Table of Contents

Preamble e15 1. Introduction e16 1.1. Methodology and Evidence Review e16 1.2. Organization of the Writing Committee e17 1.3. Document Review and Approval e18 1.4. Scope of the Guideline e18 1.5. Abbreviations and Acronyms e18 2. BP and CVD Risk e19 2.1. Observational Relationship e19 2.2. BP Components e20 2.3. Population Risk e20 2.4. Coexistence of Hypertension and Related Chronic Conditions e20 3. Classification of BP e21 3.1. Definition of High BP e21 3.2. Lifetime Risk of Hypertension e22 3.3. Prevalence of High BP e22 3.4. Awareness, Treatment, and Control e22 4. Measurement of BP e23 4.1. Accurate Measurement of BP in the Office e23 4.2. Out-of-Office and Self-Monitoring of BP e24 4.3. Ambulatory BP Monitoring e25 4.4. Masked and White Coat Hypertension e26 5. Causes of Hypertension e28 5.1. Genetic Predisposition e28 5.2. Environmental Risk Factors e28 5.2.1. Overweight and Obesity e28 5.2.2. Sodium Intake e29 5.2.3. Potassium e29 5.2.4. Physical Fitness e29 5.2.5. Alcohol e29 5.3. Childhood Risk Factors and BP Tracking e31 5.4. Secondary Forms of Hypertension e32 5.4.1. Drugs and Other Substances With Potential to Impair BP Control e32 5.4.2. Primary Aldosteronism e32 5.4.3. Renal Artery Stenosis e34 5.4.4. Obstructive Sleep Apnea e34 6. Nonpharmacological Interventions e35 6.1. Strategies e35 6.2. Nonpharmacological Interventions e35 7. Patient Evaluation e38 7.1. Laboratory Tests and Other Diagnostic Procedures e38 7.2. Cardiovascular Target Organ Damage e38 8. Treatment of High BP e39 8.1. Pharmacological Treatment e39 8.1.1. Initiation of Pharmacological BP Treatment in the Context of Overall CVD Risk e39 8.1.2. BP Treatment Threshold and the Use of CVD Risk Estimation to Guide Drug Treatment of Hypertension e40 8.1.3. Follow-Up After Initial BP Evaluation e42 8.1.4. General Principles of Drug Therapy e42 8.1.5. BP Goal for Patients With Hypertension e43 8.1.6. Choice of Initial Medication e46 8.2. Achieving BP Control in Individual Patients e47 8.3. Follow-Up of BP During Antihypertensive Drug Therapy e48 8.3.1. Follow-Up After Initiating Antihypertensive Drug Therapy e48 8.3.2. Monitoring Strategies to Improve Control of BP in Patients on Drug Therapy for High BP e48 9. Hypertension in Patients With Comorbidities e48 9.1. Stable Ischemic Heart Disease e49 9.2. Heart Failure e50 9.2.1. Heart Failure With Reduced Ejection Fraction e50 9.2.2. Heart Failure With Preserved Ejection Fraction e51 9.3. Chronic Kidney Disease e51 9.3.1. Hypertension After Renal Transplantation e53 9.4. Cerebrovascular Disease e53 9.4.1. Acute Intracerebral Hemorrhage e54 9.4.2. Acute Ischemic Stroke e54 9.4.3. Secondary Stroke Prevention e56 9.5. Peripheral Artery Disease e57 9.6. Diabetes Mellitus e58 9.7. Metabolic Syndrome e59 9.8. Atrial Fibrillation e59 9.9. Valvular Heart Disease e60 9.10. Aortic Disease e60 10. Special Patient Groups e60 10.1. Race and Ethnicity e60 10.1.1. Racial and Ethnic Differences in Treatment e61 10.2. Sex-Related Issues e61 10.2.1. Women e62 10.2.2. Pregnancy e62 10.3. Age-Related Issues e63 10.3.1. Older Persons e63 10.3.2. Children and Adolescents e64 11. Other Considerations e64 11.1. Resistant Hypertension e64 11.2. Hypertensive Crises—Emergencies and Urgencies e65 11.3. Cognitive Decline and Dementia e68 11.4. Sexual Dysfunction and Hypertension e69 11.5. Patients Undergoing Surgical Procedures e69 12. Strategies to Improve Hypertension Treatment and Control e71 12.1. Adherence Strategies for Treatment of Hypertension e71 12.1.1. Antihypertensive Medication Adherence Strategies e71 12.1.2. Strategies to Promote Lifestyle Modification e71 12.1.3. Improving Quality of Care for Resource-Constrained Populations e72 12.2. Structured, Team-Based Care Interventions for Hypertension Control e73 12.3. Health Information Technology–Based Strategies to Promote Hypertension Control e73 12.3.1. EHR and Patient Registries e73 12.3.2. Telehealth Interventions to Improve Hypertension Control e74 12.4. Improving Quality of Care for Patients With Hypertension e74 12.4.1. Performance Measures e74 12.4.2. Quality Improvement Strategies e74 12.5. Financial Incentives e75 13. The Plan of Care for Hypertension e75 13.1. Health Literacy e76 13.2. Access to Health Insurance and Medication Assistance Plans e76 13.3. Social and Community Services e76 14. Summary of BP Thresholds and Goals for Pharmacological Therapy e77 15. Evidence Gaps and Future Directions e77 References e79 Appendix 1: Author Relationships With Industry and Other Entities (Relevant) e108 Appendix 2: Reviewer Relationships With Industry and Other Entities (Comprehensive) e110

Preamble

Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated scientific evidence into clinical practice guidelines (guidelines) with recommendations to improve cardiovascular health. In 2013, the National Heart, Lung, and Blood Institute (NHLBI) Advisory Council recommended that the NHLBI focus specifically on reviewing the highest-quality evidence and partner with other organizations to develop recommendations.P-1,P-2 Accordingly, the ACC and AHA collaborated with the NHLBI and stakeholder and professional organizations to complete and publish 4 guidelines (on assessment of cardiovascular risk, lifestyle modifications to reduce cardiovascular risk, management of blood cholesterol in adults, and management of overweight and obesity in adults) to make them available to the widest possible constituency. In 2014, the ACC and AHA, in partnership with several other professional societies, initiated a guideline on the prevention, detection, evaluation, and management of high blood pressure (BP) in adults. Under the management of the ACC/AHA Task Force, a Prevention Subcommittee was appointed to help guide development of the suite of guidelines on prevention of cardiovascular disease (CVD). These guidelines, which are based on systematic methods to evaluate and classify evidence, provide a cornerstone for quality cardiovascular care. The ACC and AHA sponsor the development and publication of guidelines without commercial support, and members of each organization volunteer their time to the writing and review efforts. Guidelines are official policy of the ACC and AHA.

Intended Use

Practice guidelines provide recommendations applicable to patients with or at risk of developing CVD. The focus is on medical practice in the United States, but guidelines developed in collaboration with other organizations can have a global impact. Although guidelines may be used to inform regulatory or payer decisions, they are intended to improve patients’ quality of care and align with patients’ interests. Guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances and should not replace clinical judgment.

Clinical Implementation

Management in accordance with guideline recommendations is effective only when followed by both practitioners and patients. Adherence to recommendations can be enhanced by shared decision making between clinicians and patients, with patient engagement in selecting interventions on the basis of individual values, preferences, and associated conditions and comorbidities.

Methodology and Modernization

The ACC/AHA Task Force on Clinical Practice Guidelines (Task Force) continuously reviews, updates, and modifies guideline methodology on the basis of published standards from organizations, including the Institute of Medicine,P-3,P-4 and on the basis of internal reevaluation. Similarly, the presentation and delivery of guidelines are reevaluated and modified on the basis of evolving technologies and other factors to facilitate optimal dissemination of information to healthcare professionals at the point of care.

Toward this goal, this guideline continues the introduction of an evolved format of presenting guideline recommendations and associated text called the “modular knowledge chunk format.” Each modular “chunk” includes a table of related recommendations, a brief synopsis, recommendation-specific supportive text, and when appropriate, flow diagrams or additional tables. References are provided within the modular chunk itself to facilitate quick review. Additionally, this format will facilitate seamless updating of guidelines with focused updates as new evidence is published, as well as content tagging for rapid electronic retrieval of related recommendations on a topic of interest. This evolved approach format was instituted when this guideline was near completion; therefore, the present document represents a transitional format that best suits the text as written. Future guidelines will fully implement this format, including provisions for limiting the amount of text in a guideline.

Recognizing the importance of cost–value considerations in certain guidelines, when appropriate and feasible, an analysis of the value of a drug, device, or intervention may be performed in accordance with the ACC/AHA methodology.P-5

To ensure that guideline recommendations remain current, new data are reviewed on an ongoing basis, with full guideline revisions commissioned in approximately 6-year cycles. Publication of new, potentially practice-changing study results that are relevant to an existing or new drug, device, or management strategy will prompt evaluation by the Task Force, in consultation with the relevant guideline writing committee, to determine whether a focused update should be commissioned. For additional information and policies regarding guideline development, we encourage readers to consult the ACC/AHA guideline methodology manualP-6 and other methodology articles.P-7–P-10

Selection of Writing Committee Members

The Task Force strives to avoid bias by selecting experts from a broad array of backgrounds. Writing committee members represent different geographic regions, sexes, ethnicities, races, intellectual perspectives/biases, and scopes of clinical practice. The Task Force may also invite organizations and professional societies with related interests and expertise to participate as partners, collaborators, or endorsers.

Relationships With Industry and Other Entities

The ACC and AHA have rigorous policies and methods to ensure that guidelines are developed without bias or improper influence. The complete relationships with industry and other entities (RWI) policy can be found online. Appendix 1 of the present document lists writing committee members’ relevant RWI. For the purposes of full transparency, writing committee members’ comprehensive disclosure information is available online. Comprehensive disclosure information for the Task Force is available online.

Evidence Review and Evidence Review Committees

In developing recommendations, the writing committee uses evidence-based methodologies that are based on all available data.P-6–P-9 Literature searches focus on randomized controlled trials (RCTs) but also include registries, nonrandomized comparative and descriptive studies, case series, cohort studies, systematic reviews, and expert opinion. Only key references are cited.

An independent evidence review committee (ERC) is commissioned when there are 1 or more questions deemed of utmost clinical importance that merit formal systematic review. The systematic review will determine which patients are most likely to benefit from a drug, device, or treatment strategy and to what degree. Criteria for commissioning an ERC and formal systematic review include: a) the absence of a current authoritative systematic review, b) the feasibility of defining the benefit and risk in a time frame consistent with the writing of a guideline, c) the relevance to a substantial number of patients, and d) the likelihood that the findings can be translated into actionable recommendations. ERC members may include methodologists, epidemiologists, healthcare providers, and biostatisticians. The recommendations developed by the writing committee on the basis of the systematic review are marked with “SR.”

Guideline-Directed Management and Therapy

The term guideline-directed management and therapy (GDMT) encompasses clinical evaluation, diagnostic testing, and pharmacological and procedural treatments. For these and all recommended drug treatment regimens, the reader should confirm the dosage by reviewing product insert material and evaluate the treatment regimen for contraindications and interactions. The recommendations are limited to drugs, devices, and treatments approved for clinical use in the United States.

