2018 ESC/ESH Guidelines for the management of arterial hypertension(I)

The Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH)

Table of Contents

• 1 Preamble3025

• 2 Introduction3025

•  2.1 What is new and what has changed in the 2018 European Society of Cardiology/European Society of Hypertension arterial hypertension Guidelines?3027

• 3 Definition, classification, and epidemiological aspects of hypertension3030

•  3.1 Definition of hypertension3030

•  3.2 Classification of blood pressure3030

•  3.3 Prevalence of hypertension3030

•  3.4 Blood pressure relationship with risk of cardiovascular and renal events3032

•  3.5 Hypertension and total cardiovascular risk assessment3032

•  3.6 Importance of hypertension-mediated organ damage in refining cardiovascular risk assessment in hypertensive patients3033

•  3.7 Challenges in cardiovascular risk assessment3034

• 4 Blood pressure measurement3035

•  4.1 Conventional office blood pressure measurement3035

•  4.2 Unattended office blood pressure measurement3035

•  4.3 Out-of-office blood pressure measurement3036

•  4.4 Home blood pressure monitoring3036

•  4.5 Ambulatory blood pressure monitoring3036

•  4.6 Advantages and disadvantages of ambulatory blood pressure monitoring and home blood pressure monitoring3037

•  4.7 White-coat hypertension and masked hypertension3037

•    4.7.1 White-coat hypertension3037

•    4.7.2 Masked hypertension3038

•  4.8 Screening for the detection of hypertension3038

•  4.9 Confirming the diagnosis of hypertension3038

•  4.10 Clinical indications for out-of-office blood pressure measurements3038

•  4.11 Blood pressure during exercise and at high altitude3040

•  4.12 Central aortic pressure3040

• 5 Clinical evaluation and assessment of hypertension-mediated organ damage in patients with hypertension3041

•  5.1 Clinical evaluation3041

•  5.2 Medical history3041

•  5.3 Physical examination and clinical investigations3042

•  5.4 Assessment of hypertension-mediated organ damage3042

•    5.4.1 Using hypertension-mediated organ damage to help stratify risk in hypertensive patients3042

•  5.5 Characteristics of hypertension-mediated organ damage3044

•    5.5.1 The heart in hypertension3044

•    5.5.2 The blood vessels in hypertension3044

•    5.5.3 The kidney in hypertension3045

•    5.5.4 Hypertensive retinopathy3045

•    5.5.5 The brain in hypertension3045

•  5.6 Hypertension-mediated organ damage regression and cardiovascular risk reduction with antihypertensive treatment3045

•  5.7 When to refer a patient with hypertension for hospital-based care3046

• 6 Genetics and hypertension3047

• 7 Treatment of hypertension3048

•  7.1 Beneficial effects of blood pressure-lowering therapy in hypertension3048

•  7.2. When to initiate antihypertensive treatment3048

•    7.2.1 Recommendations in previous guidelines3048

•    7.2.2 Drug treatment for patients with grade 1 hypertension at low–moderate cardiovascular risk3048

•    7.2.3 Initiation of blood pressure-lowering drug treatment in older people with grade 1 hypertension3049

•    7.2.4 Initiation of blood pressure-lowering drug treatment in patients with high–normal blood pressure3049

•    7.2.5 Should blood pressure-lowering drug treatment be initiated on the basis of blood pressure values or the level of total cardiovascular risk?3050

•    7.2.6 Initiation of blood pressure-lowering drug treatment3050

•  7.3 Blood pressure treatment targets3052

•    7.3.1 New evidence on systolic blood pressure and diastolic blood pressure treatment targets3052

•    7.3.2 Blood pressure targets in specific subgroups of hypertensive patients3052

•  7.4 Treatment of hypertension3054

•    7.4.1 Lifestyle changes3054

•    7.4.2 Dietary sodium restriction3054

•    7.4.3 Moderation of alcohol consumption3055

•    7.4.4 Other dietary changes3055

•    7.4.5 Weight reduction3055

•    7.4.6 Regular physical activity3056

•    7.4.7 Smoking cessation3056

•  7.5. Pharmacological therapy for hypertension3056

•    7.5.1 Drugs for the treatment of hypertension3056

•    7.5.2 Hypertension drug treatment strategy3059

•    7.5.3 The drug treatment algorithm for hypertension3063

•  7.6 Device-based hypertension treatment3067

•    7.6.1 Carotid baroreceptor stimulation (pacemaker and stent)3067

•    7.6.2 Renal denervation3067

•    7.6.3 Creation of an arteriovenous fistula3068

•    7.6.4 Other devices3068

• 8 Hypertension in specific circumstances3068

•  8.1 Resistant hypertension3068

•    8.1.1 Definition of resistant hypertension3068

•    8.1.2 Pseudo-resistant hypertension3069

•    8.1.3 Diagnostic approach to resistant hypertension3069

•    8.1.4 Treatment of resistant hypertension3070

•  8.2 Secondary hypertension3071

•    8.2.1 Drugs and other substances that may cause secondary hypertension3071

•    8.2.2 Genetic causes of secondary hypertension3071

•  8.3 Hypertension urgencies and emergencies3074

•    8.3.1 Acute management of hypertensive emergencies3075

•    8.3.2 Prognosis and follow-up3075

•  8.4 White-coat hypertension3076

•  8.5 Masked hypertension3077

•  8.6 Masked uncontrolled hypertension3077

•  8.7 Hypertension in younger adults (age<50 years)3077

•    8.7.1 Isolated systolic hypertension in the young3078

•  8.8 Hypertension in older patients (age ≥65 years)3078

•  8.9 Women, pregnancy, oral contraception, and hormone-replacement therapy3079

•    8.9.1 Hypertension and pregnancy3079

•    8.9.2 Oral contraceptive pills and hypertension3081

•    8.9.3 Hormone-replacement therapy and hypertension3081

•  8.10 Hypertension in different ethnic groups3081

•  8.11 Hypertension in diabetes mellitus3082

•  8.12 Hypertension and chronic kidney disease3083

•  8.13 Hypertension and chronic obstructive pulmonary disease3084

•  8.14 Hypertension and heart disease3084

•    8.14.1 Coronary artery disease3084

•    8.14.2 Left ventricular hypertrophy and heart failure3085

•  8.15 Cerebrovascular disease and cognition3086

•    8.15.1 Acute intracerebral haemorrhage3086

•    8.15.2 Acute ischaemic stroke3086

•    8.15.3 Previous stroke or transient ischaemic attack3086

•    8.15.4 Cognitive dysfunction and dementia3087

•  8.16 Hypertension, atrial fibrillation, and other arrhythmias3087

•    8.16.1 Oral anticoagulants and hypertension3088

•  8.17 Hypertension and vascular disease3088

•    8.17.1 Carotid atherosclerosis3088

•    8.17.2 Arteriosclerosis and increased arterial stiffness3088

•    8.17.3 Lower extremity arterial disease3089

•  8.18 Hypertension in valvular disease and aortopathy3089

•    8.18.1 Coarctation of the aorta3089

•    8.18.2 Prevention of aortic dilation and dissection in high-risk subjects3089

•    8.18.3 Hypertension bicuspid aortic valve-related aortopathy3089

•  8.19 Hypertension and sexual dysfunction3089

•  8.20 Hypertension and cancer therapy3090

•  8.21 Perioperative management of hypertension3090

• 9 Managing concomitant cardiovascular disease risk3091

•  9.1 Statins and lipid-lowering drugs3091

•  9.2 Antiplatelet therapy and anticoagulant therapy3091

•  9.3. Glucose-lowering drugs and blood pressure3092

• 10 Patient follow-up3092

•  10.1 Follow-up of hypertensive patients3092

•  10.2 Follow-up of subjects with high–normal blood pressure and white-coat hypertension3092

•  10.3 Elevated blood pressure at control visits3093

•  10.4 Improvement in blood pressure control in hypertension: drug adherence3093

