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). ESC and ESH Guidelines represent the official position of the two Societies on a given topic and are regularly updated.
Members of this Task Force were selected by the ESC and ESH to represent professionals involved with the medical care of patients with this pathology. Selected experts in the field undertook a comprehensive review of the published evidence for management of a given condition according to ESC Committee for Practice Guidelines (CPG) policy and approved by the ESH. A critical evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk–benefit ratio. The level of evidence and the strength of the recommendation of particular management options were weighed and graded according to predefined scales, as outlined in Tables 1 and 2.
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TABLE 1: ESC Classes of recommendations
TABLE 2: ESC Levels of evidence
The experts of the writing and reviewing panels provided declaration of interest forms for all relationships that might be perceived as real or potential sources of conflicts of interest. These forms were compiled into one file and can be found on the ESC website (http://www.escardio.org/guidelines). Any changes in declarations of interest that arise during the writing period were notified to the ESC and ESH and updated. The Task Force received its entire financial support from the ESC and ESH without any involvement from the healthcare industry.
The ESC CPG supervises and coordinates the preparation of new Guidelines. The Committee is also responsible for the endorsement process of these Guidelines. The ESC Guidelines undergo extensive review by the CPG and external experts, and in this case by ESH-appointed experts. After appropriate revisions the Guidelines are approved by all the experts involved in the Task Force. The finalized document is approved by the CPG and ESH for publication in the European Heart Journal and in the Journal of Hypertension as well as 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]. A number of proven, highly effective, and well tolerated lifestyle and drug treatment strategies can achieve this reduction in BP. Despite this, BP control rates remain poor worldwide and are far from satisfactory across Europe. Consequently, hypertension remains the major preventable cause of cardiovascular disease (CVD) and all-cause death globally and in our continent [11–14].
These 2018 ESC/ESH Guidelines for the management of arterial hypertension are designed for adults with hypertension, 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]. However, in practice, cut-off BP values are used for pragmatic reasons to simplify the diagnosis and decisions about treatment. Epidemiological associations between BP and cardiovascular risk extend from very low levels of BP (i.e. SBP >115 mmHg). However, ‘hypertension’ is defined as the level of BP at which the benefits of treatment (either with lifestyle interventions or drugs) unequivocally outweigh the risks of treatment, as documented by clinical trials. This evidence has been reviewed (see Section 7.2 for detailed discussion of hypertension diagnostic thresholds) and provides the basis for the recommendation that the classification of BP and definition of hypertension remain unchanged from previous ESH/ESC Guidelines (Table 3) [15–17].
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], with a prevalence of over 150 million in central and Eastern Europe. The overall prevalence of hypertension in adults is around 30–45% [12], with a global age-standardized prevalence of 24 and 20% in men and women, respectively, in 2015 [5]. This high prevalence of hypertension is consistent across the world, irrespective of income status, that is in lower, middle and higher income countries [12]. Hypertension becomes progressively more common with advancing age, with a prevalence of more than 60% in people aged more than 60 years [12]. As populations age, adopt more sedentary lifestyles, and increase their body weight, the prevalence of hypertension worldwide will continue to rise. It is estimated that the number of people with hypertension will increase by 15–20% by 2025, reaching close to 1.5 billion [19].
3.4 Blood pressure relationship with risk of cardiovascular and renal events
Elevated BP was the leading global contributor to premature death in 2015, accounting for almost 10 million deaths and over 200 million disability-adjusted life years [3]. Importantly, despite advances in diagnosis and treatment over the past 30 years, the disability-adjusted life years attributable to hypertension have increased by 40% since 1990 [3]. SBP at least 140 mmHg accounts for most of the mortality and disability burden (70%), and the largest number of SBP-related deaths per year are due to ischaemic heart disease (4.9 million), haemorrhagic stroke (2.0 million), and ischaemic stroke (1.5 million) [3].
Both office BP and out-of-office BP have an independent and continuous relationship with the incidence of several 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]. Accumulating evidence is closely linking hypertension with an increased risk of developing atrial fibrillation (AF) [20], and evidence is emerging that links early elevations of BP to increased risk of cognitive decline and dementia [21,22].
