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Clinical Review & Education
2014 Evidence-Based Guideline for the Managementof High Blood Pressure in AdultsReport From the Panel Members Appointedto the Eighth Joint National Committee (JNC 8) Paul A. James, MD; Suzanne Oparil, MD; Barry L. Carter, PharmD; William C. 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;Sidney C. Smith Jr, MD; Laura P. Svetkey, MD, MHS; Sandra J. Taler, MD; Raymond R. Townsend, MD;Jackson T. Wright Jr, MD, PhD; Andrew S. Narva, MD; Eduardo Ortiz, MD, MPH Editorial pages 472, 474, and Hypertension is the most common condition seen in primary care and leads to myocardial infarction, stroke, renal failure, and death if not detected early and treated appropriately.
Author Audio Interview at Patients want to be assured that blood pressure (BP) treatment will reduce their disease burden, while clinicians want guidance on hypertension management using the best scientific Supplemental content at evidence. This report takes a rigorous, evidence-based approach to recommend treatment thresholds, goals, and medications in the management of hypertension in adults. Evidencewas drawn from randomized controlled trials, which represent the gold standard for CME Quiz atjamanetworkcme.com and determining efficacy and effectiveness. Evidence quality and recommendations were graded CME Questions page 522 based on their effect on important outcomes.
There is strong evidence to support treating hypertensive persons aged 60 years or older to aBP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to adiastolic goal of less than 90 mm Hg; however, there is insufficient evidence in hypertensivepersons younger than 60 years for a systolic goal, or in those younger than 30 years for adiastolic goal, so the panel recommends a BP of less than 140/90 mm Hg for those groupsbased on expert opinion. The same thresholds and goals are recommended for hypertensiveadults with diabetes or nondiabetic chronic kidney disease (CKD) as for the generalhypertensive population younger than 60 years. There is moderate evidence to supportinitiating drug treatment with an angiotensin-converting enzyme inhibitor, angiotensinreceptor blocker, calcium channel blocker, or thiazide-type diuretic in the nonblackhypertensive population, including those with diabetes. In the black hypertensive population,including those with diabetes, a calcium channel blocker or thiazide-type diuretic isrecommended as initial therapy. There is moderate evidence to support initial or add-onantihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensinreceptor blocker in persons with CKD to improve kidney outcomes.
Although this guideline provides evidence-based recommendations for the management ofhigh BP and should meet the clinical needs of most patients, these recommendations are nota substitute for clinical judgment, and decisions about care must carefully consider andincorporate the clinical characteristics and circumstances of each individual patient.
Author Affiliations: Author
affiliations are listed at the end of this
article.
Corresponding Author: Paul A.
James, MD, University of Iowa, 200
Hawkins Dr, 01286-D PFP, Iowa City,
IA 52242-1097 (paul-james@uiowa Published online December 18, 2013.
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Clinical Review & Education Special Communication 2014 Guideline for Management of High Blood Pressure able contributors to disease and death. Abundant evi- tant related fields. Sixteen individual reviewers and 5 federal dence from randomized controlled trials (RCTs) has shown agencies responded. Reviewers' comments were collected, col- benefit of antihypertensive drug treatment in reducing important lated, and anonymized. Comments were reviewed and discussed health outcomes in persons with hypertension.1-3 Clinical guide- by the panel from March through June 2013 and incorporated lines are at the intersection between research evidence and clinical into a revised document. (Reviewers' comments and suggestions, actions that can improve patient outcomes. The Institute of Medi- and responses and disposition by the panel are available on cine Report Clinical Practice Guidelines We Can Trust outlined a path- request from the authors.) way to guideline development and is the approach that this panelaspired to in the creation of this report.4 The panel members appointed to the Eighth Joint National Questions Guiding the Evidence Review Committee (JNC 8) used rigorous evidence-based methods,developing Evidence Statements and recommendations for blood This evidence-based hypertension guideline focuses on the pan- pressure (BP) treatment based on a systematic review of the lit- el's 3 highest-ranked questions related to high BP management iden- erature to meet user needs, tified through a modified Delphi technique.5 Nine recommenda- especially the needs of the tions are made reflecting these questions. These questions address primary care clinician. This thresholds and goals for pharmacologic treatment of hypertension ARB angiotensin receptor blocker
report is an executive sum- and whether particular antihypertensive drugs or drug classes im- BP blood pressure
mary of the evidence and is prove important health outcomes compared with other drug classes.
CCB calcium channel blocker
designed to provide clear 1. In adults with hypertension, does initiating antihypertensive phar- CKD chronic kidney disease
recommendations for all macologic therapy at specific BP thresholds improve health out- CVD cardiovascular disease
clinicians. Major differ- ences from the previous 2. In adults with hypertension, does treatment with antihyperten- ESRD end-stage renal disease
JNC report are summarized sive pharmacologic therapy to a specified BP goal lead to im- GFR glomerular filtration rate
in Table 1. The complete provements in health outcomes? HF heart failure
evidence summar y and 3. In adults with hypertension, do various antihypertensive drugs detailed description of the evidence review and methods are pro- or drug classes differ in comparative benefits and harms on spe- vided online (see Supplement).
cific health outcomes? The Evidence Review The panel members appointed to JNC 8 were selected from more The evidence review focused on adults aged 18 years or older with than 400 nominees based on expertise in hypertension (n = 14), hypertension and included studies with the following prespecified primary care (n = 6), including geriatrics (n = 2), cardiology (n = 2), subgroups: diabetes, coronary artery disease, peripheral artery dis- nephrology (n = 3), nursing (n = 1), pharmacology (n = 2), clinical ease, heart failure, previous stroke, chronic kidney disease (CKD), trials (n = 6), evidence-based medicine (n = 3), epidemiology proteinuria, older adults, men and women, racial and ethnic groups, (n = 1), informatics (n = 4), and the development and implementa- and smokers. Studies with sample sizes smaller than 100 were ex- tion of clinical guidelines in systems of care (n = 4).
cluded, as were studies with a follow-up period of less than 1 year, The panel also included a senior scientist from the National In- because small studies of brief duration are unlikely to yield enough stitute of Diabetes and Digestive and Kidney Diseases (NIDDK), a se- health-related outcome information to permit interpretation of treat- nior medical officer from the National Heart, Lung, and Blood Insti- ment effects. Studies were included in the evidence review only if tute (NHLBI), and a senior scientist from NHLBI, who withdrew from they reported the effects of the studied interventions on any of these authorship prior to publication. Two members left the panel early important health outcomes: in the process before the evidence review because of new job com- • Overall mortality, cardiovascular disease (CVD)–related mortality, mitments that prevented them from continuing to serve. Panel mem- CKD-related mortality bers disclosed any potential conflicts of interest including studies • Myocardial infarction, heart failure, hospitalization for heart fail- evaluated in this report and relationships with industry. Those with conflicts were allowed to participate in discussions as long as they • Coronary revascularization (includes coronary artery bypass sur- declared their relationships, but they recused themselves from vot- gery, coronary angioplasty and coronary stent placement), other ing on evidence statements and recommendations relevant to their revascularization (includes carotid, renal, and lower extremity re- relationships or conflicts. Four panel members (24%) had relation- ships with industry or potential conflicts to disclose at the outset of • End-stage renal disease (ESRD) (ie, kidney failure resulting in di- the process.
alysis or transplantation), doubling of creatinine level, halving of In January 2013, the guideline was submitted for external glomerular filtration rate (GFR).