•  10.5 Continued search for asymptomatic hypertension-mediated organ damage3094

•  10.6 Can antihypertensive medications be reduced or stopped?3094

• 11 Gaps in the evidence3095

• 12 Key messages3096

• 13 ‘What to do’ and ‘what not to do’ messages from the Guidelines3098

• 14 Appendix3100

• 15 References3100

Abbreviations and acronyms

• ABI

  Ankle–brachial index

• ABPM

  Ambulatory blood pressure monitoring

• ACCOMPLISH

  Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension

• ACCORD

  Action to Control Cardiovascular Risk in Diabetes

• ACE

  Angiotensin-converting enzyme

• ACEi

  Angiotensin-converting enzyme inhibitor

• ACR

  Albumin:creatinine ratio

• ADVANCE

  Action in Diabetes and Vascular Disease: Preterax and Diamicron – MR Controlled Evaluation

• AF

  Atrial fibrillation

• ALLHAT

  Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

• ALTITUDE

  Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints

• ARB

  Angiotensin receptor blocker

• ASCOT

  Anglo-Scandinavian Cardiac Outcomes Trial

• AV

  Atrioventricular

• BMI

  Body mass index

• BP

  Blood pressure

• bpm

  Beats per minute

• BSA

  Body surface area

• CAD

  Coronary artery disease

• CAPPP

  Captopril Prevention Project

• CCB

  Calcium channel blocker

• CHA2DS2-VASc

  Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65–74 years, Sex category (female)

• CKD

  Chronic kidney disease

• CK-MB

  Creatinine kinase-muscle/brain

• CMR

  Cardiac magnetic resonance

• COLM

  Combination of OLMesartan and a calcium channel blocker or diuretic in Japanese elderly hypertensive patients

• CONVINCE

  Controlled Onset Verapamil Investigation of Cardiovascular End Points

• COPD

  Chronic obstructive pulmonary disease

• COPE

  Combination Therapy of Hypertension to Prevent Cardiovascular Events

• CT

  Computed tomography

• CV

  Cardiovascular

• CVD

  Cardiovascular disease

• DBP

  Diastolic blood pressure

• DENERHTN

  Renal Denervation for Hypertension

• DHP

  Dihydropyridine

• ECG

  Electrocardiogram

• eGFR

  Estimated glomerular filtration rate

• ELSA

  European Lacidipine Study on Atherosclerosis

• ENaC

  Epithelial sodium channel

• ESC

  European Society of Cardiology

• ESH

  European Society of Hypertension

• FEVER

  Felodipine Event Reduction

• HAS-BLED

  Hypertension, Abnormal renal/liver function (1 point each), Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65), Drugs/alcohol concomitantly (1 point each)

• HbA1c

  Haemoglobin A1c

• HBPM

  Home blood pressure monitoring

• HDL-C

  HDL cholesterol

• HELLP

  Haemolysis, elevated liver enzymes, and low platelets

• HFpEF

  Heart failure with preserved ejection fraction

• HFrEF

  Heart failure with reduced ejection fraction

• HMOD

  Hypertension-mediated organ damage

• HOPE

  Heart Outcomes Prevention Evaluation

• HYVET

  Hypertension in the Very Elderly Trial

• i.v.

  Intravenous

• IMT

  Intima-media thickness

• INVEST

  International Verapamil-Trandolapril Study

• ISH

  Isolated systolic hypertension

• JUPITER

  Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin

• LDH

  Lactate dehydrogenase

• LDL-C

  LDL cholesterol

• LEAD

  Lower extremity artery disease

• LIFE

  Losartan Intervention For Endpoint reduction in hypertension

• LV

  Left ventricular

• LVH

  Left ventricular hypertrophy

• MAP

  Mean arterial pressure

• MI

  Myocardial infarction

• MR

  Magnetic resonance

• MRA

  Mineralocorticoid receptor antagonist

• MRI

  Magnetic resonance imaging

• MUCH

  Masked uncontrolled hypertension

• NORDIL

  Nordic Diltiazem

• NS

  Non-significant

• NT-proBNP

  N-terminal pro-B natriuretic peptide

• o.d.

  Omni die (every day)

• ONTARGET

  Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial

• PAC

  Plasma aldosterone concentration

• PAD

  Peripheral artery disease

• PATHS

  Prevention and Treatment of Hypertension Study

• PRA

  Plasma renin activity

• PRC

  Plasma renin concentration

• PROGRESS

  Perindopril protection against recurrent stroke study

• PWV

  Pulse wave velocity

• RAS

  Renin–angiotensin system

• RCT

  Randomized controlled trial

• RWT

  Relative wall thickness

• SBP

  Systolic blood pressure

• SCOPE

  Study on Cognition and Prognosis in the Elderly

• SCORE

  Systematic COronary Risk Evaluation

• SHEP

  Systolic Hypertension in the Elderly Program

• SPC

  Single-pill combination

• SPRINT

  Systolic Blood Pressure Intervention Trial

• STOP-H

  Swedish Trial in Old Patients with Hypertension

• SUCH

  Sustained uncontrolled hypertension

• Syst-China

  Systolic Hypertension in China

• Syst-Eur

  Systolic Hypertension in Europe

• TIA

  Transient ischaemic attack

• TTE

  Transthoracic echocardiography

• VALUE

  Valsartan Antihypertensive Long-term Use Evaluation

• VEGF

  Vascular endothelial growth factor

• WUCH

  White-coat uncontrolled hypertension

1 Preamble

Guidelines summarize and evaluate available evidence with the aim of assisting health professionals in selecting the best management strategies for an individual patient with a given condition. Guidelines and their recommendations should facilitate decision making of health professionals in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible health professional(s) in consultation with the patient and caregiver as appropriate.

A great number of guidelines have been issued in recent years by the European Society of Cardiology (ESC) and by the European Society of Hypertension (ESH), as well as by other societies and organisations. Because of the impact on clinical practice, quality criteria for the development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines can be found on the ESC website (http://www.escardio.org/Guidelines-&-Education/Clinical-Practice-Guidelines/Guidelines-development/Writing-ESC-Guidelines). ESC Guidelines represent the official position of the ESC on a given topic and are regularly updated.

Members of this Task Force were selected by the ESC and ESH to represent professionals involved with the medical care of patients with this pathology. Selected experts in the field undertook a comprehensive review of the published evidence for management of a given condition according to ESC Committee for Practice Guidelines (CPG) policy and approved by the ESH. A critical evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk–benefit ratio. The level of evidence and the strength of the recommendation of particular management options were weighed and graded according to predefined scales, as outlined in Tables 1 and 2.

Table 1

ESC Classes of recommendations

Table 2

ESC Levels of evidence

The experts of the writing and reviewing panels provided declaration of interest forms for all relationships that might be perceived as real or potential sources of conflicts of interest. These forms were compiled into one file and can be found on the ESC website (http://www.escardio.org/guidelines). Any changes in declarations of interest that arise during the writing period were notified to the ESC and ESH and updated. The Task Force received its entire financial support from the ESC and ESH without any involvement from the healthcare industry.

The ESC CPG supervises and coordinates the preparation of new Guidelines. The Committee is also responsible for the endorsement process of these Guidelines. The ESC Guidelines undergo extensive review by the CPG and external experts, and in this case by ESH -appointed experts. After appropriate revisions the Guidelines are approved by all the experts involved in the Task Force. The finalized document is approved by the CPG and ESH for publication in the European Heart Journal and in the Journal of Hypertension as well as Blood Pressure. The Guidelines were developed after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating.

The task of developing ESC and ESH Guidelines also includes the creation of educational tools and implementation programmes for the recommendations including condensed pocket guideline versions, summary slides, booklets with essential messages, summary cards for non-specialists and an electronic version for digital applications (smartphones, etc.). These versions are abridged and thus, if needed, one should always refer to the full text version, which is freely available via the ESC AND ESH websites and hosted on the EHJ AND JOURNAL OF HYPERTENSION websites. The National Societies of the ESC are encouraged to endorse, translate and implement all ESC Guidelines. Implementation programmes are needed because it has been shown that the outcome of disease may be favourably influenced by the thorough application of clinical recommendations.

Surveys and registries are needed to verify that real-life daily practice is in keeping with what is recommended in the guidelines, thus completing the loop between clinical research, writing of guidelines, disseminating them and implementing them into clinical practice.

Health professionals are encouraged to take the ESC and ESH Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies. However, the ESC and ESH Guidelines do not override in any way whatsoever the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and in consultation with that patient or the patient's caregiver where appropriate and/or necessary. It is also the health professional's responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.