The continuous relationship between BP and risk of events has been shown at all ages [23] and in all ethnic groups [24,25], and extends from high BP levels to relatively low values. SBP appears to be a better predictor of events than DBP after the age of 50 years [23,26,27]. High DBP is associated with increased cardiovascular risk and is more commonly elevated in younger (<50 years) vs. older patients. DBP tends to decline from midlife as a consequence of arterial stiffening; consequently, SBP assumes even greater importance as a risk factor from midlife [26]. In middle-aged and older people, increased pulse pressure (the difference between SBP and DBP values) has additional adverse prognostic significance [28,29].
3.5 Hypertension and total cardiovascular risk assessment
Hypertension rarely occurs in isolation, and often clusters with other cardiovascular risk factors such as dyslipidaemia and glucose intolerance [30,31]. This metabolic risk factor clustering has a multiplicative effect on cardiovascular risk [32]. Consequently, quantification of total cardiovascular risk (i.e. the likelihood of a person developing a cardiovascular event over a defined period) is an important part of the risk stratification process for patients with hypertension.
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). The SCORE system estimates the 10-year risk of a first fatal atherosclerotic event, in relation to age, sex, smoking habits, total cholesterol level, and SBP. The SCORE system also allows calibration for different cardiovascular risk levels across numerous European countries and has been externally validated [33]. A previous limitation of the SCORE system was that it applied only to patients aged 40–65 years; however, the SCORE system has recently been adapted for patients over the age of 65 years [34]. Detailed information on cardiovascular risk assessment is available [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]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]; and the presence of multiple HMODs in the same patient is also common, and further increases cardiovascular risk [39–41]. Consequently, the inclusion of HMOD assessment is important in patients with hypertension and helps identify high-risk or very high-risk hypertensive patients who may otherwise be misclassified as having a lower level of risk by the SCORE system [42]. This is especially true for the presence of left ventricular hypertrophy (LVH), CKD with albuminuria or proteinuria, or arterial stiffening [43] (see Section 5). The impact of progression of the stages of hypertension-associated disease (from uncomplicated through to asymptomatic or established disease), according to different grades of hypertension and the presence of cardiovascular risk factors, HMOD, or comorbidities, is illustrated in 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]. This works by illustrating how a younger patient (e.g. a 40-year-old) with risk factors but low absolute risk has a cardiovascular risk equivalent to a much older person (60 years) with optimal risk factors; thus, the cardiovascular risk age of the younger patient is 60 years. The cardiovascular risk age can be automatically calculated using HeartScore (www.heartscore.org).
A second consideration is that the presence of concomitant disease is often recorded in a binary way in 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]. BP should initially be measured in both upper arms, using an appropriate cuff size for the arm circumference. A consistent and significant SBP difference between arms (i.e. >15 mmHg) is associated with an increased cardiovascular risk [45], most likely due to atheromatous vascular disease. Where there is a difference in BP between arms, ideally established by simultaneous measurement, the arm with the higher BP values should be used for all subsequent measurements.
In older people, people with diabetes, or people with other causes of orthostatic hypotension, BP should also be measured 1 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]. Heart rate should also be recorded at the time of BP measurements because resting heart rate is an independent predictor of cardiovascular morbid or fatal events [47], although heart rate is not included in any cardiovascular risk algorithm. Table 8 summarizes the recommended procedure for routine office BP measurement. It is emphasized that office BP is often performed improperly, with inadequate attention to the standardized conditions recommended for a valid measurement of office BP. Improper measurement of office BP can lead to inaccurate classification, overestimation of a patient's true BP, and unnecessary treatment.
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] or eliminated [49]. Moreover, the BP values are lower than those obtained by conventional office BP measurement and are similar to, or even less than, those provided by daytime ambulatory blood pressure monitoring (ABPM) or home blood pressure monitoring (HBPM) [50]. Use of unattended office BP measurement in a recent clinical trial [the Systolic Blood Pressure Intervention Trial (SPRINT)] [51] generated controversy about its quantitative relationship to conventional office BP measurement (which has been the basis for all previous epidemiological and clinical trial data); its feasibility in routine clinical practice has also been questioned. Presently, the relationship between BP readings obtained with conventional office BP measurement and unattended office BP measurement remains unclear, but available evidence suggests that conventional office SBP readings may be at least 5–15 mmHg higher than SBP levels obtained by unattended office BP measurements [52]. There is also very limited evidence on the prognostic value of unattended office BP measurements, that is whether they guarantee at least the same ability to predict outcomes as conventional office BP measurements [53].