peer review by NHLBI to 20 reviewers, all of whom had expertise The panel limited its evidence review to RCTs because they are in hypertension, and to 16 federal agencies. Reviewers also had less subject to bias than other study designs and represent the gold expertise in cardiology, nephrology, primary care, pharmacology, standard for determining efficacy and effectiveness.6 The studies JAMA February 5, 2014 Volume 311, Number 5
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2014 Guideline for Management of High Blood Pressure Special Communication Clinical Review & Education Table 1. Comparison of Current Recommendations With JNC 7 Guidelines 2014 Hypertension Guideline Nonsystematic literature review by expert committee including a Critical questions and review criteria defined by expert panel with range of study designs input from methodology team Recommendations based on consensus Initial systematic review by methodologists restricted to RCTevidenceSubsequent review of RCT evidence and recommendations by thepanel according to a standardized protocol Defined hypertension and prehypertension Definitions of hypertension and prehypertension not addressed,but thresholds for pharmacologic treatment were defined Separate treatment goals defined for "uncomplicated" hypertension Similar treatment goals defined for all hypertensive populations and for subsets with various comorbid conditions except when evidence review supports different goals for a particu- (diabetes and CKD) lar subpopulation Recommended lifestyle modifications based on literature review and Lifestyle modifications recommended by endorsing the evidence- based Recommendations of the Lifestyle Work Group Recommended 5 classes to be considered as initial therapy but rec- Recommended selection among 4 specific medication classes (ACEI ommended thiazide-type diuretics as initial therapy for most pa- or ARB, CCB or diuretics) and doses based on RCT evidence tients without compelling indication for another class Recommended specific medication classes based on evidence review Specified particular antihypertensive medication classes for patients for racial, CKD, and diabetic subgroups with compelling indications, ie, diabetes, CKD, heart failure, myocar- Panel created a table of drugs and doses used in the outcome trials dial infarction, stroke, and high CVD riskIncluded a comprehensive table of oral antihypertensive drugs in-cluding names and usual dose ranges Addressed multiple issues (blood pressure measurement methods, Evidence review of RCTs addressed a limited number of questions, patient evaluation components, secondary hypertension, adherence those judged by the panel to be of highest priority.
to regimens, resistant hypertension, and hypertension in specialpopulations) based on literature review and expert opinion Reviewed by the National High Blood Pressure Education Program Reviewed by experts including those affiliated with professional and Coordinating Committee, a coalition of 39 major professional, pub- public organizations and federal agencies; no official sponsorship by lic, and voluntary organizations and 7 federal agencies any organization should be inferred Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, kidney disease; CVD, cardiovascular disease; JNC, Joint National Committee; angiotensin receptor blocker; CCB, calcium channel blocker; CKD, chronic RCT, randomized controlled trial in the evidence review were from original publications of eligible rated for quality using NHLBI's standardized quality rating tool (see RCTs. These studies were used to create evidence tables and sum- Supplement) and were only included if rated as good or fair.
mary tables that were used by the panel for their deliberations (see An external methodology team performed the literature re- Supplement). Because the panel conducted its own systematic re- view, summarized data from selected papers into evidence tables, view using original studies, systematic reviews and meta-analyses and provided a summary of the evidence. From this evidence re- of RCTs conducted and published by other groups were not in- view, the panel crafted evidence statements and voted on agree- cluded in the formal evidence review.
ment or disagreement with each statement. For approved evi- Initial search dates for the literature review were January 1, 1966, dence statements, the panel then voted on the quality of the through December 31, 2009. The search strategy and PRISMA dia- evidence (Table 2). Once all evidence statements for each critical gram for each question is in the online Supplement. To ensure that question were identified, the panel reviewed the evidence state- no major relevant studies published after December 31, 2009, were ments to craft the clinical recommendations, voting on each rec- excluded from consideration, 2 independent searches of PubMed ommendation and on the strength of the recommendation (Table 3).
and CINAHL between December 2009 and August 2013 were con- For both evidence statements and recommendations, a record of ducted with the same MeSH terms as the original search. Three panel the vote count (for, against, or recusal) was made without attribu- members reviewed the results. The panel limited the inclusion cri- tion. The panel attempted to achieve 100% consensus whenever teria of this second search to the following. (1) The study was a ma- possible, but a two-thirds majority was considered acceptable, with jor study in hypertension (eg, ACCORD-BP, SPS3; however, SPS3 did the exception of recommendations based on expert opinion, which not meet strict inclusion criteria because it included nonhyperten- required a 75% majority agreement to approve.
sive participants. SPS3 would not have changed our conclusions/recommendations because the only significant finding supportinga lower goal for BP occurred in an infrequent secondary outcome).7,8 (2) The study had at least 2000 participants. (3) The study was mul-ticentered. (4) The study met all the other inclusion/exclusion cri- The following recommendations are based on the systematic evi- teria. The relatively high threshold of 2000 participants was used dence review described above (Box). Recommendations 1 through because of the markedly lower event rates observed in recent RCTs 5 address questions 1 and 2 concerning thresholds and goals for BP such as ACCORD, suggesting that larger study populations are treatment. Recommendations 6, 7, and 8 address question 3 con- needed to obtain interpretable results. Additionally, all panel mem- cerning selection of antihypertensive drugs. Recommendation 9 is bers were asked to identify newly published studies for consider- a summary of strategies based on expert opinion for starting and add- ation if they met the above criteria. No additional clinical trials met ing antihypertensive drugs. The evidence statements supporting the the previously described inclusion criteria. Studies selected were recommendations are in the online Supplement.
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Clinical Review & Education Special Communication 2014 Guideline for Management of High Blood Pressure Table 2. Evidence Quality Rating Well-designed, well-executed RCTs that adequately represent populations to which the results are applied and directly assess 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 RCTs with minor limitations affecting confidence in, or applicability of, the results Well-designed, well-executed non–randomized controlled studies and well-designed, well-executed observational studiesWell-conducted meta-analyses of such studiesModerately certain about the estimate of effect; further research may have an impact on our confidence in the estimateof effect and may change the estimate RCTs with major limitations Non–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.
Abbreviations: RCT, randomized controlled trial panels and work groups during this project. As a result, it includes the evidence aThe evidence quality rating system used in this guideline was developed by the quality rating for many types of studies, including studies that were not used in National Heart, Lung, and Blood Institute's (NHLBI's) Evidence-Based this guideline. Additional details regarding the evidence quality rating system Methodology Lead (with input from NHLBI staff, external methodology team, are available in the online Supplement.
and guideline panels and work groups) for use by all the NHLBI CVD guideline Table 3. Strength of Recommendation Strength of Recommendation Strong RecommendationThere is high certainty based on evidence that the net benefita is substantial.
The strength of recommendation Moderate Recommendation grading system used in this guideline There is moderate certainty based on evidence that the net benefit is moderate to substantial or there is high was developed by the National Heart, certainty that the net benefit is moderate.
Lung, and Blood Institute's (NHLBI's) Weak Recommendation Evidence-Based Methodology Lead There is at least moderate certainty based on evidence that there is a small net benefit.
(with input from NHLBI staff, external Recommendation against methodology team, and guideline There is at least moderate certainty based on evidence that it has no net benefit or that risks/harms outweigh panels and work groups) for use by all the NHLBI CVD guideline panels and Expert Opinion ("There is insufficient evidence or evidence is unclear or conflicting, but this is what the work groups during this project.
committee recommends.") Additional details regarding the Net benefit is unclear. Balance of benefits and harms cannot be determined because of no evidence, insuffi- strength of recommendation grading cient evidence, unclear evidence, or conflicting evidence, but the committee thought it was important toprovide clinical guidance and make a recommendation. Further research is recommended in this area.
system are available in the onlineSupplement.
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- aNet benefit is defined as benefits cient evidence, unclear evidence, or conflicting evidence, and the committee thought no recommendation minus the risks/harms of the should be made. Further research is recommended in this area.
duces stroke, heart failure, and coronary heart disease (CHD). There In the general population aged 60 years or older, initiate pharma- is also evidence (albeit low quality) from evidence statement 6, ques- cologic treatment to lower BP at systolic blood pressure (SBP) of 150 tion 2 that setting a goal SBP of lower than 140 mm Hg in this age mm Hg or higher or diastolic blood pressure (DBP) of 90 mm Hg or group provides no additional benefit compared with a higher goal higher and treat to a goal SBP lower than 150 mm Hg and goal DBP SBP of 140 to 160 mm Hg or 140 to 149 mm Hg.9,10 lower than 90 mm Hg.
