Table of Contents
1 PREAMBLE 1956
2 INTRODUCTION 1957
2.1 What is new and what has changed in the 2018 ESC/ESH Arterial Hypertension Guidelines? 1958
3 DEFINITION, CLASSIFICATION, AND EPIDEMIOLOGICAL ASPECTS OF HYPERTENSION 1960
3.1 Definition of hypertension 1960
3.2 Classification of blood pressure 1960
3.3 Prevalence of hypertension 1960
3.4 Blood pressure relationship with risk of cardiovascular and renal events 1961
3.5 Hypertension and total cardiovascular risk assessment 1961
3.6 Importance of hypertension-mediated organ damage in refining cardiovascular risk assessment in hypertensive patients 1962
3.7 Challenges in cardiovascular risk assessment 1963
4 BLOOD PRESSURE MEASUREMENT 1964
4.1 Conventional office blood pressure measurement 1964
4.2 Unattended office blood pressure measurement 1964
4.3 Out-of-office blood pressure measurement 1965
4.4 Home blood pressure monitoring 1965
4.5 Ambulatory blood pressure monitoring 1965
4.6 Advantages and disadvantages of ambulatory blood pressure monitoring and home blood pressure monitoring 1965
4.7 White-coat hypertension and masked hypertension 1966
4.7.1 White-coat hypertension 1966
4.7.2 Masked hypertension 1967
4.8 Screening for the detection of hypertension 1967
4.9 Confirming the diagnosis of hypertension 1967
4.10 Clinical indications for out-of-office blood pressure measurements 1967
4.11 Blood pressure during exercise and at high altitude 1968
4.12 Central aortic pressure 1968
5 CLINICAL EVALUATION AND ASSESSMENT OF HYPERTENSION-MEDIATED ORGAN DAMAGE IN PATIENTS WITH HYPERTENSION 1969
5.1 Clinical evaluation 1969
5.2 Medical history 1969
5.3 Physical examination and clinical investigations 1970
5.4 Assessment of hypertension-mediated organ damage 1970
5.4.1 Using hypertension-mediated organ damage to help stratify risk in hypertensive patients 1971
5.5 Characteristics of hypertension-mediated organ damage 1972
5.5.1 The heart in hypertension 1972
5.5.2 The blood vessels in hypertension 1972
5.5.3 The kidney in hypertension 1973
5.5.4 Hypertensive retinopathy 1973
5.5.5 The brain in hypertension 1973
5.6 Hypertension-mediated organ damage regression and cardiovascular risk reduction with antihypertensive treatment 1974
5.7 When to refer a patient with hypertension for hospital-based care 1974
6 GENETICS AND HYPERTENSION 1975
7 TREATMENT OF HYPERTENSION 1976
7.1 Beneficial effects of blood pressure-lowering therapy in hypertension 1976
7.2 When to initiate antihypertensive treatment 1976
7.2.1 Recommendations in previous guidelines 1976
7.2.2 Drug treatment for patients with grade 1 hypertension at low–moderate cardiovascular risk 1976
7.2.3 Initiation of blood pressure-lowering drug treatment in older people with grade 1 hypertension 1977
7.2.4 Initiation of blood pressure-lowering drug treatment in patients with high–normal blood pressure 1977
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? 1978
7.2.6 Initiation of blood pressure-lowering drug treatment 1978
7.3 Blood pressure treatment targets 1979
7.3.1 New evidence on SBP and diastolic blood pressure treatment targets 1979
7.3.2 Blood pressure targets in specific subgroups of hypertensive patients 1980
7.4 Treatment of hypertension 1982
7.4.1 Lifestyle changes 1982
7.4.2 Dietary sodium restriction 1982
7.4.3 Moderation of alcohol consumption 1983
7.4.4 Other dietary changes 1983
7.4.5 Weight reduction 1983
7.4.6 Regular physical activity 1983
7.4.7 Smoking cessation 1984
7.5 Pharmacological therapy for hypertension 1985
7.5.1 Drugs for the treatment of hypertension 1985
7.5.2 Drug treatment strategy for hypertension 1986
7.5.3 The drug treatment algorithm for hypertension 1990
7.6 Device-based hypertension treatment 1991
7.6.1 Carotid baroreceptor stimulation (pacemaker and stent) 1991
7.6.2 Renal denervation 1992
7.6.3 Creation of an arteriovenous fistula 1994
7.6.4 Other devices 1994
8 HYPERTENSION IN SPECIFIC CIRCUMSTANCES 1995
8.1 Resistant hypertension 1960
8.1.1 Definition of resistant hypertension 1960
8.1.2 Pseudo-resistant hypertension 1960
8.1.3 Diagnostic approach to resistant hypertension 1960
8.1.4 Treatment of resistant hypertension 1960
8.2 Secondary hypertension 1960
8.2.1 Drugs and other substances that may cause secondary hypertension 1960
8.2.2 Genetic causes of secondary hypertension 1960
8.3 Hypertension urgencies and emergencies 1960
8.3.1 Acute management of hypertensive emergencies 1960
8.3.2 Prognosis and follow-up 1960
8.4 White-coat hypertension 1960
8.5 Masked hypertension 1960
8.6 Masked uncontrolled hypertension 1960
8.7 Hypertension in younger adults (age < 50 years) 1960
8.7.1 Isolated systolic hypertension in the young 1960
8.8 Hypertension in older patients (age ≥65 years) 1960
8.9 Women, pregnancy, oral contraception and hormone-replacement therapy 1960
8.9.1 Hypertension and pregnancy 1960
8.9.2 Oral contraceptive pills and hypertension 1960
8.9.3 Hormone-replacement therapy and hypertension 1960
8.10 Hypertension in different ethnic groups 1960
8.11 Hypertension in diabetes mellitus 1960
8.12 Hypertension and chronic kidney disease 1960
8.13 Hypertension and chronic obstructive pulmonary disease 1960
8.14 Hypertension and heart disease 1960
8.14.1 Coronary artery disease 1960
8.14.2 Left ventricular hypertrophy and heart failure 1960
8.15 Cerebrovascular disease and cognition 1960
8.15.1 Acute intracerebral haemorrhage 1960
8.15.2 Acute ischaemic stroke 1960
8.15.3 Previous stroke or transient ischaemic attack 1960
8.15.4 Cognitive dysfunction and dementia 1960
8.16 Hypertension, atrial fibrillation, and other arrhythmias 1960
8.16.1 Oral anticoagulants and hypertension 1960
8.17 Hypertension and vascular disease 1960
8.17.1 Carotid atherosclerosis 1960
8.17.2 Arteriosclerosis and increased arterial stiffness 1960
8.17.3 Lower extremity arterial disease 1960
8.18 Hypertension in valvular disease and aortopathy 1960
8.18.1 Coarctation of the aorta 1960
8.18.2 Prevention of aortic dilation and dissection in high-risk subjects 1960
8.18.3 Hypertension bicuspid aortic valve-related aortopathy 1960
8.19 Hypertension and sexual dysfunction 1960
8.20 Hypertension and cancer therapy 1960
8.21 Perioperative management of hypertension 1960
9 MANAGING CONCOMITANT CARDIOVASCULAR DISEASE RISK 1960
9.1 Statins and lipid-lowering drugs 1960
9.2 Antiplatelet therapy and anticoagulant therapy 1960
9.3. Glucose-lowering drugs and blood pressure 1960
10 PATIENT FOLLOW-UP 1960
10.1 Follow-up of hypertensive patients 1960
10.2 Follow-up of subjects with high–normal blood pressure and white-coat hypertension 1960
10.3 Elevated blood pressure at control visits 1960
10.4 Improvement in blood pressure control in hypertension: drug adherence 1960
10.5 Continued search for asymptomatic hypertension-mediated organ damage 1960
10.6 Can antihypertensive medications be reduced or stopped? 1960
11 GAPS IN THE EVIDENCE 1960
12 KEY MESSAGES 1960
13 ‘WHAT TO DO’ AND ‘WHAT NOT TO DO’ MESSAGES FROM THE GUIDELINES 1960
14 APPENDIX 1960
15 REFERENCES 1960
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 organizations. 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
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
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 in a shortened version in 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 nonspecialists and an electronic version for digital applications (smartphones, APPs, 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 European Heart Journal 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 judgement, 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] [11–14]
These 2018 ESC/ESH Guidelines for the management of arterial hypertension are designed for adults with hypertension, that is aged at least 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 to base recommendations on properly conducted studies, identified from an extensive review of the literature; to give the highest priority to data from randomized controlled trials (RCTs); 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 nonrandomized); 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; to grade the level of scientific evidence and the strength of recommendations according to ESC recommendations (see Section 1); to recognize that opinions may differ on key recommendations, which are resolved by voting; and 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 and renal events is continuous, making the distinction between normotension and hypertension, based on cut-off BP values, somewhat arbitrary [2,4,8] Table 3 ) [15–17]
TABLE 3: Classification of office blood pressurea and definitions of hypertension gradeb
Hypertension is defined as office SBP values at least 140 mmHg and/or diastolic BP (DBP) values at least 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 or less of age can be found in the 2016 ESH Guidelines for children and adolescents [18]
3.2 Classification of blood pressure
Classification of BP
3.3 Prevalence of hypertension
Based on office BP, the global prevalence of hypertension was estimated to be 1.13 billion in 2015 [5] [12] [5] [12] [12] [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] [3] [3]
Both office BP and out-of-office BP have an independent and continuous relationship with the incidence of several cardiovascular events [haemorrhagic stroke, ischaemic stroke, myocardial infarction, sudden death, heart failure, and peripheral artery disease (PAD)], as well as end-stage renal disease [4] [20] [21,22]
The continuous relationship between BP and risk of events has been shown at all ages [23] [24,25] [23,26,27] [26] [28,29]
3.5 Hypertension and total cardiovascular risk assessment
Hypertension rarely occurs in isolation, and often clusters with other cardiovascular risk factors such as dyslipidaemia and glucose intolerance [30,31] [32]
Many cardiovascular 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 [33] [34] [35]
Factors influencing cardiovascular 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 cardiovascular risk (Table 5 ). Such patients do not need formal cardiovascular risk estimation to determine their need for treatment of their hypertension and other cardiovascular risk factors. For all other hypertensive patients, estimation of 10-year cardiovascular risk using the SCORE system is recommended. Estimation should be complemented by assessment of hypertension-mediated organ damage (HMOD), which can also increase cardiovascular risk to a higher level, even when asymptomatic (see Table 4 and Sections 3.6 and 4).
TABLE 4: Factors influencing cardiovascular risk in patients with hypertension
TABLE 5: Ten year cardiovascular risk categories (Systematic COronary Risk Evaluation system)
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 cardiovascular 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 cardiovascular events. The risk of total cardiovascular events (fatal and nonfatal) is approximately three times higher than the rate of fatal cardiovascular 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 cardiovascular risk (Table 6 ) as well as specific cardiovascular risk modifiers for patients with hypertension. Cardiovascular risk modifiers are particularly important at the cardiovascular 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 cardiovascular risk factor management. Furthermore, cardiovascular risk estimates by the SCORE system may be modified in first-generation immigrants to Europe and cardiovascular risk scores in such patients may be adjusted by correction factors (Table 7 ). Further details of the impact of cardiovascular risk modifiers are available from the ESC 2016 CVD prevention Guidelines [35]
TABLE 6: Risk modifiers increasing cardiovascular risk estimated by the Systemic COronary Risk Evaluation (SCORE) system
[35] TABLE 7: Correction factors for the Systemic COronary Risk Evaluation (SCORE) cardiovascular risk estimates in first-generation immigrants to Europe
[35] 3.6 Importance of hypertension-mediated organ damage in refining cardiovascular risk assessment in hypertensive patients
A unique and important aspect of cardiovascular 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: 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 cardiovascular risk even in the absence of classical cardiovascular risk factors; the presence of HMOD is common and often goes undetected [38] [39–41] [42] [43] Figure 1 for middle-aged individuals.
FIGURE 1: Classification of hypertension stages according to blood pressure levels, presence of cardiovascular risk factors, hypertension-mediated organ damage, or comorbidities. Cardiovascular risk is illustrated for a middle-aged male. The cardiovascular risk does not necessarily correspond to the actual risk at different ages. The use of the SCORE system is recommended for formal estimation of cardiovascular risk for treatment decisions. BP, blood pressure; CKD, chronic kidney disease; DBP, diastolic blood pressure; HMOD, hypertension-mediated organ damage; SBP, systolic blood pressure; SCORE, Systematic COronary Risk Evaluation.
3.7 Challenges in cardiovascular risk assessment
Cardiovascular risk is strongly influenced by age (i.e. older people are invariably at high absolute cardiovascular 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 ‘cardiovascular 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] www.heartscore.org
A second consideration is that the presence of concomitant disease is often recorded in a binary way in cardiovascular risk assessment systems (e.g. diabetes, yes/no). This does not reflect the impact of the severity or duration of concomitant diseases on total cardiovascular 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 cardiovascular risk assessment in a patient who is receiving treatment for hypertension. If treatment was commenced recently, it seems appropriate to use the pretreatment 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 cardiovascular 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 cardiovascular risk in clinical practice.
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] [45]
In older people, people with diabetes, or people with other causes of orthostatic hypotension, BP should also be measured 1 and 3 min after standing. Orthostatic hypotension is defined as a reduction in SBP of at least 20 mmHg or in DBP of at least 10 mmHg within 3 min of standing, and is associated with an increased risk of mortality and cardiovascular events [46] [47] 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.
TABLE 8: Office blood pressure measurement
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 reduced [48] [49] [50] [51] [52] [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 ABPM [54] [55] [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 at least 135/85 mmHg (equivalent to office BP at least 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] [59] [60,61] [62] [63,64]
TABLE 9: Definitions of hypertension according to office, ambulatory, and home blood pressure levels
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, nighttime, 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 at least 130/80 mmHg over 24 h, at least 135/85 mmHg for the daytime average, and at least 120/70 for the nighttime average (all equivalent to office BP ≥140/90 mmHg), see Table 9 .
ABPM is a better predictor of HMOD than office BP [65] [66–68] [68–72]
BP normally decreases during sleep. Although the degree of nighttime 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 more than 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] [54] [54] [54] [74] [75]
A number of additional indices derived from ABPM recordings have some prognostic value, including 24 h BP variability [76] [77] [78]
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]
TABLE 10: Comparison of ambulatory blood pressure monitoring and home blood pressure monitoring
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-guided 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] [81] [82] [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]
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 nonsmokers. 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 [68,85,86] [87] [82] [85,86,88–90] [91] [68] [82]
4.7.2 Masked hypertension
Masked hypertension can be found in approximately 15% of patients with a normal office BP [17] [54] [17] [92] [81,93] [68] [68,93–96] [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]
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, cardiovascular 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 (Fig. 2 ) [99] [100] 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 ).