Class of Recommendation and Level of Evidence

The Class of Recommendation (COR) indicates the strength of the recommendation, encompassing the estimated magnitude and certainty of benefit in proportion to risk. The Level of Evidence (LOE) rates the quality of scientific evidence that supports the intervention on the basis of the type, quantity, and consistency of data from clinical trials and other sources (Table 1).P-6–P-8

Table 1. Applying Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care* (Updated August 2015) Table 1. Applying Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care* (Updated August 2015)

Glenn N. Levine, MD, FACC, FAHA

Chair, ACC/AHA Task Force on Clinical Practice Guidelines

1. Introduction

As early as the 1920s, and subsequently in the 1959 Build and Blood Pressure StudyS1.5-1 of almost 5 million adults insured between 1934 and 1954, a strong direct relationship was noted between level of BP and risk of clinical complications and death. In the 1960s, these findings were confirmed in a series of reports from the Framingham Heart Study.S1.5-2 The 1967 and 1970 Veterans Administration Cooperative Study Group reports ushered in the era of effective treatment for high BP.S1.5-3,S1.5-4 The first comprehensive guideline for detection, evaluation, and management of high BP was published in 1977, under the sponsorship of the NHLBI.S1.5-5 In subsequent years, a series of Joint National Committee (JNC) BP guidelines were published to assist the practice community and improve prevention, awareness, treatment, and control of high BP.S1.5-5–S1.5-7 The present guideline updates prior JNC reports.

1.1. Methodology and Evidence Review

An extensive evidence review, which included literature derived from research involving human subjects, published in English, and indexed in MEDLINE (through PubMed), EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline, was conducted between February and August 2015. Key search words included but were not limited to the following: adherence; aerobic; alcohol intake; ambulatory care; antihypertensive: agents, drug, medication, therapy; beta adrenergic blockers; blood pressure: arterial, control, determination, devices, goal, high, improve, measurement, monitoring, ambulatory; calcium channel blockers; diet; diuretic agent; drug therapy; heart failure: diastolic, systolic; hypertension: white coat, masked, ambulatory, isolated ambulatory, isolated clinic, diagnosis, reverse white coat, prevention, therapy, treatment, control; intervention; lifestyle: measures, modification; office visits; patient outcome; performance measures; physical activity; potassium intake; protein intake; renin inhibitor; risk reduction: behavior, counseling; screening; sphygmomanometers; spironolactone; therapy; treatment: adherence, compliance, efficacy, outcome, protocol, regimen; weight. Additional relevant studies published through June 2016, during the guideline writing process, were also considered by the writing committee and added to the evidence tables when appropriate. The final evidence tables included in the Online Data Supplement summarize the evidence used by the writing committee to formulate recommendations.

As noted in the preamble, an independent ERC was commissioned to perform a formal systematic review of 4 critical clinical questions related to hypertension (Table 2), the results of which were considered by the writing committee for incorporation into this guideline. Concurrent with this process, writing committee members evaluated other published data relevant to the guideline. The findings of the ERC and the writing committee members were formally presented and discussed, and then guideline recommendations were developed. The systematic review report, “Systematic Review for the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults,” is published in conjunction with this guideline,S1.5-8 and its respective data supplements are available online. No writing committee member reported a RWI. Drs. Whelton, Wright, and Williamson had leadership roles in SPRINT (Systolic Blood Pressure Intervention Trial). Dr. Carey chaired committee discussions in which the SPRINT results were considered.

Table 2. Systematic Review Questions on High BP in Adults Question Number Question Section Number 1 Is there evidence that self-directed monitoring of BP and/or ambulatory BP monitoring are superior to office-based measurement of BP by a healthcare worker for 1) preventing adverse outcomes for which high BP is a risk factor and 2) achieving better BP control? 4.2 2 What is the optimal target for BP lowering during antihypertensive therapy in adults? 8.1.59.39.6 3 In adults with hypertension, do various antihypertensive drug classes differ in their comparative benefits and harms? 8.1.68.2 4 In adults with hypertension, does initiating treatment with antihypertensive pharmacological monotherapy versus initiating treatment with 2 drugs (including fixed-dose combination therapy), either of which may be followed by the addition of sequential drugs, differ in comparative benefits and/or harms on specific health outcomes? 8.1.6.1

1.2. Organization of the Writing Committee

The writing committee consisted of clinicians, cardiologists, epidemiologists, internists, an endocrinologist, a geriatrician, a nephrologist, a neurologist, a nurse, a pharmacist, a physician assistant, and 2 lay/patient representatives. It included representatives from the ACC, AHA, American Academy of Physician Assistants (AAPA), Association of Black Cardiologists (ABC), American College of Preventive Medicine (ACPM), American Geriatrics Society (AGS), American Pharmacists Association (APhA), American Society of Hypertension (ASH), American Society for Preventive Cardiology (ASPC), National Medical Association (NMA), and Preventive Cardiovascular Nurses Association (PCNA).

1.3. Document Review and Approval

This document was reviewed by 2 official reviewers nominated by the ACC and AHA; 1 reviewer each from the AAPA, ABC, ACPM, AGS, APhA, ASH, ASPC, NMA, and PCNA; and 38 individual content reviewers. Reviewers’ RWI information was distributed to the writing committee and is published in this document (Appendix 2).

This document was approved for publication by the governing bodies of the ACC, AHA, AAPA, ABC, ACPM, AGS, APhA, ASH, ASPC, NMA, and PCNA.

1.4. Scope of the Guideline

The present guideline is intended to be a resource for the clinical and public health practice communities. It is designed to be comprehensive but succinct and practical in providing guidance for prevention, detection, evaluation, and management of high BP. It is an update of the NHLBI publication, “The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure” (JNC 7).S1.5-7 It incorporates new information from studies of office-based BP-related risk of CVD, ambulatory blood pressure monitoring (ABPM), home blood pressure monitoring (HBPM), telemedicine, and various other areas. This guideline does not address the use of BP-lowering medications for the purposes of prevention of recurrent CVD events in patients with stable ischemic heart disease (SIHD) or chronic heart failure (HF) in the absence of hypertension; these topics are the focus of other ACC/AHA guidelines.S1.5-9,S1.5-10 In developing the present guideline, the writing committee reviewed prior published guidelines, evidence reviews, and related statements. Table 3 contains a list of publications and statements deemed pertinent to this writing effort and is intended for use as a resource, thus obviating the need to repeat existing guideline recommendations.

Table 3. Associated Guidelines and Statements Title Organization Publication Year Guidelines Lower-extremity peripheral artery disease AHA/ACC 2016S1.5-11 Management of primary aldosteronism: case detection, diagnosis, and treatment Endocrine Society 2016S1.5-12 Stable ischemic heart disease ACC/AHA/AATS/PCNA/SCAI/STS 2014S1.5-13* 2012S1.5-9 Pheochromocytoma and paraganglioma Endocrine Society 2014S1.5-14 Atrial fibrillation AHA/ACC/HRS 2014S1.5-15 Valvular heart disease ACC/AHA 2017S1.5-16 Assessment of cardiovascular risk ACC/AHA 2013S1.5-17 Hypertension in pregnancy ACOG 2013S1.5-18 Heart failure ACC/AHA 2017S1.5-19 2013S1.5-10 Lifestyle management to reduce cardiovascular risk AHA/ACC 2013S1.5-20 Management of arterial hypertension ESH/ESC 2013S1.5-21 Management of overweight and obesity in adults AHA/ACC/TOS 2013S1.5-22 ST-elevation myocardial infarction ACC/AHA 2013S1.5-23 Treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults ACC/AHA 2013S1.5-24 Cardiovascular diseases during pregnancy ESC 2011S1.5-25 Effectiveness-based guidelines for the prevention of cardiovascular disease in women AHA/ACC 2011S1.5-26 Secondary prevention and risk-reduction therapy for patients with coronary and other atherosclerotic vascular disease AHA/ACC 2011S1.5-27 Assessment of cardiovascular risk in asymptomatic adults ACC/AHA 2010S1.5-28 Thoracic aortic disease ACC/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM 2010S1.5-29 Diagnosis, evaluation, and treatment of high blood pressure in children and adolescents NHLBI 2004S1.5-30 Statements Salt sensitivity of blood pressure AHA 2016S1.5-31 Cardiovascular team-based care and the role of advanced practice providers ACC 2015S1.5-32 Treatment of hypertension in patients with coronary artery disease AHA/ACC/ASH 2015S1.5-33 Ambulatory blood pressure monitoring in children and adolescents AHA 2014S1.5-34 An effective approach to high blood pressure control AHA/ACC/CDC 2014S1.5-35 Ambulatory blood pressure monitoring ESH 2013S1.5-36 Performance measures for adults with coronary artery disease and hypertension ACC/AHA/AMA-PCPI 2011S1.5-37 Interventions to promote physical activity and dietary lifestyle changes for cardiovascular risk factor reduction in adults AHA 2010S1.5-38 Resistant hypertension: diagnosis, evaluation, and treatment AHA 2008S1.5-39

1.5. Abbreviations and Acronyms

Abbreviation/Acronym Meaning/Phrase ABPM ambulatory blood pressure monitoring ACE angiotensin-converting enzyme AF atrial fibrillation ARB angiotensin receptor blocker BP blood pressure CCB calcium channel blocker CHD coronary heart disease CKD chronic kidney disease CPAP continuous positive airway pressure CVD cardiovascular disease DBP diastolic blood pressure DM diabetes mellitus ECG electrocardiogram ESRD end-stage renal disease GDMT guideline-directed management and therapy GFR glomerular filtration rate HBPM home blood pressure monitoring EHR electronic health record HF heart failure HFpEF heart failure with preserved ejection fraction HFrEF heart failure with reduced ejection fraction ICH intracerebral hemorrhage JNC Joint National Commission LV left ventricular LVH left ventricular hypertrophy MI myocardial infarction MRI magnetic resonance imaging PAD peripheral artery disease RAS renin-angiotensin system RCT randomized controlled trial SBP systolic blood pressure SIHD stable ischemic heart disease TIA transient ischemic attack

2. BP and CVD Risk

2.1. Observational Relationship

Observational studies have demonstrated graded associations between higher systolic blood pressure (SBP) and diastolic blood pressure (DBP) and increased CVD risk.S2.1-1,S2.1-2 In a meta-analysis of 61 prospective studies, the risk of CVD increased in a log-linear fashion from SBP levels <115 mm Hg to >180 mm Hg and from DBP levels <75 mm Hg to >105 mm Hg.S2.1-1 In that analysis, 20 mm Hg higher SBP and 10 mm Hg higher DBP were each associated with a doubling in the risk of death from stroke, heart disease, or other vascular disease. In a separate observational study including >1 million adult patients ≥30 years of age, higher SBP and DBP were associated with increased risk of CVD incidence and angina, myocardial infarction (MI), HF, stroke, peripheral artery disease (PAD), and abdominal aortic aneurysm, each evaluated separately.S2.1-2 An increased risk of CVD associated with higher SBP and DBP has been reported across a broad age spectrum, from 30 years to >80 years of age. Although the relative risk of incident CVD associated with higher SBP and DBP is smaller at older ages, the corresponding high BP–related increase in absolute risk is larger in older persons (≥65 years) given the higher absolute risk of CVD at an older age.S2.1-1