To answer question 2 about goal BP, the panel reviewed all RCTs Strong Recommendation – Grade A that met the eligibility criteria and that either compared treatment witha particular goal vs no treatment or placebo or compared treatment Corollary Recommendation with one BP goal with treatment to another BP goal. The trials on In the general population aged 60 years or older, if pharmacologic which these evidence statements and this recommendation are based treatment for high BP results in lower achieved SBP (for example, include HYVET, Syst-Eur, SHEP, JATOS, VALISH, and CARDIO-SIS.1-3,9-11 <140 mm Hg) and treatment is not associated with adverse effects on health or quality of life, treatment does not need to be adjusted.
review are presented in the evidence statement narratives and clearly Expert Opinion – Grade E support the benefit of treating to a BP lower than 150 mm Hg.
The corollary to recommendation 1 reflects that there are many Recommendation 1 is based on evidence statements 1 through treated hypertensive patients aged 60 years or older in whom SBP 3 from question 2 in which there is moderate- to high-quality evi- is currently lower than 140 mm Hg, based on implementation of pre- dence from RCTs that in the general population aged 60 years or vious guideline recommendations.12 The panel's opinion is that in older, treating high BP to a goal of lower than 150/90 mm Hg re- these patients, it is not necessary to adjust medication to allow BP JAMA February 5, 2014 Volume 311, Number 5
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2014 Guideline for Management of High Blood Pressure Special Communication Clinical Review & Education to increase. In 2 of the trials that provide evidence supporting an SBP Box. Recommendations for Management of Hypertension goal lower than 150 mm Hg, the average treated SBP was 143 to 144mm Hg.2,3 Many participants in those studies achieved an SBP lower than 140 mm Hg with treatment that was generally well tolerated.
In the general population aged ⱖ60 years, initiate pharmacologic treat-ment to lower blood pressure (BP) at systolic blood pressure (SBP) ⱖ150 Two other trials9,10 suggest there was no benefit for an SBP goal lower mm Hg or diastolic blood pressure (DBP) ⱖ90 mm Hg and treat to a goal than 140 mm Hg, but the confidence intervals around the effect sizes SBP <150 mm Hg and goal DBP <90 mm Hg. (Strong Recommendation – were wide and did not exclude the possibility of a clinically impor- tant benefit. Therefore, the panel included a corollary recommen- dation based on expert opinion that treatment for hypertension does In the general population aged ⱖ60 years, if pharmacologic treatment for not need to be adjusted if treatment results in SBP lower than 140 high BP results in lower achieved SBP (eg, <140 mm Hg) and treatment is mm Hg and is not associated with adverse effects on health or qual- well tolerated and without adverse effects on health or quality of life, treat- ity of life.
ment does not need to be adjusted. (Expert Opinion – Grade E) While all panel members agreed that the evidence supporting recommendation 1 is very strong, the panel was unable to reach una- In the general population <60 years, initiate pharmacologic treatment to nimity on the recommendation of a goal SBP of lower than 150 mm lower BP at DBP ⱖ90 mm Hg and treat to a goal DBP <90 mm Hg. (For ages30-59 years, Strong Recommendation – Grade A; For ages 18-29 years, Hg. Some members recommended continuing the JNC 7 SBP goal Expert Opinion – Grade E) of lower than 140 mm Hg for individuals older than 60 years basedon expert opinion.12 These members concluded that the evidence In the general population <60 years, initiate pharmacologic treatment to was insufficient to raise the SBP target from lower than 140 to lower lower BP at SBP ⱖ140 mm Hg and treat to a goal SBP <140 mm Hg. (Expert than 150 mm Hg in high-risk groups, such as black persons, those Opinion – Grade E) with CVD including stroke, and those with multiple risk factors. The panel agreed that more research is needed to identify optimal goals In the population aged ⱖ18 years with chronic kidney disease (CKD), ini- of SBP for patients with high BP.
tiate pharmacologic treatment to lower BP at SBP ⱖ140 mm Hg or DBP ⱖ90mm Hg and treat to goal SBP <140 mm Hg and goal DBP <90 mm Hg. (Expert Opinion – Grade E) In the general population younger than 60 years, initiate pharma- cologic treatment to lower BP at DBP of 90 mm Hg or higher and In the population aged ⱖ18 years with diabetes, initiate pharmacologic treat- treat to a goal DBP of lower than 90 mm Hg.
ment to lower BP at SBP ⱖ140 mm Hg or DBP ⱖ90 mm Hg and treat to a goal For ages 30 through 59 years, Strong Recommendation – Grade A SBP <140 mm Hg and goal DBP <90 mm Hg. (Expert Opinion – Grade E) For ages 18 through 29 years, Expert Opinion – Grade E In the general nonblack population, including those with diabetes, initial Recommendation 2 is based on high-quality evidence from 5 antihypertensive treatment should include a thiazide-type diuretic, cal- DBP trials (HDFP, Hypertension-Stroke Cooperative, MRC, ANBP, and cium channel blocker (CCB), angiotensin-converting enzyme inhibitor VA Cooperative) that demonstrate improvements in health out- (ACEI), or angiotensin receptor blocker (ARB). (Moderate Recommenda-tion – Grade B) comes among adults aged 30 through 69 years with elevated BP.13-18Initiation of antihypertensive treatment at a DBP threshold of 90 mm Hg or higher and treatment to a DBP goal of lower than 90 mm In the general black population, including those with diabetes, initial anti-hypertensive treatment should include a thiazide-type diuretic or CCB. (For Hg reduces cerebrovascular events, heart failure, and overall mor- general black population: Moderate Recommendation – Grade B; for black tality (question 1, evidence statements 10, 11, 13; question 2, evi- patients with diabetes: Weak Recommendation – Grade C) dence statement 10). In further support for a DBP goal of lower than 90 mm Hg, the panel found evidence that there is no benefit in treat- In the population aged ⱖ18 years with CKD, initial (or add-on) antihyper- ing patients to a goal of either 80 mm Hg or lower or 85 mm Hg or tensive treatment should include an ACEI or ARB to improve kidney out- lower compared with 90 mm Hg or lower based on the HOT trial, in comes. This applies to all CKD patients with hypertension regardless of race which patients were randomized to these 3 goals without statisti- or diabetes status. (Moderate Recommendation – Grade B) cally significant differences between treatment groups in the pri- mary or secondary outcomes (question 2, evidence statement 14).19 The main objective of hypertension treatment is to attain and maintain goal In adults younger than 30 years, there are no good- or fair- BP. If goal BP is not reached within a month of treatment, increase the dose quality RCTs that assessed the benefits of treating elevated DBP on of the initial drug or add a second drug from one of the classes in recom-mendation 6 (thiazide-type diuretic, CCB, ACEI, or ARB). The clinician should health outcomes (question 1, evidence statement 14). In the ab- continue to assess BP and adjust the treatment regimen until goal BP is sence of such evidence, it is the panel's opinion that in adults younger reached. If goal BP cannot be reached with 2 drugs, add and titrate a third than 30 years, the DBP threshold and goal should be the same as in drug from the list provided. Do not use an ACEI and an ARB together in the adults 30 through 59 years of age.
same patient. If goal BP cannot be reached using only the drugs in recom-mendation 6 because of a contraindication or the need to use more than 3drugs to reach goal BP, antihypertensive drugs from other classes can be used. Referral to a hypertension specialist may be indicated for patients in In the general population younger than 60 years, initiate pharma- whom goal BP cannot be attained using the above strategy or for the man- cologic treatment to lower BP at SBP of 140 mm Hg or higher and agement of complicated patients for whom additional clinical consulta- treat to a goal SBP of lower than 140 mm Hg.