2 Introduction

Substantial progress has been made in understanding the epidemiology, pathophysiology, and risk associated with hypertension, and a wealth of evidence exists to demonstrate that lowering blood pressure (BP) can substantially reduce premature morbidity and mortality.1–10 A number of proven, highly effective, and well-tolerated lifestyle and drug treatment strategies can achieve this reduction in BP. Despite this, BP control rates remain poor worldwide and are far from satisfactory across Europe. Consequently, hypertension remains the major preventable cause of cardiovascular disease (CVD) and all-cause death globally and in our continent.11–14

These 2018 ESC/ESH Guidelines for the management of arterial hypertension are designed for adults with hypertension, i.e. aged ≥18 years. The purpose of the review and update of these Guidelines was to evaluate and incorporate new evidence into the Guideline recommendations. The specific aims of these Guidelines were to produce pragmatic recommendations to improve the detection and treatment of hypertension, and to improve the poor rates of BP control by promoting simple and effective treatment strategies.

These joint 2018 Guidelines follow the same principles upon which a series of hypertension Guidelines were jointly issued by the two societies in 2003, 2007, and 2013. These fundamental principles are: (i) to base recommendations on properly conducted studies, identified from an extensive review of the literature; (ii) to give the highest priority to data from randomized controlled trials (RCTs); (iii) to also consider well-conducted meta-analyses of RCTs as strong evidence (this contrasts with network meta-analyses, which we do not consider to have the same level of evidence because many of the comparisons are non-randomized); (iv) to recognize that RCTs cannot address many important questions related to the diagnosis, risk stratification, and treatment of hypertension, which can be addressed by observational or registry-based studies of appropriate scientific calibre; (v) to grade the level of scientific evidence and the strength of recommendations according to ESC recommendations (see section 1); (vi) to recognize that opinions may differ on key recommendations, which are resolved by voting; and (vii) to recognize that there are circumstances in which there is inadequate or no evidence, but that the question is important for clinical practice and cannot be ignored. In these circumstances, we resort to pragmatic expert opinion and endeavour to explain its rationale.

Each member of the Task Force was assigned specific writing tasks, which were reviewed by section co-ordinators and then by the two chairs, one appointed by the ESC and the other by the ESH. The text was developed over approximately 24 months, during which the Task Force members met collectively and corresponded intensively with one another between meetings. Before publication, the document was reviewed by European reviewers selected by the ESC and ESH, and by representatives of ESC National Cardiac Societies and ESH National Hypertension Societies.

2.1 What is new and what has changed in the 2018 ESC/ESH Arterial Hypertension Guidelines?

3 Definition, classification, and epidemiological aspects of hypertension

3.1 Definition of hypertension

The relationship between BP and cardiovascular (CV) and renal events is continuous, making the distinction between normotension and hypertension, based on cut-off BP values, somewhat arbitrary.2,4,8 However, in practice, cut-off BP values are used for pragmatic reasons to simplify the diagnosis and decisions about treatment. Epidemiological associations between BP and CV risk extend from very low levels of BP [i.e. systolic BP (SBP) >115 mmHg]. However, ‘hypertension’ is defined as the level of BP at which the benefits of treatment (either with lifestyle interventions or drugs) unequivocally outweigh the risks of treatment, as documented by clinical trials. This evidence has been reviewed (see section 7.2 for detailed discussion of hypertension diagnostic thresholds) and provides the basis for the recommendation that the classification of BP and definition of hypertension remain unchanged from previous ESH/ESC Guidelines (Table 3).15,16,17

Hypertension is defined as office SBP values ≥140 mmHg and/or diastolic BP (DBP) values ≥90 mmHg. This is based on evidence from multiple RCTs that treatment of patients with these BP values is beneficial (see section 7). The same classification is used in younger, middle-aged, and older people, whereas BP centiles are used in children and teenagers, in whom data from interventional trials are not available. Details on BP classification in boys and girls ≤ 16 years of age can be found in the 2016 ESH Guidelines for children and adolescents.18

3.2 Classification of blood pressure

Classification of BP

BP = blood pressure.

a

Class of recommendation

b

Level of evidence.

3.3 Prevalence of hypertension

Based on office BP, the global prevalence of hypertension was estimated to be 1.13 billion in 2015,5 with a prevalence of over 150 million in central and eastern Europe. The overall prevalence of hypertension in adults is around 30 − 45%,12 with a global age-standardized prevalence of 24 and 20% in men and women, respectively, in 2015.5 This high prevalence of hypertension is consistent across the world, irrespective of income status, i.e. in lower, middle, and higher income countries.12Hypertension becomes progressively more common with advancing age, with a prevalence of >60% in people aged >60 years.12 As populations age, adopt more sedentary lifestyles, and increase their body weight, the prevalence of hypertension worldwide will continue to rise. It is estimated that the number of people with hypertension will increase by 15–20% by 2025, reaching close to 1.5 billion.19

3.4 Blood pressure relationship with risk of cardiovascular and renal events

Elevated BP was the leading global contributor to premature death in 2015, accounting for almost 10 million deaths and over 200 million disability-adjusted life years.3 Importantly, despite advances in diagnosis and treatment over the past 30 years, the disability-adjusted life years attributable to hypertension have increased by 40% since 1990.3 SBP ≥140 mmHg accounts for most of the mortality and disability burden (∼70%), and the largest number of SBP-related deaths per year are due to ischaemic heart disease (4.9 million), haemorrhagic stroke (2.0 million), and ischaemic stroke (1.5 million).3

Both office BP and out-of-office BP have an independent and continuous relationship with the incidence of several CV events [haemorrhagic stroke, ischaemic stroke, myocardial infarction, sudden death, heart failure, and peripheral artery disease (PAD)], as well as end-stage renal disease.4 Accumulating evidence is closely linking hypertension with an increased risk of developing atrial fibrillation (AF),20and evidence is emerging that links early elevations of BP to increased risk of cognitive decline and dementia.21,22

The continuous relationship between BP and risk of events has been shown at all ages23 and in all ethnic groups,24,25 and extends from high BP levels to relatively low values. SBP appears to be a better predictor of events than DBP after the age of 50 years.23,26,27 High DBP is associated with increased CV risk and is more commonly elevated in younger (<50 years) vs. older patients. DBP tends to decline from midlife as a consequence of arterial stiffening; consequently, SBP assumes even greater importance as a risk factor from midlife.26 In middle-aged and older people, increased pulse pressure (the difference between SBP and DBP values) has additional adverse prognostic significance.28,29

3.5 Hypertension and total cardiovascular risk assessment

Hypertension rarely occurs in isolation, and often clusters with other CV risk factors such as dyslipidaemia and glucose intolerance.30,31 This metabolic risk factor clustering has a multiplicative effect on CV risk.32 Consequently, quantification of total CV risk (i.e. the likelihood of a person developing a CV event over a defined period) is an important part of the risk stratification process for patients with hypertension.

Many CV risk assessment systems are available and most project 10 year risk. Since 2003, the European Guidelines on CVD prevention have recommended use of the Systematic COronary Risk Evaluation (SCORE) system because it is based on large, representative European cohort data sets (available at: http://www.escardio.org/Guidelines-&-Education/Practice-tools/CVD-prevention-toolbox/SCORE-Risk-Charts). The SCORE system estimates the 10 year risk of a first fatal atherosclerotic event, in relation to age, sex, smoking habits, total cholesterol level, and SBP. The SCORE system also allows calibration for different CV risk levels across numerous European countries and has been externally validated.33 A previous limitation of the SCORE system was that it applied only to patients aged 40–65 years; however, the SCORE system has recently been adapted for patients over the age of 65 years.34 Detailed information on CV risk assessment is available.35

Factors influencing CV risk factors in patients with hypertension are shown in Table 4. Hypertensive patients with documented CVD, including asymptomatic atheromatous disease on imaging, type 1 or type 2 diabetes, very high levels of individual risk factors (including grade 3 hypertension), or chronic kidney disease (CKD; stages 3 − 5), are automatically considered to be at very high (i.e. ≥10% CVD mortality) or high (i.e. 5 − 10% CVD mortality) 10 year CV risk (Table 5). Such patients do not need formal CV risk estimation to determine their need for treatment of their hypertension and other CV risk factors. For all other hypertensive patients, estimation of 10 year CV risk using the SCORE system is recommended. Estimation should be complemented by assessment of hypertension-mediated organ damage (HMOD), which can also increase CV risk to a higher level, even when asymptomatic (see Table 4 and sections 3.6 and 4).