FIGURE 2: Screening and diagnosis of hypertension. ABPM, ambulatory blood pressure monitoring; BP, blood pressure; HBPM, home blood pressure monitoring.
TABLE 11: Clinical indications for home blood pressure monitoring or ambulatory blood pressure monitoring
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]
4.11 Blood pressure during exercise and at high altitude
It is important to recognize that BP increases during dynamic and static exercise, and that the increase is more pronounced for SBP than for DBP [103] [104]
Evidence is available that BP increases with high altitude exposure, especially above 3000 m and possibly above 2000 m [105] [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] [108] [109] [110,111]
BP measurement
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 cardiovascular risk factors (including lifestyle and family history); identify concomitant diseases and establish whether there is evidence of HMOD or existing cardiovascular, 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 cardiovascular 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
TABLE 12: Key information to be collected in personal and family medical history
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 .
TABLE 13: Key steps in physical examination
TABLE 14: Routine workup for evaluation of hypertensive patients
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 preclinical or asymptomatic CVD [112] [43] [16,113,114] [115,116] [116] Table 15 .
TABLE 15: Assessment of hypertension-mediated organ damage
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 cardiovascular 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 risk [35]
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] [114] 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]
5.5 Characteristics of hypertension-mediated organ damage
5.5.1 The heart in hypertension
Chronically increased left ventricular workload in hypertensive patients can result in LVH, impaired left ventricular 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 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 cardiovascular risk factors and echocardiographic left ventricular mass [118] [119] [120] Table 16 .
TABLE 16: The most commonly used simple criteria and recognized cut-off points for definitions of electrocardiogram left ventricular hypertrophy
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] [125] [123,126,127] [123,126,128] Table 17 .
TABLE 17: Echocardiographic definitions of left ventricular hypertrophy, concentric geometry, left ventricular chamber size, and left atrial dilatation
Three-dimensional TTE is a more reliable method for quantitative analysis [129] [130] [131] [43] [132–134]
Abnormal left ventricular geometry in hypertensive patients is frequently associated with diastolic dysfunction [127,135] [136] [128,137] [138] [139,140] [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 cardiovascular risk [42,142] [143] [144] [42,142] [145] [146,147]
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 [148] [149] [150] [149] [151]
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] [153] [153] [153,154]
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] [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 cardiovascular 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] [160]
5.5.4 Hypertensive retinopathy
The prognostic significance of hypertensive retinopathy by fundoscopy has been well documented [161] [161,162] [163] [164] [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 MRI as white matter hyperintensities, silent microinfarcts, (most of which are small and deep, i.e. lacunar infarctions), microbleeds and brain atrophy [166,167] [166–169] [168,169] [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 cardiovascular risk, thereby providing additional information on the effectiveness of treatment in individual patients [16,104,171] [125,172,173] [174] [175–179] [180] [181,182] [183,184]
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 [185] [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
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
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] [193] [194–196] [197–200]
Genetic testing and hypertension
7 TREATMENT OF HYPERTENSION
7.1 Beneficial effects of blood pressure-lowering therapy in hypertension
There are two well established strategies to lower BP: lifestyle interventions and drug treatment. Device-based therapy is also emerging, but is not yet proven as an effective treatment option. Lifestyle interventions can undoubtedly lower BP and in some cases cardiovascular risk (see Section 7.4.1), but most patients with hypertension will also require drug treatment. The drug treatment of hypertension is founded on very solid evidence, underpinned by the largest number of outcome-based RCTs in clinical medicine. Meta-analyses of RCTs including several hundred thousand patients have shown that a 10 mmHg reduction in SBP or a 5 mmHg reduction in DBP is associated with significant reductions in all major cardiovascular events by 20%, all-cause mortality by 10–15%, stroke by 35%, coronary events by 20%, and heart failure by 40% [2,8] [2,201]
Relative outcome reductions calculated by two recent meta-analyses are similar to those provided by the original meta-analysis of the effects of BP lowering on outcomes in 1994 [202]
Another important objective of antihypertensive therapy is to reduce the development of CKD; however, the slow rate of decline in renal function in most hypertensive patients makes the demonstration of potential benefits of BP lowering difficult. Consequently, the protective effect of BP reduction on kidney function can be less obvious and has been restricted to patients with diabetes or CKD, in whom there is a faster rate of disease progression [203] [2]
The recommendations that follow are based on outcome evidence from RCTs; however, it must be acknowledged that RCTs based on clinical outcomes have limitations, the most important of which are that the data are largely limited to older and high-risk patients, preferentially recruited to increase statistical power, and over a relatively short duration of follow-up, rarely beyond 5 years. This means that recommendations for life-long treatment for younger and lower risk patients are necessarily based on considerable extrapolation. Big data, now being collected by national health system registries, health insurance companies, and prolonged observational follow-up of RCTs, are becoming an important source of long-term information on the effects of chronic treatment [204] [205–207] [206]
7.2 When to initiate antihypertensive treatment
7.2.1 Recommendations in previous guidelines
All guidelines agree that patients with grade 2 or 3 hypertension should receive antihypertensive drug treatment alongside lifestyle interventions [208] [17,209,210]
7.2.2 Drug treatment for patients with grade 1 hypertension at low-moderate cardiovascular risk
Recent meta-analyses show significant treatment-induced reductions in cardiovascular events and mortality in patients with grade 1 hypertension [8,201,211] [211] [8] [201] [212]
Based on these new data, this Task Force now recommends that lifestyle advice should be accompanied by BP-lowering drug treatment in patients with grade 1 hypertension at low–moderate cardiovascular risk.
7.2.3 Initiation of blood pressure-lowering drug treatment in older people with grade 1 hypertension
Discussion about the treatment of ‘the elderly’ or ‘older’ people has been complicated by the various definitions of older age used in RCTs. For example, older was defined as more than 60 years in the earliest trials, then as 65, 70 and finally 75 [51] [213] [17] [210,214]
Undoubtedly, there are RCTs showing outcome benefits with BP-lowering treatment in older patients whose baseline BP was in a lower SBP range, but these patients were often on background antihypertensive treatment, thus they cannot be defined as having true grade 1 hypertension. This is also the case for the data recently published from the SPRINT trial, which included a cohort of patients older than 75 years, in whom more intense BP lowering reduced the risk of major cardiovascular events and mortality [51,215] [212]
The evidence supports the recommendation that older patients (>65 years, including patients over 80 years) should be offered BP-lowering treatment if their SBP is at least 160 mmHg. There is also justification to now recommend BP-lowering treatment for old patients (aged >65 but not >80 years) at a lower BP (i.e. grade 1 hypertension; SBP = 140–159 mmHg) [201] [213] [216] [214]
7.2.4 Initiation of blood pressure-lowering drug treatment in patients with high-normal blood pressure
The previous (2013) Guidelines [17]
In all RCTs (including SPRINT) [51] [2] [8]
The HOPE-3 trial [212]
A meta-analysis of 13 RCTs or RCT subgroups (involving 21 128 individuals) in patients at low–moderate cardiovascular risk and untreated baseline BP in the high–normal and normal range, showed no effect of BP-lowering treatment on any cardiovascular outcomes [217]
Another recent analysis, including patients with high–normal BP, concluded that primary preventive BP lowering was associated with reduced risk for death and incident CVD if baseline SBP was 140 mmHg or higher, but at lower BP levels [i.e. high–normal BP (<140/90 mmHg)], treatment was not associated with any benefit in primary prevention [201]
The situation may be different in very high-risk patients with a high–normal BP and established CVD. In a meta-analysis of 10 RCTs or RCT subgroups that also included individuals at high or very high cardiovascular risk, mostly with previous CVD and untreated high–normal and normal BP (n = 26 863), BP-lowering drug treatment, achieving an SBP reduction of 4 mmHg, reduced the risk of stroke but not any other cardiovascular events [217] [201]
We recommend that patients with high–normal BP and low–moderate cardiovascular risk should be offered lifestyle advice, because this reduces their risk of progressing to established hypertension and may further reduce their cardiovascular risk. These patients should not be offered BP-lowering drug treatment. Nevertheless, based on the data from the HOPE-3 trial, drug treatment may be considered in these patients if their BP is close to the hypertension diagnostic threshold of 140/90 mmHg, after a prolonged attempt to control BP with lifestyle changes.
BP-lowering drugs may be considered for patients with high–normal BP and established CVD, especially CAD. In these patients, monotherapy may be sufficient.
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?
Two recent meta-analyses of RCTs [8,218] [218] [8] [201]
7.2.6 Initiation of blood pressure-lowering drug treatment
In patients with grade 2 or 3 hypertension, it is recommended that BP-lowering drug treatment should be initiated alongside lifestyle interventions. In patients with grade 1 hypertension at high risk or with HMOD, drug treatment should also be initiated simultaneously with lifestyle interventions. In lower-risk patients with grade 1 hypertension, BP-lowering drug treatment should be initiated after 3–6 months if BP is not controlled by lifestyle interventions alone (Fig. 3 ). Recommended BP thresholds for the initiation of antihypertensive drug treatment are shown in Table 19 .
Initiation of hypertension treatment according to office BP
Figure FIGURE 3: Initiation of blood pressure-lowering treatment (lifestyle changes and medication) at different initial office blood pressure levels. BP, blood pressure; CAD, coronary artery disease; CVD, cardiovascular disease; HMOD, hypertension-mediated organ damage.
TABLE 19: Summary of office blood pressure thresholds for treatment
7.3 Blood pressure treatment targets
7.3.1 New evidence on SBP and diastolic blood pressure treatment targets
The 2013 ESH/ESC hypertension Guidelines [17] [222–224]
A recent RCT relevant to the issue of target BP is SPRINT, which compared two different SBP targets (<140 or <120 mmHg) in more than 9000 patients at high cardiovascular risk, but excluded patients with diabetes or previous stroke. More intensive BP-lowering treatment (achieved SBP 121 vs. 136 mmHg) was associated with a 25% reduction in major cardiovascular events and a 27% reduction in all-cause death (but no significant reduction in stroke or myocardial infarction) [51] [225] [52,54]
Some new information on SBP and DBP targets for drug treatment has been provided by two recent, large meta-analyses of RCTs of BP lowering. In the first of these meta-analyses, achieved SBP was stratified according to three SBP target ranges (149–140, 139–130 and <130 mmHg) [226] [226]
The second meta-analysis, which also included the SPRINT trial [2]
Finally, in the first meta-analysis [226] [227]
Whilst considering BP targets, it is important to acknowledge that less than 50% of patients treated for hypertension currently achieve a target office SBP of less than 140 mmHg [11,12]
This Task Force recommends that when BP-lowering drugs are used, the first objective should be to lower BP to <140/90 mmHg in all patients. Provided that the treatment is well tolerated, treated BP values should be targeted to 130/80 mmHg or lower in most patients, although in some groups the evidence is less compelling. In older patients (>65 years), SBP should be targeted to between 130 and 140 mmHg, and DPB to less than 80 mmHg. Treated SBP should not be targeted to less than 120 mmHg.
Importantly, we specify a target range because the lower safety boundary assumes greater importance when BP is targeted to lower levels. Furthermore, in general, when SBP is lowered to less than 120 mmHg in patients included in RCTs (i.e. older and higher-risk patients, often with comorbidities and CVD), the risk of harm appears to increase and outweigh the benefits [222]
7.3.2 Blood pressure targets in specific subgroups of hypertensive patients
7.3.2.1 Diabetes mellitus
RCTs in type 1 diabetes mellitus demonstrate that BP-lowering treatment has a renoprotective effect [228]
In contrast, there have been many BP-lowering treatment RCTs, either exclusively dedicated to patients with type 2 diabetes or hypertension trials that have included a large cohort of patients with type 2 diabetes [2]
A large RCT in patients with type 2 diabetes has shown that an achieved SBP of less than 135 mmHg, compared with 140 mmHg, was associated with a significant reduction in cardiovascular and all-cause mortality [229]
Evidence from another large RCT in patients with type 2 diabetes showed that, compared with patients with an on-treatment SBP of 135 mmHg, reducing SBP to 121 mmHg did not reduce cardiovascular morbidity and mortality or all-cause death, but substantially reduced the risk of stroke [230]
Although one recent meta-analysis concluded that most of the benefit associated with BP lowering was obtained at higher BP targets (i.e. <150 mmHg but not <140 mmHg) [231] [1,232–234]
Two of the meta-analyses concluded that the overall benefit of lowering BP in patients with type 2 diabetes (unlike patients without type 2 diabetes) largely disappears when SBP is lowered to less than 130/80 mmHg [1,235]
Similar evidence for stroke benefit from lower achieved SBP has also been reported from post-hoc analysis of diabetic patients in the ONTARGET (Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) study. In addition, reanalysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) [230] [236]
Further recent analysis of the ACCORD trial has shown that reducing SBP to less than 120 mmHg was associated with increased risk of major cardiovascular events [236]
With regard to DBP, earlier evidence suggested a benefit on major cardiovascular events when DBP was lowered to less than 85 mmHg [237,238] [229]
In summary, in patients with diabetes receiving BP-lowering drugs, it is recommended that office BP should be targeted to an SBP of 130 mmHg [229] [213] [239–241]
7.3.2.2 Older patients
The definition of ‘older’ is complex. As populations age, there is increasingly wide variation between a patient's chronological age and their functional status, ranging from fit, active, and independent, through to frail and dependent. The anticipated benefits vs. potential harm of BP treatment in older patients will be influenced by the patient's ability to tolerate treatment and their health and functional status. For the purposes of these Guidelines, ‘older’ patients are defined as those aged at least 65 years.