tion is needed. (Expert Opinion – Grade E) Expert Opinion – Grade E JAMA February 5, 2014 Volume 311, Number 5
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Clinical Review & Education Special Communication 2014 Guideline for Management of High Blood Pressure Recommendation 3 is based on expert opinion. While there is a lower BP goal (<130/80 mm Hg), and this related to kidney out- high-quality evidence to support a specific SBP threshold and goal comes only.22 Although post hoc observational analyses of data for persons aged 60 years or older (See recommendation 1), the panel from this trial and others suggested benefit from the lower goal at found insufficient evidence from good- or fair-quality RCTs to sup- lower levels of proteinuria, this result was not seen in the primary port a specific SBP threshold or goal for persons younger than 60 analyses or in AASK or REIN-2 (question 2, evidence statement years. In the absence of such evidence, the panel recommends an SBP treatment threshold of 140 mm Hg or higher and an SBP treat- Based on available evidence the panel cannot make a recom- ment goal of lower than 140 mm Hg based on several factors.
mendation for a BP goal for people aged 70 years or older with First, in the absence of any RCTs that compared the current SBP GFR less than 60 mL/min/1.73m2. The commonly used estimating standard of 140 mm Hg with another higher or lower standard in this equations for GFR were not developed in populations with signifi- age group, there was no compelling reason to change current rec- cant numbers of people older than 70 years and have not been ommendations. Second, in the DBP trials that demonstrated the ben- validated in older adults. No outcome trials reviewed by the panel efit of treating DBP to lower than 90 mm Hg, many of the study par- included large numbers of adults older than 70 years with CKD.
ticipants who achieved DBP of lower than 90 mm Hg were also likely Further, the diagnostic criteria for CKD do not consider age-related to have achieved SBPs of lower than 140 mm Hg with treatment. It decline in kidney function as reflected in estimated GFR. Thus, is not possible to determine whether the outcome benefits in these when weighing the risks and benefits of a lower BP goal for people trials were due to lowering DBP, SBP, or both. Third, given the rec- aged 70 years or older with estimated GFR less than 60 mL/min/ ommended SBP goal of lower than 140 mm Hg in adults with dia- 1.73m2, antihypertensive treatment should be individualized, tak- betes or CKD (recommendations 4 and 5), a similar SBP goal for the ing into consideration factors such as frailty, comorbidities, and general population younger than 60 years may facilitate guideline In the population aged 18 years or older with diabetes, initiate phar- In the population aged 18 years or older with CKD, initiate pharma- macologic treatment to lower BP at SBP of 140 mm Hg or higher or cologic treatment to lower BP at SBP of 140 mm Hg or higher or DBP DBP of 90 mm Hg or higher and treat to a goal SBP of lower than of 90 mm Hg or higher and treat to goal SBP of lower than 140 mm 140 mm Hg and goal DBP lower than 90 mm Hg.
Hg and goal DBP lower than 90 mm Hg.
Expert Opinion – Grade E Expert Opinion – Grade E Recommendation 5 is based on evidence statements 18-21 from Based on the inclusion criteria used in the RCTs reviewed by question 2, which address BP goals in adults with both diabetes and the panel, this recommendation applies to individuals younger hypertension. There is moderate-quality evidence from 3 trials (SHEP, than 70 years with an estimated GFR or measured GFR less than Syst-Eur, and UKPDS) that treatment to an SBP goal of lower than 60 mL/min/1.73 m2 and in people of any age with albuminuria 150 mm Hg improves cardiovascular and cerebrovascular health out- defined as greater than 30 mg of albumin/g of creatinine at any comes and lowers mortality (see question 2, evidence statement 18) level of GFR.
in adults with diabetes and hypertension.23-25 No RCTs addressed Recommendation 4 is based on evidence statements 15-17 from whether treatment to an SBP goal of lower than 140 mm Hg com- question 2. In adults younger than 70 years with CKD, the evidence pared with a higher goal (for example, <150 mm Hg) improves health is insufficient to determine if there is a benefit in mortality, or car- outcomes in adults with diabetes and hypertension. In the absence diovascular or cerebrovascular health outcomes with antihyperten- of such evidence, the panel recommends an SBP goal of lower than sive drug therapy to a lower BP goal (for example, <130/80 mm Hg) 140 mm Hg and a DBP goal lower than 90 mm Hg in this population compared with a goal of lower than 140/90 mm Hg (question 2, evi- based on expert opinion, consistent with the BP goals in recom- dence statement 15). There is evidence of moderate quality dem- mendation 3 for the general population younger than 60 years with onstrating no benefit in slowing the progression of kidney disease hypertension. Use of a consistent BP goal in the general population from treatment with antihypertensive drug therapy to a lower BP younger than 60 years and in adults with diabetes of any age may goal (for example, <130/80 mm Hg) compared with a goal of lower facilitate guideline implementation. This recommendation for an SBP than 140/90 mm Hg (question 2, evidence statement 16).
goal of lower than 140 mm Hg in patients with diabetes is also sup- Three trials that met our criteria for review addressed the ported by the ACCORD-BP trial, in which the control group used this effect of antihypertensive drug therapy on change in GFR or time goal and had similar outcomes compared with a lower goal.7 to development of ESRD, but only one trial addressed cardiovas- The panel recognizes that the ADVANCE trial tested the ef- cular disease end points. Blood pressure goals differed across the fects of treatment to lower BP on major macrovascular and micro- trials, with 2 trials (AASK and MDRD) using mean arterial pressure vascular events in adults with diabetes who were at increased risk and different targets by age, and 1 trial (REIN-2) using only DBP of CVD, but the study did not meet the panel's inclusion criteria be- goals.20-22 None of the trials showed that treatment to a lower BP cause participants were eligible irrespective of baseline BP, and there goal (for example, <130/80 mm Hg) significantly lowered kidney were no randomized BP treatment thresholds or goals.26 or cardiovascular disease end points compared with a goal of The panel also recognizes that an SBP goal of lower than 130 lower than 140/90 mm Hg.
mm Hg is commonly recommended for adults with diabetes and hy- For patients with proteinuria (>3 g/24 hours), post hoc analy- pertension. However, this lower SBP goal is not supported by any sis from only 1 study (MDRD) indicated benefit from treatment to RCT that randomized participants into 2 or more groups in which JAMA February 5, 2014 Volume 311, Number 5
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2014 Guideline for Management of High Blood Pressure Special Communication Clinical Review & Education treatment was initiated at a lower SBP threshold than 140 mm Hg effects on health outcomes were reviewed; placebo-controlled or into treatment groups in which the SBP goal was lower than 140 RCTs were not included. However, the evidence review was mm Hg and that assessed the effects of a lower SBP threshold or goal informed by major placebo-controlled hypertension trials, includ- on important health outcomes. The only RCT that compared an SBP ing 3 federally funded trials (VA Cooperative Trial, HDFP, and treatment goal of lower than 140 mm Hg with a lower SBP goal and SHEP), that were pivotal in demonstrating that treatment of assessed the effects on important health outcomes is ACCORD-BP, hypertension with antihypertensive medications reduces cardio- which compared an SBP treatment goal of lower than 120 mm Hg vascular or cerebrovascular events and/or mortality.3,13,18 These with a goal lower than 140 mm Hg.7 There was no difference in the trials all used thiazide-type diuretics compared with placebo or primary outcome, a composite of cardiovascular death, nonfatal usual care as the basis of therapy. Additional evidence that BP myocardial infarction, and nonfatal stroke. There were also no dif- lowering reduces risk comes from trials of β-blocker vs ferences in any of the secondary outcomes except for a reduction placebo16,27 and CCB vs placebo.1 in stroke. However, the incidence of stroke in the group treated to Each of the 4 drug classes recommended by the panel in rec- lower than 140 mm Hg was much lower than expected, so the ab- ommendation 6 yielded comparable effects on overall mortality and solute difference in fatal and nonfatal stroke between the 2 groups cardiovascular, cerebrovascular, and kidney outcomes, with one ex- was only 0.21% per year. The panel concluded that the results from ception: heart failure. Initial treatment with a thiazide-type di- ACCORD-BP did not provide sufficient evidence to recommend an uretic was more effective than a CCB or ACEI (question 3, evidence SBP goal of lower than 120 mm Hg in adults with diabetes and hy- statements 14 and 15), and an ACEI was more effective than a CCB (question 3, evidence statement 1) in improving heart failure out- The panel similarly recommends the same goal DBP in adults comes. While the panel recognized that improved heart failure out- with diabetes and hypertension as in the general population (<90 comes was an important finding that should be considered when se- mm Hg). Despite some existing recommendations that adults with lecting a drug for initial therapy for hypertension, the panel did not diabetes and hypertension should be treated to a DBP goal of lower conclude that it was compelling enough within the context of the than 80 mm Hg, the panel did not find sufficient evidence to sup- overall body of evidence to preclude the use of the other drug classes port such a recommendation. For example, there are no good- or for initial therapy. The panel also acknowledged that the evidence fair-quality RCTs with mortality as a primary or secondary prespeci- supported BP control, rather than a specific agent used to achieve fied outcome that compared a DBP goal of lower than 90 mm Hg that control, as the most relevant consideration for this recommen- with a lower goal (evidence statement 21).