Table 5

Ten year cardiovascular risk categories (Systematic COronary Risk Evaluation system)

BP = blood pressure; CKD = chronic kidney disease; CVD = cardiovascular disease; eGFR = estimated glomerular filtration rate; LVH = left ventricular hypertrophy; TIA = transient ischaemic attack; PAD = peripheral artery disease; SCORE = Systematic COronary Risk Evaluation.

There is also emerging evidence that an increase in serum uric acid to levels lower than those typically associated with gout is independently associated with increased CV risk in both the general population and in hypertensive patients. Measurement of serum uric acid is recommended as part of the screening of hypertensive patients.36

The SCORE system only estimates the risk of fatal CV events. The risk of total CV events (fatal and non-fatal) is approximately three times higher than the rate of fatal CV events in men and four times higher in women. This multiplier is attenuated to less than three times in older people in whom a first event is more likely to be fatal.37

There are important general modifiers of CV risk (Table 6) as well as specific CV risk modifiers for patients with hypertension. CV risk modifiers are particularly important at the CV risk boundaries, and especially for patients at moderate-risk in whom a risk modifier might convert moderate-risk to high risk and influence treatment decisions with regard to CV risk factor management. Furthermore, CV risk estimates by the SCORE system may be modified in first-generation immigrants to Europe and CV risk scores in such patients may be adjusted by correction factors (Table 7). Further details of the impact of CV risk modifiers are available from the ESC 2016 CVD prevention Guidelines.35

3.6 Importance of hypertension-mediated organ damage in refining cardiovascular risk assessment in hypertensive patients

A unique and important aspect of CV risk estimation in hypertensive patients is the need to consider the impact of HMOD. This was previously termed ‘target organ damage’, but HMOD more accurately describes hypertension-induced structural and/or functional changes in major organs (i.e. the heart, brain, retina, kidney, and vasculature) (Table 4). There are three important considerations: (i) not all features of HMOD are included in the SCORE system (CKD and established vascular disease are included) and several hypertensive HMODs (e.g. cardiac, vascular, and retinal) have well-established adverse prognostic significance (see section 5) and may, especially if HMOD is pronounced, lead to a high CV risk even in the absence of classical CV risk factors; (ii) the presence of HMOD is common and often goes undetected;38 and (iii) the presence of multiple HMODs in the same patient is also common, and further increases CV risk.39–41 Consequently, the inclusion of HMOD assessment is important in patients with hypertension and helps identify high-risk or very high-risk hypertensive patients who may otherwise be misclassified as having a lower level of risk by the SCORE system.42 This is especially true for the presence of left ventricular hypertrophy (LVH), CKD with albuminuria or proteinuria, or arterial stiffening43 (see section 5). The impact of progression of the stages of hypertension-associated disease (from uncomplicated through to asymptomatic or established disease), according to different grades of hypertension and the presence of CV risk factors, HMOD, or comorbidities, is illustrated in Figure 1 for middle-aged individuals.

Figure 1

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Classification of hypertension stages according to blood pressure levels, presence of cardiovascular risk factors, hypertension-mediated organ damage, or comorbidities. CV risk is illustrated for a middle-aged male. The CV risk does not necessarily correspond to the actual risk at different ages. The use of the SCORE system is recommended for formal estimation of CV risk for treatment decisions. BP = blood pressure; CKD = chronic kidney disease; CV = cardiovascular; DBP = diastolic blood pressure; HMOD = hypertension-mediated organ damage; SBP = systolic blood pressure; SCORE = Systematic COronary Risk Evaluation.

Figure 2

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Screening and diagnosis of hypertension. ABPM = ambulatory blood pressure monitoring; BP = blood pressure; HBPM = home blood pressure monitoring.

aAfter detecting a specific BP category on screening, either confirm BP elevation with repeated office BP measurements on repeat visits or arrange use of out-of-office BP to confirm the diagnosis of hypertension.

3.7 Challenges in cardiovascular risk assessment

CV risk is strongly influenced by age (i.e. older people are invariably at high absolute CV risk). In contrast, the absolute risk of younger people, particularly younger women, is invariably low, even in those with a markedly abnormal risk factor profile. In the latter, relative risk is elevated even if absolute risk is low. The use of ‘CV risk age’ has been proposed as a useful way of communicating risk and making treatment decisions, especially for younger people at low absolute risk but with high relative risk.35 This works by illustrating how a younger patient (e.g. a 40-year-old) with risk factors but low absolute risk has a CV risk equivalent to a much older person (60 years) with optimal risk factors; thus, the CV risk age of the younger patient is 60 years. The CV risk age can be automatically calculated using HeartScore (www.heartscore.org).

A second consideration is that the presence of concomitant disease is often recorded in a binary way in CV risk assessment systems (e.g. diabetes, yes/no). This does not reflect the impact of the severity or duration of concomitant diseases on total CV risk. For example, long-standing diabetes is clearly associated with high risk, whereas the risk is less certain for recent-onset diabetes.34

A third conundrum specific to hypertension is what BP value to use in CV risk assessment in a patient who is receiving treatment for hypertension. If treatment was commenced recently, it seems appropriate to use the pre-treatment BP value. If treatment has been long-standing, using the current treated BP value will invariably underestimate risk because it does not reflect prior longer-term exposure to higher BP levels, and antihypertensive treatment does not completely reverse the risk even when BP is well controlled. If treatment has been long-standing, then the ‘treated BP value’ should be used, with the caveat that the calculated CV risk will be lower than the patient’s actual risk. A fourth conundrum is how to impute out-of-office BP values into risk calculators that have been calibrated according to office BP readings. These various limitations should be kept in mind when estimating CV risk in clinical practice.

Hypertension and CV risk assessment

CVD = cardiovascular disease; LVH = left ventricular hypertrophy; SCORE = Systematic COronary Risk Evaluation.

a

Class of recommendation.

b

Level of evidence.

4 Blood pressure measurement

4.1 Conventional office blood pressure measurement

Auscultatory or oscillometric semiautomatic or automatic sphygmomanometers are the preferred method for measuring BP in the doctor’s office. These devices should be validated according to standardized conditions and protocols.44 BP should initially be measured in both upper arms, using an appropriate cuff size for the arm circumference. A consistent and significant SBP difference between arms (i.e. >15 mmHg) is associated with an increased CV risk,45 most likely due to atheromatous vascular disease. Where there is a difference in BP between arms, ideally established by simultaneous measurement, the arm with the higher BP values should be used for all subsequent measurements.

In older people, people with diabetes, or people with other causes of orthostatic hypotension, BP should also be measured 1 min and 3 min after standing. Orthostatic hypotension is defined as a reduction in SBP of ≥20 mmHg or in DBP of ≥10 mmHg within 3 min of standing, and is associated with an increased risk of mortality and CV events.46 Heart rate should also be recorded at the time of BP measurements because resting heart rate is an independent predictor of CV morbid or fatal events,47although heart rate is not included in any CV risk algorithm. Table 8 summarizes the recommended procedure for routine office BP measurement. It is emphasized that office BP is often performed improperly, with inadequate attention to the standardized conditions recommended for a valid measurement of office BP. Improper measurement of office BP can lead to inaccurate classification, overestimation of a patient’s true BP, and unnecessary treatment.