In the 2013 ESH/ESC hypertension Guidelines, the target SBP for older hypertensive patients was set at 140–150 mmHg because this was the range of systolic values achieved by major outcome trials demonstrating a beneficial effect of antihypertensive treatment in these patients. A similar SBP target was suggested by the HYVET trial, in which treating to an SBP target of less than 150 mmHg (achieving a mean SBP of 144 mmHg) in the very old (>80 years) demonstrated significant reductions in mortality, fatal stroke, and heart failure, with the caveat that the ‘very old’ patients in this study were active and independent [213]
The SPRINT trial included a high proportion of patients over the age of 75 years (n = 2636) and demonstrated that more intensive BP-lowering treatment (mean achieved BP = 124/62 mmHg) significantly reduced the risk of major cardiovascular events, heart failure, and all-cause death (all by >30%) compared with standard treatment (mean achieved BP = 135/67 mmHg) [215] [225,242]
Although HYVET and most other RCTs in older patients have recruited relatively fit and independent patients, the SPRINT study also suggested that there are benefits of more intensive treatment being extended to older patients who are at the frailer end of the spectrum of patients meeting the recruitment criteria, with reduced gait speed [215]
Based on the new data, the targets suggested by the previous Guidelines now appear too conservative for many old and very old patients, especially those who are active and independent. Consequently, we recommend that in older patients treated for hypertension, BP should be lowered to less than 140/80 mmHg, but not below an SBP of 130 mmHg. Importantly, the impact of BP-lowering on the well being of the patient should be closely monitored, because the increased risk of adverse events (e.g. injurious falls) with lower BP values could be more pronounced in older patients in the real-life setting than in the closely monitored conditions of RCTs. Further details on the approach to treatment of the frail older patient are discussed in Section 8.8.
7.3.2.3 Office vs. home and ambulatory blood pressure targets
No outcome-based RCT has used ABPM or HBPM to guide the treatment of hypertension. Thus, ABPM and HBPM BP targets are based on extrapolation from observational data rather than on outcome trials. Although we do not provide formal ABPM or HBPM BP targets for treated patients, it should be noted that:
In population studies, the difference between office and out-of-office BP levels decreases as office BP decreases, to a point of around 115–120/70 mmHg, at which office and 24 h ABPM mean BP values are usually similar [54]
This convergence has also been confirmed in treated patients [243]
In treated patients, a target office SBP of 130 mmHg might therefore correspond to a slightly lower mean 24 h SBP, that is approximately 125 mmHg.
Although there are no available data, the home SBP target, to be equivalent to an office SBP target of 130 mmHg, might also be lower than 130 mmHg.
Office BP treatment targets in hypertensive patients
7.4 Treatment of hypertension
7.4.1 Lifestyle changes
Healthy lifestyle choices can prevent or delay the onset of hypertension and can reduce cardiovascular risk [17,35] [245,246] [17] [35]
7.4.2 Dietary sodium restriction
There is evidence of a causal relationship between sodium intake and BP, and excessive sodium consumption (>5 g sodium per day, e.g. one small teaspoon of salt per day) has been shown to have a pressor effect and be associated with an increased prevalence of hypertension and the rise in SBP with age [247] [248] [249] [250,251]
The effect of reduced dietary sodium on cardiovascular events remains unclear [252–255] [256] [257] [254,255,258] [259]
Globally, usual sodium intake is between 3.5 and 5.5 g/day (which corresponds to 9–12 g of salt per day), with marked differences between countries and even between regions within countries. We recommend sodium intake to be limited to approximately 2.0 g/day (equivalent to approximately 5.0 g salt per day) in the general population and to try to achieve this goal in all hypertensive patients. Effective salt reduction is not easy and there is often poor appreciation of which foods contain high salt levels. Advice should be given to avoid added salt and high-salt foods. A reduction in population salt intake remains a public health priority but requires a combined effort between the food industry, governments, and the public in general, as 80% of salt consumption involves hidden salt in processed foods.
7.4.3 Moderation of alcohol consumption
There is a long-established positive linear association between alcohol consumption, BP, the prevalence of hypertension and CVD risk. Binge drinking can have a strong pressor effect [17] [260] [261] [35]
7.4.4 Other dietary changes
Hypertensive patients should be advised to eat a healthy balanced diet containing vegetables, legumes, fresh fruits, low-fat dairy products, whole grains, fish, and unsaturated fatty acids (especially olive oil), and to have a low consumption of red meat and saturated fatty acids [262–264] [262–265] [265] [266] [35]
With regard to coffee consumption, caffeine has been shown to have an acute pressor effect [267] [267] [268,269]
Regular consumption of sugar-sweetened soft drinks has been associated with overweight, metabolic syndrome, type 2 diabetes, and higher cardiovascular risk. The consumption of these drinks should be discouraged [35]
Thus, adopting a healthy and balanced diet may assist in BP reduction and also reduce cardiovascular risk.
7.4.5 Weight reduction
Excessive weight gain is associated with hypertension, and reducing weight towards an ideal body weight decreases BP [270] [271] [272] 2 , whereas a more recent meta-analysis concluded that mortality was lowest in subjects with overweight [273,274] 2 in people <60 years of age; higher in older patients) and waist circumference (<94 cm for men and <80 cm for women) is recommended for nonhypertensive individuals to prevent hypertension, and for hypertensive patients to reduce BP [35] [35,275] [276]
7.4.6 Regular physical activity
Physical activity induces an acute rise in BP, especially SBP, followed by a short-lived decline in BP below baseline. Epidemiological studies suggest that regular aerobic physical activity may be beneficial for both the prevention and treatment of hypertension, and to lower cardiovascular risk and mortality. A meta-analysis of RCTs, which rely on self-reported exercise and are by necessity unblinded, has shown that aerobic endurance training, dynamic resistance training and isometric training reduce resting SBP and DBP by 3.5/2.5, 1.8/3.2 and 10.9/6.2 mmHg, respectively, in general populations [277] [278,279] [35] [280]
7.4.7 Smoking cessation
Smoking is a major risk factor for CVD and cancer. Although the rate of smoking is declining in most European countries, especially in men, it is still common in many regions and age groups, and overall the prevalence remains high at 20–35% in Europe [281] [282] [283] [284] [285,286]
Brief advice from a physician has a small but significant effect of 1–3% over and above the unassisted 12-month quit rate [287] [288] [289]
Lifestyle interventions for patients with hypertension or high-normal BP
7.5 Pharmacological therapy for hypertension
7.5.1 Drugs for the treatment of hypertension
Most patients will require drug therapy in addition to lifestyle measures to achieve optimal BP control. In the previous Guidelines, five major drug classes were recommended for the treatment of hypertension: ACE inhibitors, ARBs, beta-blockers, CCBs, and diuretics (thiazides and thiazide-like diuretics such as chlorthalidone and indapamide), based on: proven ability to reduce BP; evidence from placebo-controlled studies that they reduce cardiovascular events; and evidence of broad equivalence on overall cardiovascular morbidity and mortality, with the conclusion that benefit from their use predominantly derives from BP lowering. These conclusions have since been confirmed by recent meta-analyses [1,2,217,292] Table 20 ) and preferential use of some drugs for some conditions, as discussed below. There is also evidence that there are differences in the persistence and discontinuation rates of the major drug classes [293,294]
TABLE 20: Compelling and possible contraindications to the use of specific antihypertensive drugs
Other classes of drugs have been less widely studied in event-based RCTs or are known to be associated with a higher risk of adverse effects [e.g. alpha-blockers, centrally acting agents, and mineralocorticoid receptor antagonists (MRAs)]. These are useful additions to the antihypertensive armamentarium in patients whose BP cannot be controlled by proven combinations of the aforementioned major drug classes.
7.5.1.1 Blockers of the renin-angiotensin system (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers)
Both ACE inhibitors and ARBs are among the most widely used classes of antihypertensive drugs. They have similar effectiveness [295,296] [2,292] [297] [294] [298,299] [291]
Both ACE inhibitors and ARBs reduce albuminuria more than other BP-lowering drugs and are effective at delaying the progression of diabetic and nondiabetic CKD [217] [217]
ACE inhibitors and ARBs also appear effective in preventing or regressing HMOD, such as LVH and small artery remodelling, for an equivalent reduction in BP [292] [292]
ACE inhibitors are associated with a small increased risk of angioneurotic oedema, especially in people of black African origin and, in such patients, when RAS blockers are used, an ARB may be preferred.
7.5.1.2 Calcium channel blockers
CCBs are widely used for the treatment of hypertension and have similar effectiveness as other major drug classes on BP, major cardiovascular events, and mortality outcomes [2,292] [2,292] [17]
CCBs are a heterogeneous class of agents. Most RCTs demonstrating the benefits of CCBs on outcomes have used dihydropyridines (especially amlodipine). A smaller number of RCTs have compared nondihydropyridines (verapamil and diltiazem) with other drugs, and meta-analyses evaluating the two subclasses (vs. other drugs) have not shown substantial differences in effectiveness [292]
7.5.1.3 Thiazide/thiazide-like diuretics (e.g. chlorthalidone and indapamide)
Diuretics have remained the cornerstone of antihypertensive treatment since their introduction in the 1960s. Their effectiveness in preventing all types of cardiovascular morbidities and mortality has been confirmed in RCTs and meta-analyses [300] [292] [301] [302] [303] [300] [293,300] [304] [305]
7.5.1.4 Beta-blockers
RCTs and meta-analyses demonstrate that when compared with placebo, beta-blockers significantly reduce the risk of stroke, heart failure, and major cardiovascular events in hypertensive patients [300] [1,2,217] [108] [17] [306] [293]
Beta-blockers have been shown to be particularly useful for the treatment of hypertension in specific situations such as symptomatic angina, for heart rate control, postmyocardial infarction, HFrEF, and as an alternative to ACE inhibitors or ARBs in younger hypertensive women planning pregnancy or of child-bearing potential.
Finally, beta-blockers are not a homogeneous class. In recent years, the use of vasodilating beta-blockers – such as labetalol, nebivolol, celiprolol, and carvedilol – has increased. Studies on nebivolol have shown that it has more favourable effects on central BP, aortic stiffness, endothelial dysfunction, and so on. It has no adverse effect on the risk of new-onset diabetes and a more favourable side effect profile than classical beta-blockers [307,308] [136]
7.5.1.5 Other antihypertensive drugs
Centrally active drugs were widely used in the earliest decades of antihypertensive treatment when other treatments were not available, but are less frequently used now, principally because of their poorer tolerability relative to the newer major classes of drugs. The alpha-blocker doxazosin was effective in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) as third-line therapy (with no increase in the risk of heart failure) [309] [310]
7.5.2 Drug treatment strategy for hypertension
Guidelines have generated a variety of different strategies to initiate and escalate BP-lowering medication to improve BP control rates. In previous Guidelines, the emphasis was on initial use of different monotherapies, increasing their dose, or substituting for another monotherapy. However, increasing the dose of monotherapy produces little additional BP lowering and may increase the risk of adverse effects, while switching from one monotherapy to another is frustrating, time consuming, and often ineffective. For these reasons, more recent Guidelines have increasingly focused on the stepped-care approach, initiating treatment with different monotherapies and then sequentially adding other drugs until BP control is achieved. Despite this, BP control rates have remained poor worldwide. As shown by recent observations, irrespective of the world region, whether high-income or low-income economies, or the level of sophistication of healthcare provision, only 40% of patients with hypertension are treated; of these, only 35% are controlled to a BP of less than 140/90 mmHg [12]
Several reasons need to be considered to identify why the current treatment strategy has failed to achieve better BP control rates:
Efficacy of pharmacological therapies . Are the best available treatments, in whatever combination, incapable of controlling BP in most patients? The evidence from RCTs demonstrating that BP control can be achieved in most recruited patients, and that no more than 5–10% of these patients exhibit resistance to the selected treatment regimen, suggests that ineffective drug therapy is not the source of the problem.Physician or treatment inertia . (i.e. failure to adequately uptitrate treatment). Evidence suggests that inertia [311] [12] Patient adherence to treatment . Evidence is accumulating that adherence is a much more important factor than previously recognized. Studies using urine or blood assays for the presence or absence of medication have shown that adherence to treatment is low. This is supported by studies in the general population in which adherence to treatment, based on prescription refilling, was <50% of the treatment in half of the patients [312] [313] Insufficient use of combination treatment . BP is a multiregulated variable depending on many compensating pathways. Consequently, combinations of drugs, working through different mechanisms, are required to reduce BP in most people with hypertension. Thus, monotherapy is likely to be inadequate therapy in most patients. Indeed, almost all patients in RCTs have required combinations of drugs to control their BP [314] Complexity of current treatment strategies . There is also evidence that adherence to treatment is adversely affected by the complexity of the prescribed treatment regimen. In a recent study, adherence to treatment was strongly influenced by the number of pills that a patient was prescribed for the treatment of hypertension [315] [315]
The above considerations suggest that the most effective evidence-based treatment strategy to improve BP control is one that: encourages the use of combination treatment in most patients, especially in the context of lower BP targets; enables the use of SPC therapy for most patients, to improve adherence to treatment; and follows a treatment algorithm that is simple, applies to all patients, and is pragmatic, with the use of SPC therapy as initial therapy for most patients, except those with BP in the high–normal range and in frail older patients (see below).
7.5.2.1 Drug combinations for hypertension treatment
Among the large number of RCTs of antihypertensive therapy, only a few have directly compared different two-drug combinations, with systematic use of the two combinations in both arms. In other trials, treatment was initiated using monotherapy in either arm and another drug (and sometimes more than one drug) was added, usually in a nonrandomized fashion, according to a prespecified treatment algorithm. In a few trials, the design precluded the use of what might be considered optimal combinations because multiple monotherapies were being evaluated [e.g. the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), where the add-on therapy to either a diuretic, CCB, ACE inhibitor, or alpha-blocker was a beta-blocker, clonidine, or reserpine] [316]
With this caveat, Table 21 shows that a variety of drug combinations have been used in at least one active arm of placebo-controlled trials and have been associated with significant benefit on major cardiovascular events. In trials comparing different regimens (Table 22 ), all combinations have been used in a larger or smaller proportion of patients, without major differences in benefits. The only exceptions are two trials in which a large proportion of the patients received either an ARB–diuretic combination [317] [318] [233,234,316,319–321] [322–324] [325] [310,326] [305]
TABLE 21: Major drug combinations used in trials of antihypertensive treatment in a stepped approach or as a randomized combination (combinations vs. placebo or monotherapy)
TABLE 22: Major drug combinations used in trials of antihypertensive treatment in a stepped approach or as a randomized combination (combinations vs. other combinations)
Three outcome trials directly compared two different combinations, each involving a combination of a RAS blocker (ACE inhibitor or ARB) and a CCB with other combinations. In the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial, the ACE inhibitor–CCB combination was superior to the same ACE inhibitor in combination with a thiazide diuretic at preventing major cardiovascular outcomes, despite no apparent BP difference between the two arms [327] [328] [329]
Based on the results of outcome RCTs and recent meta-analyses, and evidence of BP-lowering effectiveness, all five major drug classes can, in principle, be combined with one another, except for ACE inhibitors and ARBs, whose concomitant use may lead to no additional benefit but increased adverse effects and is thus discouraged. We recommend that the treatment of hypertension should be preferentially based on combinations of an ACE inhibitor or ARB with a CCB and/or a thiazide/thiazide-like diuretic. These combinations are now widely available in a single pill and in a range of doses, facilitating simplification of treatment, flexible prescribing, and uptitration from lower to higher doses. Combination therapy that includes an ACE inhibitor or ARB with either a CCB or thiazide/thiazide-like diuretic are complementary because both CCBs or diuretics activate the RAS, which will be counteracted by their combination with an ACE inhibitor or ARB. These combinations will also limit potential adverse effects associated with diuretic or CCB monotherapy, reducing the risk of hypokalaemia due to diuretics and reducing the prevalence of peripheral oedema due to CCBs. These combinations also ensure that the RAS is inhibited as part of the treatment strategy, which is an important consideration for many patient groups (e.g. diabetes, LVH, proteinuria).