In the HOT trial, which is frequently cited to support a lower DBP The panel did not recommend β-blockers for the initial treat- goal, investigators compared a DBP goal of 90 mm Hg or lower vs a ment of hypertension because in one study use of β-blockers re- goal of 80 mm Hg or lower.19 The lower goal was associated with a sulted in a higher rate of the primary composite outcome of cardio- reduction in a composite CVD outcome (question 2, evidence state- vascular death, myocardial infarction, or stroke compared to use of ment 20), but this was a post hoc analysis of a small subgroup (8%) an ARB, a finding that was driven largely by an increase in stroke of the study population that was not prespecified. As a result, the (question 3, evidence statement 22).28 In the other studies that com- evidence was graded as low quality.
pared a β-blocker to the 4 recommended drug classes, the β-blocker Another commonly cited study to support a lower DBP goal is performed similarly to the other drugs (question 3, evidence state- UKPDS,25 which had a BP goal of lower than 150/85 mm Hg in the ment 8) or the evidence was insufficient to make a determination more-intensively treated group compared with a goal of lower than (question 3, evidence statements 7, 12, 21, 23, and 24).
180/105 mm Hg in the less-intensively treated group. UKPDS did α-Blockers were not recommended as first-line therapy be- show that treatment in the lower goal BP group was associated with cause in one study initial treatment with an α-blocker resulted in a significantly lower rate of stroke, heart failure, diabetes-related end worse cerebrovascular, heart failure, and combined cardiovascular points, and deaths related to diabetes. However, the comparison in outcomes than initial treatment with a diuretic (question 3, evi- UKPDS was a DBP goal of lower than 85 mm Hg vs lower than105 dence statement 13).29 There were no RCTs of good or fair quality mm Hg; therefore, it is not possible to determine whether treat- comparing the following drug classes to the 4 recommended classes: ment to a DBP goal of lower than 85 mm Hg improves outcomes dual α - + β-blocking agents (eg, carvedilol), vasodilating β-block- compared with treatment to a DBP goal of lower than 90 mm Hg.
ers (eg, nebivolol), central α -adrenergic agonists (eg, clonidine), di- In addition, UKPDS was a mixed systolic and diastolic BP goal study rect vasodilators (eg, hydralazine), aldosterone receptor antago- (combined SBP and DBP goals), so it cannot be determined if the nists (eg, spironolactone), adrenergic neuronal depleting agents benefits were due to lowering SBP, DBP, or both.
(reserpine), and loop diuretics (eg, furosemide) (question 3, evi-dence statement 30). Therefore, these drug classes are not recom- mended as first-line therapy. In addition, no eligible RCTs were iden- In the general nonblack population, including those with diabetes, tified that compared a diuretic vs an ARB, or an ACEI vs an ARB.
initial antihypertensive treatment should include a thiazide-type di- ONTARGET was not eligible because hypertension was not re- uretic, calcium channel blocker (CCB), angiotensin-converting en- quired for inclusion in the study.30 zyme inhibitor (ACEI), or angiotensin receptor blocker (ARB).
Similar to those for the general population, this recommenda- Moderate Recommendation – Grade B tion applies to those with diabetes because trials including partici-pants with diabetes showed no differences in major cardiovascular For this recommendation, only RCTs that compared one class or cerebrovascular outcomes from those in the general population of antihypertensive medication to another and assessed the (question 3, evidence statements 36-48).
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Clinical Review & Education Special Communication 2014 Guideline for Management of High Blood Pressure Table 4. Evidence-Based Dosing for Antihypertensive Drugs Initial Daily Dose, mg in RCTs Reviewed, mg No. of Doses per Day Angiotensin receptor blockers Calcium channel blockers Diltiazem extended release Thiazide-type diuretics Abbreviations: ACE, angiotensin-converting enzyme; RCT, randomized controlled trial.
Current recommended evidence-based dose that balances efficacy and safety is 25-50 mg daily.
The following important points should be noted. First, many This recommendation stems from a prespecified subgroup people will require treatment with more than one antihyperten- analysis of data from a single large trial (ALLHAT) that was rated sive drug to achieve BP control. While this recommendation ap- good.31 In that study, a thiazide-type diuretic was shown to be plies only to the choice of the initial antihypertensive drug, the panel more effective in improving cerebrovascular, heart failure, and suggests that any of these 4 classes would be good choices as add-on combined cardiovascular outcomes compared to an ACEI in the agents (recommendation 9). Second, this recommendation is spe- black patient subgroup, which included large numbers of diabetic cific for thiazide-type diuretics, which include thiazide diuretics, and nondiabetic participants (question 3, evidence statements 10, chlorthalidone, and indapamide; it does not include loop or potas- 15 and 17). Therefore, the recommendation is to choose thiazide- sium-sparing diuretics. Third, it is important that medications be type diuretics over ACEI for black patients. Although a CCB was dosed adequately to achieve results similar to those seen in the RCTs less effective than a diuretic in preventing heart failure in the black (Table 4). Fourth, RCTs that were limited to specific nonhyperten- subgroup of this trial (question 3, evidence statement 14), there sive populations, such as those with coronary artery disease or heart were no differences in other outcomes (cerebrovascular, CHD, failure, were not reviewed for this recommendation. Therefore, rec- combined cardiovascular, and kidney outcomes, or overall mortal- ommendation 6 should be applied with caution to these popula- ity) between a CCB and a diuretic (question 3, evidence state- tions. Recommendations for those with CKD are addressed in rec- ments 6, 8, 11, 18, and 19). Therefore, both thiazide-type diuretics ommendation 8.
and CCBs are recommended as first-line therapy for hypertensionin black patients.
The panel recommended a CCB over an ACEI as first-line therapy in black patients because there was a 51% higher rate In the general black population, including those with diabetes, ini- (relative risk, 1.51; 95% CI, 1.22-1.86) of stroke in black persons in tial antihypertensive treatment should include a thiazide-type di- ALLHAT with the use of an ACEI as initial therapy compared with uretic or CCB.
use of a CCB (question 3, evidence statement 2).32 The ACEI was For general black population: Moderate Recommendation – Grade B also less effective in reducing BP in black individuals compared For black patients with diabetes: Weak Recommendation – Grade C with the CCB (question 3, evidence statement 2).32 There were no Recommendation 7 is based on evidence statements from ques- outcome studies meeting our eligibility criteria that compared tion 3. In cases for which evidence for the black population was the diuretics or CCBs vs β-blockers, ARBs, or other renin-angiotensin same as for the general population, the evidence statements for the system inhibitors in black patients.
general population apply to the black population. However, there The recommendation for black patients with diabetes is weaker are some cases for which the results for black persons were differ- than the recommendation for the general black population be- ent from the results for the general population (question 3, evi- cause outcomes for the comparison between initial use of a CCB com- dence statements 2, 10, and 17). In those cases, separate evidence pared to initial use of an ACEI in black persons with diabetes were statements were developed.
not reported in any of the studies eligible for our evidence review.