4.2 Unattended office blood pressure measurement

Automated multiple BP readings in the doctor’s office improve the reproducibility of BP measurement, and if the patient is seated alone and unobserved, the ‘white-coat effect’ (see section 4.7.1) can be substantially reduced48 or eliminated.49 Moreover, the BP values are lower than those obtained by conventional office BP measurement and are similar to, or even less than, those provided by daytime ambulatory blood pressure monitoring (ABPM) or home blood pressure monitoring (HBPM).50 Use of unattended office BP measurement in a recent clinical trial [the Systolic Blood Pressure Intervention Trial (SPRINT)]51 generated controversy about its quantitative relationship to conventional office BP measurement (which has been the basis for all previous epidemiological and clinical trial data); its feasibility in routine clinical practice has also been questioned. Presently, the relationship between BP readings obtained with conventional office BP measurement and unattended office BP measurement remains unclear, but available evidence suggests that conventional office SBP readings may be at least 5–15 mmHg higher than SBP levels obtained by unattended office BP measurements.52 There is also very limited evidence on the prognostic value of unattended office BP measurements, i.e. whether they guarantee at least the same ability to predict outcomes as conventional office BP measurements.53

4.3 Out-of-office blood pressure measurement

Out-of-office BP measurement refers to the use of either HBPM or ABPM, the latter usually over 24 h. It provides a larger number of BP measurements than conventional office BP in conditions that are more representative of daily life. Recent position papers and practice guidelines provide comprehensive details for ABPM54 and HBPM,55 and are briefly summarized below.54,56

4.4 Home blood pressure monitoring

Home BP is the average of all BP readings performed with a semiautomatic, validated BP monitor, for at least 3 days and preferably for 6–7 consecutive days before each clinic visit, with readings in the morning and the evening, taken in a quiet room after 5 min of rest, with the patient seated with their back and arm supported. Two measurements should be taken at each measurement session, performed 1–2 min apart.57

Compared with office BP, HBPM values are usually lower, and the diagnostic threshold for hypertension is ≥135/85 mmHg (equivalent to office BP ≥140/90 mmHg) (Table 9) when considering the average of 3–6 days of home BP values. Compared with office BP, HBPM provides more reproducible BP data and is more closely related to HMOD, particularly LVH.58 Recent meta-analyses of the few available prospective studies have further indicated that HBPM better predicts cardiovascular morbidity and mortality than office BP.59 There is also evidence that patient self-monitoring may have a beneficial effect on medication adherence and BP control,60,61 especially when combined with education and counselling.62Telemonitoring and smartphone applications may offer additional advantages,63,64such as an aid to memory to make BP measurements, and as a convenient way to store and review BP data in a digital diary and transmit them. We do not recommend the use of apps as a cuff-independent means of measuring BP.

4.5 Ambulatory blood pressure monitoring

ABPM provides the average of BP readings over a defined period, usually 24 h. The device is typically programmed to record BP at 15 − 30 min intervals, and average BP values are usually provided for daytime, night-time, and 24 h. A diary of the patient’s activities and sleep time can also be recorded. A minimum of 70% usable BP recordings are required for a valid ABPM measurement session. ABPM values are, on average, lower than office BP values, and the diagnostic threshold for hypertension is ≥130/80 mmHg over 24 h, ≥135/85 mmHg for the daytime average, and ≥120/70 for the night-time average (all equivalent to office BP ≥140/90 mmHg), see Table 9.

ABPM is a better predictor of HMOD than office BP.65 Furthermore, 24 h ambulatory BP mean has been consistently shown to have a closer relationship with morbid or fatal events,66–68 and is a more sensitive risk predictor than office BP of CV outcomes such as coronary morbid or fatal events and stroke.68–72

BP normally decreases during sleep. Although the degree of night-time BP dipping has a normal distribution in a population setting, an arbitrary cut-off has been proposed to define patients as ‘dippers’ if their nocturnal BP falls by >10% of the daytime average BP value; however, the ‘dipping’ status is often highly variable from day to day and thus is poorly reproducible.73 Recognised reasons for an absence of nocturnal BP dipping are sleep disturbance, obstructive sleep apnoea, obesity, high salt intake in salt-sensitive subjects, orthostatic hypotension, autonomic dysfunction, CKD, diabetic neuropathy, and old age.54 Studies that accounted for daytime and night-time BP in the same statistical model found that night-time BP is a stronger predictor of outcomes than daytime BP.54 The night-to-day ratio is also a significant predictor of outcome, and patients with a reduced night-time dip in BP (i.e.<10% of="" the="" daytime="" average="" bp="" or="" a="" night-to-day="" ratio="">0.9) have an increased cardiovascular risk.54 Moreover, in those in whom there is no night-time dip in BP or a higher night-time than daytime average BP, there is a substantially increase in risk.74 Paradoxically, there is also some evidence of increased risk in patients who have extreme dipping of their night-time BP,75 although the limited prevalence and reproducibility of this phenomenon makes interpretation of data difficult.

A number of additional indices derived from ABPM recordings have some prognostic value, including 24 h BP variability,76 morning BP surge,77 and the ambulatory arterial stiffness index.78 However, their incremental predictive value is not yet clear. Thus, these indices should be regarded as research tools, with no current indication for routine clinical use.

4.6 Advantages and disadvantages of ambulatory blood pressure monitoring and home blood pressure monitoring

A major advantage of both ABPM and HBPM is that they enable the diagnosis of white-coat and masked hypertension (see section 4.7). The relative advantages and disadvantages of HBPM and ABPM are shown in Table 10. A particularly important advantage of HBPM is that it is much cheaper and thus more available than ABPM. Another is that it provides multiple measurements over several days or even longer periods, which is clinically relevant because day-to-day BP variability may have an independent prognostic value.79 Unlike ABPM, typical HBPM devices do not provide BP measurements during routine daily activities and during sleep, although recent technical advances may allow BP during sleep to be measured by HBPM. A further consideration is the potential impact of impaired cognition on the reliability of HBPM measurements and rare instances of obsessional behaviour, circumstances that may favour the use of ABPM if out-of-office BP readings are required. In general, both methods should be regarded as complementary rather than absolute alternatives.

Despite the advances in out-of-office BP measurement over the past 50 years, some fundamental questions remain, the most important of which is whether HBPM- or ABPM-guided therapy results in greater reductions in morbidity and mortality than conventional office BP-guided treatment, which has been the diagnostic strategy for all clinical outcome trials.

4.7 White-coat hypertension and masked hypertension

White-coat hypertension refers to the untreated condition in which BP is elevated in the office, but is normal when measured by ABPM, HBPM, or both.80 Conversely, ‘masked hypertension’ refers to untreated patients in whom the BP is normal in the office, but is elevated when measured by HBPM or ABPM.81 The term ‘true normotension’ is used when both office and out-of-office BP measurements are normal, and ‘sustained hypertension’ is used when both are abnormal. In white-coat hypertension, the difference between the higher office and the lower out-of-office BP is referred to as the ‘white-coat effect’, and is believed to mainly reflect the pressor response to an alerting reaction elicited by office BP measurements by a doctor or a nurse,82 although other factors are probably also involved.83

Although the terms white-coat and masked hypertension were originally defined for people who were not being treated for hypertension, they are now also used to describe discrepancies between office and out-of-office BP in patients treated for hypertension, with the terms masked uncontrolled hypertension (MUCH) (office BP controlled but home or ambulatory BP elevated) and white-coat uncontrolled hypertension (WUCH) (office BP elevated but home or ambulatory BP controlled), compared with sustained uncontrolled hypertension (SUCH)84 (both office and home or ambulatory BP are uncontrolled).

The white-coat effect is used to describe the difference between an elevated office BP (treated or untreated) and a lower home or ambulatory BP in both untreated and treated patients.

4.7.1 White-coat hypertension

Although the prevalence varies between studies, white-coat hypertension can account for up to 30 − 40% of people (and >50% in the very old) with an elevated office BP. It is more common with increasing age, in women, and in non-smokers. Its prevalence is lower in patients with HMOD, when office BP is based on repeated measurements, or when a doctor is not involved in the BP measurement. A significant white-coat effect can be seen at all grades of hypertension (including resistant hypertension), but the prevalence of white-coat hypertension is greatest in grade 1 hypertension.

HMOD is less prevalent in white-coat hypertension than in sustained hypertension, and recent studies show that the risk of cardiovascular events associated with white-coat hypertension is also lower than that in sustained hypertension.68,85,86Conversely, compared with true normotensives, patients with white-coat hypertension have increased adrenergic activity,87 a greater prevalence of metabolic risk factors, more frequent asymptomatic cardiac and vascular damage, and a greater long-term risk of new-onset diabetes and progression to sustained hypertension and LVH.82 In addition, although the out-of-office BP values are, by definition, normal in white-coat hypertension, they tend to be higher than those of true normotensive people, which may explain the increased long-term risk of CV events reported in white-coat hypertension by recent studies after adjustment for demographic and metabolic risk factors.85,86,88–90 White-coat hypertension has also been shown to have a greater CV risk in isolated systolic hypertension and older patients,91 and does not appear to be clinically innocent.68 The diagnosis should be confirmed by repeated office and out-of-office BP measurements, and should include an extensive assessment of risk factors and HMOD. Both ABPM and HBPM are recommended to confirm white-coat hypertension, because the CV risk appears to be lower (and close to sustained normotension) in those in whom both ABPM and HBPM are both normal;82 for treatment considerations see section 8.4.