4.3 Out-of-office blood pressure measurement
Out-of-office BP measurement refers to the use of either HBPM or ABPM, the latter usually over 24 h. It provides a larger number of BP measurements than conventional office BP in conditions that are more representative of daily life. Recent position papers and practice guidelines provide comprehensive details for ABPM [54] and HBPM [55], and are briefly summarized below [54,56].
4.4 Home blood pressure monitoring
Home BP is the average of all BP readings performed with a semiautomatic, validated BP monitor, for at least 3 days and preferably for 6–7 consecutive days before each clinic visit, with readings in the morning and the evening, taken in a quiet room after 5 min of rest, with the patient seated with their back and arm supported. Two measurements should be taken at each measurement session, performed 1–2 min apart [57].
Compared with office BP, HBPM values are usually lower, and the diagnostic threshold for hypertension is 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]. Recent meta-analyses of the few available prospective studies have further indicated that HBPM better predicts cardiovascular morbidity and mortality than office BP [59]. There is also evidence that patient self-monitoring may have a beneficial effect on medication adherence and BP control [60,61], especially when combined with education and counselling [62]. Telemonitoring and smartphone applications may offer additional advantages [63,64], such as an aid to memory to make BP measurements, and as a convenient way to store and review BP data in a digital diary and transmit them. We do not recommend the use of apps as a cuff-independent means of measuring BP.
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]. Furthermore, 24 h ambulatory BP mean has been consistently shown to have a closer relationship with morbid or fatal events [66–68], and is a more sensitive risk predictor than office BP of cardiovascular outcomes such as coronary morbid or fatal events and stroke [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]. Recognized reasons for an absence of nocturnal BP dipping are sleep disturbance, obstructive sleep apnoea, obesity, high salt intake in salt-sensitive subjects, orthostatic hypotension, autonomic dysfunction, CKD, diabetic neuropathy, and old age [54]. Studies that accounted for daytime and nighttime BP in the same statistical model found that nighttime BP is a stronger predictor of outcomes than daytime BP [54]. The night-to-day ratio is also a significant predictor of outcome, and patients with a reduced nighttime dip in BP (i.e. <10% of the daytime average BP or a night-to-day ratio >0.9) have an increased cardiovascular risk [54]. Moreover, in those in whom there is no nighttime dip in BP or a higher nighttime than daytime average BP, there is a substantially increase in risk [74]. Paradoxically, there is also some evidence of increased risk in patients who have extreme dipping of their nighttime BP [75], although the limited prevalence and reproducibility of this phenomenon makes interpretation of data difficult.
A number of additional indices derived from ABPM recordings have some prognostic value, including 24 h BP variability [76], morning BP surge [77] and the ambulatory arterial stiffness index [78]. However, their incremental predictive value is not yet clear. Thus, these indices should be regarded as research tools, with no current indication for routine clinical use.
4.6 Advantages and disadvantages of ambulatory blood pressure monitoring and home blood pressure monitoring
A major advantage of both ABPM and HBPM is that they enable the diagnosis of white-coat and masked hypertension (see Section 4.7). The relative advantages and disadvantages of HBPM and ABPM are shown in Table 10. A particularly important advantage of HBPM is that it is much cheaper and thus more available than ABPM. Another is that it provides multiple measurements over several days or even longer periods, which is clinically relevant because day-to-day BP variability may have an independent prognostic value [79]. Unlike ABPM, typical HBPM devices do not provide BP measurements during routine daily activities and during sleep, although recent technical advances may allow BP during sleep to be measured by HBPM. A further consideration is the potential impact of impaired cognition on the reliability of HBPM measurements and rare instances of obsessional behaviour, circumstances that may favour the use of ABPM if out-of-office BP readings are required. In general, both methods should be regarded as complementary rather than absolute alternatives.
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]. Conversely, ‘masked hypertension’ refers to untreated patients in whom the BP is normal in the office, but is elevated when measured by HBPM or ABPM [81]. The term ‘true normotension’ is used when both office and out-of-office BP measurements are normal, and ‘sustained hypertension’ is used when both are abnormal. In white-coat hypertension, the difference between the higher office and the lower out-of-office BP is referred to as the ‘white-coat effect’, and is believed to mainly reflect the pressor response to an alerting reaction elicited by office BP measurements by a doctor or a nurse [82], although other factors are probably also involved [83].