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2014 Guideline for Management of High Blood Pressure Special Communication Clinical Review & Education Therefore, this evidence was extrapolated from findings in the black ticipated that an ACEI or ARB will be used either as initial therapy or participants in ALLHAT, 46% of whom had diabetes. Additional sup- as second-line therapy in addition to a diuretic or CCB in black pa- port comes from a post hoc analysis of black participants in ALL- tients with CKD.
HAT that met the criteria for the metabolic syndrome, 68% of whom Recommendation 8 applies to adults aged 18 years or older with had diabetes.33 However, this study did not meet the criteria for our CKD, but there is no evidence to support renin-angiotensin system review because it was a post hoc analysis. This recommendation also inhibitor treatment in those older than 75 years. Although treat- does not address black persons with CKD, who are addressed in rec- ment with an ACEI or ARB may be beneficial in those older than 75 ommendation 8.
years, use of a thiazide-type diuretic or CCB is also an option for in-dividuals with CKD in this age group.
Use of an ACEI or an ARB will commonly increase serum creati- In the population aged 18 years or older with CKD and hyperten- nine and may produce other metabolic effects such as hyperkale- sion, initial (or add-on) antihypertensive treatment should include mia, particularly in patients with decreased kidney function. Al- an ACEI or ARB to improve kidney outcomes. This applies to all CKD though an increase in creatinine or potassium level does not always patients with hypertension regardless of race or diabetes status.
require adjusting medication, use of renin-angiotensin system in- Moderate Recommendation – Grade B hibitors in the CKD population requires monitoring of electrolyte andserum creatinine levels, and in some cases, may require reduction The evidence is moderate (question 3, evidence statements 31- in dose or discontinuation for safety reasons.
32) that treatment with an ACEI or ARB improves kidney outcomesfor patients with CKD. This recommendation applies to CKD pa- tients with and without proteinuria, as studies using ACEIs or ARBs The main objective of hypertension treatment is to attain and showed evidence of improved kidney outcomes in both groups.
maintain goal BP. If goal BP is not reached within a month of treat- This recommendation is based primarily on kidney outcomes ment, increase the dose of the initial drug or add a second drug because there is less evidence favoring ACEI or ARB for cardiovas- from one of the classes in recommendation 6 (thiazide-type cular outcomes in patients with CKD. Neither ACEIs nor ARBs im- diuretic, CCB, ACEI, or ARB). The clinician should continue to proved cardiovascular outcomes for CKD patients compared with assess BP and adjust the treatment regimen until goal BP is a β-blocker or CCB (question 3, evidence statements 33-34). One trial reached. If goal BP cannot be reached with 2 drugs, add and (IDNT) did show improvement in heart failure outcomes with an ARB titrate a third drug from the list provided. Do not use an ACEI and compared with a CCB, but this trial was restricted to a population an ARB together in the same patient. If goal BP cannot be reached with diabetic nephropathy and proteinuria (question 3, evidence using the drugs in recommendation 6 because of a contraindica- statement 5).34 There are no RCTs in the evidence review that di- tion or the need to use more than 3 drugs to reach goal BP, anti- rectly compared ACEI to ARB for any cardiovascular outcome. How- hypertensive drugs from other classes can be used. Referral to a ever, both are renin-angiotensin system inhibitors and have been hypertension specialist may be indicated for patients in whom shown to have similar effects on kidney outcomes (question 3, evi- goal BP cannot be attained using the above strategy or for the dence statements 31-32).
management of complicated patients for whom additional clinical Recommendation 8 is specifically directed at those with CKD consultation is needed.
and hypertension and addresses the potential benefit of specific Expert Opinion – Grade E drugs on kidney outcomes. The AASK study showed the benefit ofan ACEI on kidney outcomes in black patients with CKD and pro- Recommendation 9 was developed by the panel in response to vides additional evidence that supports ACEI use in that population.21 a perceived need for further guidance to assist in implementation Additional trials that support the benefits of ACEI or ARB therapy of recommendations 1 through 8. Recommendation 9 is based on did not meet our inclusion criteria because they were not re- strategies used in RCTs that demonstrated improved patient out- stricted to patients with hypertension.35,36 Direct renin inhibitors comes and the expertise and clinical experience of panel members.
are not included in this recommendation because there were no stud- This recommendation differs from the other recommendations be- ies demonstrating their benefits on kidney or cardiovascular out- cause it was not developed in response to the 3 critical questions using a systematic review of the literature. The Figure is an algo- The panel noted the potential conflict between this recommen- rithm summarizing the recommendations. However, this algo- dation to use an ACEI or ARB in those with CKD and hypertension rithm has not been validated with respect to achieving improved pa- and the recommendation to use a diuretic or CCB (recommenda- tient outcomes.
tion 7) in black persons: what if the person is black and has CKD? To How should clinicians titrate and combine the drugs recom- answer this, the panel relied on expert opinion. In black patients with mended in this report? There were no RCTs and thus the panel CKD and proteinuria, an ACEI or ARB is recommended as initial relied on expert opinion. Three strategies (Table 5) have been therapy because of the higher likelihood of progression to ESRD.21 used in RCTs of high BP treatment but were not compared with In black patients with CKD but without proteinuria, the choice for each other. Based on the evidence reviewed for questions 1 initial therapy is less clear and includes a thiazide-type diuretic, CCB, through 3 and on the expert opinion of the panel members, it is ACEI, or ARB. If an ACEI or ARB is not used as the initial drug, then not known if one of the strategies results in improved cardiovas- an ACEI or ARB can be added as a second-line drug if necessary to cular outcomes, cerebrovascular outcomes, kidney outcomes, or achieve goal BP. Because the majority of patients with CKD and hy- mortality compared with an alternative strategy. There is not pertension will require more than 1 drug to achieve goal BP, it is an- likely to be evidence from well-designed RCTs that compare these JAMA February 5, 2014 Volume 311, Number 5
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Clinical Review & Education Special Communication 2014 Guideline for Management of High Blood Pressure Figure. 2014 Hypertension Guideline Management Algorithm Adult aged ≥18 years with hypertension Implement lifestyle interventions(continue throughout management).
Set blood pressure goal and initiate blood pressure lowering-medication based on age, diabetes, and chronic kidney disease (CKD).
General population(no diabetes or CKD) Diabetes or CKD present CKD present with or without diabetes Blood pressure goal Blood pressure goal Blood pressure goal Blood pressure goal SBP <150 mm Hg SBP <140 mm Hg SBP <140 mm Hg SBP <140 mm Hg Initiate thiazide-type diuretic Initiate thiazide-type diuretic Initiate ACEI or ARB, alone or ACEI or ARB or CCB, alone or in combination with other or in combination.a or in combination.
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.
At goal blood pressure? 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.
At goal blood pressure? 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).
At goal blood pressure? 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 At goal blood pressure? treatment and monitoring.b SBP indicates systolic blood pressure; DBP, diastolic blood pressure; ACEI, a ACEIs and ARBs should not be used in combination.
angiotensin-converting enzyme; ARB, angiotensin receptor blocker; and CCB, b If blood pressure fails to be maintained at goal, reenter the algorithm where calcium channel blocker.
appropriate based on the current individual therapeutic plan.