4.7.2 Masked hypertension

Masked hypertension can be found in approximately 15% of patients with a normal office BP.17 The prevalence is greater in younger people, men, smokers, and those with higher levels of physical activity, alcohol consumption, anxiety, and job stress.54Obesity, diabetes, CKD, family history of hypertension, and high–normal office BP are also associated with an increased prevalence of masked hypertension.17 Masked hypertension is associated with dyslipidaemia and dysglycaemia, HMOD,92adrenergic activation, and increased risk of developing diabetes and sustained hypertension.81,93 Meta-analyses and recent studies68 have shown that the risk of CV events is substantially greater in masked hypertension compared with normotension, and close to or greater than that of sustained hypertension.68,93–96Masked hypertension has also been found to increase the risk of CV and renal events in diabetes, especially when the BP elevation occurs during the night.95,97

4.8 Screening for the detection of hypertension

Hypertension is predominantly an asymptomatic condition that is best detected by structured population screening programmes or opportunistic measurement of BP. When structured population screening programmes have been undertaken, an alarming number of people (>50%) were unaware they had hypertension.12,98 This high rate of undetected hypertension occurred irrespective of the income status of the countries studied across the world.

All adults should have their BP recorded in their medical record and be aware of their BP, and further screening should be undertaken at regular intervals with the frequency dependent on the BP level. For healthy people with an optimal office BP (<120/80 mmHg), BP should be remeasured at least every 5 years and more frequently when opportunities arise. In patients with a normal BP (120–129/80–84), BP should be remeasured at least every 3 years. Patients with high–normal BP (130–139/85–89 mmHg) should have their BP recorded annually because of the high rates of progression of high–normal BP to hypertension. This is true also for people in whom masked hypertension is detected.

4.9 Confirming the diagnosis of hypertension

BP can be highly variable, thus the diagnosis of hypertension should not be based on a single set of BP readings at a single office visit, unless the BP is substantially increased (e.g. grade 3 hypertension) and there is clear evidence of HMOD (e.g. hypertensive retinopathy with exudates and haemorrhages, or LVH, or vascular or renal damage). For all others (i.e. almost all patients), repeat BP measurements at repeat office visits have been a long-standing strategy to confirm a persistent elevation in BP, as well as for the classification of the hypertension status in clinical practice and RCTs. The number of visits and the time interval between visits varies according to the severity of the hypertension, and is inversely related to the severity of hypertension. Thus, more substantial BP elevation (e.g. grade 2 or more) requires fewer visits and shorter time intervals between visits (i.e. a few days or weeks), depending on the severity of BP elevation and whether there is evidence of CVD or HMOD. Conversely, in patients with BP elevation in the grade 1 range, the period of repeat measurements may extend over a few months, especially when the patient is at low risk and there is no HMOD. During this period of BP assessment, CV risk assessment and routine screening tests are usually performed (see section 3).

These Guidelines also support the use of out-of-office BP measurements (i.e. HBPM and/or ABPM) as an alternative strategy to repeated office BP measurements to confirm the diagnosis of hypertension, when these measurements are logistically and economically feasible (Figure 2).99 This approach can provide important supplementary clinical information, e.g. detecting white-coat hypertension (see section 4.7.1), which should be suspected, especially in people with grade 1 hypertension on office BP measurement and in whom there is no evidence of HMOD or CVD100 (Table 11). A particular challenge is the detection of masked hypertension (see section 4.7.2). Masked hypertension is more likely in people with a BP in the high–normal range in whom out-of-office BP should be considered to exclude masked hypertension (see Table 8). Out-of-office BP measurements are also indicated in specific circumstances (see section 4.10 and Table 11).

4.10 Clinical indications for out-of-office blood pressure measurements

Out-of-office BP measurements are increasingly used, especially HBPM but also ABPM, to confirm the diagnosis of hypertension. Out-of-office BP measurement provides important complementary information, as discussed above. The clinical indications for out-of-office BP measurements are shown in Table 11. HBPM is also increasingly used by patients to monitor their BP control, which increases their engagement and may improve their adherence to treatment and BP control.61,101,102 It is likely that, with increased availability and lower cost of these devices, this will become more commonplace.

4.11 Blood pressure during exercise and at high altitude

It is important to recognise that BP increases during dynamic and static exercise, and that the increase is more pronounced for SBP than for DBP,103 although only SBP can be measured reliably with non-invasive methods. There is currently no consensus on normal BP response during exercise. The increase in SBP during exercise is related to pre-exercise resting BP, age, arterial stiffness, and abdominal obesity, and is somewhat greater in women than in men and in unfit individuals. There is some evidence that an excessive rise in BP during exercise predicts the development of hypertension, independently from BP at rest.104 Nevertheless, exercise testing is not recommended as part of the routine evaluation of hypertension because of various limitations, including a lack of standardization of methodology and definitions. Importantly, except in the presence of very high BP values (grade 3 hypertension), patients, or athletes, with treated or untreated hypertension should not be discouraged from regular exercise, especially aerobic exercise, which is considered beneficial as part of lifestyle changes to reduce BP (see section 7.4.1).

Evidence is available that BP increases with high altitude exposure, especially above 3000 m and possibly above 2000 m.105 This is due to a number of factors including sympathetic activation. Patients with grade 2 hypertension and increased CV risk should check their BP values before and during high altitude (>2500 m) exposure. Patients with grade 1 hypertension may reach very high altitude (>4000 m) with adequate medical therapy; uncontrolled severe hypertensive patients (grade 3) should avoid exposure to very high altitude.105

4.12 Central aortic pressure

Various techniques allow aortic BP (central BP) to be derived from peripheral BP measurements using dedicated algorithms.106,107 Some studies and meta-analyses have shown that in hypertensive patients, central BP predicts CV events and that there is a differential effect of antihypertensive drugs on central compared with brachial BP.108 The incremental prognostic value of central vs. conventional clinic BP measurement remains unclear.109 An exception may be isolated systolic hypertension in the young, in whom peripheral BP may be disproportionately elevated relative to a normal central BP. This occurs in a small fraction of younger people, mainly men with isolated systolic hypertension, and it remains unclear whether such patients are at lower risk than suggested by their brachial office BP.110,111

BP measurement

ABPM = ambulatory blood pressure monitoring; AF = atrial fibrillation; BP = blood pressure; CV = cardiovascular; HBPM = home blood pressure monitoring; SBP = systolic blood pressure.

a

Class of recommendation.

b

Level of evidence.

5 Clinical evaluation and assessment of hypertension-mediated organ damage in patients with hypertension

5.1 Clinical evaluation

The purpose of the clinical evaluation is to establish the diagnosis and grade of hypertension, screen for potential secondary causes of hypertension, identify factors potentially contributing to the development of hypertension (lifestyle, concomitant medications, or family history), identify concomitant CV risk factors (including lifestyle and family history), identify concomitant diseases, and establish whether there is evidence of HMOD or existing CV, cerebrovascular, or renal disease.

5.2 Medical history

A thorough medical history (Table 12) should address in particular:

• Time of the first diagnosis of hypertension, including records of any previous medical screening, hospitalization, etc.

• Record any current and past BP values

• Record current and past antihypertensive medications

• Record other medications

• Family history of hypertension, CVD, stroke, or renal disease

• Lifestyle evaluation, including exercise levels, body weight changes, diet history, smoking history, alcohol use, recreational drug use, sleep history, and impact of any treatments on sexual function

• History of any concomitant CV risk factors

• Details and symptoms of past and present comorbidities

• Specific history of potential secondary causes of hypertension (see section 8.2)

• History of past pregnancies and oral contraceptive use

• History of menopause and hormone replacement therapy

• Use of liquorice

• Use of drugs that may have a pressor effect.