Although the terms white-coat and masked hypertension were originally defined for people who were not being treated for hypertension, they are now also used to describe discrepancies between office and out-of-office BP in patients treated for hypertension, with the terms masked uncontrolled hypertension (MUCH) (office BP controlled but home or ambulatory BP elevated) and white-coat uncontrolled hypertension (WUCH) (office BP elevated but home or ambulatory BP controlled), compared with sustained uncontrolled hypertension (SUCH) [84] (both office and home or ambulatory BP are uncontrolled).
The white-coat effect is used to describe the difference between an elevated office BP (treated or untreated) and a lower home or ambulatory BP in both untreated and treated patients.
4.7.1 White-coat hypertension
Although the prevalence varies between studies, white-coat hypertension can account for up to 30–40% of people (and >50% in the very old) with an elevated office BP. It is more common with increasing age, in women, and in 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]. Conversely, compared with true normotensives, patients with white-coat hypertension have increased adrenergic activity [87], a greater prevalence of metabolic risk factors, more frequent asymptomatic cardiac and vascular damage, and a greater long-term risk of new-onset diabetes and progression to sustained hypertension and LVH [82]. In addition, although the out-of-office BP values are, by definition, normal in white-coat hypertension, they tend to be higher than those of true normotensive people, which may explain the increased long-term risk of cardiovascular events reported in white-coat hypertension by recent studies after adjustment for demographic and metabolic risk factors [85,86,88–90]. White-coat hypertension has also been shown to have a greater cardiovascular risk in isolated systolic hypertension and older patients [91], and does not appear to be clinically innocent [68]. The diagnosis should be confirmed by repeated office and out-of-office BP measurements, and should include an extensive assessment of risk factors and HMOD. Both ABPM and HBPM are recommended to confirm white-coat hypertension, because the cardiovascular risk appears to be lower (and close to sustained normotension) in those in whom both ABPM and HBPM are both normal [82]; for treatment considerations see Section 8.4.
4.7.2 Masked hypertension
Masked hypertension can be found in approximately 15% of patients with a normal office BP [17]. The prevalence is greater in younger people, men, smokers, and those with higher levels of physical activity, alcohol consumption, anxiety and job stress [54]. Obesity, diabetes, CKD, family history of hypertension, and high–normal office BP are also associated with an increased prevalence of masked hypertension [17]. Masked hypertension is associated with dyslipidaemia and dysglycaemia, HMOD [92], adrenergic activation, and increased risk of developing diabetes and sustained hypertension [81,93]. Meta-analyses and recent studies [68] have shown that the risk of cardiovascular events is substantially greater in masked hypertension compared with normotension, and close to or greater than that of sustained hypertension [68,93–96]. Masked hypertension has also been found to increase the risk of cardiovascular and renal events in diabetes, especially when the BP elevation occurs during the night [95,97].
4.8 Screening for the detection of hypertension
Hypertension is predominantly an asymptomatic condition that is best detected by structured population screening programmes or opportunistic measurement of BP. When structured population screening programmes have been undertaken, an alarming number of people (>50%) were unaware they had hypertension [12,98]. This high rate of undetected hypertension occurred irrespective of the income status of the countries studied across the world.
All adults should have their BP recorded in their medical record and be aware of their BP, and further screening should be undertaken at regular intervals with the frequency dependent on the BP level. For healthy people with an optimal office BP (<120/80 mmHg), BP should be remeasured at least every 5 years and more frequently when opportunities arise. In patients with a normal BP (120–129/80–84), BP should be remeasured at least every 3 years. Patients with high–normal BP (130–139/85–89 mmHg) should have their BP recorded annually because of the high rates of progression of high–normal BP to hypertension. This is true also for people in whom masked hypertension is detected.
4.9 Confirming the diagnosis of hypertension
BP can be highly variable, thus the diagnosis of hypertension should not be based on a single set of BP readings at a single office visit, unless the BP is substantially increased (e.g. grade 3 hypertension) and there is clear evidence of HMOD (e.g. hypertensive retinopathy with exudates and haemorrhages, or LVH, or vascular or renal damage). For all others (i.e. almost all patients), repeat BP measurements at repeat office visits have been a long-standing strategy to confirm a persistent elevation in BP, as well as for the classification of the hypertension status in clinical practice and RCTs. The number of visits and the time interval between visits varies according to the severity of the hypertension, and is inversely related to the severity of hypertension. Thus, more substantial BP elevation (e.g. grade 2 or more) requires fewer visits and shorter time intervals between visits (i.e. a few days or weeks), depending on the severity of BP elevation and whether there is evidence of CVD or HMOD. Conversely, in patients with BP elevation in the grade 1 range, the period of repeat measurements may extend over a few months, especially when the patient is at low risk and there is no HMOD. During this period of BP assessment, 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]. This approach can provide important supplementary clinical information, for example detecting white-coat hypertension (see Section 4.7.1), which should be suspected, especially in people with grade 1 hypertension on office BP measurement and in whom there is no evidence of HMOD or CVD [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]. It is likely that, with increased availability and lower cost of these devices, this will become more commonplace.