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2014 Guideline for Management of High Blood Pressure Special Communication Clinical Review & Education Table 5. Strategies to Dose Antihypertensive Drugsa Start one drug, titrate to maximum If goal BP is not achieved with the initial drug, titrate the dose of the initial drug up to the maximum dose, and then add a second drug recommended 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 maximumrecommended dose to achieve goal BP Start one drug and then add a second Start with one drug then add a second drug before achieving the maximum recommended dose of the drug before achieving maximum dose initial drug, then titrate both drugs up to the maximum recommended doses of both to achieve goal BP of the initial drug If 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 Begin with 2 drugs at the same time, Initiate therapy with 2 drugs simultaneously, either as 2 separate drugs or as a single pill combination.
either as 2 separate pills or as a single Some committee members recommend starting therapy with ≥2 drugs when SBP is >160 mm Hg and/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 aThis table is not meant to exclude other agents within the classes of antihyperten- receptor blocker; BP, blood pressure; CCB, calcium channel blocker; DBP, sive medications that have been recommended but reflects those agents and dos- diastolic blood pressure; SBP, systolic blood pressure.
ing used in randomized controlled trials that demonstrated improved outcomes.
strategies and assess their effects on important health outcomes.
be considered a limitation, the panel decided to focus only on RCTs There may be evidence that different strategies result in more because they represent the best scientific evidence and because rapid attainment of BP goal or in improved adherence, but those there were a substantial number of studies that included large num- are intermediate outcomes that were not included in the evi- bers of patients and met our inclusion criteria. Randomized con- dence review. Therefore, each strategy is an acceptable pharma- trolled trials that included participants with normal BP were ex- cologic treatment strategy that can be tailored based on indi- cluded from our formal analysis. In cases in which high-quality vidual circumstances, clinician and patient preferences, and drug evidence was not available or the evidence was weak or absent, the tolerability. With each strategy, clinicians should regularly assess panel relied on fair-quality evidence, panel members' knowledge of BP, encourage evidence-based lifestyle and adherence interven- the published literature beyond the RCTs reviewed, and personal ex- tions, and adjust treatment until goal BP is attained and main- perience to make recommendations. The duration of the guideline tained. In most cases, adjusting treatment means intensifying development process following completion of the systematic search therapy by increasing the drug dose or by adding additional drugs may have caused the panel to miss studies published after our lit- to the regimen. To avoid unnecessary complexity in this report, erature review. However, a bridge search was performed through the hypertension management algorithm (Figure) does not August 2013, and the panel found no additional studies that would explicitly define all potential drug treatment strategies.
have changed the recommendations.
Finally, panel members point out that in specific situations, one Many of the reviewed studies were conducted when the over- antihypertensive drug may be replaced with another if it is per- all risk of cardiovascular morbidity and mortality was substantially ceived not to be effective or if there are adverse effects.
higher than it is today; therefore, effect sizes may have been over-estimated. Further, RCTs that enrolled prehypertensive or nonhy-pertensive individuals were excluded. Thus, our recommendations do not apply to those without hypertension. In many studies fo-cused on DBP, participants also had elevated SBP so it was not pos- This evidence-based guideline for the management of high BP in sible to determine whether the benefit observed in those trials arose adults is not a comprehensive guideline and is limited in scope be- from lowering DBP, SBP, or both. In addition, the ability to compare cause of the focused evidence review to address the 3 specific ques- studies from different time periods was limited by differences in clini- tions (Table 1). Clinicians often provide care for patients with nu- cal trial design and analytic techniques.
merous comorbidities or other important issues related to While physicians use cost, adherence, and often observational hypertension, but the decision was made to focus on 3 questions data to make treatment decisions, medical interventions should considered to be relevant to most physicians and patients. Treat- whenever possible be based first and foremost on good science dem- ment adherence and medication costs were thought to be beyond onstrating benefits to patients. Randomized controlled trials are the the scope of this review, but the panel acknowledges the impor- gold standard for this assessment and thus were the basis for pro- tance of both issues.
viding the evidence for our clinical recommendations. Although ad- The evidence review did not include observational studies, sys- verse effects and harms of antihypertensive treatment docu- tematic reviews, or meta-analyses, and the panel did not conduct mented in the RCTs were considered when the panel made its its own meta-analysis based on prespecified inclusion criteria. Thus, decisions, the review was not designed to determine whether information from these types of studies was not incorporated into therapy-associated adverse effects and harms resulted in signifi- the evidence statements or recommendations. Although this may cant changes in important health outcomes. In addition, this guide- JAMA February 5, 2014 Volume 311, Number 5
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Clinical Review & Education Special Communication 2014 Guideline for Management of High Blood Pressure Table 6. Guideline Comparisons of Goal BP and Initial Drug Therapy for Adults With Hypertension Initial Drug Treatment Options 2014 Hypertension Nonblack: thiazide-type diuretic, ACEI, ARB, or CCB; black: thiazide-type Thiazide-type diuretic, ACEI, ARB,or CCB General nonelderly General elderly <80 y Diuretic, β-blocker, CCB, ACEI, or ARB CKD no proteinuria Abbreviations: ADA, American Diabetes Association; ACEI, CKD + proteinuria Thiazide, β-blocker (age <60y), ACEI inhibitor; ARB, angiotensin receptor (nonblack), or ARB blocker; CCB, calcium channel ACEI or ARB with additional CVD risk blocker; CHEP, Canadian ACEI, ARB, thiazide, or DHPCCB without Hypertension Education Program; additional CVD risk CKD, chronic kidney disease; CVD, cardiovascular disease; DHPCCB, dihydropyridine calcium channelblocker; ESC, European Society of CKD no proteinuria Cardiology; ESH, European Society of CKD + proteinuria Hypertension; ISHIB, International <55 y: ACEI or ARB Society for Hypertension in Blacks; ≥55 y or black: CCB JNC, Joint National Committee;KDIGO, Kidney Disease: Improving Black, lower risk Global Outcome; NICE, National Target organ damage Institute for Health and Clinical line was not endorsed by any federal agency or professional society JNC 8. The charge to the committee was as follows: "The JNC 8 will prior to publication and thus is a departure from previous JNC reports.
review and synthesize the latest available scientific evidence, up- The panel anticipates that an objective assessment of this report fol- date existing clinical recommendations, and provide guidance to busy lowing publication will allow open dialogue among endorsing enti- primary care clinicians on the best approaches to manage and con- ties and encourage continued attention to rigorous methods in guide- trol hypertension in order to minimize patients' risk for cardiovas- line development, thus raising the standard for future guidelines.
cular and other complications." The committee was also asked toidentify 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 partnering with selected organizations that would develop The recommendations based on RCT evidence in this guideline dif- the guidelines.43,44 Importantly, participation in this process re- fer from recommendations in other currently used guidelines sup- quired that these organizations be involved in producing the final ported by expert consensus (Table 6). For example, JNC 7 and other content of the report. The panel elected to pursue publication in- guidelines recommended treatment to lower BP goals in patients with dependently to bring the recommendations to the public in a timely diabetes and CKD based on observational studies.12 Recently, sev- manner while maintaining the integrity of the predefined process.
eral guideline documents such as those from the American Diabetes This report is therefore not an NHLBI sanctioned report and does Association have raised the systolic BP goals to values that are simi- not reflect the views of NHLBI.
lar to those recommended in this evidence-based guideline.37-42 Otherguidelines such as those of the European Society of Hypertension/European Society of Cardiology also recommend a systolic BP goal of lower than 150 mm Hg, but it is not clear at what age cutoff in the gen-eral population this goal specifically applies.37 This changing land- It is important to note that this evidence-based guideline has not re- scape is understandable given the lack of clear RCT evidence in many defined high BP, and the panel believes that the 140/90 mm Hg defi- nition from JNC 7 remains reasonable. The relationship betweennaturally occurring BP and risk is linear down to very low BP, but the benefit of treating to these lower levels with antihypertensive drugs The panel was originally constituted as the "Eighth Joint National is not established. For all persons with hypertension, the potential Committee on the Prevention, Detection, Evaluation, and Treat- benefits of a healthy diet, weight control, and regular exercise can- ment of High Blood Pressure (JNC 8)." In March 2008 NHLBI sent not be overemphasized. These lifestyle treatments have the poten- letters inviting the co-chairs and committee members to serve on tial to improve BP control and even reduce medication needs. Al- JAMA February 5, 2014 Volume 311, Number 5
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2014 Guideline for Management of High Blood Pressure Special Communication Clinical Review & Education though the authors of this hypertension guideline did not conduct gies to achieve those goals based on evidence from RCTs. How- an evidence review of lifestyle treatments in patients taking and not ever, these recommendations are not a substitute for clinical judg- taking antihypertensive medication, we support the recommenda- ment, and decisions about care must carefully consider and tions of the 2013 Lifestyle Work Group.45 incorporate the clinical characteristics and circumstances of each in- The recommendations from this evidence-based guideline from dividual patient. We hope that the algorithm will facilitate imple- panel members appointed to the Eighth Joint National Committee mentation and be useful to busy clinicians. The strong evidence base (JNC 8) offer clinicians an analysis of what is known and not known of this report should inform quality measures for the treatment of about BP treatment thresholds, goals, and drug treatment strate- patients with hypertension.
