hg was much lower than expected, so the ab-

solute differencein fatal and nonfatal stroke between the 2 groups

wasonly 0.21% per year. Thepanel concludedthat theresults from

ACCORD-BP did not provide sufficient evidence to recommend an

SBP goal of lower than 120 mm Hg in adults with diabetes and hy-

pertension.

The panel similarly recommends the same goal DBP in adults

with diabetes and hypertension as in the general population (<90

mm Hg). Despite someexisting recommendations thatadults with

diabetesand hypertensionshouldbe treatedto a DBPgoal oflower

than 80 mm Hg, the panel did not find sufficient evidence to sup-

port such a recommendation. For example, there are no good- or

fair-qualityRCTswith mortalityas a primary or secondaryprespeci-

fied outcome that compared a DBP goal of lower than 90 mm Hg

with a lower goal (evidencestatement 21).

IntheHOTtrial,whichisfrequentlycitedtosupportalowerDBP

goal,investigatorscompareda DBPgoal of90 mmHg orlowervs a

goalof 80mm Hgor lower.19 The lower goal was associated with a

reductionin a composite CVDoutcome (question 2,evidencestate-

ment 20), butthiswasa post hocanalysisof a smallsubgroup(8%)

of the study population that was not prespecified. As a result, the

evidence was graded as lowquality.

Another commonly cited study to support a lower DBPgoal isUKPDS,25 which had a BP goal of lower than 150/85 mm Hg in the

more-intensivelytreatedgroup comparedwith a goalof lowerthan

180/105 mm Hg in the less-intensively treated group. UKPDS did

showthattreatmentin thelowergoal BPgroup wasassociated with

a significantly lowerrate of stroke, heartfailure,diabetes-relatedend

points,and deaths related todiabetes.However, thecomparison in

UKPDS was a DBP goal of lower than 85 mm Hg vs lower than105

mm Hg; therefore, it is not possible to determine whether treat-

ment to a DBP goal of lower than 85 mm Hg improves outcomes

compared with treatment to a DBP goal of lower than 90 mm Hg.

Inaddition, UKPDSwas a mixed systolic and diastolic BPgoalstudy

(combined SBP and DBP goals), so it cannot be determined if the

benefits were due to lowering SBP, DBP, or both.

Recommendation 6

In the general nonblack population, including those with diabetes,

initialantihypertensivetreatment shouldincludea thiazide-type di-

uretic, calcium channel blocker (CCB), angiotensin-converting en-

zyme inhibitor (ACEI), or angiotensin receptor blocker (ARB).

ModerateRecommendation – Grade B

For this recommendation, only RCTs that compared one class

of antihypertensive medication to another and assessed the

effects on health outcomes were reviewed; placebo-controlled

RCTs were not included. However, the evidence review was

informed by major placebo-controlled hypertension trials, includ-

ing 3 federally funded trials (VA Cooperative Trial, HDFP, and

SHEP), that were pivotal in demonstrating that treatment of

hypertension with antihypertensive medications reduces cardio-

vascular or cerebrovascular events and/or mortality.3,13,18 These

trials all used thiazide-type diuretics compared with placebo orusual care as the basis of therapy. Additional evidence that BP

lowering reduces risk comes from trials of β-blocker vs

placebo16,27 and CCB vs placebo.1

Each of the 4 drug classes recommended by the panel in rec-

ommendation6 yieldedcomparableeffects on overall mortality and

cardiovascular, cerebrovascular, and kidney outcomes,with one ex-

ception: heart failure. Initial treatment with a thiazide-type di-

ureticwasmore effective than a CCBor ACEI (question3, evidence

statements 14 and15), and an ACEI was more effectivethan a CCB

(question 3, evidence statement 1) in improving heart failure out-

comes. Whilethe panelrecognized thatimproved heartfailureout-

comeswas animportantfinding that shouldbe consideredwhen se-

lecting a drug forinitialtherapy for hypertension, thepanel didnot

conclude that it was compelling enough within the context of the

overallbodyof evidenceto precludetheuse oftheotherdrugclasses

for initial therapy. The panel also acknowledged that the evidence

supported BP control, rather than a specific agent used to achieve

thatcontrol,as themost relevantconsiderationfor thisrecommen-

dation.

The panel did not recommend β-blockers for the initial treat-

ment of hypertension because in one study use of β-blockers re-

sultedin a higherrateof theprimarycompositeoutcomeof cardio-

vasculardeath, myocardial infarction, or stroke comparedto use of

an ARB, a finding that was driven largely by an increase in stroke

(question3, evidence statement22).28 Intheotherstudiesthatcom-

paredaβ-blockertothe4recommendeddrugclasses,theβ-blocker

performed similarlyto the other drugs(question 3, evidence state-ment 8) or the evidence was insufficient to make a determination

(question3, evidence statements 7, 12,21, 23, and24).