Other combinations, such as CCB + diuretic, also have evidence from RCTs supporting their use [233,329]
Beta-blockers in combination should be preferentially used when there is a specific clinical indication for their use (e.g. in patients with symptomatic angina, for patients requiring heart rate control, postmyocardial infarction, chronic HFrEF, and as an alternative to ACE inhibitors or ARBs in younger hypertensive women planning pregnancy or of child-bearing potential). SPCs of beta-blockers with an ACE inhibitor, CCB, or diuretic are available.
7.5.2.2 Rationale for initial two-drug combination therapy for most patients
As discussed above and with the emphasis in these Guidelines on achieving a BP target in most patients of less than 130/80 mmHg, the majority of patients will require combination therapy. Initial combination therapy is invariably more effective at BP lowering than monotherapy, indeed even low-dose combination therapy is usually more effective than maximal dose monotherapy [341] [342] [341] [343] [294]
Although no RCT has compared major cardiovascular outcomes between initial combination therapy and monotherapy, observational evidence suggests that the time taken to achieve BP control is an important determinant of clinical outcomes, especially in higher risk patients, with a shorter time to control associated with lower risk [344] [341,345] [346] [347] [312,346] [348]
A consideration in the current Guidelines was to persist with the current stepped-care approach to BP treatment, which has been interpreted as recommending monotherapy as initial therapy for most patients, reflecting current practice. In fact, the previous Guidelines did acknowledge the possibility of initial combination therapy for patients with grade 2 or 3 hypertension, or patients at high or very high risk. In other words, initial monotherapy was only recommended for grade 1 hypertension and low-risk or moderate-risk patients. Thus, in reality, the shift in emphasis in this new guidance is subtle. However, normalizing the concept of initiating therapy with a two-drug combination for most patients with hypertension is likely to have a major effect on clinical practice and the speed and quality of BP control. We acknowledge that some low-risk or moderate-risk patients with grade 1 hypertension may achieve their BP target with monotherapy, but this is unlikely in patients with an initial SBP more than 150 mmHg who would require a BP reduction of at least 20 mmHg. Moreover, the possibility of starting with a low-dose combination of two antihypertensive drugs, even in grade 1 hypertensive patients with low–moderate-risk, is supported by the reduction of cardiovascular events obtained by combination therapy in the upper tertile (grade 1 hypertension) in the HOPE-3 trial [212]
7.5.2.3 Uptitration of treatment to three-drug combination therapy
Studies suggest that two-drug combination therapy will control BP in approximately two-thirds of patients [341] [349,350]
7.5.2.4 Rationale for single-pill combination therapy as usual therapy for hypertension
The 2013 ESH/ESC Guidelines [17] [346,351] [352,353] [347,354]
Polypills have also emerged as SPCs (i.e. a fixed-dose combination of one or more antihypertensive agents with a statin and low-dose aspirin), with the rationale that hypertensive patients are often at sufficient cardiovascular risk to benefit from statin therapy. Studies of bioequivalence suggest that when combined in the polypill, different agents maintain all or most of their expected effect [355] [356] [353] [355]
7.5.2.5 Further uptitration of antihypertensive therapy
When BP remains uncontrolled with three-drug combination therapy, the patient is classified as having resistant hypertension, assuming that secondary causes of hypertension and poor adherence to treatment have been excluded, and that the elevation in BP has been confirmed by repeated office BP measurement, ABPM, or HBPM (see Section 8.1). Such patients should be considered for specialist evaluation. Additional treatment options include the addition of low-dose spironolactone (25–50 mg daily)[310] [357] 2 ), beta-blockers, alpha-blockers, centrally acting agents (e.g. clonidine), or, rarely, minoxidil] (see Section 8.1).
7.5.3 The drug treatment algorithm for hypertension
Reflecting on the evidence above, and recognizing the urgent need to address the factors contributing to the poor control of BP in treated hypertensive patients (see Section 7.5.1), this drug treatment algorithm has been developed to provide a simple and pragmatic treatment recommendation for the treatment of hypertension, based on a few key recommendations:
The initiation of treatment in most patients with an SPC comprising two drugs, to improve the speed, efficiency, and predictability of BP control.
Preferred two-drug combinations are a RAS blocker with a CCB or a diuretic. A beta-blocker in combination with a diuretic or any drug from the other major classes is an alternative when there is a specific indication for a beta-blocker, for example angina, postmyocardial infarction, heart failure, or heart rate control.
Use monotherapy for low-risk patients with stage 1 hypertension whose SBP is <150 mmHg, very high-risk patients with high–normal BP, or frail older patients.
The use of a three-drug SPC comprising a RAS blocker, a CCB, and a diuretic if BP is not controlled by a two-drug SPC.
The addition of spironolactone for the treatment of resistant hypertension, unless contraindicated (see Section 8.1.4).
The use of other classes of antihypertensive drugs in the rare circumstances in which BP is not controlled by the above treatments.
Information on availability and recommended doses of individual drugs, as well as SPCs and free combinations, can be found in national formularies.
This treatment algorithm focuses on the five major classes of drugs: ACE inhibitors, ARBs, CCBs, thiazide or thiazide-like diuretics, and beta-blockers. The algorithm recommends initial therapy for most patients with a two drug-combination, ideally as an SPC. Variations from the core drug treatment algorithm for uncomplicated hypertension shown in Figure 4 are specified in Figures 5–8 . Recommended BP target ranges for treated hypertension are shown in Table 23 .
FIGURE 4: Core drug treatment strategy for uncomplicated hypertension . The core algorithm is also appropriate for most patients with HMOD, cerebrovascular disease, diabetes, or PAD. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; HMOD, hypertension-mediated organ damage; MI, myocardial infarction; o.d., once daily; PAD, peripheral artery disease.
FIGURE 5: Drug treatment strategy for hypertension and coronary artery disease . ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; CCB, calcium channel blocker; CVD, cardiovascular disease; o.d., once daily.
FIGURE 6: Drug treatment strategy for hypertension and chronic kidney disease . ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; CCB, calcium channel blocker; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; MI, myocardial infarction; o.d., once daily. a CKD is defined as an eGFR <60 ml/min/1.72 m2 with or without proteinuria. b Use loop diuretics when eGFR is <30 ml/min/1.72 m2 , because thiazide/thiazide-like diuretics are much less effective/ineffective when eGFR is reduced to this level. c Caution: risk of hyperkalaemia with spironolactone, especially when eGFR is <45 ml/min/1.72 m2 or baseline K+ ≥4.5 mmol/l.
FIGURE 7: Drug treatment strategy for hypertension and hear failure with reduced ejection fraction . Do not use nondihydropyridine CCBs (e.g. verapamil or diltiazem). ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; ESC, European Society of Cardiology; HFrEF, heart failure with reduced ejection fraction; MRA, mineralocorticoid receptor antagonist.
a Consider an angiotensin receptor/neprilysin inhibitor instead of ACEi or ARB per ESC Heart Failure Guidelines
[136] .
b Diuretic refers to thiazide/thiazide-like diuretic. Consider a loop diuretic as an alternative in patients with oedema.
c MRA (spironolactone or eplerenone).
FIGURE 8: Drug treatment strategy for hypertension and atrial fibrillation . ACEi, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; CHA2 DS2 -VASc, Cardiac failure, Hypertension, Age ≥75 (Doubled), Diabetes, Stroke (Doubled) – Vascular disease, Age 65–74 and Sex category (Female); DHP, dihydropyridine.
TABLE 23: Office blood pressure treatment target range
The drug treatment strategy for patients with hypertension should be based on the algorithm shown (Figures 4–8 ), unless there are contraindications to these drugs (Table 20 ), or concomitant conditions or diseases are present that require specific modification of the drugs, as outlined in the recommendations below.
Drug treatment strategy for hypertension
7.6 Device-based hypertension treatment
Various device-based therapies have emerged, principally targeted at the treatment of resistant hypertension. These are discussed below.
7.6.1 Carotid baroreceptor stimulation (pacemaker and stent)
Carotid baroreceptor stimulation or baroreflex amplification therapy – externally via an implantable pulse generator or internally via an implantable device designed to increase the strain on the carotid bulb – can lower BP in patients with resistant hypertension. An RCT with the first generation of an implantable pulse generator showed sustained BP-lowering efficacy (and sympathetic nervous system inhibition), but with some concerns about procedural and longer-term safety [358] [359] [360]
7.6.2 Renal denervation
The rationale for renal denervation lays with the importance of sympathetic nervous system influences on renal vascular resistance, renin release and sodium reabsorption [361] [361] [362] [363] [364] [365] [366] [367,368] [369] [370] [366]
Evaluating the efficacy of renal denervation has been challenging because the procedure needs to be applied to a population with a high probability of BP response. This is complicated by the complex pathophysiology of hypertension, the lack of clinically applicable measures of sympathetic activity, the absence of predictors of the long-term BP response following renal denervation, and the absence of reliable markers of procedural success to immediately establish whether denervation has been achieved [371] [372,373]
Major uncertainties remain as to the clinical role of renal denervation outside of clinical studies, which should be performed in carefully selected patients at specialist hypertension centres and by experienced operators.
7.6.3 Creation of an arteriovenous fistula
The central iliac arteriovenous anastomosis creates a fixed-calibre (4 mm) conduit between the external iliac artery and vein using a stent-like nitinol device (ROX arteriovenous coupler) [374,375] [374,375] [376] [377] [377,378]
7.6.4 Other devices
The carotid body is located at the bifurcation of the common carotid. It is innervated by nerve fibres from the vagus nerve through the cervical ganglion and the carotid sinus nerve [379] [380] [381]
In summary, device-based therapy for hypertension is a fast-moving field. Further sham-controlled studies are needed before device-based therapies can be recommended for the routine treatment of hypertension outside of the framework of clinical trials.
Device-based therapies for hypertension
8 HYPERTENSION IN SPECIFIC CIRCUMSTANCES
8.1 Resistant hypertension
8.1.1 Definition of resistant hypertension
Hypertension is defined as resistant to treatment when the recommended treatment strategy fails to lower office SBP and DBP values to less than 140 mmHg and/or less than 90 mmHg, respectively, and the inadequate control of BP is confirmed by ABPM or HBPM in patients whose adherence to therapy has been confirmed. The recommended treatment strategy should include appropriate lifestyle measures and treatment with optimal or best-tolerated doses of three or more drugs, which should include a diuretic, typically an ACE inhibitor or an ARB, and a CCB. Pseudo-resistant hypertension (see below) and secondary causes of hypertension should also have been excluded (see Section 8.2).
Prevalence studies of resistant hypertension have been limited by variation in the definition used, and reported prevalence rates range from 5 to 30% in patients with treated hypertension. After applying a strict definition (see above) and having excluded causes of pseudo-resistant hypertension (see Section 8.1.2), the true prevalence of resistant hypertension is likely to be less than 10% of treated patients. Patients with resistant hypertension are at higher risk of HMOD, CKD and premature cardiovascular events [382]
8.1.2 Pseudo-resistant hypertension
Several possible causes of pseudo-resistant hypertension should be evaluated and ruled out before concluding that the patient has resistant hypertension:
Poor adherence to prescribed medicines is a frequent cause of pseudo-resistant hypertension, occurring in at least 50% of patients assessed by therapeutic drug monitoring, and is directly related to the number of tablets prescribed [315] White-coat phenomenon (in which office BP is elevated but BP is controlled at ABPM or HBPM) is not uncommon in these patients, hence the recommendation to confirm office hypertension with ABPM or HBPM before confirming the diagnosis of resistant hypertension.Poor office BP measurement technique , including the use of cuffs that are too small relative to the arm circumference, can result in a spurious elevation of BP.Marked brachial artery calcification , especially in older patients with heavily calcified arteries.Clinician inertia , resulting in inadequate doses or irrational combinations of BP-lowering drug therapies.
Other causes of resistant hypertension
Lifestyle factors, such as obesity or large gains in weight, excessive alcohol consumption, and high sodium intake.
Intake of vasopressor or sodium-retaining substances, drugs prescribed for conditions other than hypertension, some herbal remedies, or recreational drug use (cocaine, anabolic steroids, etc.) (see Table 24 ).
Obstructive sleep apnoea (usually, but not invariably, associated with obesity).
Undetected secondary forms of hypertension (see Section 8.2).
Advanced HMOD, particularly CKD or large-artery stiffening.
Resistant hypertension is associated with older age (especially >75 years), male sex, black African origin, higher initial BP at diagnosis of hypertension, highest BP ever reached during the patient's lifetime, frequent outpatient visits, obesity, diabetes, atherosclerotic disease and HMOD, CKD, and a Framingham 10=year coronary risk score more than 20% [383,384]
TABLE 24: Resistant hypertension characteristics, secondary causes, and contributing factors (adapted from reference
[385] )
8.1.3 Diagnostic approach to resistant hypertension
Diagnosis of resistant hypertension requires detailed information about:
The patient's history, including lifestyle characteristics, alcohol and dietary sodium intake, interfering drugs or substances, and sleep history.
The nature and dosing of the antihypertensive treatment.
A physical examination, with a particular focus on determining the presence of HMOD and signs of secondary hypertension.
Confirmation of treatment resistance by out-of-office BP measurements (i.e. ABPM or HBPM).
Laboratory tests to detect electrolyte abnormalities (hypokalaemia), associated risk factors (diabetes), organ damage (advanced renal dysfunction), and secondary hypertension.