2.2. BP Components

Epidemiological studies have evaluated associations of SBP and DBP, as well as derived components of BP measurements (including pulse pressure, mean BP, and mid-BP), with CVD outcomes (Table 4). When considered separately, higher levels of both SBP and DBP have been associated with increased CVD risk.S2.2-1,S2.2-2 Higher SBP has consistently been associated with increased CVD risk after adjustment for, or within strata of, DBP.S2.2-3–S2.2-5 In contrast, after consideration of SBP through adjustment or stratification, DBP has not been consistently associated with CVD risk.S2.2-6,S2.2-7 Although pulse pressure and mid-BP have been associated with increased CVD risk independent of SBP and DBP in some studies, SBP (especially) and DBP are prioritized in the present document because of the robust evidence base for these measures in both observational studies and clinical trials and because of their ease of measurement in practice settings.S2.2-8–S2.2-11

Table 4. BP Measurement Definitions BP Measurement Definition SBP First Korotkoff sound* DBP Fifth Korotkoff sound* Pulse pressure SBP minus DBP Mean arterial pressure DBP plus one third pulse pressure† Mid-BP Sum of SBP and DBP, divided by 2

2.3. Population Risk

In 2010, high BP was the leading cause of death and disability-adjusted life years worldwide.S2.3-1,S2.3-2 In the United States, hypertension (see Section 3.1 for definition) accounted for more CVD deaths than any other modifiable CVD risk factor and was second only to cigarette smoking as a preventable cause of death for any reason.S2.3-3 In a follow-up study of 23 272 US NHANES (National Health and Nutrition Examination Survey) participants, >50% of deaths from coronary heart disease (CHD) and stroke occurred among individuals with hypertension.S2.3-4 Because of the high prevalence of hypertension and its associated increased risk of CHD, stroke, and end-stage renal disease (ESRD), the population-attributable risk of these outcomes associated with hypertension is high.S2.3-4,S2.3-5 In the population-based ARIC (Atherosclerosis Risk in Communities) study, 25% of the cardiovascular events (CHD, coronary revascularization, stroke, or HF) were attributable to hypertension. In the Northern Manhattan study, the percentage of events attributable to hypertension was higher in women (32%) than in men (19%) and higher in blacks (36%) than in whites (21%).S2.3-6 In 2012, hypertension was the second leading assigned cause of ESRD, behind diabetes mellitus (DM), and accounted for 34% of incident ESRD cases in the US population.S2.3-7

2.4. Coexistence of Hypertension and Related Chronic Conditions

Recommendation for Coexistence of Hypertension and Related Chronic Conditions References that support the recommendation are summarized in Online Data Supplement 1. COR LOE Recommendation I B-NR 1. Screening for and management of other modifiable CVD risk factors are recommended in adults with hypertension.S2.4-1,S2.4-2

Synopsis

Many adult patients with hypertension have other CVD risk factors; a list of such modifiable and relatively fixed risk factors is provided in Table 5. Among US adults with hypertension between 2009 and 2012, 15.5% were current smokers, 49.5% were obese, 63.2% had hypercholesterolemia, 27.2% had DM, and 15.8% had chronic kidney disease (CKD; defined as estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 and/or urine albumin:creatinine ≥300 mg/g).S2.4-3

Table 5. CVD Risk Factors Common in Patients With Hypertension Modifiable Risk Factors* Relatively Fixed Risk Factors† Current cigarette smoking, secondhand smoking CKD Family history Diabetes mellitus Increased age Dyslipidemia/hypercholesterolemia Low socioeconomic/educational status Overweight/obesity Male sex Physical inactivity/low fitness Obstructive sleep apnea Unhealthy diet Psychosocial stress

Not only are CVD risk factors common among adults with hypertension, a higher percentage of adults with CVD risk factors have hypertension. For example, 71% of US adults with diagnosed DM have hypertension.S2.4-4 In the Chronic Renal Insufficiency Cohort (CRIC), 86% of the participants had hypertension.S2.4-5 Also, 28.1% of adults with hypertension and CKD in the population-based REGARDS (Reasons for Geographic and Racial Differences in Stroke) study had apparent resistant hypertension.S2.4-6 In NHANES 1999–2010, 35.7% of obese individuals had hypertension.S2.4-7 The presence of multiple CVD risk factors in individuals with hypertension results in high absolute risks for CHD and stroke in this population. For example, among US adults with hypertension between 2009 and 2012, 41.7% had a 10-year CHD risk >20%, 40.9% had a risk of 10% to 20%, and only 18.4% had a risk <10%.S2.4-3

Modifiable risk factors for CVD that are common among adults with hypertension include cigarette smoking/tobacco smoke exposure, DM, dyslipidemia (including high levels of low-density lipoprotein cholesterol or hypercholesterolemia, high levels of triglycerides, and low levels of high-density lipoprotein cholesterol), overweight/obesity, physical inactivity/low fitness level, and unhealthy diet.S2.4-8 The relationship between hypertension and other modifiable risk factors is complex and interdependent, with several sharing mechanisms of action and pathophysiology. CVD risk factors affect BP through over activation of the renin-angiotensin-aldosterone system, activation of the sympathetic nervous system, inhibition of the cardiac natriuretic peptide system, endothelial dysfunction, and other mechanisms.S2.4-9–S2.4-11 Treating some of the other modifiable risk factors may reduce BP through modification of shared pathology, and CVD risk may be reduced by treating global risk factor burden.

Recommendation-Specific Supportive Text

Observational studies have demonstrated that CVD risk factors frequently occur in combination, with ≥3 risk factors present in 17% of patients.S2.4-1 A meta-analysis from 18 cohort studies involving 257 384 patients identified a lifetime risk of CVD death, nonfatal MI, and fatal or nonfatal stroke that was substantially higher in adults with ≥2 CVD risk factors than in those with only 1 risk factor.S2.4-1,S2.4-2

3. Classification of BP

3.1. Definition of High BP

Recommendation for Definition of High BP References that support the recommendation are summarized in Online Data Supplement 2. COR LOE Recommendation I B-NR 1. BP should be categorized as normal, elevated, or stage 1 or 2 hypertension to prevent and treat high BP (Table 6).S3.1-1–S3.1-20

Synopsis

Although a continuous association exists between higher BP and increased CVD risk (see Section 2.1), it is useful to categorize BP levels for clinical and public health decision making. In the present document, BP is categorized into 4 levels on the basis of average BP measured in a healthcare setting (office pressures): normal, elevated, and stage 1 or 2 hypertension (Table 6). Online Data Supplement C illustrates schematically the SBP and DBP categories defining normal BP, elevated BP, and stages 1 and 2 hypertension. This categorization differs from that previously recommended in the JNC 7 report, with stage 1 hypertension now defined as an SBP of 130–139 or a DBP of 80–89 mm Hg, and with stage 2 hypertension in the present document corresponding to stages 1 and 2 in the JNC 7 report.S3.1-21 The rationale for this categorization is based on observational data related to the association between SBP/DBP and CVD risk, RCTs of lifestyle modification to lower BP, and RCTs of treatment with antihypertensive medication to prevent CVD. The increased risk of CVD among adults with stage 2 hypertension is well established. An increasing number of individual studies and meta-analyses of observational data have reported a gradient of progressively higher CVD risk going from normal BP to elevated BP and stage 1 hypertension.S3.1-4–S3.1-10,S3.1-12,S3.1-13,S3.1-16 In many of these meta-analyses, the hazard ratios for CHD and stroke were between 1.1 and 1.5 for the comparison of SBP/DBP of 120–129/80–84 mm Hg versus <120/80 mm Hg and between 1.5 and 2.0 for the comparison of SBP/DBP of 130–139/85–89 mm Hg versus <120/80 mm Hg. This risk gradient was consistent across subgroups defined by sex and race/ethnicity. The relative increase in CVD risk associated with higher BP was attenuated but still present among older adults.S3.1-1 The prevalence of severe hypertension has been declining over time, but approximately 12.3% of US adults with hypertension have an average SBP ≥160 mm Hg or average DBP ≥100 mm Hg.S3.1-22 Lifestyle modification and pharmacological antihypertensive treatment recommendations for individuals with elevated BP and stages 1 and 2 hypertension are provided in Sections 6 and 8, respectively. The relationship of this classification schema with measurements obtained by ambulatory BP recording and home BP measurements is discussed in Section 4.2.

Table 6. Categories of BP in Adults* BP Category SBP DBP Normal <120 mm Hg and <80 mm Hg Elevated 120–129 mm Hg and <80 mm Hg Hypertension Stage 1 130–139 mm Hg or 80–89 mm Hg Stage 2 ≥140 mm Hg or ≥90 mm Hg

Recommendation-Specific Supportive Text

As was the case in previous BP classification systems, the choice and the naming of the categories were based on a pragmatic interpretation of BP-related CVD risk and benefit of BP reduction in clinical trials. Meta-analyses of observational studies have demonstrated that elevated BP and hypertension are associated with increased risk of CVD, ESRD, subclinical atherosclerosis, and all-cause death.S3.1-1–S3.1-17 The recommended BP classification system is most valuable in untreated adults as an aid in decisions about prevention or treatment of high BP. However, it is also useful in assessing the success of interventions to reduce BP.

3.2. Lifetime Risk of Hypertension

Observational studies have documented a relatively high incidence of hypertension over periods of 5 to 10 years of follow-up.S3.2-1,S3.2-2 Thus, there is a much higher long-term population burden of hypertension as BP progressively increases with age. Several studies have estimated the long-term cumulative incidence of developing hypertension.S3.2-3,S3.2-4 In an analysis of 1132 white male medical students (mean age: approximately 23 years at baseline) in the Johns Hopkins Precursors study, 0.3%, 6.5%, and 37% developed hypertension at age 25, 45, and 65 years, respectively.S3.2-5 In MESA (Multi-Ethnic Study of Atherosclerosis), the percentage of the population developing hypertension over their lifetimes was higher for African Americans and Hispanics than for whites and Asians.S3.2-3 For adults 45 years of age without hypertension, the 40-year risk of developing hypertension was 93% for African-American, 92% for Hispanic, 86% for white, and 84% for Chinese adults.S3.2-3 In the Framingham Heart Study, approximately 90% of adults free of hypertension at age 55 or 65 years developed hypertension during their lifetimes.S3.2-4 All of these estimates were based on use of the 140/90–mm Hg cutpoint for recognition of hypertension and would have been higher had the 130/80–mm Hg cutpoint been used.

3.3. Prevalence of High BP

Prevalence estimates are greatly influenced by the choice of cutpoints to categorize high BP, the methods used to establish the diagnosis, and the population studied.S3.3-1,S3.3-2 Most general population prevalence estimates are derived from national surveys. Table 7 provides estimates for prevalence of hypertension in the US general adult population (≥20 years of age) that are based on the definitions of hypertension recommended in the present guideline and in the JNC 7 report. The prevalence of hypertension among US adults is substantially higher when the definition in the present guideline is used versus the JNC 7 definition (46% versus 32%). However, as described in Section 8.1, nonpharmacological treatment (not antihypertensive medication) is recommended for most US adults who have hypertension as defined in the present guideline but who would not meet the JNC 7 definition for hypertension. As a consequence, the new definition results in only a small increase in the percentage of US adults for whom antihypertensive medication is recommended in conjunction with lifestyle modification.