ARTICLE INFORMATION Lilly, and Novartis; and consulting fees from final results of the Systolic Hypertension in the Published Online: December 18, 2013.
Novartis, Sciele Pharmaceuticals, Takeda, Elderly Program (SHEP). JAMA. 1991;265(24):3255- sanofi-aventis, Gilead, Calpis, Pharmacopeia, Theravance, Daiichi-Sankyo, Noven, AstraZeneca Author Affiliations: University of Iowa, Iowa City
4. Institute of Medicine. Clinical Practice Guidelines
Spain, Merck, Omron, and Janssen. Dr Townsend (James, Carter); University of Alabama at We Can Trust. Washington, DC: National Academies reports board membership with Medtronic, Birmingham School of Medicine (Oparil); Memphis Press; 2011. http://www.iom.edu/Reports/2011 consultancy for Janssen, GlaxoSmithKline, and Veterans Affairs Medical Center and the University Merck, and royalties/educational-related payments of Tennessee, Memphis (Cushman); Johns Hopkins Accessed November 4, 2013.
from Merck, UpToDate, and Medscape. Dr Wright University School of Nursing, Baltimore, Maryland reports receipt of consulting fees from Medtronic, 5. Hsu CC, Sandford BA. The Delphi technique:
(Dennison-Himmelfarb); Kaiser Permanente, CVRx, Takeda, Daiichi-Sankyo, Pfizer, Novartis, and making sense of consensus. Pract Assess Res Eval.
Anaheim, California (Handler); Medical University of Take Care Health. The other authors report no South Carolina, Charleston (Lackland); University of Accessed October 28, 2013.
Missouri, Columbia (LeFevre); Denver Health and 6. Institute of Medicine. Finding What Works in
Hospital Authority and the University of Colorado Funding/Support: The evidence review for this
Health Care: Standards for Systematic Reviews.
School of Medicine, Denver (MacKenzie); New York project was funded by the National Heart, Lung, Washington, DC: National Academies Press; 2011.
University School of Medicine, New York, New York and Blood Institute (NHLBI).
(Ogedegbe); University of North Carolina at Chapel Role of the Sponsor: The design and conduct of
Hill (Smith); Duke University, Durham, North the study; collection, management, analysis, and -Reviews.aspx. Accessed November 6, 2013.
Carolina (Svetkey); Mayo Clinic College of Medicine, interpretation of the data; preparation, review, and Rochester, Minnesota (Taler); University of approval of the manuscript; and decision to submit 7. Cushman WC, Evans GW, Byington RP, et al;
Pennsylvania, Philadelphia (Townsend); Case the manuscript for publication are the ACCORD Study Group. Effects of intensive Western Reserve University, Cleveland, Ohio responsibilities of the authors alone and blood-pressure control in type 2 diabetes mellitus.
(Wright); National Institute of Diabetes and independent of NHLBI.
N Engl J Med. 2010;362(17):1575-1585.
Digestive and Kidney Diseases, Bethesda, Maryland Disclaimer: The views expressed do not represent
8. Benavente OR, Coffey CS, Conwit R, et al; SPS3
(Narva); at the time of the project, National Heart, those of the NHLBI, the National Institute of Study Group. Blood-pressure targets in patients Lung, and Blood Institute, Bethesda, Maryland Diabetes and Digestive and Kidney Diseases, the with recent lacunar stroke: the SPS3 randomised (Ortiz); currently with ProVation Medical, Wolters National Institutes of Health, or the federal Kluwer Health, Minneapolis, Minnesota (Ortiz).
9. JATOS Study Group. Principal results of the
Author Contributions: Drs James and Oparil had
Additional Contributions: We thank Cory V. Evans,
Japanese trial to assess optimal systolic blood full access to all of the data in the study and take MPP, who at the time of the project was a senior pressure in elderly hypertensive patients (JATOS).
responsibility for the integrity of the data and the research analyst and contract lead for JNC 8 with Hypertens Res. 2008;31(12):2115-2127.
accuracy of the data analysis.
Leidos (formerly Science Applications International 10. Ogihara T, Saruta T, Rakugi H, et al; Valsartan in
Study concept and design, acquisition of data, Corporation) and Linda J. Lux, MPA, RTI Elderly Isolated Systolic Hypertension Study Group.
analysis and interpretation of data, drafting of the International, for their support. We also thank Target blood pressure for treatment of isolated manuscript, critical revision of the manuscript for Lawrence J. Fine, MD, DrPH, NHLBI, for his work systolic hypertension in the elderly: Valsartan in important intellectual content, administrative, with the panel. Those named here were Elderly Isolated Systolic Hypertension Study.
technical, and material support, and study compensated in their roles as consultants on the supervision: All authors.
11. Verdecchia P, Staessen JA, Angeli F, et al;
Conflict of Interest Disclosures: All authors have
Correction: This article was corrected for the
Cardio-Sis investigators. Usual versus tight control completed and submitted the ICMJE Form for description of reserpine in Recommendation 6, of systolic blood pressure in non-diabetic patients Disclosure of Potential Conflicts of Interest. Dr addition of a footnote to Table 5, and text in the with hypertension (Cardio-Sis): an open-label Oparil reports individual and institutional payment Discussion on January 21, 2014.
randomised trial. Lancet. 2009;374(9689): related to board membership from Bayer, Daiichi Sankyo, Novartis, Medtronic, and Takeda; individual consulting fees from Backbeat, Bayer, 12. Chobanian AV, Bakris GL, Black HR, et al;
Boehringer-Ingelheim, Bristol Myers-Squibb, Daiichi 1. Staessen JA, Fagard R, Thijs L, et al; The Systolic
National Heart, Lung, and Blood Institute Joint Sankyo, Eli Lilly, Medtronic, Merck, Pfizer, and Hypertension in Europe (Syst-Eur) Trial National Committee on Prevention, Detection, Takeda; receipt of institutional grant funding from Investigators. Randomised double-blind Evaluation, and Treatment of High Blood Pressure; AstraZeneca, Daiichi Sankyo, Eisai Inc, Gilead, comparison of placebo and active treatment for National High Blood Pressure Education Program Medtronic, Merck, Novartis, Takeda Global older patients with isolated systolic hypertension.
Coordinating Committee. The seventh report of the Research and Development Inc; individual payment Joint National Committee on Prevention, for lectures from Daiichi Sankyo, Merck, Novartis, 2. Beckett NS, Peters R, Fletcher AE, et al; HYVET
Detection, Evaluation, and Treatment of High Blood and Pfizer; individual and institutional payment for Study Group. Treatment of hypertension in patients Pressure: the JNC 7 report. JAMA.
development of educational presentations from 80 years of age or older. N Engl J Med.
ASH/AHSR (Daiichi Sankyo); and individual and 13. Hypertension Detection and Follow-up
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Program Cooperative Group. Five-year findings of Daiichi Sankyo, and LipoScience Inc for educational of stroke by antihypertensive drug treatment in the hypertension detection and follow-up program, grant(s) for the Annual UAB Vascular Biology & older persons with isolated systolic hypertension: I: reduction in mortality of persons with high blood Hypertension Symposium. Dr Cushman reports pressure, including mild hypertension. JAMA.
receipt of institutional grant support from Merck, JAMA February 5, 2014 Volume 311, Number 5
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