5.3 Physical examination and clinical investigations

Physical examination provides important indications of potential causes of secondary hypertension, signs of comorbidities, and HMOD. Office BP and heart rate should be measured as summarized in section 4. Measurements of office BP on more than one occasion are usually required to confirm the diagnosis of hypertension unless HBPM or ABPM is used to confirm the diagnosis (see section 4).

Details of the requirements for a comprehensive clinical examination are outlined in Table 13, and this should be adapted according to the severity of hypertension and clinical circumstances. Suggested routine clinical investigations are outlined in Table 14.

5.4 Assessment of hypertension-mediated organ damage

HMOD refers to structural or functional changes in arteries or end organs (heart, blood vessels, brain, eyes, and kidney) caused by an elevated BP, and is a marker of pre-clinical or asymptomatic CVD.112 HMOD is common in severe or long-standing hypertension, but can also be found in less severe hypertension. With wider use of imaging, HMOD is becoming increasingly apparent in asymptomatic patients.43 CV risk increases with the presence of HMOD, and more so when damage affects multiple organs.16,113,114 Some types of HMOD can be reversed by antihypertensive treatment, especially when used early, but with long-standing hypertension, HMOD may become irreversible despite improved BP control.115,116 Nevertheless, BP-lowering treatment is still important as it may delay the further progression of HMOD and will reduce the elevated CV risk of these patients.116 Although poor technical provision and cost may limit the search for HMOD in some countries, it is recommended that basic screening for HMOD is performed in all hypertensive patients and more detailed assessment is performed when the presence of HMOD might influence treatment decisions. The various investigations to establish HMOD are shown in Table 15.

5.4.1 Using hypertension-mediated organ damage to help stratify risk in hypertensive patients

As discussed in section 3, hypertensive patients with documented CVD, diabetes, CKD, grade 3 hypertension, or marked cholesterol elevation (e.g. familial hypercholesterolaemia) are already at high or very high CV risk (≥10% risk of a fatal event). Thus, the presence of HMOD is unlikely to influence treatment, as these patients should already receive lifestyle interventions, BP-lowering medications, statins, and in some cases antiplatelet therapy, to reduce their risk35 (see section 9).

The main advantage of detecting HMOD is that it may reclassify a patient’s SCORE risk assessment from low to moderate or from moderate to high risk.117 The specific impact of HMOD114 with regard to the reclassification of risk estimation according to the SCORE system has not been clearly defined. The SCORE system already takes account of the grade of hypertension as SBP is included in the risk calculation. Moreover, CKD and the presence of vascular disease on imaging are already specified as high or very high risk (Table 5). Conditioning of the risk score by the presence of HMOD will be most important in middle-aged patients with hypertension, many of whom will be at moderate-risk and at higher risk if HMOD is detected. Moreover, a risk-conditioning effect of HMOD will also be important in younger hypertensive patients who are invariably classified as low risk according to the SCORE system. In addition, detecting HMOD in younger patients with grade 1 hypertension provides unequivocal evidence of hypertension-mediated damage and indicates a clear need for BP-lowering treatment in patients who may be reluctant to be treated. For the same reason, the presence of HMOD in a patient with high–normal BP would also provide a rationale to consider BP-lowering treatment.

Another important consideration is whether the presence of a specific manifestation of HMOD (e.g. LVH or CKD) might influence the selection of drug treatment for hypertension. This was considered important in the previous guidelines,17 but is now considered less important. In patients more likely to have HMOD (i.e. those with high grade 1 or grade 2–3 hypertension), we now recommend initial treatment with a combination of two drugs, usually an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) in combination with a calcium channel blocker (CCB) or thiazide-type diuretic, which would be the optimal treatment for all manifestations of HMOD (see section 7).

5.5 Characteristics of hypertension-mediated organ damage

5.5.1 The heart in hypertension

Chronically increased left ventricular (LV) workload in hypertensive patients can result in LVH, impaired LV relaxation, left atrial enlargement, an increased risk of arrhythmias, especially AF, and an increased risk of heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF).

5.5.1.1 Electrocardiogram

A 12-lead electrocardiogram (ECG) should be part of the routine assessment in all hypertensive patients. The ECG is not a particularly sensitive method of detecting LVH and its sensitivity varies according to body weight. ECG LVH provides independent prognostic information, even after adjusting for other CV risk factors and echocardiographic LV mass.118 In addition to LVH, the presence of a ‘strain pattern’ on an ECG is associated with increased risk.119 The prevalence of ECG LVH increases with the severity of hypertension.120 The most commonly used criteria to define ECG LVH are shown in Table 16.

The ECG cannot exclude LVH because it has poor sensitivity. When detailed information on cardiac structure and function will influence treatment decisions, echocardiography is recommended. When LVH is present on the ECG, it can be used to detect changes in LVH during follow-up in untreated and treated patients.121,122

5.5.1.2 Transthoracic echocardiography in hypertension

Echocardiographic LVH is a potent predictor of mortality in both hypertensive patients and the general population,123,124 and regression of echocardiographic LVH due to treatment of hypertension predicts an improved prognosis.125 Two-dimensional transthoracic echocardiography (TTE) also provides information about LV geometry, left atrial volume, aortic root dimensions, LV systolic and diastolic function, pump performance, and output impedance.123,126,127 Whether additional parameters other than evidence of increased LV mass and left atrial dilatation are useful to help stratify CV risk is uncertain.123,126,128 The partition values recommended for the definition of LVH by echocardiography are shown in Table 17.

Three-dimensional TTE is a more reliable method for quantitative analysis,129specifically for LV mass,130 volumes, and ejection fraction, and has superior reproducibility to two-dimensional TTE but much less prognostic validation.131 More detailed information on the use of echocardiography to assess the hypertensive heart is available.43 Cardiac magnetic resonance is the gold standard for cardiac anatomical and functional quantification.132–134

Abnormal LV geometry in hypertensive patients is frequently associated with diastolic dysfunction,127,135 which can be further evaluated by a combination of transmitral flow and tissue Doppler studies.136 Left atrial size is also frequently increased in hypertensive patients and is associated with adverse CV events128,137 and incident AF,138 and is related to diastolic dysfunction.139,140 During the diagnostic workup for secondary hypertension, a suprasternal view should also be performed for the identification of aortic coarctation.141

5.5.2 The blood vessels in hypertension

5.5.2.1 Carotid artery

Carotid intima-media thickness (IMT) quantified by carotid ultrasound, and/or the presence of plaques, predicts CV risk.42,142 This holds true both for the IMT value at the carotid bifurcations (reflecting primarily atherosclerosis) and for the IMT value at the level of the common carotid artery (reflecting primarily hypertension-related hypertrophy). A carotid IMT >0.9 mm is considered abnormal,143 but the upper limit of normality varies with age. The presence of a plaque can be identified by an IMT ≥1.5 mm, or by a focal increase in thickness of 0.5 mm or 50% of the surrounding carotid IMT value.144 Stenotic carotid plaques have a strong predictive value for both stroke and myocardial infarction, independent of traditional CV risk factors,42,142 and confer superior prognostic accuracy for future myocardial infarction compared with IMT.145 The presence of carotid plaques will automatically reclassify patients from intermediate to high risk;146,147 however, routine carotid imaging is not recommended unless clinically indicated (i.e. presence of carotid bruit, previous TIA or cerebrovascular disease, or as part of the assessment of patients with evidence of vascular disease).

5.5.2.2 Pulse wave velocity

Large artery stiffening is the most important pathophysiological determinant of isolated systolic hypertension and age-dependent increase in pulse pressure.148Carotid-femoral pulse wave velocity (PWV) is the gold standard for measuring large artery stiffness.149 Reference values for PWV are available in healthy populations and patients at increased CV risk.150 A PWV >10 m/s is considered a conservative estimate of significant alterations of aortic function in middle-aged hypertensive patients.149The additive value of PWV above and beyond traditional risk factors, including SCORE and the Framingham risk score, has been suggested by several studies.151However, routine use of PWV measurement is not practical and is not recommended for routine practice.