Table 7. Prevalence of Hypertension Based on 2 SBP/DBP Thresholds*† SBP/DBP ≥130/80 mm Hg or Self-Reported Antihypertensive Medication† SBP/DBP ≥140/90 mm Hg or Self-Reported Antihypertensive Medication‡ Overall, crude 46% 32% Men (n=4717) Women (n=4906) Men (n=4717) Women (n=4906) Overall, age-sex adjusted 48% 43% 31% 32% Age group, y 20–44 30% 19% 11% 10% 45–54 50% 44% 33% 27% 55–64 70% 63% 53% 52% 65–74 77% 75% 64% 63% 75+ 79% 85% 71% 78% Race-ethnicity§ Non-Hispanic white 47% 41% 31% 30% Non-Hispanic black 59% 56% 42% 46% Non-Hispanic Asian 45% 36% 29% 27% Hispanic 44% 42% 27% 32%

The prevalence of hypertension rises dramatically with increasing age and is higher in blacks than in whites, Asians, and Hispanic Americans. NHANES estimates of JNC 7–defined hypertension prevalence have remained fairly stable since the early 2000s.S3.3-1 Most contemporary population surveys, including NHANES, rely on an average of BP measurements obtained at a single visit,S3.3-2 which is likely to result in an overestimate of hypertension prevalence compared with what would be found by using an average of ≥2 readings taken on ≥2 visits,S3.3-1 as recommended in current and previous BP guidelines.S3.3-3–S3.3-5 The extent to which guideline recommendations for use of BP averages from ≥2 occasions is followed in practice is unclear. Adding self-report of previously diagnosed hypertension yields a 5% to 10% higher estimate of prevalence.S3.3-1,S3.3-6,S3.3-7 Most individuals who were added by use of this expanded definition have been diagnosed as having hypertension by a health professional on >1 occasion, and many have been advised to change their lifestyle.S3.3-2,S3.3-6

3.4. Awareness, Treatment, and Control

Prevalence estimates for awareness, treatment, and control of hypertension are usually based on self-reports of the hypertension diagnosis (awareness), use of BP-lowering medications in those with hypertension (treatment), and achievement of a satisfactory SBP/DBP during treatment of hypertension (control). Before the present publication, awareness and treatment in adults were based on the SBP/DBP cutpoints of 140/90 mm Hg, and control was based on an SBP/DBP <140/90 mm Hg. In the US general adult population, hypertension awareness, treatment, and control have been steadily improving since the 1960s,S3.4-1–S3.4-4 with NHANES 2009 to 2012 prevalence estimates for men and women, respectively, being 80.2% and 85.4% for awareness, 70.9% and 80.6% for treatment (88.4% and 94.4% in those who were aware), 69.5% and 68.5% for control in those being treated, and 49.3% and 55.2% for overall control in adults with hypertension.S3.4-5 The NHANES experience may underestimate awareness, treatment, and control of hypertension because it is based on BP estimates derived from an average of readings obtained at a single visit, whereas guidelines recommend use of BP averages of ≥2 readings obtained on ≥2 occasions. In addition, the current definition of control excludes the possibility of control resulting from lifestyle change or nonpharmacological interventions. NHANES hypertension control rates have been consistently higher in women than in men (55.3% versus 38.0% in 2009–2012); in whites than in blacks and Hispanics (41.3% versus 31.1% and 23.6%, respectively, in men, and 57.2% versus 43.2% and 52.9%, respectively, in women, for 2009–2012); and in older than in younger adults (50.5% in adults ≥60 years of age versus 34.4% in patients 18 to 39 years of age for 2011–2012) up to the seventh decade,S3.4-4,S3.4-5 although control rates are considerably lower for those ≥75 years (46%) and only 39.8% for adults ≥80 years.S3.4-6 In addition, control rates are higher for persons of higher socioeconomic status (43.2% for adults with an income >400% above the US government poverty line versus 30.2% for those below this line in 2003 to 2006).S3.4-5 Research studies have repeatedly demonstrated that structured, goal-oriented BP treatment initiatives with feedback and provision of free medication result in a substantial improvement in BP control.S3.4-7–S3.4-9 Control rates that are much higher than noted in the general population have been reported in care settings where a systems approach (detailed in Sections 12.2 and 12.3) has been implemented for insured adults.S3.4-10–S3.4-12

4. Measurement of BP

4.1. Accurate Measurement of BP in the Office

Recommendation for Accurate Measurement of BP in the Office COR LOE Recommendation I C-EO 1. For diagnosis and management of high BP, proper methods are recommended for accurate measurement and documentation of BP (Table 8).

Synopsis

Although measurement of BP in office settings is relatively easy, errors are common and can result in a misleading estimation of an individual’s true level of BP. There are various methods for measuring BP in the office. The clinical standard of auscultatory measures calibrated to a column of mercury has given way to oscillometric devices (in part because of toxicological issues with mercury). Oscillometric devices use a sensor that detects oscillations in pulsatile blood volume during cuff inflation and deflation. BP is indirectly calculated from maximum amplitude algorithms that involve population-based data. For this reason, only devices with a validated measurement protocol can be recommended for use (see Section 4.2 for additional details). Many of the newer oscillometric devices automatically inflate multiple times (in 1- to 2-minute intervals), allowing patients to be alone and undisturbed during measurement. Although much of the available BP-related risk information and antihypertensive treatment trial experience have been generated by using “traditional” office methods of BP measurement, there is a growing evidence base supporting the use of automated office BP measurements.S4.1-1

Recommendation-Specific Supportive Text

Accurate measurement and recording of BP are essential to categorize level of BP, ascertain BP-related CVD risk, and guide management of high BP. Most systematic errors in BP measurement can be avoided by following the suggestions provided in Table 8, including having the patient sit quietly for 5 minutes before a reading is taken, supporting the limb used to measure BP, ensuring the BP cuff is at heart level, using the correct cuff size (Table 9), and, for auscultatory readings, deflating the cuff slowly.S4.1-2 In those who are already taking medication that affects BP, the timing of BP measurements in relation to ingestion of the patient’s medication should be standardized. Because individual BP measurements tend to vary in an unpredictable or random fashion, a single reading is inadequate for clinical decision-making. An average of 2 to 3 BP measurements obtained on 2 to 3 separate occasions will minimize random error and provide a more accurate basis for estimation of BP. In addition to clinicians, other caregivers and patients who perform BP self-monitoring should be trained to follow the checklist in Table 8. Common errors in clinical practice that can lead to inaccurate estimation of BP include failure to allow for a rest period and/or talking with the patient during or immediately before the recording, improper patient positioning (eg, sitting or lying on an examination table), rapid cuff deflation (for auscultatory readings), and reliance on BPs measured at a single occasion.

Table 8. Checklist for Accurate Measurement of BPS4.1-3,S4.1-4 Key Steps for Proper BP Measurements Specific Instructions Step 1: Properly prepare the patient 1. Have the patient relax, sitting in a chair (feet on floor, back supported) for >5 min.2. The patient should avoid caffeine, exercise, and smoking for at least 30 min before measurement.3. Ensure patient has emptied his/her bladder.4. Neither the patient nor the observer should talk during the rest period or during the measurement.5. Remove all clothing covering the location of cuff placement.6. Measurements made while the patient is sitting or lying on an examining table do not fulfill these criteria. Step 2: Use proper technique for BP measurements 1. Use a BP measurement device that has been validated, and ensure that the device is calibrated periodically.*2. Support the patient’s arm (eg, resting on a desk).3. Position the middle of the cuff on the patient’s upper arm at the level of the right atrium (the midpoint of the sternum).4. Use the correct cuff size, such that the bladder encircles 80% of the arm, and note if a larger- or smaller-than-normal cuff size is used (Table 9).5. Either the stethoscope diaphragm or bell may be used for auscultatory readings.S4.1-5,S4.1-6 Step 3: Take the proper measurements needed for diagnosis and treatment of elevated BP/hypertension 1. At the first visit, record BP in both arms. Use the arm that gives the higher reading for subsequent readings.2. Separate repeated measurements by 1–2 min.3. For auscultatory determinations, use a palpated estimate of radial pulse obliteration pressure to estimate SBP. Inflate the cuff 20–30 mm Hg above this level for an auscultatory determination of the BP level.4. For auscultatory readings, deflate the cuff pressure 2 mm Hg per second, and listen for Korotkoff sounds. Step 4: Properly document accurate BP readings 1. Record SBP and DBP. If using the auscultatory technique, record SBP and DBP as onset of the first Korotkoff sound and disappearance of all Korotkoff sounds, respectively, using the nearest even number.2. Note the time of most recent BP medication taken before measurements. Step 5: Average the readings Use an average of ≥2 readings obtained on ≥2 occasions to estimate the individual’s level of BP. Step 6: Provide BP readings to patient Provide patients the SBP/DBP readings both verbally and in writing.

Table 9. Selection Criteria for BP Cuff Size for Measurement of BP in Adults Arm Circumference Usual Cuff Size 22–26 cm Small adult 27–34 cm Adult 35–44 cm Large adult 45–52 cm Adult thigh

4.2. Out-of-Office and Self-Monitoring of BP

Recommendation for Out-of-Office and Self-Monitoring of BP References that support the recommendation are summarized in Online Data Supplement 3 and Systematic Review Report. COR LOE Recommendation I ASR 1. Out-of-office BP measurements are recommended to confirm the diagnosis of hypertension (Table 11) and for titration of BP-lowering medication, in conjunction with telehealth counseling or clinical interventions.S4.2-1–S4.2-4

Synopsis

Out-of-office measurement of BP can be helpful for confirmation and management of hypertension. Self-monitoring of BP refers to the regular measurement of BP by an individual at home or elsewhere outside the clinic setting. Among individuals with hypertension, self-monitoring of BP, without other interventions, has shown limited evidence for treatment-related BP reduction and achievement of BP control.S4.2-1,S4.2-5,S4.2-6 However, with the increased recognition of inconsistencies between office and out-of-office BPs (see Section 4.4) and greater reduction in BP being recommended for hypertension control, increased attention is being paid to out-of-office BP readings. Although ABPM is generally accepted as the best out-of-office measurement method, HBPM is often a more practical approach in clinical practice. Recommended procedures for the collection of HBPM data are provided in Table 10. If self-monitoring is used, it is important to ensure that the BP measurement device used has been validated with an internationally accepted protocol and the results have been published in a peer-reviewed journal.S4.2-7 A guide to the relationship between HBPM BP readings and corresponding readings obtained in the office and by ABPM is presented in Table 11. The precise relationships between office readings, ABPM, and HBPM are unsettled, but there is general agreement that office BPs are often higher than ABPM or HBPM BPs, especially at higher BPs.

Table 10. Procedures for Use of HBPMS4.2-5–S4.2-7 Patient training should occur under medical supervision, including: Information about hypertension Selection of equipment Acknowledgment that individual BP readings may vary substantially Interpretation of results Devices: Verify use of automated validated devices. Use of auscultatory devices (mercury, aneroid, or other) is not generally useful for HBPM because patients rarely master the technique required for measurement of BP with auscultatory devices. Monitors with provision for storage of readings in memory are preferred. Verify use of appropriate cuff size to fit the arm (Table 9). Verify that left/right inter-arm differences are insignificant. If differences are significant, instruct patient to measure BPs in the arm with higher readings. Instructions on HBPM procedures: Remain still: Avoid smoking, caffeinated beverages, or exercise within 30 min before BP measurements. Ensure ≥5 min of quiet rest before BP measurements. Sit correctly: Sit with back straight and supported (on a straight-backed dining chair, for example, rather than a sofa). Sit with feet flat on the floor and legs uncrossed. Keep arm supported on a flat surface (such as a table), with the upper arm at heart level. Bottom of the cuff should be placed directly above the antecubital fossa (bend of the elbow). Take multiple readings: Take at least 2 readings 1 min apart in morning before taking medications and in evening before supper. Optimally, measure and record BP daily. Ideally, obtain weekly BP readings beginning 2 weeks after a change in the treatment regimen and during the week before a clinic visit. Record all readings accurately: Monitors with built-in memory should be brought to all clinic appointments. BP should be based on an average of readings on ≥2 occasions for clinical decision making. The information above may be reinforced with videos available online.