4.11 Blood pressure during exercise and at high altitude
It is important to recognize that BP increases during dynamic and static exercise, and that the increase is more pronounced for SBP than for DBP [103], although only SBP can be measured reliably with noninvasive methods. There is currently no consensus on normal BP response during exercise. The increase in SBP during exercise is related to preexercise resting BP, age, arterial stiffness and abdominal obesity, and is somewhat greater in women than in men and in unfit individuals. There is some evidence that an excessive rise in BP during exercise predicts the development of hypertension, independently from BP at rest [104]. Nevertheless, exercise testing is not recommended as part of the routine evaluation of hypertension because of various limitations, including a lack of standardization of methodology and definitions. Importantly, except in the presence of very high BP values (grade 3 hypertension), patients or athletes, with treated or untreated hypertension should not be discouraged from regular exercise, especially aerobic exercise, which is considered beneficial as part of lifestyle changes to reduce BP (see Section 7.4.1).
Evidence is available that BP increases with high altitude exposure, especially above 3000 m and possibly above 2000 m [105]. This is due to a number of factors including sympathetic activation. Patients with grade 2 hypertension and increased cardiovascular risk should check their BP values before and during high altitude (>2500 m) exposure. Patients with grade 1 hypertension may reach very high altitude (>4000 m) with adequate medical therapy; uncontrolled severe hypertensive patients (grade 3) should avoid exposure to very high altitude [105].
4.12 Central aortic pressure
Various techniques allow aortic BP (central BP) to be derived from peripheral BP measurements using dedicated algorithms [106,107]. Some studies and meta-analyses have shown that in hypertensive patients, central BP predicts cardiovascular events and that there is a differential effect of antihypertensive drugs on central compared with brachial BP [108]. The incremental prognostic value of central vs. conventional clinic BP measurement remains unclear [109]. An exception may be isolated systolic hypertension in the young, in whom peripheral BP may be disproportionately elevated relative to a normal central BP. This occurs in a small fraction of younger people, mainly men with isolated systolic hypertension, and it remains unclear whether such patients are at lower risk than suggested by their brachial office BP [110,111].
BP measurement
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]. HMOD is common in severe or long-standing hypertension, but can also be found in less severe hypertension. With wider use of imaging, HMOD is becoming increasingly apparent in asymptomatic patients [43]. Cardiovascular risk increases with the presence of HMOD, and more so when damage affects multiple organs [16,113,114]. Some types of HMOD can be reversed by antihypertensive treatment, especially when used early, but with long-standing hypertension, HMOD may become irreversible despite improved BP control [115,116]. Nevertheless, BP-lowering treatment is still important as it may delay the further progression of HMOD and will reduce the elevated cardiovascular risk of these patients [116]. Although poor technical provision and cost may limit the search for HMOD in some countries, it is recommended that basic screening for HMOD is performed in all hypertensive patients and more detailed assessment is performed when the presence of HMOD might influence treatment decisions. The various investigations to establish HMOD are shown in Table 15.
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] (see Section 9).
The main advantage of detecting HMOD is that it may reclassify a patient's SCORE risk assessment from low to moderate or from moderate to high risk [117]. The specific impact of HMOD [114] with regard to the reclassification of risk estimation according to the SCORE system has not been clearly defined. The SCORE system already takes account of the grade of hypertension as SBP is included in the risk calculation. Moreover, CKD and the presence of vascular disease on imaging are already specified as high or very high risk (Table 5). Conditioning of the risk score by the presence of HMOD will be most important in middle-aged patients with hypertension, many of whom will be at moderate-risk and at higher risk if HMOD is detected. Moreover, a risk-conditioning effect of HMOD will also be important in younger hypertensive patients who are invariably classified as low risk according to the SCORE system. In addition, detecting HMOD in younger patients with grade 1 hypertension provides unequivocal evidence of hypertension-mediated damage and indicates a clear need for BP-lowering treatment in patients who may be reluctant to be treated. For the same reason, the presence of HMOD in a patient with high–normal BP would also provide a rationale to consider BP-lowering treatment.