α-Blockers were not recommended as first-line therapy be-

cause in one study initial treatment with an α-blocker resulted in

worsecerebrovascular, heartfailure,and combined cardiovascular

outcomes than initial treatment with a diuretic (question 3, evi-

dence statement 13).29 There were no RCTs of good or fair quality

comparingthefollowingdrugclassestothe4recommendedclasses:

dual α1- + β-blocking agents (eg, carvedilol), vasodilating β-block-

ers(eg, nebivolol), centralα2-adrenergicagonists(eg, clonidine), di-

rect vasodilators (eg, hydralazine), aldosterone receptor antago-

nists(eg, spironolactone),peripherally acting adrenergicantagonists

(reserpine), and loop diuretics (eg, furosemide) (question 3, evi-dencestatement30). Therefore, these drugclassesare notrecom-

mended asfirst-linetherapy. In addition, noeligible RCTs wereiden-

tified that compared a diuretic vs an ARB, or an ACEI vs an ARB.

ONTARGET was not eligible because hypertension was not re-

quired for inclusion in thestudy.30

Similar to those for the general population, this recommenda-

tion applies to those with diabetes because trialsincluding partici-

pants withdiabetesshowedno differences in major cardiovascular

or cerebrovascular outcomes fromthose in the general population

(question 3, evidence statements 36-48).








The following important points should be noted. First, many

people will require treatment with more than one antihyperten-

sive drug to achieve BP control. While this recommendation ap-

plies only tothe choiceof theinitialantihypertensivedrug, thepanel

suggests that anyofthese4 classes wouldbe good choices asadd-on

agents (recommendation 9). Second, thisrecommendation is spe-

cific for thiazide-type diuretics, which include thiazide diuretics,

chlorthalidone,and indapamide; it does not include loop or potas-

sium-sparing diuretics. Third, it is important that medications bedosed adequatelyto achieve resultssimilarto thoseseen inthe RCTs

(Table 4). Fourth, RCTs that were limited to specific nonhyperten-

sive populations,such asthosewithcoronaryarterydisease orheart

failure, werenot reviewedfor this recommendation.Therefore,rec-

ommendation 6 should be applied with caution to these popula-

tions. Recommendations forthosewith CKDare addressed in rec-

ommendation 8.

Recommendation 7

In thegeneral black population, includingthosewith diabetes,ini-

tial antihypertensive treatment should include a thiazide-type di-

ureticor CCB.

Forgeneral blackpopulation:ModerateRecommendation–GradeBForblack patientswithdiabetes:Weak Recommendation – Grade C

Recommendation7isbasedonevidencestatementsfromques-

tion 3.In cases forwhich evidence forthe black population was the

sameas forthe generalpopulation, theevidence statementsfor the

general population apply to the black population. However, there

are some cases forwhichthe results forblack persons were differ-

ent from the results for the general population (question 3, evi-

dence statements 2, 10, and 17). In those cases, separate evidence

statements were developed.

This recommendation stems from a prespecified subgroup

analysis of data from a single large trial (ALLHAT) that was rated

good.31 In that study, a thiazide-type diuretic was shown to be

more effective in improving cerebrovascular, heart failure, and

combined cardiovascular outcomes compared to an ACEI in the

black patient subgroup, which included large numbers of diabetic

and nondiabetic participants (question 3, evidence statements 10,

15 and 17). Therefore, the recommendation is to choose thiazide-

type diuretics over ACEI for black patients. Although a CCB wasless effective than a diuretic in preventing heart failure in the black

subgroup of this trial (question 3, evidence statement 14), there

were no differences in other outcomes (cerebrovascular, CHD,

combined cardiovascular, and kidney outcomes, or overall mortal-

ity) between a CCB and a diuretic (question 3, evidence state-

ments 6, 8, 11, 18, and 19). Therefore, both thiazide-type diuretics

and CCBs are recommended as first-line therapy for hypertension

in black patients.

The panel recommended a CCB over an ACEI as first-line

therapy in black patients because there was a 51% higher rate

(relative risk, 1.51; 95% CI, 1.22-1.86) of stroke in black persons in

ALLHAT with the use of an ACEI as initial therapy compared with

use of a CCB (question 3, evidence statement 2).32 The ACEI was

also less effective in reducing BP in black individuals compared

with the CCB (question 3, evidence statement 2).32 There were no

outcome studies meeting our eligibility criteria that compared

diuretics or CCBs vs β-blockers, ARBs, or other renin-angiotensin

system inhibitors in black patients.