Confirmation of adherence to BP-lowering therapy.
Patients should be screened for a secondary cause of hypertension, especially primary aldosteronism [386] [387] [388] [389] [390]
8.1.4 Treatment of resistant hypertension
Effective treatment combines lifestyle changes (especially the reduction of sodium intake), discontinuation of interfering substances, and the sequential addition of antihypertensive drugs to the initial triple therapy. Ultimately, replacing all current drugs by a simpler treatment regimen using SPC treatment is recommended to reduce pill burden and improve adherence to treatment. The optimal drug treatment of resistant hypertension has been poorly studied. The most effective strategy seems to be additional diuretic treatment to decrease volume overload, together with the restriction of salt intake, particularly in patients with CKD. BP control may be improved by increasing the dose of the existing diuretic or by switching to a more potent thiazide-like diuretic (chlorthalidone or indapamide). A loop diuretic should replace thiazides/thiazide-like diuretics if the eGFR is less than 30 ml/min. Although resistant hypertension may show a BP reduction if the existing diuretic dose is further increased, most patients require the administration of additional drugs. There is growing evidence to suggest that the fourth-line treatment should involve a blockade of the biological effects of aldosterone through the use of MRAs [391] [357] [392–394] [357] [310]
New BP-lowering drugs (nitric oxide donors, vasopressin antagonists, aldosterone synthase inhibitors, neutral endopeptidase inhibitors, and endothelin antagonists) are all under investigation [388]
Resistant hypertension
8.2 Secondary hypertension
Secondary hypertension is hypertension due to an identifiable cause, which may be treatable with an intervention specific to the cause. A high index of suspicion and early detection of secondary causes of hypertension are important because interventions may be curative, especially in younger patients [e.g. corrective surgery for aortic coarctation, renal angioplasty in younger patients with renal artery fibromuscular dysplasia, reversal of an endocrine cause of hypertension (e.g. by removal of an adrenal adenoma), or drug treatment of a monogenic disorder affecting a specific drug-sensitive ion channel (e.g. selective use of amiloride in Liddle's syndrome)]. Interventions that treat the cause of secondary hypertension later in life are less likely to be curative (i.e. remove the need for antihypertensive medication) because longstanding hypertension results in vascular and other organ damage that sustains the elevated BP, but intervention is still important because it will often result in much better BP control with less medication.
The prevalence of secondary hypertension is reported to be 5–15% [396] Table 25 ).
TABLE 25: Patient characteristics that should raise the suspicion of secondary hypertension
It is beyond the scope of these Guidelines to describe the detailed clinical management of specific causes of secondary hypertension. However, the commoner causes of secondary hypertension, clinical history, and screening tests are described in Table 26 , and the typical age distribution of these causes of secondary hypertension is shown in Table 27 . Review of these tables demonstrates that most screening can be undertaken with blood and urine tests, abdominal ultrasound, and echocardiography. Referral to a specialist centre is recommended for additional investigations to confirm a suspected diagnosis of secondary hypertension and for clinical management. Other causes of secondary hypertension due to drugs and substances, and rarer monogenic causes, are described below and are summarized in Tables 28 and 29 .
TABLE 26: Common causes of secondary hypertension
TABLE 27: Incidence and typical causes of secondary hypertension according to age
TABLE 28: Medications and other substances that may increase blood pressure
[397] TABLE 29: Rare genetic causes of secondary hypertension
8.2.1 Drugs and other substances that may cause secondary hypertension
Medications and other substances may cause a sufficient increase in BP to raise the suspicion of secondary hypertension [397] Table 28 ). Consequently, a careful drug history is important when considering a diagnosis of secondary hypertension. Moreover, other commonly used drugs such as nonsteroidal anti-inflammatory drugs or glucocorticoids can antagonize the BP-lowering effect of antihypertensive medications in patients treated for hypertension and may contribute to a loss of BP control.
8.2.2 Genetic causes of secondary hypertension
Genetic causes of secondary hypertension are usually due to single-gene disorders (see Section 6) [194,195] Table 29 ) [194,195]
8.3 Hypertension urgencies and emergencies
Hypertension emergencies are situations in which severe hypertension (grade 3) is associated with acute HMOD, which is often life-threatening and requires immediate but careful intervention to lower BP, usually with intravenous (i.v.) therapy [398] [399]
Patients with malignant hypertension , characterized by severe hypertension (usually grade 3) associated with funduscopic changes (flame haemorrhages and/or papilloedema), microangiopathy, and disseminated intravascular coagulation, and can be associated with encephalopathy (in about 15% of cases) [400] [401–404] Patients with severe hypertension associated with other clinical conditions who are likely to require an urgent reduction of BP, for example acute aortic dissection, acute myocardial ischaemia, or acute heart failure.Patients with sudden severe hypertension due to phaeochromocytoma , associated with organ damage.Pregnant women with severe hypertension or preeclampsia (see Section 8.9.1).
The most common emergency symptoms will depend of the organs affected but may include headache, visual disturbances, chest pain, dyspnoea, dizziness, and other neurological deficits. In patients with hypertensive encephalopathy, the presence of somnolence, lethargy, tonic clonic seizures and cortical blindness may precede a loss of consciousness; however, focal neurological lesions are rare and should raise the suspicion of stroke.
Acute stroke , especially intracerebral haemorrhage, when associated with severe hypertension has often been termed a hypertension emergency, but a more cautious approach is now recommended for acute BP lowering in the emergency setting of acute stroke (see Section 8.15).
The term ‘hypertension urgency’ has also been used to describe severe hypertension in patients presenting to the emergency department in whom there is no clinical evidence of acute HMOD [405] Figure 4 . However, these patients will require urgent outpatient review to ensure that their BP is coming under control.
Acute and severe increases in BP can sometimes be precipitated by ingestion of sympathomimetics such as meta-amphetamine or cocaine. This can result in a hypertension emergency when there is evidence of acute HMOD.
It is emphasized that many patients in an emergency department with acute pain or distress may experience an acute elevation in BP that will be restored to normal when the pain and distress are relieved, rather than requiring any specific intervention to lower BP.
For patients with a suspected hypertension emergency, a diagnostic workup is shown in Table 30 .
TABLE 30: Diagnostic workup for patients with a suspected hypertension emergency
8.3.1 Acute management of hypertensive emergencies
Apart from acute BP lowering in stroke, there are no RCTs evaluating different treatment strategies for hypertensive emergencies. The key considerations in defining the treatment strategy are:
Establishing the target organs that are affected, whether they require any specific interventions other than BP lowering, and whether there is a precipitating cause for the acute rise in BP that might affect the treatment plan (e.g. pregnancy);
The recommended timescale and magnitude of BP lowering required for safe BP reduction;
The type of BP-lowering treatment required. With regard to drug treatment, in a hypertension emergency, i.v. treatment with a drug with a short half-life is ideal to allow careful titration of the BP response to treatment in a higher dependency clinical area with facilities for continuous haemodynamic monitoring.
Recommended drug treatments for specific hypertension emergencies [398,406] Table 31 and an expanded range of possible drug choices [398] Table 32 . Rapid uncontrolled BP lowering is not recommended as this can lead to complications [397]
TABLE 31: Hypertensive emergencies requiring immediate blood pressure lowering with intravenous drug therapy
TABLE 32: Drug types, doses, and characteristics for treatment of hypertension emergencies
Although i.v. drug administration is recommended for most hypertension emergencies, oral therapy with ACE inhibitors, ARBs, or beta-blockers is sometimes very effective in malignant hypertension because the renin system is activated by renal ischaemia. However, low initial doses should be used because these patients can be very sensitive to these agents and treatment should take place in hospital. Further comprehensive details on the clinical management of hypertension emergencies are available [398]
8.3.2 Prognosis and follow-up
The survival of patients with hypertension emergencies has improved dramatically over past decades [407] [408,409]
8.4 White-coat hypertension
As discussed in Section 4, white-coat hypertension is defined as an elevated office BP despite a normal out-of-office BP. White-coat hypertension may be present in many people with an increased office BP, with a maximum in grade 1 hypertension, and very old people (>50%). Compared with normotensive people, white-coat hypertension is associated with an increased prevalence of dysmetabolic risk factors and asymptomatic organ damage. It is also associated with a greater risk of developing type 2 diabetes and sustained hypertension, as well as an overall increased risk of cardiovascular events [68,410–412] [85,86,89]
Whether or not patients with white-coat hypertension should receive antihypertensive drugs is unresolved. In white-coat hypertension, antihypertensive drugs have been shown to effectively and persistently lower office BP, with no concomitant reduction (indeed, even a small increase) of ambulatory BP values [413,414] [415] [416] [417–420] [418,421]
8.5 Masked hypertension
As reported in Section 4.7.2, masked hypertension is defined in people whose BP is normal in the office but elevated on out-of-office BP measurements. Such people usually have dysmetabolic risk factors and asymptomatic organ damage, which are substantially more frequent than in people who are truly normotensive [93,410–412,422] [68,81,93,95,423] [68,74]
8.6 Masked uncontrolled hypertension
MUCH occurs in some treated patients in whom the office BP appears controlled to recommended BP targets, but BP is elevated and thus uncontrolled according to out-of-office BP measurements (ABPM or HBPM) [84] [84] [84]
Management of white coat and masked hypertension
8.7 Hypertension in younger adults (age <50 years)
The prevalence of hypertension increases with age. Most hypertension across the age span is due to systolic hypertension; however, elevations of DBP and isolated diastolic hypertension, when they occur, are more common in younger rather than older patients [211]
All younger adults with grade 2 or more severe hypertension should be offered lifestyle advice and drug treatment, as well as high-risk younger adults with grade 1 hypertension (i.e. with HMOD, CVD, diabetes, CKD, or those at high CVD risk, although cardiovascular risk is often underestimated in younger adults over shorter-term projections, such as 10 years) [35]
There is controversy about whether younger adults with uncomplicated grade 1 hypertension should be treated because of the obvious difficulty in conducting conventional clinical outcome trials in younger adults in whom the outcomes only occur after many years [424] [425] [424,426] [23] [427]
8.7.1 Isolated systolic hypertension in the young
Some young, healthy people, and men in particular, may present with isolated grade 1 systolic hypertension (i.e. brachial SBP at least 140–159 mmHg and a normal DBP <90 mmHg), and this may be associated with a normal central aortic SBP due to excessive peripheral systolic pressure amplification [428] [429] [430]
8.8 Hypertension in older patients (age 65 years)
The prevalence of hypertension increases with age, with a prevalence of 60% over the age of 60 years and 75% over the age of 75 years. For the purposes of these Guidelines, older is defined as at least 65 years and the very old as at least 80 years.
For many years, advanced age has been a barrier to the treatment of hypertension because of concerns about potentially poor tolerability, and even harmful effects of BP-lowering interventions in people in whom mechanisms preserving BP homeostasis and vital organ perfusion may be more frequently impaired. This approach is not appropriate, because evidence from RCTs has shown that in old and very old patients, antihypertensive treatment substantially reduces cardiovascular morbidity and cardiovascular and all-cause mortality [220,431] [432]
It is recommended that older patients are treated according to the treatment algorithm outlined in Section 7. In very old patients, it may be appropriate to initiate treatment with monotherapy. In all older patients, when combination therapy is used, it is recommended that this is initiated at the lowest available doses. In all older patients, and especially very old or frail patients, the possible occurrence of postural BP should be closely monitored and symptoms of possible hypotensive episodes checked by ABPM. Unless required for concomitant diseases, loop diuretics and alpha-blockers should be avoided because of their association with injurious falls [433,434]
An important consideration is frail, dependent older patients, including those with orthostatic hypotension. These have been excluded from RCTs. The SPRINT trial showed the benefits of BP-lowering treatment being extended to recruited patients who were at the frailer end of the spectrum, including those with reduced gait speed [215] [214]
In some patients, the best achievable BP may be higher than the recommended target, but it should be recognized that any amount of BP lowering is likely to be worthwhile and associated with a reduced risk of major cardiovascular events (especially stroke and heart failure) and mortality.
8.9 Women, pregnancy, oral contraception and hormone-replacement therapy
8.9.1 Hypertension and pregnancy
Hypertensive disorders in pregnancy affect 5–10% of pregnancies worldwide and remain a major cause of maternal, foetal, and neonatal morbidity and mortality. Maternal risks include placental abruption, stroke, multiple organ failure, and disseminated intravascular coagulation. The fetus is at high risk of intrauterine growth retardation (25% of cases of preeclampsia), prematurity (27% of cases of preeclampsia), and intrauterine death (4% of cases of preeclampsia) [435]
8.9.1.1 Definition and classification of hypertension in pregnancy
The definition of hypertension in pregnancy is based on office BP values, SBP at least 140 mmHg and/or DBP at least 90 mmHg [436,437]
Hypertension in pregnancy is not a single entity but comprises:
Preexisting hypertension: precedes pregnancy or develops before 20 weeks of gestation, and usually persists for more than 6 weeks postpartum and may be associated with proteinuria.Gestational hypertension: develops after 20 weeks of gestation and usually resolves within 6 weeks postpartum.Preexisting hypertension plus superimposed gestational hypertension with proteinuria .Preeclampsia: gestational hypertension with significant proteinuria (>0.3 g/24 h or ≥30 mg/mmol ACR). It occurs more frequently during the first pregnancy, in multiple pregnancy, in hydatidiform mole, in antiphospholipid syndrome, or with preexisting hypertension, renal disease, or diabetes. It is often associated with foetal growth restriction due to placental insufficiency and is a common cause of prematurity [438] Antenatally unclassifiable hypertension: this term is used when BP is first recorded after 20 weeks of gestation and it is unclear if hypertension was preexisting. Reassessment 6 weeks postpartum will help distinguish preexisting from gestational hypertension.
8.9.1.2 Blood pressure measurement in pregnancy
BP in pregnancy should be measured in the sitting position (or the left lateral recumbent during labour) with an appropriately sized arm cuff at heart level and using Korotkoff V for DBP. Manual auscultation remains the gold standard for BP measurement in pregnancy, because automated devices tend to under-record the BP and are unreliable in severe preeclampsia. Only validated devices should be used in pregnancy [439] [440]
8.9.1.3 Investigation of hypertension in pregnancy
Basic laboratory investigations recommended for monitoring pregnant hypertensive women include urine analysis, blood count, haematocrit, liver enzymes, serum creatinine and serum uric acid (increased in clinically evident preeclampsia). Hyperuricaemia in hypertensive pregnancies identifies women at increased risk of adverse maternal and foetal outcomes [441]
All pregnant women should be assessed for proteinuria in early pregnancy to detect preexisting renal disease and, in the second half of pregnancy, to screen for preeclampsia. A dipstick test of at least 1+ should prompt evaluation of ACR in a single spot urine sample and a value less than 30 mg/ mmol can reliably rule out proteinuria in pregnancy [442]
In addition to basic laboratory tests, the following investigations may be considered:
Ultrasound investigation of the kidneys and adrenals, and plasma or urinary fractionated metanephrine assays in pregnant women with a history suggestive of phaeochromocytoma.