Another important consideration is whether the presence of a specific manifestation of HMOD (e.g. LVH or CKD) might influence the selection of drug treatment for hypertension. This was considered important in the previous guidelines [17], but is now considered less important. In patients more likely to have HMOD (i.e. those with high grade 1 or grade 2–3 hypertension), we now recommend initial treatment with a combination of two drugs, usually an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) in combination with a calcium channel blocker (CCB) or thiazide-type diuretic, which would be the optimal treatment for all manifestations of HMOD (see Section 7).
5.5 Characteristics of hypertension-mediated organ damage
5.5.1 The heart in hypertension
Chronically increased left ventricular 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]. In addition to LVH, the presence of a ‘strain pattern’ on an ECG is associated with increased risk [119]. The prevalence of ECG LVH increases with the severity of hypertension [120]. The most commonly used criteria to define ECG LVH are shown in Table 16.
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], and regression of echocardiographic LVH due to treatment of hypertension predicts an improved prognosis [125]. Two-dimensional transthoracic echocardiography (TTE) also provides information about left ventricular geometry, left atrial volume, aortic root dimensions, left ventricular systolic and diastolic function, pump performance, and output impedance [123,126,127]. Whether additional parameters other than evidence of increased left ventricular mass and left atrial dilatation are useful to help stratify cardiovascular risk is uncertain [123,126,128]. The partition values recommended for the definition of LVH by echocardiography are shown in 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], specifically for left ventricular mass [130], volumes, and ejection fraction, and has superior reproducibility to two-dimensional TTE but much less prognostic validation [131]. More detailed information on the use of echocardiography to assess the hypertensive heart is available [43]. Cardiac magnetic resonance is the gold standard for cardiac anatomical and functional quantification [132–134].
Abnormal left ventricular geometry in hypertensive patients is frequently associated with diastolic dysfunction [127,135], which can be further evaluated by a combination of transmitral flow and tissue Doppler studies [136]. Left atrial size is also frequently increased in hypertensive patients and is associated with adverse cardiovascular events [128,137] and incident AF [138], and is related to diastolic dysfunction [139,140]. During the diagnostic workup for secondary hypertension, a suprasternal view should also be performed for the identification of aortic coarctation [141].
5.5.2 The blood vessels in hypertension
5.5.2.1 Carotid artery
Carotid intima–media thickness (IMT) quantified by carotid ultrasound, and/or the presence of plaques, predicts cardiovascular risk [42,142]. This holds true both for the IMT value at the carotid bifurcations (reflecting primarily atherosclerosis) and for the IMT value at the level of the common carotid artery (reflecting primarily hypertension-related hypertrophy). A carotid IMT more than 0.9 mm is considered abnormal [143], but the upper limit of normality varies with age. The presence of a plaque can be identified by an IMT at least 1.5 mm, or by a focal increase in thickness of 0.5 mm or 50% of the surrounding carotid IMT value [144]. Stenotic carotid plaques have a strong predictive value for both stroke and myocardial infarction, independent of traditional cardiovascular risk factors [42,142], and confer superior prognostic accuracy for future myocardial infarction compared with IMT [145]. The presence of carotid plaques will automatically reclassify patients from intermediate to high risk [146,147]; however, routine carotid imaging is not recommended unless clinically indicated (i.e. presence of carotid bruit, previous transient ischemic attack (TIA) or cerebrovascular disease, or as part of the assessment of patients with evidence of vascular disease).
5.5.2.2 Pulse wave velocity
Large artery stiffening is the most important pathophysiological determinant of isolated systolic hypertension and age-dependent increase in pulse pressure [148]. Carotid-femoral pulse wave velocity (PWV) is the gold standard for measuring large artery stiffness [149]. Reference values for PWV are available in healthy populations and patients at increased cardiovascular risk [150]. A PWV more than 10 m/s is considered a conservative estimate of significant alterations of aortic function in middle-aged hypertensive patients [149]. The additive value of PWV above and beyond traditional risk factors, including SCORE and the Framingham risk score, has been suggested by several studies [151]. However, routine use of PWV measurement is not practical and is not recommended for routine practice.