Therecommendationfor black patients with diabetesis weaker

than the recommendation for the general black population be-

causeoutcomesforthecomparisonbetweeninitialuseofaCCBcom-

pared to initial use of an ACEI in black persons with diabetes were

not reported in any of the studies eligible forour evidence review.

Table 4. Evidence-Based Dosing for AntihypertensiveDrugs

Antihypertensive Medication Initial Daily Dose, mgTarget Dose

in RCTs Reviewed, mg No. of Doses per Day

ACE inhibitors

Captopril 50 150-200 2

Enalapril 5 20 1-2

Lisinopril 10 40 1

Angiotensin receptor blockers

Eprosartan 400 600-800 1-2

Candesartan 4 12-32 1

Losartan 50 100 1-2

Valsartan 40-80 160-320 1

Irbesartan 75 300 1

β-Blockers

Atenolol 25-50 100 1

Metoprolol 50 100-200 1-2

Calcium channel blockers

Amlodipine 2.5 10 1

Diltiazem extended release 120-180 360 1

Nitrendipine 10 20 1-2

Thiazide-type diuretics

Bendroflumethiazide 5 10 1Chlorthalidone 12.5 12.5-25 1

Hydrochlorothiazide 12.5-25 25-100a 1-2

Indapamide 1.25 1.25-2.5 1

Abbreviations: ACE,

angiotensin-converting enzyme; RCT,randomizedcontrolledtrial.

aCurrent recommended

evidence-based dose thatbalances

efficacy andsafety is 25-50 mgdaily.








Therefore,this evidencewasextrapolatedfrom findingsin theblack

participants in ALLHAT, 46%of whomhad diabetes.Additionalsup-

port comes from a post hoc analysis of black participants in ALL-

HATthatmetthecriteriaforthemetabolicsyndrome,68%ofwhom

haddiabetes.33However,thisstudydidnotmeetthecriteriaforour

reviewbecause itwas a post hocanalysis.Thisrecommendationalso

doesnotaddressblackpersonswithCKD,who areaddressed in rec-

ommendation 8.

Recommendation 8

In the population aged 18 years or older with CKD and hyperten-

sion, initial (or add-on) antihypertensive treatment should include

anACEIor ARBtoimprovekidney outcomes.This applies toallCKD

patients with hypertension regardless of race or diabetes status.

ModerateRecommendation – Grade B

Theevidence is moderate(question3, evidencestatements31-

32)that treatmentwith an ACEIor ARBimproveskidney outcomes

for patients with CKD. This recommendation applies to CKD pa-

tients withand without proteinuria, as studies usingACEIs or ARBs

showed evidence of improved kidneyoutcomesin both groups.

This recommendation is based primarily on kidney outcomes

because there is less evidence favoring ACEI or ARBfor cardiovas-

cular outcomes in patients with CKD. Neither ACEIs nor ARBs im-

proved cardiovascular outcomes for CKD patients compared with

aβ-blockerorCCB(question3,evidencestatements33-34).Onetrial

(IDNT)did show improvement inheartfailureoutcomeswithan ARB

compared with a CCB, but this trial was restricted to a population

with diabetic nephropathy and proteinuria (question 3, evidence

statement 5).34 There are no RCTs in the evidence review that di-

rectly comparedACEIto ARBfor anycardiovascular outcome.How-

ever, both are renin-angiotensin system inhibitors and have been

shown to have similar effects on kidney outcomes(question 3, evi-

dence statements 31-32).

Recommendation 8 is specifically directed at those with CKDand hypertension and addresses the potential benefit of specific

drugs on kidneyoutcomes. TheAASK studyshowed the benefit of

an ACEI on kidney outcomes in black patients with CKD and pro-

videsadditional evidencethatsupportsACEIuse inthat population.21

Additional trials that support the benefits of ACEI or ARB therapy

did not meet our inclusion criteria because they were not re-

stricted to patients with hypertension.35,36 Direct renin inhibitors

arenotincludedinthisrecommendationbecausetherewerenostud-

ies demonstrating their benefits on kidney or cardiovascular out-

comes.