Doppler ultrasound of uterine arteries (performed after 20 weeks of gestation) to detect those at higher risk of gestational hypertension, preeclampsia, and intrauterine growth retardation [443]
A soluble fms-like tyrosine kinase 1:placental growth factor ratio of at least 38 can be used to exclude the development of preeclampsia in the next week when suspected clinically [444]
8.9.1.4 Prevention of hypertension and preeclampsia
Women at high or moderate-risk of preeclampsia should be advised to take 100–150 mg of aspirin daily from weeks 12–36 [445]
Hypertensive disease during a previous pregnancy
CKD
Autoimmune disease such as systemic lupus erythematosus or antiphospholipid syndrome
Type 1 or type 2 diabetes
Chronic hypertension
Moderate-risk of preeclampsia includes one or more of the following risk factors:
First pregnancy
Age of at least 40 years
Pregnancy interval of more than 10 years
BMI of at least 35 kg/m2 at first visit
Family history of preeclampsia
Multiple pregnancy
8.9.1.5 Clinical management of hypertension in pregnancy
Mild hypertension of pregnancy (BP 140–159/90–109 mmHg). The goal of drug treatment of hypertension in pregnancy is to reduce maternal risk; however, the agents selected must be safe for the fetus. The benefits of drug treatment for mother and fetus in hypertension in pregnancy have not been extensively studied, with the best data from a single trial using alpha-methyldopa, performed 40 years ago [446–448] [446]
Most women with preexisting hypertension and normal renal function will not have severe hypertension and are a low risk for developing complications during pregnancy. Indeed, some of these women may be able to withdraw their medication in the first half of pregnancy because of the physiological fall in BP. Despite the paucity of evidence, European Guidelines [17,449,450]
In all women with persistent elevation of BP at least 150/95 mmHg;
In women with gestational hypertension (with or without proteinuria), preexisting hypertension with the superimposition of gestational hypertension, or hypertension with subclinical HMOD, when BP is more than 140/90 mmHg.
Women with preexisting hypertension may continue their current antihypertensive medication, but ACE inhibitors, ARBs, and direct renin inhibitors are contraindicated due to adverse foetal and neonatal outcomes. Methyldopa, labetalol, and CCBs are the drugs of choice. Beta-blockers may induce foetal bradycardia; consequently, if used, their type and dose should be carefully selected, with atenolol best avoided. Diuretic therapy is generally avoided because plasma volume is reduced in women who develop preeclampsia.
There are no data to define the optimal BP treatment target in pregnant women. Nevertheless, for pragmatic reasons, if treatment is initiated it is important to suggest a treatment target to calibrate how much treatment to give. A BP target of less than 140/90 is suggested for pregnant women receiving antihypertensive therapy.
Severe hypertension of pregnancy (160/110 mmHg). There is no agreed definition of severe hypertension, with values ranging between 160 and 180 mmHg/more than 110 mmHg. The 2018 ESC Task Force on CVD during pregnancy [435] [451]
In hypertensive crises, that is in patients with eclampsia or severe preeclampsia (with or without haemolysis, elevated liver enzymes, and low platelets syndrome), hospitalization and BP-lowering therapy is essential, and delivery needs to be considered after the maternal condition has stabilized [435] [452]
Delivery is indicated urgently in preeclampsia with visual disturbances or haemostatic disorders, and at 37 weeks in asymptomatic women [453]
Blood pressure postpartum. Postpartum hypertension is common in the first week. Any drug recommended can be used according to the hypertension treatment algorithm shown in Figure 4 , with the caveats: methyldopa should be avoided because of the risk of postpartum depression and consideration should be given to drug choice in breastfeeding women.
8.9.1.6 Hypertension and breastfeeding
All antihypertensive drugs taken by the nursing mother are excreted into breast milk. Most are present at very low concentrations except for propranolol and nifedipine, with breast milk concentrations similar to those in maternal plasma. Reference to prescribing information in breastfeeding women is important.
8.9.1.7 Risk of recurrence of hypertensive disorders in a subsequent pregnancy
Women experiencing hypertension in their first pregnancy are at increased risk in a subsequent pregnancy. The earlier the onset of hypertension in the first pregnancy, the higher the risk of recurrence in a subsequent pregnancy.
8.9.1.8 Long-term cardiovascular consequences of gestational hypertension
Women who develop gestational hypertension or preeclampsia are at increased risk of hypertension, stroke, and ischaemic heart disease in later adult life [454,455]
Further detail on the management of hypertension and other cardiovascular disorders in pregnancy is available [435]
Management of hypertension in pregnancy
8.9.2 Oral contraceptive pills and hypertension
Combined oestrogen–progesterone oral contraceptive pills can be associated with a small but significant increase in BP and the development of hypertension in about 5% of users [456,457] [458] [459] [460]
8.9.3 Hormone-replacement therapy and hypertension
Cross-sectional studies have long established that menopause doubles the risk of developing hypertension, even after adjusting for factors such as age and BMI [461] [462]
8.10 Hypertension in different ethnic groups
In comparison with the nonblack population, hypertension is more prevalent in the black population living in Europe [463] [464] [463] [463] [464] [465,466] [467] [464] [468] [316,469,470] [463,471]
8.11 Hypertension in diabetes mellitus
High BP is a common feature of type 1 and, particularly, type 2 diabetes. Moreover, masked hypertension and a blunted nocturnal fall in BP are not infrequent in people with diabetes [472] [231,235] [1] [1]
When considering treatment for hypertension, it is important to exclude significant postural hypotension, which can be marked in people with diabetes due to autonomic neuropathy [235] [235] [298,473,474]
Recent RCTs have shown that some antidiabetic agents (the selective inhibitors of sodium glucose cotransporter 2 in the kidney) can reduce office and ambulatory BP by several mmHg [475,476] [477] [478–481]
There has been considerable debate about the target BP that should be achieved in people with diabetes (see Section 7). We recommend that in people with diabetes, the first objective should be to lower BP to less than 140/80 mmHg, aiming at an SBP of 130 mmHg. Provided that the treatment is well tolerated, treated SBP values of less than 130 mmHg should be considered because of the benefits on stroke prevention. Achieved SBP values of less than 120 mmHg should always be avoided. BP targets for renoprotection for patients with diabetic kidney disease are discussed in Section 8.12.
Treatment strategies in people with diabetes
8.12 Hypertension and chronic kidney disease
Hypertension is a major risk factor for the development and progression of CKD, irrespective of the cause of CKD. In patients with CKD, resistant hypertension, masked hypertension, and elevated nighttime BP are common, and are associated with a lower eGFR, higher levels of albuminuria, and HMOD [483,484]
The effects of lowering BP in patients with CKD have been the subject of many meta-analyses. A recent meta-analysis has shown that BP lowering significantly reduced end-stage renal disease in patients with CKD, but only in those with albuminuria and without any beneficial effect on cardiovascular events [203] [485]
Reduction of albuminuria has also been considered as a therapeutic target. Analyses of data from RCTs have reported that changes in urinary albumin excretion are predictors of renal and cardiovascular events [186,486] [175] [176,291]
Patients with CKD should receive lifestyle advice, especially sodium restriction, and drug treatment when their office BP is more than 140/90 mmHg. Achieving recommended BP targets in CKD usually requires combination therapy, which should be initiated as a combination of a RAS blocker with a CCB or diuretic in these patients. The combination of two RAS blockers is not recommended [291] 2 .
The evidence with respect to BP targets in patients with CKD is complex. In patients with nondiabetic CKD, one meta-analysis showed that the slowest progression on CKD was obtained with a treated SBP in the range of 110–119 mmHg in patients with albuminuria more than 1 g/day [487] [487] [488] [489]
Current evidence suggests that in patients with CKD, BP should be lowered to less than 140/90 mmHg and towards 130/80 mmHg. Lifestyle advice, especially sodium restriction, may be especially effective at aiding BP lowering in patients with CKD. Because BP lowering reduces renal perfusion pressure, it is expected and not unusual for eGFR to be reduced by 10–20% in patients treated for hypertension. Thus, careful monitoring of blood electrolytes and eGFR is essential, but clinicians should not be alarmed by the anticipated decline in GFR when treatment is initiated. This decline usually occurs within the first few weeks of treatment and stabilizes thereafter. If the decline in GFR continues or is more severe, the treatment should be stopped, and the patient investigated to determine the presence of renovascular disease.
Therapeutic strategies for treatment of hypertension in CKD
8.13 Hypertension and chronic obstructive pulmonary disease
Hypertension is the most frequent comorbidity in patients with COPD, and coincidence of the two diseases may affect 2.5% of the adult population [490] [490,491] [490,491] [492,493] [494] [490,495]
In conclusion, management of hypertensive patients with COPD should include lifestyle changes, among which cessation of smoking is essential. CCBs, ARBs or ACEIs, or the CCB/RAS blocker combination are recommended as the initial drugs of choice. If the BP response is poor, or depending on other comorbidities, thiazides or thiazide-like diuretics and beta1-selective beta-blockers can be considered.
8.14 Hypertension and heart disease
8.14.1 Coronary artery disease
There are strong epidemiological relationships between CAD and hypertension. The INTERHEART study showed that 50% of the population-attributable risk of a myocardial infarction can be accounted for by lipids, with hypertension accounting for 25% [10] [7]
More compelling is the beneficial effect of BP treatment on reducing the risk of myocardial infarction. A recent meta-analysis of RCTs of antihypertensive therapy showed that for every 10 mmHg reduction in SBP, CAD was reduced by 17% [2] [496] [231,425]
There remains some inconsistency over the optimal BP target in less than patients with overt CAD, and especially whether there is a J-curve relationship between achieved BP and cardiovascular outcomes in CAD [497–500] [501] [222] [239] [502]
In hypertensive patients with CAD, beta-blockers and RAS blockers may improve outcomes in postmyocardial infarction [503]
Therapeutic strategies in hypertensive patients with CAD
8.14.2 Left ventricular hypertrophy and heart failure
Hypertension is the leading risk factor for the development of heart failure [7]
Treating hypertension has a major impact on reducing the risk of incident heart failure and heart failure hospitalization, especially in old and very old patients [51,213,316] [504]
Reducing BP can also lead to the regression of LVH, which has been shown to be accompanied by a reduction of cardiovascular events and mortality [125] [505,506] [173]
In patients with HFrEF, antihypertensive drug treatment should start (if not already initiated) when BP is more than 140/90 mmHg. It is unclear how low BP should be lowered in patients with heart failure. Outcomes for patients with heart failure have repeatedly been shown to be poor if BP values are low, which suggests (although data interpretation is made difficult by the possibility of reversed causality) that it may be wise to avoid actively lowering BP to less than 120/70 mmHg. However, some patients may achieve even lower BP levels than this because of the desirability to remain on treatment with guideline-directed heart failure medications, which, if tolerated, should be continued because of their protective effect [136]
Heart failure guideline-directed medications are recommended for the treatment of hypertension in patients with HFrEF [136] [507]
Antihypertensive treatment is commonly needed in patients with HFpEF; the same BP threshold and target for drug treatment indicated for HFrEF should be used. The optimal treatment strategy for hypertensive patients with HFpEF is not known, but the strategy outlined above for HFrEF patients might also be the one to adopt in HFpEF patients. HFpEF patients commonly have multiple comorbidities that may adversely affect outcomes and complicate management.
Therapeutic strategies in hypertensive patients with heart failure or LVH
8.15 Cerebrovascular disease and cognition
Hypertension is a major risk factor for haemorrhagic and ischaemic stroke, and a risk factor for recurrent stroke. BP management during the acute phase of haemorrhagic and ischaemic stroke remains an area of uncertainty. BP is often elevated at presentation with acute stroke, but often declines without intervention [508]
8.15.1 Acute intracerebral haemorrhage
In acute intracerebral haemorrhage, an increased BP is common and is associated with a greater risk of haematoma expansion, increased risk of death, and a worse prognosis for neurological recovery [509,510] [511] [512] [513] [511]
8.15.2 Acute ischaemic stroke
The beneficial effects of BP reduction are even less clear in acute ischaemic stroke. A key consideration is whether the patient will receive thrombolysis, because observational studies have reported an increased risk of intracerebral haemorrhage in patients with a markedly elevated BP who received thrombolysis [514,515] [516,517] [516,518–520] [516,521] [522]
8.15.3 Previous stroke or transient ischaemic attack
RCTs of antihypertensive treatment (placebo controlled) in patients with a previous stroke or TIA, in a stable clinical condition, and with BP more than 140/90 mmHg, have shown that BP lowering reduces the risk of recurrent stroke [338,523]
The appropriate BP targets to prevent recurrent stroke are uncertain, but should be considered in the context of a consistent finding in many meta-analyses that stroke is the one major cardiovascular event that is reduced at lower achieved BP levels. This is supported by the results from the recent Secondary Prevention of Small Subcortical Strokes 3 study [244,524] [525] [526]
Prevention of stroke is a consistent benefit of antihypertensive therapy and has been observed in all large RCTs using different drug regimens. However, individual RCTs comparing modern treatment regimens [317,527] [2,528] [529]
8.15.4 Cognitive dysfunction and dementia
Several epidemiological and clinical studies have shown that hypertension in midlife predicts cognitive decline and dementia (both Alzheimer's disease and vascular dementia) in older patients [530–533] [534] [535]
Trials are urgently needed to better define the potential impact of BP lowering on preventing cognitive decline or in delaying dementia when cognitive dysfunction is already present.