Table 11. Corresponding Values of SBP/DBP for Clinic, HBPM, Daytime, Nighttime, and 24-Hour ABPM Measurements Clinic HBPM Daytime ABPM Nighttime ABPM 24-Hour ABPM 120/80 120/80 120/80 100/65 115/75 130/80 130/80 130/80 110/65 125/75 140/90 135/85 135/85 120/70 130/80 160/100 145/90 145/90 140/85 145/90

Recommendation-Specific Supportive Text

ABPM is used to obtain out-of-office BP readings at set intervals, usually over a period of 24 hours. HBPM is used to obtain a record of out-of-office BP readings taken by a patient. Both ABPM and HBPM typically provide BP estimates that are based on multiple measurements. A systematic review conducted by the US Preventive Services Task Force reported that ABPM provided a better method to predict long-term CVD outcomes than did office BPs. It incorporates new information from studies of HBPM, ABPM, the relationship of overall CVD risk to the effectiveness of blood pressure lowering, clinical outcomes related to different blood pressure goals, strategies to improve blood pressure control and various other areas. A small body of evidence suggested, but did not confirm, that HBPM could serve as a similar predictor of outcomes.S4.2-4 Meta-analyses of RCTs have identified clinically useful reductions in SBP and DBP and achievement of BP goals at 6 months and 1 year when self-monitoring of BP has been used in conjunction with other interventions, compared with usual care. Meta-analyses of RCTs have identified only small net reductions in SBP and DBP at 6 months and 1 year for use of self-monitoring of BP on its own, as compared with usual care.S4.2-1,S4.2-5,S4.2-6 See Section 4.4 for additional details of diagnostic classification and Section 12 for additional details of telehealth and out-of-office BP measurement for management of high BP.

4.3. Ambulatory BP Monitoring

All of the major RCTs have been based on use of clinic BP readings. However, ABPM is often used to supplement BP readings obtained in office settings.S4.3-1 The monitors are usually programmed to obtain readings every 15 to 30 minutes throughout the day and every 15 minutes to 1 hour during the night. ABPM is conducted while individuals go about their normal daily activities. ABPM can a) provide estimates of mean BP over the entire monitoring period and separately during nighttime and daytime, b) determine the daytime-to-nighttime BP ratio to identify the extent of nocturnal “dipping,” c) identify the early-morning BP surge pattern, d) estimate BP variability, and e) allow for recognition of symptomatic hypotension. The US Centers for Medicaid & Medicare Services and other agencies provide reimbursement for ABPM in patients with suspected white coat hypertension.S4.3-2 Medicare claims for ABPM between 2007 and 2010 were reimbursed at a median of $52 and were submitted for <1% of beneficiaries.S4.3-3,S4.3-4 A list of devices validated for ABPM is available.S4.3-5,S4.3-6

ABPM and HBPM definitions of high BP use different BP thresholds than those used by the previously mentioned office-based approach to categorize high BP identified in Section 3.1. Table 11 provides best estimates for corresponding home, daytime, nighttime, and 24-hour ambulatory levels of BP, including the values recommended for identification of hypertension with office measurements. Typically, a clinic BP of 140/90 mm Hg corresponds to home BP values of 135/85 mm Hg and to ABPM values defined as a daytime SBP/DBP of 135/85 mm Hg, a nighttime SBP/DBP of 120/70 mm Hg, and a 24-hour SBP/DBP of 130/80 mm Hg.S4.3-7,S4.3-8 These thresholds are based on data from European, Australian, and Asian populations, with few data available for establishing appropriate thresholds for US populations.S4.3-9–S4.3-13 They are provided as a guide but should be interpreted with caution. Higher daytime SBP measurements from ABPM can be associated with an increased risk of CVD and all-cause death independent of clinic-measured BP.S4.3-14 A meta-analysis of observational studies that included 13 844 individuals suggested nighttime BP is a stronger risk factor for CHD and stroke than either clinic or daytime BP.S4.3-15

Methodological issues complicate the interpretation of data from studies that report office and out-of-office BP readings. Definitions and diagnostic methods for identifying white coat hypertension and masked hypertension (see Section 4.4) have not been standardized. The available studies have differed with regard to number of office readings obtained, use of 24-hour ABPM, use of daytime-only ABPM, inclusion of daytime and nighttime BP readings as separate categories, HBPM for monitoring out-of-office BP levels, and even the BP thresholds used to define hypertension with ABPM or HBPM readings. In addition, there are few data that address reproducibility of these hypertension profiles over time, with several studies suggesting progression of white coat hypertension and especially of masked hypertension to sustained office-measured hypertension.S4.3-16–S4.3-22

4.4. Masked and White Coat Hypertension

Recommendations for Masked and White Coat Hypertension References that support recommendations are summarized in Online Data Supplements 4, 5, and 6. COR LOE Recommendations IIa B-NR 1. In adults with an untreated SBP greater than 130 mm Hg but less than 160 mm Hg or DBP greater than 80 mm Hg but less than 100 mm Hg, it is reasonable to screen for the presence of white coat hypertension by using either daytime ABPM or HBPM before diagnosis of hypertension.S4.4-1–S4.4-8 IIa C-LD 2. In adults with white coat hypertension, periodic monitoring with either ABPM or HBPM is reasonable to detect transition to sustained hypertension (S4.4-2,S4.4-5,S4.4-7). IIa C-LD 3. In adults being treated for hypertension with office BP readings not at goal and HBPM readings suggestive of a significant white coat effect, confirmation by ABPM can be useful (S4.4-9,S4.4-10). IIa B-NR 4. In adults with untreated office BPs that are consistently between 120 mm Hg and 129 mm Hg for SBP or between 75 mm Hg and 79 mm Hg for DBP, screening for masked hypertension with HBPM (or ABPM) is reasonable (S4.4-3,S4.4-4,S4.4-6,S4.4-8,S4.4-11). IIb C-LD 5. In adults on multiple-drug therapies for hypertension and office BPs within 10 mm Hg above goal, it may be reasonable to screen for white coat effect with HBPM (or ABPM) (S4.4-3,S4.4-7,S4.4-12). IIb C-EO 6. It may be reasonable to screen for masked uncontrolled hypertension with HBPM in adults being treated for hypertension and office readings at goal, in the presence of target organ damage or increased overall CVD risk. IIb C-EO 7. In adults being treated for hypertension with elevated HBPM readings suggestive of masked uncontrolled hypertension, confirmation of the diagnosis by ABPM might be reasonable before intensification of antihypertensive drug treatment.

Synopsis

The availability of noninvasive BP monitoring techniques has resulted in differentiation of hypertension into several clinically useful categories that are based on the place of BP measurement (Table 12).S4.4-1,S4.4-13,S4.4-14 These include masked hypertension and white coat hypertension, in addition to sustained hypertension. White coat hypertension is characterized by elevated office BP but normal readings when measured outside the office with either ABPM or HBPM. In contrast, masked hypertension is characterized by office readings suggesting normal BP but out-of-office (ABPM/HBPM) readings that are consistently above normal.S4.4-15 In sustained hypertension, BP readings are elevated in both office and out-of-office settings.

Table 12. BP Patterns Based on Office and Out-of-Office Measurements Office/Clinic/Healthcare Setting Home/Nonhealthcare/ABPM Setting Normotensive No hypertension No hypertension Sustained hypertension Hypertension Hypertension Masked hypertension No hypertension Hypertension White coat hypertension Hypertension No hypertension

In patients treated for hypertension, both “white coat effect” (higher office BPs than out-of-office BPs) and “masked uncontrolled hypertension” (controlled office BPs but uncontrolled BPs in out-of-office settings) categories have been reported.S4.4-5,S4.4-15,S4.4-16 The white coat effect (usually considered clinically significant when office SBP/DBPs are >20/10 mm Hg higher than home or ABPM SBP/DBPs) has been implicated in “pseudo-resistant hypertension” (see Section 11.1) and results in an underestimation of office BP control rates.S4.4-17,S4.4-18 The prevalence of masked hypertension varies from 10% to 26% (mean 13%) in population-based surveys and from 14% to 30% in normotensive clinic populations.S4.4-6,S4.4-16,S4.4-19–S4.4-21

The risk of CVD and all-cause mortality in persons with masked hypertension is similar to that noted in those with sustained hypertension and about twice as high as the corresponding risk in their normotensive counterparts.S4.4-3,S4.4-4,S4.4-6,S4.4-8,S4.4-11 The prevalence of masked hypertension increases with higher office BP readings.S4.4-20,S4.4-22,S4.4-23

The prevalence of white coat hypertension is higher with increasing age,S4.4-24 female versus male sex, nonsmoking versus current smoking status, and routine office measurement of BP by clinician observers versus unattended BP measurements. Many, but not all, studiesS4.4-4,S4.4-6,S4.4-8,S4.4-25,S4.4-26 have identified a minimal increase in risk of CVD complications or all-cause mortality in patients who have white coat hypertension. This has resulted in a recommendation by some panels to screen for white coat hypertension with ABPM (or HBPM) to avoid initiating antihypertensive drug treatment in such individuals.S4.4-2,S4.4-5,S4.4-27 The white coat effect and masked uncontrolled hypertension appear to follow the risk profiles of their white coat hypertension and masked hypertension counterparts, respectively.S4.4-3,S4.4-12

There are no data on the risks and benefits of treating white coat and masked hypertension. Despite these methodological differences, the data are consistent in indicating that masked hypertension and masked uncontrolled hypertension are associated with an increased prevalence of target organ damage and risk of CVD, stroke, and mortality compared with normotensive individuals and those with white coat hypertension.

Figure 1. Detection of white coat hypertension or masked hypertension in patients not on drug therapy. Colors correspond to Class of Recommendation in Table 1. ABPM indicates ambulatory blood pressure monitoring; BP, blood pressure; and HBPM, home blood pressure monitoring.

Figure 2. Detection of white coat effect or masked uncontrolled hypertension in patients on drug therapy. Colors correspond to Class of Recommendation in Table 1. See Section 8 for treatment options. ABPM indicates ambulatory blood pressure monitoring; BP, blood pressure; CVD, cardiovascular disease; and HBPM, home blood pressure monitoring.

Figure 1 is an algorithm on the detection of white coat hypertension or masked hypertension in patients not on drug therapy. Figure 2 is an algorithm on detection of white coat effect or masked uncontrolled hypertension in patients on drug therapy. Table 12 is a summary of BP patterns based on office and out-of-office measurements.