Thepanelnoted thepotential conflict betweenthisrecommen-

dation to use an ACEI or ARB in those with CKD and hypertension

and the recommendation to use a diuretic or CCB (recommenda-tion 7)in blackpersons:what ifthe personis blackand hasCKD?To

answerthis,thepanelreliedonexpertopinion.In blackpatientswith

CKD and proteinuria, an ACEI or ARB is recommended as initial

therapy because of the higher likelihood of progression to ESRD.21

In black patients with CKD but without proteinuria, the choice for

initialtherapy is lessclearand includesa thiazide-type diuretic,CCB,

ACEI, or ARB. If an ACEIor ARB is not used asthe initial drug, then

an ACEI or ARB can be added as a second-line drug if necessary to

achieve goalBP. Because themajority ofpatientswithCKD andhy-

pertensionwillrequire more than 1 drug toachievegoalBP, it is an-

ticipatedthatan ACEIor ARBwillbe used eitheras initial therapy or

as second-line therapy in addition to a diuretic or CCB in black pa-

tients with CKD.

Recommendation 8 appliesto adultsaged18 years orolderwith

CKD, but there is no evidence to support renin-angiotensinsystem

inhibitor treatment in those older than 75 years. Although treat-

mentwith anACEI orARB may bebeneficial inthoseolder than75

years,use of a thiazide-type diuretic or CCB is also anoption forin-dividualswith CKDin this age group.

Useof anACEIor anARB will commonlyincreaseserumcreati-

nine and may produce other metabolic effects such as hyperkale-

mia, particularly in patients with decreased kidney function. Al-

though anincreasein creatinine or potassiumleveldoes notalways

require adjusting medication, use of renin-angiotensin system in-

hibitors in theCKD populationrequires monitoringof electrolyteand

serum creatinine levels, and in some cases, may require reduction

in dose or discontinuation for safety reasons.

Recommendation 9

The main objective of hypertension treatment is to attain and

maintaingoal BP. If goal BP is not reached withina month of treat-

ment, increase the dose of the initial drug or add a second drug

from one of the classes in recommendation 6 (thiazide-type

diuretic, CCB, ACEI, or ARB). The clinician should continue to

assess BP and adjust the treatment regimen until goal BP is

reached. If goal BP cannot be reached with 2 drugs, add and

titrate a third drug from the list provided. Do not use an ACEI and

an ARBtogether in the same patient. If goal BP cannotbe reached

using the drugs in recommendation 6 because of a contraindica-

tion or the need to use more than 3 drugs to reach goal BP, anti-

hypertensive drugs from other classes can be used. Referral to a

hypertension specialist may be indicated for patients in whom

goal BP cannot be attained using the above strategy or for the

management of complicated patients for whom additional clinical

consultation is needed.


Recommendation9 wasdeveloped by thepanel inresponseto

a perceived need for further guidance to assist in implementation

of recommendations 1 through 8. Recommendation 9 is based on

strategies used in RCTs that demonstrated improved patient out-

comesand theexpertiseand clinicalexperience of panelmembers.

Thisrecommendationdiffersfrom theother recommendations be-

cause it was not developed in response to the 3 critical questions

using a systematic review of the literature. The Figure is an algo-

rithm summarizing the recommendations. However, this algo-

rithm hasnotbeen validated with respectto achievingimproved pa-

tientoutcomes.How should clinicians titrate and combine the drugs recom-

mended in this report? There were no RCTs and thus the panel

relied on expert opinion. Three strategies (Table 5) have been

used in RCTs of high BP treatment but were not compared with

each other. Based on the evidence reviewed for questions 1

through 3 and on the expert opinion of the panel members, it is

not known if one of the strategies results in improved cardiovas-

cular outcomes, cerebrovascular outcomes, kidney outcomes, or

mortality compared with an alternative strategy. There is not

likelyto be evidence from well-designed RCTs that compare these








Figure. 2014 HypertensionGuideline Management Algorithm

Adult aged ≥18 years with hypertension

Select a drug treatment titration strategy

A. Maximize first medication before adding second or

B. Add second medication before reaching maximum dose of first medication or

C. Start with 2 medication classes separately or as fixed-dose combination.

Reinforce medication and lifestyle adherence.For strategies A and B, add and titrate thiazide-type diuretic or ACEI or ARB or CCB (use

medication class not previously selected and avoid combined use of ACEI and ARB).

For strategy C, titrate doses of initial medications to maximum.

Reinforce medication and lifestyle adherence.

Add and titrate thiazide-type diuretic or ACEI or ARB or CCB (use medication class

not previously selected and avoid combined use of ACEI and ARB).

Reinforce medication and lifestyle adherence.

Add additional medication class (eg, β-blocker, aldosterone antagonist, or others)and/or refer to physician with expertise in hypertension management.