5.5.2.3 Ankle–brachial index
Ankle-brachial index (ABI) may be measured either with automated devices, or with a continuous wave Doppler unit and a BP sphygmomanometer. A low ABI (i.e. <0.9) indicates lower extremity artery disease (LEAD), is usually indicative of advanced atherosclerosis [152], and has predictive value for cardiovascular events [153], being associated with an almost two-fold greater 10-year cardiovascular mortality and major coronary event rate, compared with the overall rate in each Framingham category [153]. Even asymptomatic LEAD, detected by a low ABI, is associated in men with a high incidence of cardiovascular morbid and fatal events, approaching 20% in 10 years [153,154]. Routine use of ABI is not recommended in hypertensive patients, but should be considered in patients with symptoms or signs of LEAD, or in moderate-risk patients in whom a positive test would reclassify the patient as high-risk.
5.5.3 The kidney in hypertension
Hypertension is the second most important cause of CKD after diabetes. Hypertension may also be the presenting feature of asymptomatic primary renal disease. An alteration of renal function is most commonly detected by an increase in serum creatinine. This is an insensitive marker of renal impairment because a major reduction in renal function is needed before serum creatinine rises. Furthermore, BP reduction by antihypertensive treatment often leads to an acute increase in serum creatinine by as much as 20–30%, especially with renin–angiotensin system (RAS) blockers, which has a functional basis and does not usually reflect manifest renal injury, but the long-term clinical significance is unclear [155,156]. The diagnosis of hypertension-induced renal damage is based on the finding of reduced renal function and/or the detection of albuminuria. CKD is classified according to estimated glomerular filtration rate (eGFR), calculated by the 2009 CKD-Epidemiology Collaboration formula [157].
The albumin:creatinine ratio (ACR) is measured from a spot urine sample (preferably early morning urine), and is the preferred method to quantify urinary albumin excretion. A progressive reduction in eGFR and increased albuminuria indicate progressive loss of renal function, and are both independent and additive predictors of increased 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]. One negative urinary dipstick test does not rule out albuminuria, in contrast to a normal ACR [160].
5.5.4 Hypertensive retinopathy
The prognostic significance of hypertensive retinopathy by fundoscopy has been well documented [161]. Detection of retinal haemorrhages, microaneurysms, hard exudates, cotton wool spots, and papilloedema is highly reproducible, indicates severe hypertensive retinopathy, and is highly predictive of mortality [161,162]. In contrast, evidence of arteriolar narrowing, either focal or general, and arteriovenous nicking at early stages of hypertensive retinopathy have less predictive value [163], and limited interobserver and intraobserver reproducibility, even with experienced observers [164]. Fundoscopy should be performed in patients with grade 2 or 3 hypertension or hypertensive patients with diabetes, in whom significant retinopathy is more likely. Fundoscopy may be considered in other hypertensive patients. The increasing emergence of new techniques to visualize the fundus through smartphone technologies should increase the feasibility of more routine fundoscopy [165].
5.5.5 The brain in hypertension
Hypertension increases the prevalence of brain damage, of which transient ischaemic attack (TIA) and stroke are the most dramatic acute clinical manifestations. In the asymptomatic phase, brain damage can be detected by MRI as white matter hyperintensities, silent microinfarcts, (most of which are small and deep, i.e. lacunar infarctions), microbleeds and brain atrophy [166,167]. White matter hyperintensities and silent infarcts are associated with an increased risk of stroke and cognitive decline due to degenerative and vascular dementia [166–169]. Availability and cost do not permit the widespread use of brain MRI for the evaluation of hypertensive patients, but white matter hyperintensity and silent brain infarcts should be sought in all hypertensive patients with neurological disturbances, cognitive decline, and, particularly, memory loss [168,169]. A family history of cerebral haemorrhage at middle age and early-onset dementia should prompt MRI. Cognitive impairment in older patients is, at least in part, hypertension-related, and cognitive evaluation tests should be considered in the clinical assessment of hypertensive patients with a history suggestive of early cognitive impairment. The Mini-Mental State Examination has been the most widely used method in clinical trials, but is now being superseded by more sophisticated cognitive tests that are more suitable for routine clinic visits [170].