Recommendation-Specific Supportive Text

White coat hypertension prevalence averages approximately 13% and as high as 35% in some hypertensive populations,S4.4-1,S4.4-2 and ABPM and HBPM are better predictors of CVD risk due to elevated BP than are office BP measurements, with ABPM being the preferred measurement option. The major clinical relevance of white coat hypertension is that it has typically been associated with a minimal to only slightly increased risk of CVD and all-cause mortality risk.S4.4-3,S4.4-4,S4.4-7,S4.4-11,S4.4-24 If ABPM resources are not readily available, HBPM provides a reasonable but less desirable alternative to screen for white coat hypertension, although the overlap with ABPM is only 60% to 70% for detection of white coat hypertension.S4.4-5,S4.4-9,S4.4-27–S4.4-30 The incidence of white coat hypertension converting to sustained hypertension (justifying the addition of antihypertensive drug therapy to lifestyle modification) is 1% to 5% per year by ABPM or HBPM, with a higher incidence of conversion in those with elevated BP, older age, obesity, or black race.S4.4-2,S4.4-7 The overlap between HBPM and both daytime and 24-hour ABPM in diagnosing white coat hypertension is only 60% to 70%, and the data for prediction of CVD risk are stronger with ABPM than with office measurements.S4.4-5,S4.4-9,S4.4-27–S4.4-30 Because a diagnosis of white coat hypertension may result in a decision not to treat or intensify treatment in patients with elevated office BP readings, confirmation of BP control by ABPM in addition to HBPM provides added support for this decision. In contrast to white coat hypertension, masked hypertension is associated with a CVD and all-cause mortality risk twice as high as that seen in normotensive individuals, with a risk range similar to that of patients with sustained hypertension.S4.4-3,S4.4-4,S4.4-6,S4.4-8,S4.4-11,S4.4-31 Therefore, out-of-office readings are reasonable to confirm BP control seen with office readings. The white coat effect has been implicated in office-measured uncontrolled hypertension and pseudo-resistant hypertension, which may result in BP control being underestimated when subsequently assessed by ABPM.S4.4-17,S4.4-18 The risk of vascular complications in patients with office-measured uncontrolled hypertension with a white coat effect is similar to the risk in those with controlled hypertension.S4.4-3,S4.4-4,S4.4-7,S4.4-11,S4.4-12 White coat hypertension and white coat effect raise the concern that unnecessary antihypertensive drug therapy may be initiated or intensified. Because a diagnosis of white coat hypertension or white coat effect would result in a decision to not treat elevated office BP readings, confirmation of BP control by HBPM (or ABPM) provides more definitive support for the decision not to initiate antihypertensive drug therapy or accelerate treatment. Analogous to masked hypertension in untreated patients, masked uncontrolled hypertension is defined in treated patients with hypertension by office readings suggesting adequate BP control but out-of-office readings (HBPM) that remain consistently above goal.S4.4-3,S4.4-15,S4.4-16,S4.4-32,S4.4-33 The CVD risk profile for masked uncontrolled hypertension appears to follow the risk profile for masked hypertension.S4.4-3,S4.4-12,S4.4-34 Although the evidence is consistent in identifying the increased risk of masked uncontrolled hypertension, evidence is lacking on whether the treatment of masked hypertension or masked uncontrolled hypertension reduces clinical outcomes. A suggestion for assessing CVD risk is provided in Section 8. Although both ABPM and HBPM are better predictors of CVD risk than are office BP readings, ABPM confirmation of elevated BP by HBPM might be reasonable because of the more extensive documentation of CVD risk with ABPM. However, unlike the documentation of a significant white coat effect to justify the decision to not treat an elevated clinic BP, it is not mandatory to confirm masked uncontrolled hypertension determined by HBPM.

5. Causes of Hypertension

5.1. Genetic Predisposition

Hypertension is a complex polygenic disorder in which many genes or gene combinations influence BP.S5.1-1,S5.1-2 Although several monogenic forms of hypertension have been identified, such as glucocorticoid-remediable aldosteronism, Liddle’s syndrome, Gordon’s syndrome, and others in which single-gene mutations fully explain the pathophysiology of hypertension, these disorders are rare.S5.1-3 The current tabulation of known genetic variants contributing to BP and hypertension includes more than 25 rare mutations and 120 single-nucleotide polymorphisms.S5.1-3,S5.1-4 However, even with the discovery of multiple single-nucleotide polymorphisms influencing control of BP since completion of the Human Genome Project in 2003, the associated variants have only small effects. Indeed, at present, the collective effect of all BP loci identified through genome-wide association studies accounts for only about 3.5% of BP variability.S5.1-4 The presence of a high number of small-effect alleles associated with higher BP results in a more rapid increase in BP with age.S5.1-5 Future studies will need to better elucidate genetic expression, epigenetic effects, transcriptomics, and proteomics that link genotypes with underlying pathophysiological mechanisms.

5.2. Environmental Risk Factors

Various environmental exposures, including components of diet, physical activity, and alcohol consumption, influence BP. Many dietary components have been associated with high BP.S5.2-1,S5.2-2 Some of the diet-related factors associated with high BP include overweight and obesity, excess intake of sodium, and insufficient intake of potassium, calcium, magnesium, protein (especially from vegetables), fiber, and fish fats. Poor diet, physical inactivity, and excess intake of alcohol, alone or in combination, are the underlying cause of a large proportion of hypertension. Gut microbiota have also been linked to hypertension, especially in experimental animals.S5.2-3 Some of the best-proven environmental relationships with high BP are briefly reviewed below, and nonpharmacological interventions to lower BP are discussed in Section 6.2.

5.2.1. Overweight and Obesity

Insurance industry actuarial reports have identified a striking relationship between body weight and high BPS5.2.1-1 and a direct relationship between overweight/obesity and hypertension.S5.2.1-2 Epidemiological studies, including the Framingham Heart StudyS5.2.1-3 and the Nurses’ Health Study,S5.2.1-4 have consistently identified a direct relationship between body mass index and BP that is continuous and almost linear, with no evidence of a threshold.S5.2.1-5,S5.2.1-6 The relationship with BP is even stronger for waist-to-hip ratio and computed tomographic measures of central fat distribution.S5.2.1-7 Attributable risk estimates from the Nurses’ Health Study suggest that obesity may be responsible for about 40% of hypertension, and in the Framingham Offspring Study, the corresponding estimates were even higher (78% in men and 65% in women).S5.2.1-8,S5.2.1-9 The relationship between obesity at a young age and change in obesity status over time is strongly related to future risk of hypertension. In combined data from 4 longitudinal studies begun in adolescence with repeat examination in young adulthood to early middle age, being obese continuously or acquiring obesity was associated with a relative risk of 2.7 for developing hypertension. Becoming normal weight reduced the risk of developing hypertension to a level similar to those who had never been obese.S5.2.1-10

5.2.2. Sodium Intake

Sodium intake is positively associated with BP in migrant,S5.2.2-11 cross-sectional,S5.2.2-12–S5.2.2-14 and prospective cohort studiesS5.2.2-15 and accounts for much of the age-related increase in BP.S5.2.2-11,S5.2.2-16 In addition to the well-accepted and important relationship of dietary sodium with BP, excessive consumption of sodium is independently associated with an increased risk of stroke,S5.2.2-17,S5.2.2-18 CVD,S5.2.2-19 and other adverse outcomes.S5.2.2-20 Certain groups with various demographic, physiological, and genetic characteristics tend to be particularly sensitive to the effects of dietary sodium on BP.S5.2.2-21–S5.2.2-23 Salt sensitivity is a quantitative trait in which an increase in sodium load disproportionately increases BP.S5.2.2-21,S5.2.2-24 Salt sensitivity is especially common in blacks, older adults, and those with a higher level of BP or comorbidities such as CKD, DM, or the metabolic syndrome.S5.2.2-25 In aggregate, these groups constitute more than half of all US adults.S5.2.2-26 Salt sensitivity may be a marker for increased CVD and all-cause mortality risk independently of BP,S5.2.2-27,S5.2.2-28 and the trait has been demonstrated to be reproducible.S5.2.2-29 Current techniques for recognition of salt sensitivity are impractical in routine clinical practice, so salt sensitivity is best considered as a group characteristic.

5.2.3. Potassium

Potassium intake is inversely related to BP in migrant,S5.2.3-30 cross-sectional,S5.2.2-13,S5.2.2-16,S5.2.3-31,S5.2.3-32 and prospective cohortS5.2.3-33 studies. It is also inversely related to stroke.S5.2.3-34–S5.2.3-36 A higher level of potassium seems to blunt the effect of sodium on BP,S5.2.3-37 with a lower sodium–potassium ratio being associated with a lower level of BP than that noted for corresponding levels of sodium or potassium on their own.S5.2.3-38 Likewise, epidemiological studies suggest that a lower sodium–potassium ratio may result in a reduced risk of CVD as compared with the pattern for corresponding levels of either cation on its own.S5.2.3-39

5.2.4. Physical Fitness

Epidemiological studies have demonstrated an inverse relationship between physical activity and physical fitness and level of BP and hypertension.S5.2.4-40 Even modest levels of physical activity have been associated with a decrease in the risk of incident hypertension.S5.2.4-41 In several observational studies, the relationship between physical activity and BP has been most apparent in white men.S5.2.4-40 With the advent of electronic activity trackers and ABPM, it has become increasingly feasible to conduct studies that relate physical activity and BP.S5.2.4-42 Physical fitness, measured objectively by graded exercise testing, attenuates the rise of BP with age and prevents the development of hypertension. In the CARDIA (Coronary Artery Risk Development in Young Adults) study,S5.2.4-43 physical fitness measured at 18 to 30 years of age in the upper 2 deciles of an otherwise healthy population was associated with one third the risk of developing hypertension 15 years later, and one half the risk after adjustment for body mass index, as compared with the lowest quintile. Change in fitness assessed 7 years later further modified risk.S5.2.4-43 In a cohort of men 20 to 90 years of age who were followed longitudinally for 3 to 28 years, higher physical fitness decreased the rate of rise in SBP over time and delayed the time to onset of hypertension.S5.2.4-44

5.2.5. Alcohol

The presence of a direct relationship between alcohol consumption and BP was first reported in 1915S5.2.5-45 and has been repeatedly identified in contemporary cross-sectional and prospective cohort studies.S5.2.5-46 Estimates of the contribution of alcohol consumption to population incidence and prevalence of hypertension vary according to level of intake. In the United States, it seems likely that alcohol may account for close to 10% of the population burden of hypertension (higher in men than in women). In contrast to its detrimental effect on BP, alcohol intake is associated with a higher level of high-density lipoprotein cholesterol and, within modest ranges of intake, a lower level of CHD than that associated with abstinence.S5.2.3-35

5.3. Childhood Risk Factors and BP Tracking

BP distribution in the general population increases with age. Multiple longitudinal studies have investigated the relationship of childhood BP to adult BP. A meta-analysis of 50 such studies showed correlation coefficients of about 0.38 for SBP and 0.28 for DBP, with BPs in the upper range of the pediatric distribution (particularly BPs obtained in adolescence) predicting hypertension in adulthood.S5.3-1 Several factors, including genetic factors and development of obesity, increase the likelihood that a high childhood BP will lead to future hypertension.S5.3-2 Premature birth is associated with a 4–mm Hg higher SBP and a 3–mm Hg higher DBP in adulthood, with somewhat larger effects in women than in men.S5.3-3 Low birth weight from other causes also contributes to higher BP in later life.S5.3-4

5.4. Secondary Forms of Hypertension

Recommendations for Secondary Forms of Hypertension COR LOE Recommendations I C-EO 1. Screening for specific form(s) of secondary hypertension is recommended when the clinical indications and physical examination findings listed in Table 13 are present or in adults with resistant hypertension. IIb C-EO 2. If an adult with sustained hypertension screens positive for a form of secondary hypertension, referral to a physician with expertise in that form of hypertension may be reasonable for diagnostic confirmation and treatment.