Continue current

treatment andmonitoring.b

Black All racesNonblack

Age ≥60 years

Blood pressure goal

SBP <150 mm Hg

DBP <90 mm Hg

Blood pressure goal

SBP <140 mm Hg

DBP <90 mm Hg

Age <60 years

Blood pressure goal

SBP <140 mm Hg

DBP <90 mm Hg

All ages

Diabetes present

No CKD

Blood pressure goal

SBP <140 mm Hg

DBP <90 mm Hg

All ages

CKD present with

or without diabetes

At goal blood pressure?

No

Yes


No

Yes


No

Yes

YesNo

Initiate thiazide-type diuretic

or CCB, alone

or in combination.

Initiate thiazide-type diuretic

or ACEI or ARB or CCB, alone

or in combination.a

Initiate ACEI or ARB, alone

or in combination with otherdrug class.a

Set blood pressure goal and initiate blood pressure lowering-medicationbased on age, diabetes, and chronic kidney disease (CKD).

Implement lifestyle interventions

(continue throughout management).

Diabetes or CKD present

General population

(no diabetes or CKD)


SBP indicates systolic blood pressure; DBP, diastolic blood pressure; ACEI,

angiotensin-converting enzyme; ARB, angiotensinreceptorblocker;and CCB,

calciumchannelblocker.

a ACEIs andARBsshouldnot beused incombination.bIf blood pressure fails to bemaintainedat goal, reenter thealgorithm where

appropriatebased on thecurrent individual therapeutic plan.








strategies and assess their effects on important health outcomes.

There may be evidence that different strategies result in more

rapid attainment of BP goal or in improved adherence, but those

are intermediate outcomes that were not included in the evi-

dence review. Therefore, each strategy is an acceptable pharma-

cologic treatment strategy that can be tailored based on indi-

vidual circumstances, clinician and patient preferences, and drug

tolerability. With each strategy, clinicians should regularly assess

BP, encourage evidence-based lifestyle and adherence interven-

tions, and adjust treatment until goal BP is attained and main-

tained. In most cases, adjusting treatment means intensifying

therapy by increasing the drug dose or by adding additional drugs

to the regimen. To avoid unnecessary complexity in this report,

the hypertension management algorithm (Figure) does not

explicitly define all potential drug treatment strategies.

Finally, panel members point outthat inspecificsituations,oneantihypertensive drug may be replaced with another if it is per-

ceivednot to be effectiveor if there are adverse effects.

Limitations

This evidence-based guideline for the management of high BP in

adultsis nota comprehensiveguideline andis limited in scope be-

causeofthefocusedevidencereviewtoaddressthe3specificques-

tions (Table 1). Clinicians often provide care for patients with nu-

merous comorbidities or other important issues related to

hypertension, but the decision was made to focus on 3 questions

considered to be relevant to most physicians and patients. Treat-ment adherenceand medication costs were thought tobe beyond

the scope of this review, but the panel acknowledges the impor-

tance of both issues.

Theevidence review didnot includeobservationalstudies,sys-

tematic reviews, or meta-analyses, and the panel did not conduct

itsown meta-analysis based onprespecifiedinclusioncriteria.Thus,

information from these types of studies was notincorporated into

the evidence statements or recommendations. Although this may

be considered a limitation,the panel decided tofocusonlyon RCTs

because they represent the best scientific evidence and because

there werea substantialnumberof studiesthatincluded large num-

bers of patients and met our inclusion criteria. Randomized con-

trolled trials that included participants with normal BP were ex-

cluded from our formal analysis. In cases in which high-quality

evidencewas notavailableor theevidencewas weakor absent, the

panel relied onfair-quality evidence,panelmembers’knowledge of

thepublished literature beyondthe RCTs reviewed,and personal ex-

perience to makerecommendations.The duration of the guideline

developmentprocess followingcompletionof thesystematicsearch

may have caused the panel to miss studies published after our lit-

erature review. However, a bridge search was performed through

August2013, andthe panel found noadditional studies that would

have changed the recommendations.

Many of the reviewed studies were conducted when theover-

all risk of cardiovascular morbidity and mortality was substantially

higherthan it is today; therefore, effectsizesmay have been over-estimated. Further, RCTs that enrolled prehypertensive or nonhy-

pertensiveindividualswere excluded.Thus, ourrecommendations

do not apply to those without hypertension. In many studies fo-

cused onDBP, participantsalsohadelevatedSBP soit was notpos-

sible todeterminewhether thebenefitobserved inthosetrials arose

fromloweringDBP, SBP, or both. In addition,the ability to compare

studiesfromdifferenttimeperiodswaslimitedbydifferencesinclini-

cal trialdesign and analytic techniques.