8.16 Hypertension, atrial fibrillation, and other arrhythmias
Hypertension predisposes to cardiac arrhythmias, including ventricular arrhythmias, but most commonly AF [536–538] [539] [540,541] [542]
Most patients show a high ventricular rate with AF [542] [542]
In RCTs of hypertensive patients with LVH and/or high cardiovascular risk [543,544] [545–547] [548–550] [551] [552] [553]
Therapeutic strategies in hypertensive patients with acute stroke and cerebrovascular disease
8.16.1 Oral anticoagulants and hypertension
Many patients requiring oral anticoagulants (e.g. with AF) will be hypertensive. Hypertension is not a contraindication to oral anticoagulant use. However, although its role has been unappreciated in most old and more recent RCTs on anticoagulant treatment [537] [526,536] [554,555]
8.17 Hypertension and vascular disease
8.17.1 Carotid atherosclerosis
A small number of studies have reported the effects of the various pharmacological classes of antihypertensive drugs on carotid IMT, and very few on carotid plaques. Reducing BP regresses carotid IMT and may delay the intimal atherosclerotic process. There appear to be differential drug effects on IMT regression, with CCBs having greater efficacy than diuretics and beta-blockers [146] [557] [184,558]
8.17.2 Arteriosclerosis and increased arterial stiffness
Large artery stiffening is a major factor contributing to the rise in SBP and fall in DBP with ageing. Arterial stiffness is usually measured in studies as PWV. Arterial stiffening results from arteriosclerotic structural changes in large conduit arteries, leading to a loss of arterial elasticity, and the distending force resulting from the pressure exerted on the arterial wall. Thus, all antihypertensive drugs, by reducing BP, reduce arterial stiffness, as the reduction in BP unloads the stiff components of the arterial wall, leading to a passive decrease in PWV. Pharmacodynamic RCTs [559] [560,561] [562] [563]
Therapeutic strategies in hypertensive patients with AF
8.17.3 Lower extremity arterial disease
LEAD is often a manifestation of more widespread atherosclerosis and especially atherosclerotic renal artery disease [564] [190] [565,566] [190]
Therapeutic strategies in hypertensive patients with LEAD
8.18 Hypertension in valvular disease and aortopathy
8.18.1 Coarctation of the aorta
When feasible, treatment of aortic coarctation is predominantly surgical and usually done in childhood. Even after surgical correction, these patients may develop systolic hypertension at a young age and require long-term follow-up. Few patients with aortic coarctation remain undetected until adult life, and by then often have severe hypertension, HMOD (especially LVH and left ventricular dysfunction), and an extensive collateral circulation below the coarctation. Such patients should be evaluated in a specialist centre. The medical therapy for hypertension in patients with aortic coarctation should follow the treatment algorithm outlined in Section 7, as there have been no formal RCTs to define optimal treatment strategies [567]
8.18.2 Prevention of aortic dilation and dissection in high-risk subjects
Chronic hypertension can be associated with modest aortic root dilatation. When more extensive aortic root dilatation is present or the dilatation extends beyond the aortic root, an additional cause for aortopathy should be sought. All hypertensive patients with aortic dilatation, whether associated with Marfan syndrome, bicuspid aortic valve disease, or not, should have their BP controlled ≤130/80 mmHg [568] [568–570]
8.18.3 Hypertension bicuspid aortic valve-related aortopathy
Bicuspid aortic valve disease occurs in 1 in 100 people, more often men, and is associated with coexistent aortic coarctation, which should be excluded in patients with bicuspid aortic valve disease. Bicuspid aortic valve disease is associated with an aortopathy, and the risk of development of aortic dilation is higher in patients with bicuspid aortic valve disease than in the normal population [571] [572] [573]
8.19 Hypertension and sexual dysfunction
Sexual dysfunction may have an important negative effect on the quality of life of both men and women. Compared with the normotensive population, the prevalence of sexual dysfunction is greater in hypertensive individuals, in whom it presents an important cause of low adherence to or discontinuation of antihypertensive treatment [574] [575] [576] [574,577] [578] [577] [575] [577,579] [579]
It is recommended that information on sexual dysfunction is collected in all hypertensive patients at diagnosis and regularly at the follow-up visits, with special attention to its possible relationship with reluctance to start or adherence to drug treatment. In men reporting sexual dysfunction, the antihypertensive agents more likely to be associated with this effect (e.g. beta-blockers and thiazide diuretics) should be avoided or replaced, unless strictly necessary for the patient's clinical condition.
8.20 Hypertension and cancer therapy
Hypertension is the most common cardiovascular comorbidity reported in cancer registries, in which an elevated BP is usually found in more than one-third of the patients [580] [581]
In patients under treatment with the above-mentioned anticancer drugs, a BP increase has been reported in a variable but overall high percent of patients (≤30%). The increase frequently occurs during the first months after starting the anticancer therapy, the temporal association providing evidence for the anticancer drug's pathophysiological role. It follows that office BP should be measured weekly during the initial part of the first cycle of therapy and at least every 2–3 weeks thereafter [582] [583] [584]
8.21 Perioperative management of hypertension
With the increasing number of patients undergoing surgery, management of hypertension in the perioperative period (a term that includes the intraoperative phase) has emerged as an important issue in clinical practice [585] [586] [537,586] [537,586] [587] [588,589] [586,588,589] [586] [537] [586,590] [591]
Perioperative management of hypertension
9 MANAGING CONCOMITANT CARDIOVASCULAR DISEASE RISK
9.1 Statins and lipid-lowering drugs
Patients with hypertension, and more so those with type 2 diabetes or metabolic syndrome, often have atherogenic dyslipidaemia characterized by elevated triglycerides and LDL cholesterol (LDL-C), and low HDL cholesterol (HDL-C) [595] [596] [16,35] [597] [343,598] [599]
As detailed in the recent ESC/EAS Guidelines [599] [600–602] [602] [525]
9.2 Antiplatelet therapy and anticoagulant therapy
The most common complications of hypertension are related to thrombosis [603] [603]
Antiplatelet and anticoagulant therapy use in patients with hypertension was addressed in a Cochrane systematic review [604] [604] [604]
Benefit has not been demonstrated for anticoagulation therapy, alone or in combination with aspirin, in patients with hypertension in the absence of other indications requiring anticoagulants, such as AF or venous thromboembolism [604] [605] [606] [607]
In summary, aspirin is not recommended for primary prevention in hypertensive patients without CVD [35] [35,604]
Treatment of CV risk factors associated with hypertension
9.3 Glucose-lowering drugs and blood pressure
The impact of new glucose-lowering drugs on BP and the reduction in cardiovascular and renal risk, beyond their effect of glucose control, have received attention after the publication of the US Food and Drug Administration recommendations for evaluating cardiovascular risk in new therapies to treat type 2 diabetes. New generations of antidiabetes drugs, that is dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 agonists, slightly reduce BP, and also body weight with glucagon-like peptide 1 agonists. Two glucagon-like peptide 1 agonists (liraglutide and semaglutide) reduced cardiovascular and total mortality, but not heart failure, in patients with type 2 diabetes [608,609]
Inhibitors of sodium-glucose co-transporter-2 are the only glucose-lowering drug class to reduce BP beyond the projected impact of weight reduction on BP. Empaglifozine [475] [476]
10 PATIENT FOLLOW-UP
10.1 Follow-up of hypertensive patients
After the initiation of antihypertensive drug therapy, it is important to revisit the patient at least once within the first 2 months to evaluate the effects on BP and assess possible side effects until BP is under control. The frequency of revisiting will depend on the severity of hypertension, the urgency to achieve BP control, and the patient's comorbidities. SPC therapy should reduce BP within 1–2 weeks and may continue to reduce BP over the next 2 months. Once the BP target is reached, a visit interval of a few months is reasonable and evidence has been obtained that no difference exists in BP control between 3-month and 6-month intervals [610] [611] [60,612,613]
10.2 Follow-up of subjects with high–normal blood pressure and white-coat hypertension
Patients with high–normal BP or white-coat hypertension frequently have additional risk factors, including HMOD, and have a higher risk of developing sustained hypertension [427,614–618]
10.3 Elevated blood pressure at control visits
The finding of an elevated BP should always lead physicians to search for the cause(s), particularly the most common ones such as poor adherence to the prescribed treatment regimen, persistence of a white-coat effect, and occasional or more regular consumption of salt, drugs, or substances that raise BP or oppose the antihypertensive effect of treatment (e.g. alcohol or nonsteroidal anti-inflammatory drugs). This may require tactful but stringent questioning of the patient (and his/her relatives) to identify interfering factors, as well as repeated measurements of BP in the following weeks to ensure that BP has returned to controlled values. If ineffective treatment is regarded as the reason for inadequate BP control, the treatment regimen should be uptitrated in a timely fashion (see Section 7); this avoids clinical inertia, a major contributor to poor BP control worldwide [311]
10.4 Improvement in blood pressure control in hypertension: drug adherence
There is growing evidence that poor adherence to treatment – in addition to physician inertia (i.e. lack of therapeutic action when the patient's BP is uncontrolled) – is the most important cause of poor BP control [293,619–621] [312,622]
Early discontinuation of treatment and suboptimal daily use of the prescribed regimens are the most common facets of poor adherence. After 6 months, more than one-third, and after 1 year, about one-half of patients may stop their initial treatment [623] [352,624] [625]
A major emphasis of these Guidelines has been to simplify the treatment strategy to try and improve adherence to treatment and BP control, by prescribing a single pill to most patients with hypertension. This is a response to the fact that despite the clear-cut benefits of BP treatment in trials, most treated patients do not achieve recommended BP targets in real life. The lower BP targets recommended in these Guidelines will mean that BP control rates will be even worse unless action is taken to ensure that patients are more likely to adhere to logical combinations of treatment.
Several methods are available to detect poor adherence, but most are indirect, poorly reliable, and provide little information on the most important issue: dosing history. Today, the most accurate methods that can be recommended, despite their limitations, are the detection of prescribed drugs in blood or urine samples. Directly observed treatment, followed by BP measurement over subsequent hours via HBPM or ABPM, can also be very useful to determine if BP really is poorly controlled despite witnessed consumption of medication in patients with apparent resistant hypertension. In contrast, questionnaires frequently overestimate drug adherence. The assessment of adherence should be improved with the development of cheaper and more reliable methods of detection that are easily applicable in daily practice [354,626]
Barriers to optimal adherence may be linked with physician attitudes, patient beliefs and behaviour, the complexity and tolerability of drug therapies, the healthcare system, and several other factors. Therefore, the assessment of adherence should always be conducted in a no-blame approach, and should favour an open discussion to identify the specific barriers limiting the patient's ability to follow the therapeutic recommendations. Individualized solutions should be found. Patients should be encouraged to take responsibility for their own cardiovascular health.
Patient adherence to therapy can be improved by several interventions. The most useful interventions are those linking drug intake with habits [347] [64] [627]
Prescription of an appropriate therapeutic regimen is crucial [389] [628,629]
Compared with the large number of trials for individual drugs and treatments, there are only a limited number of rigorous trials on adherence interventions. Thus, the level of evidence indicating that a sustained improvement in medication adherence can be achieved within the resources available today in clinical practice is low. This is essentially due to the short duration of most studies, their heterogeneity, and their questionable designs. Whether available interventions ameliorate treatment outcomes remains to be demonstrated in adequate trials.
A list of the interventions associated with improved patient adherence to treatment is shown in Table 33 .
TABLE 33: Interventions that may improve drug adherence in hypertension
10.5 Continued search for asymptomatic hypertension-mediated organ damage
The importance and need to detect HMOD at initial assessment to help risk stratify the patient, and to review the progression or regression of HMOD during follow-up, have been described in Section 4. The presence of HMOD demonstrates that BP is elevated and that the patient would benefit from treatment. The regression of asymptomatic organ damage occurring during treatment can often indicate an improved prognosis (see Section 5).
10.6 Can antihypertensive medications be reduced or stopped?
In some patients in whom treatment is accompanied by effective BP control for an extended period, it may be possible to reduce the number and/or dosage of drugs. This may particularly be the case if BP control is accompanied by healthy lifestyle changes such as weight loss, exercise habit, and a low-fat and low-salt diet, which remove environmental pressor influences. A reduction of medications should be made gradually, and the patient should be checked frequently because reappearance of hypertension can occur quickly, within weeks, or may take many months. Patients with prior HMOD or previous accelerated hypertension should not have their treatment withdrawn.