Synopsis

A specific, remediable cause of hypertension can be identified in approximately 10% of adult patients with hypertension.S5.4-1 If a cause can be correctly diagnosed and treated, patients with secondary hypertension can achieve a cure or experience a marked improvement in BP control, with reduction in CVD risk. All new patients with hypertension should be screened with a history, physical examination, and laboratory investigations, as recommended in Section 7, before initiation of treatment.

Secondary hypertension can underlie severe elevation of BP, pharmacologically resistant hypertension, sudden onset of hypertension, increased BP in patients with hypertension previously controlled on drug therapy, onset of diastolic hypertension in older adults, and target organ damage disproportionate to the duration or severity of the hypertension. Although secondary hypertension should be suspected in younger patients (<30 years of age) with elevated BP, it is not uncommon for primary hypertension to manifest at a younger age, especially in blacks,S5.4-2 and some forms of secondary hypertension, such as renovascular disease, are more common at older age. Many of the causes of secondary hypertension are strongly associated with clinical findings or groups of findings that suggest a specific disorder.

Figure 3 is an algorithm on screening for secondary hypertension. Table 13 is a detailed list of clinical indications and diagnostic screening tests for secondary hypertension, and Table 14 is a list of drugs that can induce secondary hypertension.

Table 13. Causes of Secondary Hypertension With Clinical Indications and Diagnostic Screening Tests Prevalence Clinical Indications Physical Examination Screening Tests Additional/Confirmatory Tests Common causes Renal parenchymal diseaseS5.4-1,S5.4-3 1%–2% Urinary tract infections; obstruction, hematuria; urinary frequency and nocturia; analgesic abuse; family history of polycystic kidney disease; elevated serum creatinine; abnormal urinalysis Abdominal mass (polycystic kidney disease); skin pallor Renal ultrasound Tests to evaluate cause of renal disease Renovascular diseaseS5.4-4 5%–34%* Resistant hypertension; hypertension of abrupt onset or worsening or increasingly difficult to control; flash pulmonary edema (atherosclerotic); early-onset hypertension, especially in women (fibromuscular hyperplasia) Abdominal systolic-diastolic bruit; bruits over other arteries (carotid – atherosclerotic or fibromuscular dysplasia), femoral Renal Duplex Doppler ultrasound; MRA; abdominal CT Bilateral selective renal intra-arterial angiography Primary aldosteronismS5.4-5,S5.4-6 8%–20%† Resistant hypertension; hypertension with hypokalemia (spontaneous or diuretic induced); hypertension and muscle cramps or weakness; hypertension and incidentally discovered adrenal mass; hypertension and obstructive sleep apnea; hypertension and family history of early-onset hypertension or stroke Arrhythmias (with hypokalemia); especially atrial fibrillation Plasma aldosterone/renin ratio under standardized conditions (correction of hypokalemia and withdrawal of aldosterone antagonists for 4–6 wk) Oral sodium loading test (with 24-h urine aldosterone) or IV saline infusion test with plasma aldosterone at 4 h of infusion Adrenal CT scan, adrenal vein sampling. Obstructive sleep apneaS5.4-7‡ 25%–50% Resistant hypertension; snoring; fitful sleep; breathing pauses during sleep; daytime sleepiness Obesity, Mallampati class III–IV; loss of normal nocturnal BP fall Berlin Questionnaire;S5.4-8 Epworth Sleepiness Score;S5.4-9 overnight oximetry Polysomnography Drug or alcohol inducedS5.4-10§ 2%–4% Sodium-containing antacids; caffeine; nicotine (smoking); alcohol; NSAIDs; oral contraceptives; cyclosporine or tacrolimus; sympathomimetics (decongestants, anorectics); cocaine, amphetamines and other illicit drugs; neuropsychiatric agents; erythropoiesis-stimulating agents; clonidine withdrawal; herbal agents (Ma Huang, ephedra) Fine tremor, tachycardia, sweating (cocaine, ephedrine, MAO inhibitors); acute abdominal pain (cocaine) Urinary drug screen (illicit drugs) Response to withdrawal of suspected agent Uncommon causes Pheochromocytoma/paragangliomaS5.4-11 0.1%–0.6% Resistant hypertension; paroxysmal hypertension or crisis superimposed on sustained hypertension; “spells,” BP lability, headache, sweating, palpitations, pallor; positive family history of pheochromocytoma/paraganglioma; adrenal incidentaloma Skin stigmata of neurofibromatosis (café-au-lait spots; neurofibromas); Orthostatic hypotension 24-h urinary fractionated metanephrines or plasma metanephrines under standard conditions (supine position with indwelling IV cannula) CT or MRI scan of abdomen/pelvis Cushing’s syndromeS5.4-12 <0.1% Rapid weight gain, especially with central distribution; proximal muscle weakness; depression; hyperglycemia Central obesity, “moon” face, dorsal and supraclavicular fat pads, wide (1-cm) violaceous striae, hirsutism Overnight 1-mg dexamethasone suppression test 24-h urinary free cortisol excretion (preferably multiple); midnight salivary cortisol HypothyroidismS5.4-10 <1% Dry skin; cold intolerance; constipation; hoarseness; weight gain Delayed ankle reflex; periorbital puffiness; coarse skin; cold skin; slow movement; goiter Thyroid-stimulating hormone; free thyroxine None HyperthyroidismS5.4-10 <1% Warm, moist skin; heat intolerance; nervousness; tremulousness; insomnia; weight loss; diarrhea; proximal muscle weakness Lid lag; fine tremor of the outstretched hands; warm, moist skin Thyroid-stimulating hormone; free thyroxine Radioactive iodine uptake and scan Aortic coarctation (undiagnosed or repaired)S5.4-13 0.1% Young patient with hypertension (<30 y of age) BP higher in upper extremities than in lower extremities; absent femoral pulses; continuous murmur over patient’s back, chest, or abdominal bruit; left thoracotomy scar (postoperative) Echocardiogram Thoracic and abdominal CT angiogram or MRA Primary hyperpara-thyroidismS5.4-14 Rare Hypercalcemia Usually none Serum calcium Serum parathyroid hormone Congenital adrenal hyperplasiaS5.4-15 Rare Hypertension and hypokalemia; virilization (11-beta-hydroxylase deficiency [11-beta-OH]); incomplete masculinization in males and primary amenorrhea in females (17-alpha-hydroxylase deficiency [17-alpha-OH]) Signs of virilization (11-beta-OH) or incomplete masculinization (17-alpha-OH) Hypertension and hypokalemia with low or normal aldosterone and renin 11-beta-OH: elevated deoxycorticosterone (DOC), 11-deoxycortisol, and androgens17-alpha-OH; decreased androgens and estrogen; elevated deoxycorticosterone and corticosterone Mineralocorticoid excess syndromes other than primary aldosteronismS5.4-15 Rare Early-onset hypertension; resistant hypertension; hypokalemia or hyperkalemia Arrhythmias (with hypokalemia) Low aldosterone and renin Urinary cortisol metabolites; genetic testing AcromegalyS5.4-16 Rare Acral features, enlarging shoe, glove, or hat size; headache, visual disturbances; diabetes mellitus Acral features; large hands and feet; frontal bossing Serum growth hormone ≥1 ng/mL during oral glucose load Elevated age- and sex-matched IGF-1 level; MRI scan of the pituitary

Table 14. Frequently Used Medications and Other Substances That May Cause Elevated BP* Agent Possible Management Strategy Alcohol Limit alcohol to ≤1 drink daily for women and ≤2 drinks for menS5.4.1-7 Amphetamines (eg, amphetamine, methylphenidate dexmethylphenidate, dextroamphetamine) Discontinue or decrease doseS5.4.1-8Consider behavioral therapies for ADHDS5.4.1-9 Antidepressants (eg, MAOIs, SNRIs, TCAs) Consider alternative agents (eg, SSRIs) depending on indicationAvoid tyramine-containing foods with MAOIs Atypical antipsychotics (eg, clozapine, olanzapine) Discontinue or limit use when possibleConsider behavior therapy where appropriateRecommend lifestyle modification (see Section 6.2)Consider alternative agents associated with lower risk of weight gain, diabetes mellitus, and dyslipidemia (eg, aripiprazole, ziprasidone)S5.4.1-10,S5.4.1-11 Caffeine Generally limit caffeine intake to <300 mg/dAvoid use in patients with uncontrolled hypertensionCoffee use in patients with hypertension is associated with acute increases in BP; long-term use is not associated with increased BP or CVDS5.4.1-12 Decongestants (eg, phenylephrine, pseudoephedrine) Use for shortest duration possible, and avoid in severe or uncontrolled hypertensionConsider alternative therapies (eg, nasal saline, intranasal corticosteroids, antihistamines) as appropriate Herbal supplements (eg, Ma Huang [ephedra], St. John’s wort [with MAO inhibitors, yohimbine]) Avoid use Immunosuppressants (eg, cyclosporine) Consider converting to tacrolimus, which may be associated with fewer effects on BPS5.4.1-13–S5.4.1-15 Oral contraceptives Use low-dose (eg, 20–30 mcg ethinyl estradiol) agentsS5.4.1-16 or a progestin-only form of contraception, or consider alternative forms of birth control where appropriate (eg, barrier, abstinence, IUD)Avoid use in women with uncontrolled hypertensionS5.4.1-16 NSAIDs Avoid systemic NSAIDs when possibleConsider alternative analgesics (eg, acetaminophen, tramadol, topical NSAIDs), depending on indication and risk Recreational drugs (eg, “bath salts” [MDPV], cocaine, methamphetamine, etc.) Discontinue or avoid use Systemic corticosteroids (eg, dexamethasone, fludrocortisone, methylprednisolone, prednisone, prednisolone) Avoid or limit use when possibleConsider alternative modes of administration (eg, inhaled, topical) when feasible Angiogenesis inhibitor (eg, bevacizumab) and tyrosine kinase inhibitors (eg, sunitinib, sorafenib) Initiate or intensify antihypertensive therapy

Recommendation-Specific Supportive Text

The causes of secondary hypertension and recommended screening tests are provided in Table 13, and drugs that can induce secondary hypertension are provided in Table 14. Diagnosis of many of these disorders requires a complex set of measurements, specialized technical expertise, and/or experience in data interpretation. Similarly, specific treatment often requires a level of technical training and experience.

Figure 3. Screening for secondary hypertension. Colors correspond to Class of Recommendation in Table 1. TOD indicates target organ damage (eg, cerebrovascular disease, hypertensive retinopathy, left ventricular hypertrophy, left ventricular dysfunction, heart failure, coronary artery disease, chronic kidney disease, albuminuria, peripheral artery disease).

5.4.1. Drugs and Other Substances With Potential to Impair BP Control

Numerous substances, including prescription medications, over-the-counter medications, herbals, and food substances, may affect BP (Table 14).S5.4.1-1–S5.4.1-6 Changes in BP that occur because of drugs and other agents have been associated with the development of hypertension, worsening control in a patient who already has hypertension, or attenuation of the BP-lowering effects of antihypertensive therapy. A change in BP may also result from drug–drug or drug–food interactions.S5.4.1-2,S5.4.1-4 In the clinical assessment of hypertension, a careful history should be taken with regard to substances that may impair BP control, with close attention paid to not only prescription medications, but also over-the-counter substances, illicit drugs, and herbal products. When feasible, drugs associated with increased BP should be reduced or discontinued, and alternative agents should be used.