Whilephysicians use cost, adherence,and oftenobservational

data to make treatment decisions, medical interventions should

wheneverpossiblebebasedfirstandforemostongoodsciencedem-

onstratingbenefits to patients. Randomized controlled trialsare the

gold standard for this assessment andthus were thebasis for pro-viding theevidencefor ourclinical recommendations. Althoughad-

verse effects and harms of antihypertensive treatment docu-

mented in the RCTs were considered when the panel made its

decisions, the review was not designed to determine whether

therapy-associated adverse effects and harms resulted in signifi-

cantchanges in importanthealthoutcomes. In addition,this guide-

line was not endorsed by any federal agency or professional soci-

ety prior to publication and thus is a departure from previous JNC

reports. The panelanticipates thatan objective assessmentof this

reportfollowingpublicationwill allowopen dialogue amongendors-

Table 5. Strategies to DoseAntihypertensive Drugs

Strategy Description Details

A S ta rt o ne drug, t it ra te t o m axi mumdose, and then add a second drug

If goal BP is not achieved with the initial drug, titrate the dose of the initial drug up to the maximumrecommended dose to achieve goal BPIf goal BP is not achieved with the use of one drug despite titration to the maximum recommendeddose, add a second drug from the list (thiazide-type diuretic, CCB, ACEI, or ARB) and titrate up to themaximum recommended dose of the second drug to achieve goal BPIf goal BP is not achieved with 2 drugs, select a third drug from the list (thiazide-type diuretic, CCB,ACEI, or ARB), avoiding the combined use of ACEI and ARB. Titrate the third drug up to the maximum

recommended dose to achieve goal BPB S ta rt o ne drug a nd t hen a dd a s ec on d

drug before achieving maximum doseof the initial drug

Start with one drug then add a second drug before achieving the maximum recommended dose of theinitial drug, then titrate both drugs up to the maximum recommended doses of both to achieve goal BPIf goal BP is not achieved with 2 drugs, select a third drug from the list (thiazide-type diuretic, CCB,ACEI, or ARB), avoiding the combined use of ACEI and ARB. Titrate the third drug up to the maximumrecommended dose to achieve goal BP

C B egin w it h 2 d rugs a t t he sa me t im e,either as 2 separate pills or as a singlepill combination

Initiate therapy with 2 drugs simultaneously, either as 2 separate drugs or as a single pill combination.Some committee members recommend starting therapy with ≥2 drugs when SBP is >160 mm Hgand/or DBP is >100 mm Hg, or if SBP is >20 mm Hg above goal and/or DBP is >10 mm Hg above goal. Ifgoal BP is not achieved with 2 drugs, select a third drug from the list (thiazide-type diuretic, CCB,ACEI, or ARB), avoiding the combined use of ACEI and ARB. Titrate the third drug up to the maximumrecommended dose.

Abbreviations: ACEI,angiotensin-converting enzyme; ARB,angiotensin receptor blocker; BP, bloodpressure; CCB, calcium channel blocker; DBP, diastolic blood

pressure; SBP, systolic blood pressure.








ing entities and encourage continued attention to rigorous meth-

ods in guideline development, thus raising the standard for future

guidelines.

Discussion

The recommendations basedon RCTevidence in thisguideline dif-

fer from recommendations in other currently used guidelines sup-

portedbyexpertconsensus(Table6).Forexample,JNC7andother

guidelines recommended treatment to lower BP goals in patients

with diabetes and CKD basedon observational studies.12 Recently,

several guidelinedocuments suchas those fromthe American Dia-

betes Associationhaveraisedthe systolic BPgoalsto valuesthatare

similar to thoserecommendedin thisevidence-based guideline.37-42

Other guidelines such as those of the European Society of Hyper-

tension also recommend a systolic BP goal of lower than 150 mm

Hg, albeit in patients older than 80 years (not 60 years as recom-mendedinthisguideline).37Thischanging landscape is understand-

ablegiven thelack of clear RCTevidencein manyclinical situations.

History of JNC 8

The panel was originally constituted as the “Eighth Joint National

Committee on the Prevention, Detection, Evaluation, and Treat-

ment of High Blood Pressure (JNC 8).” In March 2008 NHLBI sent

letters inviting the co-chairs and committee members to serve on

JNC8. The chargeto thecommittee was asfollows: “The JNC8 will

review and synthesize the latest available scientific evidence, up-

dateexistingclinical recommendations,and provideguidanceto busy

primary care clinicians onthe best approaches tomanage and con-

trol hypertension in order to minimize patients’ risk for cardiovas-

cular and other complications.” The committee was also asked to

identify and prioritize the most important questions for the evi-dence review. In June 2013, NHLBI announced its decision to dis-

continue developing clinical guidelines including those in process,

instead partneringwith selected organizationsthat woulddevelop

the guidelines.43,44 Importantly, participation in this process re-

quired that these organizations be involved in producing the final

content of the report. The panel elected to pursue publication in-

dependently tobring therecommendationsto thepublicin a timely

manner while maintaining the integrity of the predefined process.