5.5.2.3 Ankle–brachial index

Ankle−brachial index (ABI) may be measured either with automated devices, or with a continuous wave Doppler unit and a BP sphygmomanometer. A low ABI (i.e.<0.9) indicates lower extremity artery disease (LEAD), is usually indicative of advanced atherosclerosis,152 and has predictive value for CV events,153 being associated with an almost two-fold greater 10 year CV mortality and major coronary event rate, compared with the overall rate in each Framingham category.153 Even asymptomatic LEAD, detected by a low ABI, is associated in men with a high incidence of CV morbid and fatal events, approaching 20% in 10 years.153,154 Routine use of ABI is not recommended in hypertensive patients, but should be considered in patients with symptoms or signs of LEAD, or in moderate-risk patients in whom a positive test would reclassify the patient as high-risk.

5.5.3 The kidney in hypertension

Hypertension is the second most important cause of CKD after diabetes. Hypertension may also be the presenting feature of asymptomatic primary renal disease. An alteration of renal function is most commonly detected by an increase in serum creatinine. This is an insensitive marker of renal impairment because a major reduction in renal function is needed before serum creatinine rises. Furthermore, BP reduction by antihypertensive treatment often leads to an acute increase in serum creatinine by as much as 20–30%, especially with renin−angiotensin system (RAS) blockers, which has a functional basis and does not usually reflect manifest renal injury, but the long-term clinical significance is unclear.155,156 The diagnosis of hypertension-induced renal damage is based on the finding of reduced renal function and/or the detection of albuminuria. CKD is classified according to estimated glomerular filtration rate (eGFR), calculated by the 2009 CKD-Epidemiology Collaboration formula.157

The albumin:creatinine ratio (ACR) is measured from a spot urine sample (preferably early morning urine), and is the preferred method to quantify urinary albumin excretion. A progressive reduction in eGFR and increased albuminuria indicate progressive loss of renal function, and are both independent and additive predictors of increased CV risk and progression of renal disease.158

Serum creatinine, eGFR, and ACR should be documented in all hypertensive patients, and if CKD is diagnosed, repeated at least annually.159 One negative urinary dipstick test does not rule out albuminuria, in contrast to a normal ACR.160

5.5.4 Hypertensive retinopathy

The prognostic significance of hypertensive retinopathy by fundoscopy has been well documented.161 Detection of retinal haemorrhages, microaneurysms, hard exudates, cotton wool spots, and papilloedema is highly reproducible, indicates severe hypertensive retinopathy, and is highly predictive of mortality.161,162 In contrast, evidence of arteriolar narrowing, either focal or general, and arteriovenous nicking at early stages of hypertensive retinopathy have less predictive value,163 and limited interobserver and intraobserver reproducibility, even with experienced observers.164Fundoscopy should be performed in patients with grade 2 or 3 hypertension or hypertensive patients with diabetes, in whom significant retinopathy is more likely. Fundoscopy may be considered in other hypertensive patients. The increasing emergence of new techniques to visualize the fundus through smartphone technologies should increase the feasibility of more routine fundoscopy.165

5.5.5 The brain in hypertension

Hypertension increases the prevalence of brain damage, of which transient ischaemic attack (TIA) and stroke are the most dramatic acute clinical manifestations. In the asymptomatic phase, brain damage can be detected by magnetic resonance imaging (MRI) as white matter hyperintensities, silent microinfarcts, (most of which are small and deep, i.e. lacunar infarctions), microbleeds, and brain atrophy.166,167 White matter hyperintensities and silent infarcts are associated with an increased risk of stroke and cognitive decline due to degenerative and vascular dementia.166–169 Availability and cost do not permit the widespread use of brain MRI for the evaluation of hypertensive patients, but white matter hyperintensity and silent brain infarcts should be sought in all hypertensive patients with neurological disturbances, cognitive decline, and, particularly, memory loss.168,169 A family history of cerebral haemorrhage at middle age and early-onset dementia should prompt MRI. Cognitive impairment in older patients is, at least in part, hypertension-related, and cognitive evaluation tests should be considered in the clinical assessment of hypertensive patients with a history suggestive of early cognitive impairment. The Mini-Mental State Examination has been the most widely used method in clinical trials, but is now being superseded by more sophisticated cognitive tests that are more suitable for routine clinic visits.170

5.6 Hypertension-mediated organ damage regression and cardiovascular risk reduction with antihypertensive treatment

As discussed above, HMOD assessment may play a role in stratifying the risk of patients with hypertension. In post hoc analyses, BP treatment-induced regression of some (but not all) manifestations of asymptomatic HMOD, as a consequence of treatment, is associated with a reduction in CV risk, thereby providing additional information on the effectiveness of treatment in individual patients.16,104,171 This has been best illustrated for the treatment-induced regression of LVH measured by either ECG or echocardiography.125,172,173 A reduced incidence of CV events and slower progression of renal disease has been reported with a treatment-induced reduction in urinary protein excretion in both diabetic and non-diabetic patients, especially for microalbuminuria,174 but results are discordant.175–179 There is also evidence that treatment-induced changes in eGFR predict CV events180 and progression to end-stage renal disease.181,182 Two meta-analyses183,184 failed to document any predictive value of treatment-induced reductions in carotid IMT for CV events. Evidence on the predictive power of treatment-induced changes on other measures of HMOD (PWV and ABI) are either limited or absent. Regression of HMOD might not be possible even when BP is controlled, particularly when HMOD is advanced, because some of the changes become irreversible.

The information available on the sensitivity and timing of changes in HMOD during antihypertensive treatment is summarized in Table 18. If, when, and how often the assessment of HMOD should be performed has not been validated in follow-up studies. HMOD can also develop during the course of antihypertensive treatment,185and this may be accompanied by increased risk.186–188

Table 18

Sensitivity to detect treatment-induced changes, reproducibility and operator independence, time to changes, and prognostic value of changes provided by markers of hypertension-mediated organ damage

CMR = cardiac magnetic resonance; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; HMOD = hypertension-mediated organ damage; IMT = intima-media thickness; LVH = left ventricular hypertrophy; PWV = pulse wave velocity.

5.7 When to refer a patient with hypertension for hospital-based care

Hypertension is a very common condition and most patients with hypertension, in most healthcare systems, will be managed in the primary care setting. However, there are circumstances in which a referral for routine hospital-based evaluation and treatment may be required, keeping in mind that in some instances out-of-office or office-based care of hypertensive patients depends on the healthcare organization of a given country:

• Patients in whom secondary hypertension is suspected (see section 8.2)

• Younger patients (<40 years) with grade 2 or more severe hypertension in whom secondary hypertension should be excluded

• Patients with treatment-resistant hypertension (see section 8.1)

• Patients in whom more detailed assessment of HMOD would influence treatment decisions

• Patients with sudden onset of hypertension when BP has previously been normal

• Other clinical circumstances in which the referring doctor feels more specialist evaluation is required.

There are also rarer circumstances in which a patient with hypertension should be referred to hospital for emergency care, which will often require inpatient care (see section 8.3).

Clinical evaluation and HMOD assessment

ABI = ankle–brachial index; CT = computed tomography; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; HMOD = hypertension-mediated organ damage; LEAD = lower extremity arterial disease; LV = left ventricular; LVH = left ventricular hypertrophy; MRI = magnetic resonance imaging; PWV = pulse wave velocity; TIA = transient ischaemic attack.

a

Class of recommendation.

b

Level of evidence.

6 Genetics and hypertension

A positive family history is a frequent feature in hypertensive patients, with the heritability estimated to vary between 35 and 50% in most studies.191,192 However, hypertension is a highly heterogeneous disorder with a multifactorial aetiology. Several genome-wide association studies and their meta-analyses have identified 120 loci that are associated with BP regulation, but together these only explain about 3.5% of the trait variance.193 Several rare, monogenic forms of hypertension have been described such as glucocorticoid-remediable aldosteronism, Liddle’s syndrome, and others, where a single gene mutation fully explains the pathogenesis of hypertension and dictates the best treatment modality.194–196 There are also inherited forms of phaeochromocytoma and paraganglioma, which are also rare causes of hypertension.197–200 Outside of specialist clinics evaluating patients for these rare causes of secondary hypertension, there is no role for genetic testing in hypertension in routine clinical care.

Genetic testing and hypertension

a

Class of recommendation.

b

Level of evidence.