5.4.2. Primary Aldosteronism

Recommendations for Primary Aldosteronism COR LOE Recommendations I C-EO 1. In adults with hypertension, screening for primary aldosteronism is recommended in the presence of any of the following concurrent conditions: resistant hypertension, hypokalemia (spontaneous or substantial, if diuretic induced), incidentally discovered adrenal mass, family history of early-onset hypertension, or stroke at a young age (<40 years). I C-LD 2. Use of the plasma aldosterone: renin activity ratio is recommended when adults are screened for primary aldosteronism.S5.4.2-1 I C-EO 3. In adults with hypertension and a positive screening test for primary aldosteronism, referral to a hypertension specialist or endocrinologist is recommended for further evaluation and treatment.

Synopsis

Primary aldosteronism is defined as a group of disorders in which aldosterone production is inappropriately high for sodium status, is relatively autonomous of the major regulators of secretion (angiotensin II and potassium), and cannot be suppressed with sodium loading.S5.4.2-2,S5.4.2-3 The increased production of aldosterone induces hypertension; cardiovascular and kidney damage; sodium retention; suppressed plasma renin activity; and increased potassium excretion, which, if prolonged and severe, may cause hypokalemia. However, hypokalemia is absent in the majority of cases and has a low negative predictive value for the diagnosis of primary aldosteronism.S5.4.2-4 In about 50% of the patients, primary aldosteronism is due to increased unilateral aldosterone production (usually aldosterone-producing adenoma or, rarely, unilateral adrenal hyperplasia); in the remaining 50%, primary aldosteronism is due to bilateral adrenal hyperplasia (idiopathic hyperaldosteronism).S5.4.2-2,S5.4.2-3

Recommendation-Specific Supportive Text

Primary aldosteronism is one of the most frequent disorders (occurring in 5% to 10% of patients with hypertension and 20% of patients with resistant hypertension) that causes secondary hypertension.S5.4.2-5,S5.4.2-6 The toxic tissue effects of aldosterone induce greater target organ damage in primary aldosteronism than in primary hypertension. Patients with primary aldosteronism have a 3.7-fold increase in HF, a 4.2-fold increase in stroke, a 6.5-fold increase in MI, a 12.1-fold increase in atrial fibrillation (AF), increased left ventricular hypertrophy (LVH) and diastolic dysfunction, increased stiffness of large arteries, widespread tissue fibrosis, increased remodeling of resistance vessels, and increased kidney damage as compared with patients with primary hypertension matched for BP level.S5.4.2-6–S5.4.2-8 Because the deleterious effects of aldosterone overproduction are often reversible with unilateral laparoscopic adrenalectomy or treatment with mineralocorticoid receptor antagonists (ie, spironolactone or eplerenone), screening of patients with hypertension at increased risk of primary aldosteronism is beneficial.S5.4.2-2,S5.4.2-3 These include hypertensive patients with adrenal “incidentaloma,” an incidentally discovered adrenal lesion on a computed tomography or magnetic resonance imaging (MRI) scan performed for other purposes. Patients with hypertension and a history of early onset hypertension and/or cerebrovascular accident at a young age may have primary aldosteronism due to glucocorticoid-remediable aldosteronism (familial hyperaldosteronism type-1) and therefore warrant screening.S5.4.2-2,S5.4.2-3 The aldosterone:renin activity ratio is currently the most accurate and reliable means of screening for primary aldosteronism.S5.4.2-1 The most commonly used cutoff value is 30 when plasma aldosterone concentration is reported in nanograms per deciliter (ng/dL) and plasma renin activity in nanograms per milliliter per hour (ng/mL/h).S5.4.2-3 Because the aldosterone:renin activity ratio can be influenced by the presence of very low renin levels, the plasma aldosterone concentration should be at least 10 ng/dL to interpret the test as positive.S5.4.2-3 Patients should have unrestricted salt intake, serum potassium in the normal range, and mineralocorticoid receptor antagonists (eg, spironolactone or eplerenone) withdrawn for at least 4 weeks before testing.S5.4.2-2,S5.4.2-3 The diagnosis of primary aldosteronism generally requires a confirmatory test (intravenous saline suppression test or oral salt-loading test).S5.4.2-2,S5.4.2-3 If the diagnosis of primary aldosteronism is confirmed (and the patient agrees that surgery would be desirable), the patient is referred for an adrenal venous sampling procedure to determine whether the increased aldosterone production is unilateral or bilateral in origin. If unilateral aldosterone production is documented on adrenal venous sampling, the patient is referred for unilateral laparoscopic adrenalectomy, which improves BP in virtually 100% of patients and results in a complete cure of hypertension in about 50%.S5.4.2-2,S5.4.2-3 If the patient has bilaterally increased aldosterone secretion on adrenal venous sampling or has a unilateral source of excess aldosterone production but cannot undergo surgery, the patient is treated with spironolactone or eplerenone as agent of choice.S5.4.2-2,S5.4.2-3 Both adrenalectomy and medical ktherapy are effective in lowering BP and reversing LVH. Treating primary aldosteronism, either by mineralocorticoid receptor antagonists or unilateral adrenalectomy (if indicated), resolves hypokalemia, lowers BP, reduces the number of antihypertensive medications required, and improves parameters of impaired cardiac and kidney function.S5.4.2-9,S5.4.2-10

5.4.3. Renal Artery Stenosis

Recommendations for Renal Artery Stenosis References that support recommendations are summarized in Online Data Supplements 7 and 24. COR LOE Recommendations I A 1. Medical therapy is recommended for adults with atherosclerotic renal artery stenosis.S5.4.3-1,S5.4.3-2 IIb C-EO 2. In adults with renal artery stenosis for whom medical management has failed (refractory hypertension, worsening renal function, and/or intractable HF) and those with nonatherosclerotic disease, including fibromuscular dysplasia, it may be reasonable to refer the patient for consideration of revascularization (percutaneous renal artery angioplasty and/or stent placement).

Synopsis

Renal artery stenosis refers to a narrowing of the renal artery that can result in a restriction of blood flow. Atherosclerotic disease (90%) is by far the most common cause of renal artery stenosis, whereas nonatherosclerotic disease (of which fibromuscular dysplasia is the most common) is much less prevalent and tends to occur in younger, healthier patients.S5.4.3-3 Renal artery stenosis is a common form of secondary hypertension. Relieving ischemia and the ensuing postischemic release of renin by surgical renal artery reconstruction is an invasive strategy with a postoperative mortality as high as 13%.S5.4.3-4 With the advent of endovascular procedures to restore blood flow, several trials were designed to test the efficacy of these procedures against medical therapy, but they suggested no benefit over medical therapy alone.S5.4.3-1,S5.4.3-2

Recommendation-Specific Supportive Text

Atherosclerotic disease in the renal arteries represents systemic disease and higher risk of both renal failure and cardiovascular morbidity and mortality. No RCT to date has demonstrated a clinical advantage of renal artery revascularization (with either angioplasty or stenting) over medical therapy.S5.4.3-2 On the basis of the CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) trial, the recommended medical approach encompasses optimal management of hypertension with an antihypertensive regimen that includes a renin-angiotensin system (RAS) blocker, in addition to low-density lipoprotein cholesterol reduction with a high-intensity statin, smoking cessation, hemoglobin A1c reduction in patients with DM, and antiplatelet therapy.S5.4.3-1 Revascularization may be considered for those who do not respond to medical therapy and for those who have nonatherosclerotic disease (eg, Takayasu arteritis in Asian populations, fibromuscular dysplasia in other populations). Fibromuscular dysplasia occurs over the lifespan of women (mean: 53 years of age) with almost equal frequency in the renal and carotid circulations.S5.4.3-3 Percutaneous transluminal angioplasty alone (without stenting) can improve BP control and even normalize BP, especially in patients with recent onset of hypertension or resistant hypertension.S5.4.3-5

5.4.4. Obstructive Sleep Apnea

Recommendation for Obstructive Sleep Apnea References that support the recommendation are summarized in Online Data Supplement 8. COR LOE Recommendation IIb B-R 1. In adults with hypertension and obstructive sleep apnea, the effectiveness of continuous positive airway pressure (CPAP) to reduce BP is not well established.S5.4.4-1–S5.4.4-5

Synopsis

Obstructive sleep apnea is a common chronic condition characterized by recurrent collapse of upper airways during sleep, inducing intermittent episodes of apnea/hypopnea, hypoxemia, and sleep disruption.S5.4.4-6 Obstructive sleep apnea is a risk factor for several CVDs, including hypertension, coronary and cerebrovascular diseases, HF, and AF.S5.4.4-6–S5.4.4-9 Observational studies have shown that the presence of obstructive sleep apnea is associated with increased risk of incident hypertension.S5.4.4-10,S5.4.4-11 Obstructive sleep apnea is highly prevalent in adults with resistant hypertension (≥80%),S5.4.4-12,S5.4.4-13 and it has been hypothesized that treatment with CPAP may have more pronounced effects on BP reduction in resistant hypertension.S5.4.4-6

Recommendation-Specific Supportive Text

CPAP is an efficacious treatment for improving obstructive sleep apnea. However, studies of the effects of CPAP on BP have demonstrated only small effects on BP (eg, 2– to 3–mm Hg reductions), with results dependent on patient compliance with CPAP use, severity of obstructive sleep apnea, and presence of daytime sleepiness in study participants.S5.4.4-1–S5.4.4-5 Although many RCTs have been reported that address the effects of CPAP on BP in obstructive sleep apnea, most of the patients studied did not have documented hypertension, and the studies were too small and the follow-up period too short to allow for adequate evaluation. In addition, a well-designed RCT demonstrated that CPAP plus usual care, compared with usual care alone, did not prevent cardiovascular events in patients with moderate–severe obstructive sleep apnea and established CVD.S5.4.4-14

6. Nonpharmacological Interventions

Correcting the dietary aberrations, physical inactivity, and excessive consumption of alcohol that cause high BP is a fundamentally important approach to prevention and management of high BP, either on their own or in combination with pharmacological therapy. Prevention of hypertension and treatment of established hypertension are complementary approaches to reducing CVD risk in the population, but prevention of hypertension provides the optimal means of reducing risk and avoiding the harmful consequences of hypertension.S6-1–S6-3 Nonpharmacological therapy alone is especially useful for prevention of hypertension, including in adults with elevated BP, and for management of high BP in adults with milder forms of hypertension.S6-4,S6-5

6.1. Strategies

Nonpharmacological interventions can be accomplished by means of behavioral strategies aimed at lifestyle change, prescription of dietary supplements, or implementation of kitchen-based interventions that directly modify elements of the diet. At a societal level, policy changes can enhance the availability of healthy foods and facilitate physical activity. The goal can be to modestly reduce BP in the general population or to undertake more intensive targeted lowering of BP in adults with hypertension or at high risk of developing hypertension.S6.1-1 The intent of the general population approach is to achieve a small downward shift in the general population distribution of BP, which would be expected to result in substantial health benefits.S6.1-2 The targeted approach focuses on BP reduction in adults at greatest risk of developi