This report is therefore not an NHLBI sanctioned report and does

not reflect theviews of NHLBI.

ConclusionsItisimportanttonotethatthisevidence-basedguidelinehasnotre-

definedhighBP,andthepanelbelievesthatthe140/90mmHgdefi-

nition from JNC 7 remains reasonable. The relationship between

naturally occurringBP and risk islineardownto very lowBP, butthe

benefitof treatingto these lower levels withantihypertensive drugs

is not established. For all persons with hypertension, the potential

benefits of a healthy diet,weight control,and regular exercise can-

notbe overemphasized.These lifestyle treatmentshave thepoten-

tial to improve BP control and even reduce medication needs. Al-

Table 6. GuidelineComparisonsof GoalBP and Initial DrugTherapy forAdults WithHypertension

Guideline PopulationGoal BP,mm Hg Initial Drug Treatment Options

2014 Hypertensionguideline

General ≥60 y <150/90 Nonblack: thiazide-type diuretic, ACEI, ARB,or CCB

Gen eral <60 y <140/ 90 B la ck: t hi az id e-ty pe di uret ic o r C CB

D iabet es <14 0/90 Thiazi de- typ e diur etic, ACEI, A RB, or CCB

CKD <140/90 ACEI or ARBESH/ESC 201337 General nonelderly <140/90 β-Blocker, diuretic, CCB, ACEI, or ARB

General elderly <80 y <150/90

General ≥80 y <150/90

Diabetes <140/85 ACEI or ARB

CKD no p rote inu ria <14 0/90 ACEI or AR B

CKD + proteinuria <130/90

CHEP 201338 General <80 y <140/90 Thiazide, β-blocker (age <60y), ACEI (nonblack),or ARB

General ≥80 y <150/90

D iabet es <13 0/80 ACEI or AR B with additional CVD r iskACEI, ARB, thiazide, or DHPCCB without addi-tional CVD risk

CKD <140/90 ACEI or ARB

ADA 201339 Diabetes <140/80 ACEI or ARB

KDIGO 201240 CKD no p rote inu ria ≤14 0/90 ACEI or AR B

CKD + proteinuria ≤130/80

NICE 201141 General <80 y <140/90 <55 y: ACEI or ARB

General ≥80 y <150/90 ≥55 y or black: CCB

ISHIB 201042 B lack, lower risk <13 5/85 Diur etic or CCB

Target organ damageor CVD risk

<130/80

Abbreviations: ADA,American

Diabetes Association;ACEI,

angiotensin-converting enzyme

inhibitor; ARB, angiotensinreceptor

blocker; CCB, calciumchannel

blocker; CHEP, Canadian

Hypertension Education Program;

CKD,chronic kidney disease; CVD,

cardiovasculardisease;DHPCCB,dihydropyridine calcium channel

blocker; ESC, European Society of

Cardiology;ESH, European Society of

Hypertension; ISHIB, International

Society for Hypertension in Blacks;

JNC,Joint National Committee;

KDIGO, Kidney Disease: Improving

GlobalOutcome;NICE, National

Institutefor Health and Clinical

Excellence.








thoughthe authors of this hypertensionguideline didnot conduct

anevidencereviewof lifestyle treatmentsin patients takingand not

taking antihypertensive medication, we support therecommenda-

tions of the2013 LifestyleWork Group.45

Therecommendationsfrom thisevidence-based guideline from

panelmembers appointedto the Eighth Joint NationalCommittee

(JNC 8)offercliniciansan analysisof what isknownandnot known

about BP treatment thresholds, goals, and drug treatment strate-

gies to achieve those goals based on evidence from RCTs. How-

ever, these recommendations are not a substitute for clinical judg-

ment, and decisions about care must carefully consider and

incorporatetheclinicalcharacteristics andcircumstancesof eachin-

dividual patient. We hope that the algorithm will facilitate imple-

mentationandbe usefulto busyclinicians.Thestrongevidence base

of this report should inform quality measures for the treatmentof

patients with hypertension.

ARTICLE INFORMATION

Published Online: December 18, 2013.

doi:10.1001/jama.2013.284427.