11 GAPS IN THE EVIDENCE 12 KEY MESSAGES
BP, epidemiology, and risk. Globally, over 1 billion people have hypertension. As populations age and adopt more sedentary lifestyles, the worldwide prevalence of hypertension will continue to rise towards 1.5 billion by 2025. Elevated BP is the leading global contributor to premature death, accounting for almost 10 million deaths in 2015, 4.9 million due to ischaemic heart disease and 3.5 million due to stroke. Hypertension is also a major risk factor for heart failure, AF, CKD, PAD, and cognitive decline.Definition of hypertension. The classification of BP and the definition of hypertension is unchanged from previous European Guidelines, and is defined as an office SBP at least 140 and/or DBP at least 90 mmHg, which is equivalent to a 24 h ABPM average of at least 130/80 mmHg, or a HBPM average at least 135/85 mmHg.Screening and diagnosis of hypertension. Hypertension is usually asymptomatic (hence the term ‘silent killer’). Because of its high prevalence, screening programmes should be established to ensure that BP is measured in all adults at least every 5 years, and more frequently in people with a high–normal BP. When hypertension is suspected because of an elevated screening BP, the diagnosis of hypertension should be confirmed either by repeated office BP measurements over a number of visits or by out-of-office BP measurement using 24 h ABPM or HBPM.The importance of cardiovascular risk assessment and detection of HMOD. Other cardiovascular risk factors such as dyslipidaemia and metabolic syndrome frequently cluster with hypertension. Thus, unless the patient is already at high or very high risk due to established CVD, formal cardiovascular risk assessment is recommended using the SCORE system. However, it is important to recognize that the presence of HMOD, especially LVH, CKD, or advanced retinopathy, further increases the risk of cardiovascular morbidity and mortality, and should be screened for as part of risk assessment in hypertensive patients because the SCORE system alone may underestimate their risk.Think: could this patient have secondary hypertension? For most people with hypertension, no underlying cause will be detected. Secondary (and potentially remediable) causes of hypertension are more likely to be present in people with young onset of hypertension (<40 years), people with severe or treatment-resistant hypertension, or people who suddenly develop significant hypertension in midlife on a background of previously normal BP. Such patients should be referred for specialist evaluation.Treatment of hypertension: importance of lifestyle interventions. The treatment of hypertension involves lifestyle interventions and drug therapy. Many patients with hypertension will require drug therapy, but lifestyle interventions are important because they can delay the need for drug treatment or complement the BP-lowering effect of drug treatment. Moreover, lifestyle interventions such as sodium restriction, alcohol moderation, healthy eating, regular exercise, weight control, and smoking cessation all have health benefits beyond their impact on BP.When to consider drug treatment of hypertension. The treatment thresholds for hypertension are now less conservative than they were in previous Guidelines. We now recommend that patients with low-moderate-risk grade 1 hypertension (office BP 140–159/90–99), even if they do not have HMOD, should now receive drug treatment if their BP is not controlled after a period of lifestyle intervention alone. For higher-risk patients with grade 1 hypertension, including those with HMOD, or patients with higher grades of hypertension (e.g. grade 2 hypertension, ≥160/100 mmHg), we recommend initiating drug treatment alongside lifestyle interventions. These recommendations apply to all adults aged <80 years.Special considerations in frail and older patients. It is increasingly recognized that biological rather than chronological age, as well as consideration of frailty and independence, are important determinants of the tolerability of and likely benefit from BP-lowering medications. It is important to note that even in the very old (i.e. >80 years), BP-lowering therapy reduces mortality, stroke, and heart failure. Thus, these patients should not be denied treatment or have treatment withdrawn simply on the basis of age. For people more than 80 years who have not yet received treatment for their BP, treatment is recommended when their office SBP is at least 160 mmHg, provided that the treatment is well tolerated.How low should SBP be lowered? This has been a hotly debated topic. A key discussion point is the balance of potential benefits vs. potential harm or adverse effects. This is especially important whenever BP targets are lowered, as there is a greater potential for harm to exceed benefit. Thus, in these Guidelines, we recommend a target range. The evidence strongly suggests that lowering office SBP to <140 mmHg is beneficial for all patient groups, including independent older patients. There is also evidence to support targeting SBP to 130 mmHg for most patients, if tolerated. Even lower SBP levels (<130 mmHg) will be tolerated and potentially beneficial for some patients, especially to further reduce the risk of stroke. SBP should not be targeted to less than 120 mmHg because the balance of benefit vs. harm becomes concerning at these levels of treated SBP.BP targets in old and very old patients. As discussed above, independence, frailty, and comorbidities will all influence treatment decisions, especially in older (≥65 years) and very old (>80 years) patients. The desired SBP target range for all patients aged more than 65 years is 130–139 mmHg. This is lower than in previous Guidelines and may not be achievable in all older patients, but any BP lowering towards this target is likely to be beneficial provided that the treatment is well tolerated.BP targets in patients with diabetes and/or CKD. The BP treatment targets for patients with diabetes or kidney disease have been a moving target in previous Guidelines because of seemingly contradictory results from major outcome trials and meta-analyses. For diabetes, targeting the SBP to less than 140 mmHg and towards 130 mmHg, as recommended for all other patient groups, is beneficial on major outcomes. Moreover, targeting SBP to less than 130 mmHg, for those who will tolerate it, may further reduce the risk of stroke but not other major outcomes. SBP should not be less than 120 mmHg. For patients with CKD, the evidence suggests that the target BP range should be 130–139 mmHg.How low should DBP be lowered? The optimal DBP target has been less well defined, but a DBP target of less than 80 mmHg is recommended. Some patients with stiff arteries and isolated systolic hypertension will already have DBP levels below this target. These are high-risk patients and the low DBP should not discourage treatment of their elevated SBP to the recommended target, provided that treatment is well tolerated.The need to do better on BP control. A key message in these Guidelines is the need to do better at improving BP control rates. Despite the overwhelming evidence of treatment benefit, on average, less than 50% of patients with treated hypertension achieve an SBP target of less than 140 mmHg. Physician inertia (inadequate uptitration of treatment, especially from monotherapy) and poor patient adherence to treatment (especially when based on multiple pills) are now recognized as the major factors contributing to poor BP control.Start treatment in most patients with two drugs, not one. Monotherapy is usually inadequate therapy for most people with hypertension; this will be especially true now that the BP treatment targets for many patients are lower than in previous Guidelines. These Guidelines have set out to normalize the concept that initial therapy for the majority of patients with hypertension should be with a combination of two drugs, not a single drug. The only exception would be in a limited number of patients with a lower baseline BP close to their recommended target, who might achieve that target with a single drug, or in some frailer old or very old patients in whom more gentle reduction of BP may be desirable. Evidence suggests that this approach will improve the speed, efficiency, and consistency of initial BP lowering and BP control, and is well tolerated by patients.A single-pill strategy to treat hypertension. Poor adherence to longer-term BP-lowering medication is now recognized as a major factor contributing to poor BP control rates. Research has shown a direct correlation between the number of BP-lowering pills and poor adherence to medications. Moreover, SPC therapy has been shown to improve adherence to treatment. SPC therapy is now the preferred strategy for initial two-drug combination treatment of hypertension and for three-drug combination therapy when required. This will control the BP of most patients with a single pill and could transform BP control rates.A simplified drug treatment algorithm. We have simplified the treatment strategy so that patients with uncomplicated hypertension and many patients with a variety of comorbidities (e.g. HMOD, diabetes, PAD, or cerebrovascular disease) receive similar medication. We recommend a combination of an ACE inhibitor or ARB with a CCB or thiazide/thiazide-like diuretic as initial therapy for most patients. For those requiring three drugs, we recommend a combination of an ACE inhibitor or ARB with a CCB and a thiazide/thiazide-like diuretic. We recommend that beta-blockers be used when there is a specific indication for their use (e.g. angina, postmyocardial infarction, HFrEF, or when heart rate control is required).Hypertension in women and in pregnancy. In women with hypertension who are planning pregnancy, ACE inhibitors or ARBs and diuretics should be avoided, and the preferred medications to lower BP, if required, include alpha-methyl dopa, labetalol, or CCBs. The same drugs are suitable if BP lowering is required in pregnant women. ACE inhibitors or ARBs should not be used in pregnant women.Is there a role for device-based therapy for the treatment of hypertension? A number of device-based interventions have been developed and studied for the treatment of hypertension. To date, the results from these studies have not provided sufficient evidence to recommend their routine use. Consequently, the use of device-based therapies is not recommended for the routine treatment of hypertension, unless in the context of clinical studies and RCTs, until further evidence regarding their safety and efficacy becomes available.Managing cardiovascular disease risk in hypertensive patients beyond BP: statins. For hypertensive patients at moderate CVD risk or higher, or those with established CVD, BP lowering alone will not optimally reduce their risk. These patients would also benefit from statin therapy, which further reduces the risk of a myocardial infarction by approximately one-third and stroke by approximately one-quarter, even when BP is controlled. Similar benefits have been seen in hypertensive patients at the border between low and moderate-risk. Thus, many more hypertensive patients would benefit from statin therapy than are currently receiving this treatment.Managing cardiovascular disease risk in hypertensive patients beyond BP: antiplatelet therapy. Antiplatelet therapy, especially low-dose aspirin, is recommended for secondary prevention in hypertensive patients, but is not recommended for primary prevention (i.e. in patients without CVD).
13 ‘WHAT TO DO’ AND ‘WHAT NOT TO DO’ MESSAGES FROM THE GUIDELINES 14 APPENDIX
ESC Committee for Practice Guidelines (CPG): Stephan Windecker (Chairperson) (Switzerland), Victor Aboyans (France), Stefan Agewall (Norway), Emanuele Barbato (Italy), Héctor Bueno (Spain), Antonio Coca (Spain), Jean-Philippe Collet (France), Ioan Mircea Coman (Romania), Veronica Dean (France), Victoria Delgado (The Netherlands), Donna Fitzsimons (UK), Oliver Gaemperli (Switzerland), Gerhard Hindricks (Germany), Bernard Iung (France), Peter Jüni (Canada), Hugo A. Katus (Germany), Juhani Knuuti (Finland), Patrizio Lancellotti (Belgium), Christophe Leclercq (France), Theresa A. McDonagh (UK), Massimo Francesco Piepoli (Italy), Piotr Ponikowski (Poland), Dimitrios J. Richter (Greece), Marco Roffi (Switzerland), Evgeny Shlyakhto (Russia), Iain A. Simpson (UK), Miguel Sousa-Uva (Portugal), Jose Luis Zamorano (Spain).
ESH Council: Costas Tsioufis (President) (Greece), Empar Lurbe (Spain), Reinhold Kreutz (Germany), Murielle Bochud (Switzerland), Enrico Agabiti Rosei (Italy), Bojan Jelakovic (Croatia), Michel Azizi (France), Andrzej Januszewicz (Poland), Thomas Kahan (Sweden), Jorge Polonia (Portugal), Philippe van de Borne (Belgium), Bryan Williams (UK), Claudio Borghi (Italy), Giuseppe Mancia (Italy), Gianfranco Parati (Italy), Denis L. Clement (Belgium), Antonio Coca (Spain), Athanasios Manolis (Greece), Dragan Lovic (Serbia)
ESC National Cardiac Societies actively involved in the review process of the 2018 ESC/ESH Guidelines for the management of arterial hypertension: Algeria : Algerian Society of Cardiology, Salim Benkhedda; Armenia : Armenian Cardiologists Association, Parounak Zelveian; Austria : Austrian Society of Cardiology, Peter Siostrzonek; Azerbaijan : Azerbaijan Society of Cardiology, Ruslan Najafov; Belarus : Belorussian Scientific Society of Cardiologists, Olga Pavlova; Belgium : Belgian Society of Cardiology, Michel De Pauw; Bosnia and Herzegovina : Association of Cardiologists of Bosnia and Herzegovina, Larisa Dizdarevic-Hudic; Bulgaria : Bulgarian Society of Cardiology, Dimitar Raev; Cyprus : Cyprus Society of Cardiology, Nikos Karpettas; Czech Republic : Czech Society of Cardiology, Ales Linhart; Denmark : Danish Society of Cardiology, Michael Hecht Olsen; Egypt : Egyptian Society of Cardiology, Amin Fouad Shaker; Estonia : Estonian Society of Cardiology, Margus Viigimaa; Finland : Finnish Cardiac Society, Kaj Metsärinne; The Former Yugoslav Republic of Macedonian : Macedonian FYR Society of Cardiology, Marija Vavlukis; France : French Society of Cardiology, Jean-Michel Halimi; Georgia : Georgian Society of Cardiology, Zurab Pagava; Germany : German Cardiac Society, Heribert Schunkert; Greece : Hellenic Society of Cardiology, Costas Thomopoulos; Hungary : Hungarian Society of Cardiology, Dénes Pall; Iceland : Icelandic Society of Cardiology, Karl Andersen; Israel : Israel Heart Society, Michael Shechter; Italy : Italian Federation of Cardiology, Giuseppe Mercuro; Kosovo : Kosovo Society of Cardiology, Gani Bajraktari; Kyrgyzstan : Kyrgyz Society of Cardiology, Tatiana Romanova; Latvia : Latvian Society of Cardiology, Karlis Trusinskis; Lebanon : Lebanese Society of Cardiology, Georges A. Saade; Lithuania : Lithuanian Society of Cardiology, Gintare Sakalyte; Luxembourg : Luxembourg Society of Cardiology, Stéphanie Noppe; Malta : Maltese Cardiac Society, Daniela Cassar DeMarco; Moldova : Moldavian Society of Cardiology, Alexandru Caraus; The Netherlands : Netherlands Society of Cardiology, Janneke Wittekoek; Norway : Norwegian Society of Cardiology, Tonje Amb Aksnes; Poland : Polish Cardiac Society, Piotr Jankowski; Portugal : Portuguese Society of Cardiology, Jorge Polonia; Romania : Romanian Society of Cardiology, Dragos Vinereanu; Russian Federation : Russian Society of Cardiology, Elena I. Baranova; San Marino : San Marino Society of Cardiology, Marina Foscoli; Serbia : Cardiology Society of Serbia, Ana Djordjevic Dikic; Slovakia : Slovak Society of Cardiology, Slavomira Filipova; Slovenia : Slovenian Society of Cardiology, Zlatko Fras; Spain : Spanish Society of Cardiology, Vicente Bertomeu-Martinez; Sweden : Swedish Society of Cardiology, Bo Carlberg; Switzerland : Swiss Society of Cardiology, Thilo Burkard; Tunisia : Tunisian Society of Cardiology and Cardio-Vascular Surgery, Wissem Sdiri; Turkey : Turkish Society of Cardiology, Sinan Aydogdu; Ukraine : Ukrainian Association of Cardiology, Yuriy Sirenko; United Kingdom : British Cardiovascular Society, Adrian Brady.
ESH National Hypertension Societies actively involved in the review process of the 2018 ESC/ESH Guidelines for the management of arterial hypertension: Austria : Austrian Society of Hypertension, Thomas Weber; Belarus : Belarussian Hypertension League, Irina Lazareva; Belgium : Belgian Hypertension Committee, Tine De Backer; Bosnia and Herzegovina: Bosnia and Herzegovina Society of Hypertension, Sekib Sokolovic; Croatia : Croatian Society of Hypertension, Bojan Jelakovic; Czech Republic : Czech Society of Hypertension, Jiri Widimsky; Estonia : Estonian Society of Hypertension, Margus Viigimaa; Finland : Finnish Hypertension Society, Ilkka Pörsti; France : French Society of Hypertension, Thierry Denolle; Germany : German Hypertension Society, Bernhard K. Krämer; Greece : Hellenic Society of Hypertension, George S. Stergiou; Italy : Italian Society of Hypertension, Gianfranco Parati; Latvia : Latvian Society of Hypertension and Atherosclerosis, Karlis Trusinskis; Lithuania : Lithuanian Hypertension Society, Marius Miglinas; Norway : Norwegian Society of Hypertension, Eva Gerdts; Poland : Polish Society of Hypertension, Andrzej Tykarski; Portugal : Portuguese Society of Hypertension, Manuel de Carvalho Rodrigues; Romania : Romanian Society of Hypertension, Maria Dorobantu; Russian Federation : Russian Society of Hypertension, Irina Chazova; Serbia : Serbian Society of Hypertension, Dragan Lovic; Slovakia : Slovak Society of Hypertension, Slavomira Filipova; Slovenia : Slovenian Hypertension Society, Jana Brguljan; Spain : Spanish Society of Hypertension, Julian Segura; Sweden : Swedish Society of Hypertension, Stroke and Vascular Medicine, Anders Gottsäter; Switzerland : Swiss Society of Hypertension, Antoinette Pechère-Bertschi; Turkey : Turkish Society of Hypertension and Atherosclerosis, Serap Erdine; Ukraine : Ukrainian Antihypertensive Society, Yuriy Sirenko; United Kingdom : British and Irish Hypertension Society, Adrian Brady.
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