Author Affiliations: University of Iowa,Iowa City

(James, Carter); Universityof Alabama at

Birmingham School of Medicine (Oparil); Memphis

Veterans Affairs Medical Center and the University

of Tennessee, Memphis (Cushman);Johns Hopkins

UniversitySchool of Nursing, Baltimore, Maryland

(Dennison-Himmelfarb); Kaiser Permanente,

Anaheim, California (Handler);Medical Universityof

SouthCarolina, Charleston(Lackland); Universityof

Missouri, Columbia (LeFevre); Denver Health and

Hospital Authority and the Universityof Colorado

Schoolof Medicine, Denver (MacKenzie); New York

UniversitySchool of Medicine,New York, NewYork

(Ogedegbe); Universityof NorthCarolina at Chapel

Hill (Smith);Duke University, Durham, North

Carolina (Svetkey); MayoClinic College of Medicine,

Rochester, Minnesota (Taler);University of

Pennsylvania, Philadelphia (Townsend);Case

Western Reserve University, Cleveland,Ohio

(Wright); National Instituteof Diabetes and

Digestiveand Kidney Diseases, Bethesda, Maryland

(Narva);at thetimeof theproject,NationalHeart,

Lung,and Blood Institute,Bethesda,Maryland

(Ortiz); currently withProVationMedical,Wolters

KluwerHealth, Minneapolis,Minnesota(Ortiz).

Author Contributions: DrsJamesand Oparilhad

full accessto allof the datain the study and take

responsibility forthe integrityof thedataand theaccuracy of thedataanalysis.

Study concept and design, acquisition of data,

analysis andinterpretation of data, drafting of the

manuscript,critical revision of themanuscriptfor

important intellectual content, administrative,

technical, andmaterial support, and study

supervision: All authors.

Conflict of Interest Disclosures: All authors have

completedand submittedtheICMJEForm for

Disclosure of Potential Conflicts of Interest.Dr

Oparilreports individual and institutional payment

related to boardmembershipfrom Bayer, Daiichi

Sankyo, Novartis, Medtronic,and Takeda;individual

consulting feesfrom Backbeat, Bayer,

Boehringer-Ingelheim, Bristol Myers-Squibb, Daiichi

Sankyo, Eli Lilly, Medtronic,Merck, Pfizer, and

Takeda;receipt of institutional grantfunding fromAstraZeneca, Daiichi Sankyo, Eisai Inc, Gilead,

Medtronic, Merck, Novartis, TakedaGlobal

Research and Development Inc;individual payment

for lectures from Daiichi Sankyo, Merck, Novartis,

and Pfizer;individualand institutional payment for

developmentof educationalpresentations from

ASH/AHSR(Daiichi Sankyo); and individual and

institutional payment from AmarinPharma Inc,

Daiichi Sankyo, and LipoScienceInc for educational

grant(s) forthe AnnualUAB VascularBiology&

Hypertension Symposium.Dr Cushman reports

receipt of institutional grantsupport from Merck,

Lilly, and Novartis; and consultingfees from

Novartis, ScielePharmaceuticals, Takeda,

sanofi-aventis, Gilead, Calpis,Pharmacopeia,

Theravance, Daiichi-Sankyo,Noven, AstraZeneca

Spain, Merck, Omron, and Janssen. Dr Townsend

reportsboard membershipwith Medtronic,

consultancyfor Janssen, GlaxoSmithKline,and

Merck, and royalties/educational-related payments

from Merck, UpToDate, and Medscape.Dr Wright

reportsreceipt of consultingfees from Medtronic,

CVRx,Takeda, Daiichi-Sankyo, Pfizer, Novartis, and

TakeCareHealth.The other authors reportno

disclosures.

Funding/Support: Theevidence reviewfor this

projectwas fundedby theNational Heart,Lung,and Blood Institute(NHLBI).

Role ofthe Sponsor: Thedesignand conduct of

thestudy; collection,management, analysis, and

interpretation of thedata; preparation,review, and

approval of themanuscript;and decision to submit

themanuscriptfor publication arethe

responsibilities of the authors aloneand

independent of NHLBI.

Disclaimer: Theviews expressed do notrepresent

those of theNHLBI, theNational Instituteof

Diabetes and Digestiveand Kidney Diseases, the

National Institutesof Health, or thefederal

government.

Additional Contributions: Wethank CoryV.Evans,

MPP, whoat thetimeof theprojectwas a senior

researchanalyst andcontractleadfor JNC8 withLeidos (formerly Science ApplicationsInternational

Corporation) andLindaJ. Lux, MPA, RTI

International, for theirsupport. Wealso thank

LawrenceJ. Fine, MD, DrPH,NHLBI, forhis work

with thepanel. Thosenamedherewere

compensatedin their roles as consultants onthe

project.

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2014 evidence_based guideline for the management of high blood pressure in adults

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