5.6 Hypertension-mediated organ damage regression and cardiovascular risk reduction with antihypertensive treatment
As discussed above, HMOD assessment may play a role in stratifying the risk of patients with hypertension. In post-hoc analyses, BP treatment-induced regression of some (but not all) manifestations of asymptomatic HMOD, as a consequence of treatment, is associated with a reduction in cardiovascular risk, thereby providing additional information on the effectiveness of treatment in individual patients [16,104,171]. This has been best illustrated for the treatment-induced regression of LVH measured by either ECG or echocardiography [125,172,173]. A reduced incidence of cardiovascular events and slower progression of renal disease has been reported with a treatment-induced reduction in urinary protein excretion in both diabetic and nondiabetic patients, especially for microalbuminuria [174], but results are discordant [175–179]. There is also evidence that treatment-induced changes in eGFR predict cardiovascular events [180] and progression to end-stage renal disease [181,182]. Two meta-analyses [183,184] failed to document any predictive value of treatment-induced reductions in carotid IMT for cardiovascular events. Evidence on the predictive power of treatment-induced changes on other measures of HMOD (PWV and ABI) are either limited or absent. Regression of HMOD might not be possible even when BP is controlled, particularly when HMOD is advanced, because some of the changes become irreversible.
The information available on the sensitivity and timing of changes in HMOD during antihypertensive treatment is summarized in Table 18. If, when, and how often the assessment of HMOD should be performed has not been validated in follow-up studies. HMOD can also develop during the course of antihypertensive treatment [185], and this may be accompanied by increased risk [186–188].
TABLE 18: Sensitivity to detect treatment-induced changes, reproducibility and operator independence, time to changes, and prognostic value of changes provided by markers of hypertension-mediated organ damage
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]. However, hypertension is a highly heterogeneous disorder with a multifactorial aetiology. Several genome-wide association studies and their meta-analyses have identified 120 loci that are associated with BP regulation, but together these only explain about 3.5% of the trait variance [193]. Several rare, monogenic forms of hypertension have been described such as glucocorticoid-remediable aldosteronism, Liddle's syndrome, and others, where a single gene mutation fully explains the pathogenesis of hypertension and dictates the best treatment modality [194–196]. There are also inherited forms of phaeochromocytoma and paraganglioma, which are also rare causes of hypertension [197–200]. Outside of specialist clinics evaluating patients for these rare causes of secondary hypertension, there is no role for genetic testing in hypertension in routine clinical care.
Genetic testing and hypertension
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]. These relative risk reductions are consistent, irrespective of baseline BP within the hypertensive range, the level of cardiovascular risk, comorbidities (e.g. diabetes and CKD), age, sex, and ethnicity [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]. Thus, the benefits of antihypertensive treatment have not been attenuated by the widespread concomitant prescription of lipid-lowering and antiplatelet therapies in contemporary medicine.
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]. Some, but not all, RCTs have also shown a protective effective of BP lowering on the progression of CKD towards end-stage renal disease in both diabetic and nondiabetic nephropathy [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], which adds to that provided by observational studies over several decades [205–207]. Such evidence suggests that the benefit of continued treatment is maintained over decades [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]. Guidelines are also consistent in recommending that patients with grade 1 hypertension and high cardiovascular risk or HMOD should be treated with BP-lowering drugs. There has been less consistency about whether BP-lowering drugs should be offered to patients with grade 1 hypertension and low–moderate cardiovascular risk or grade 1 hypertension in older patients (>60 years), or the need for BP-lowering drug treatment in patients with high–normal BP levels [17,209,210]. This uncertainty relates to the fact that low-risk patients with high–normal BP or grade 1 hypertension have rarely been included in RCTs, and that in older patients, RCTs have invariably recruited patients with at least grade 2 hypertension. New analyses and RCT data have become available in these important areas and are discussed below.
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]. However, the first of these analyses included a substantial number of patients who had grade 1 hypertension despite existing treatment, and were therefore likely to have had initial BPs above the grade 1 range. Furthermore, many of the patients had diabetes and were therefore at high cardiovascular risk [211]. The second meta-analysis, limited to RCTs in patients with grade 1 hypertension and low–moderate-risk (five RCTs, 8974 patients), demonstrated a significant reduction in all major cardiovascular events by BP-lowering drug treatment [combined stroke and coronary artery disease (CAD) reduced by 34%, and all-cause mortality by 19% for an SBP reduction of 7 mmHg] [8]. A third analysis demonstrated a benefit of BP lowering in reducing death and CVD in patients with a baseline BP 140/90 mmHg or higher, but not when baseline BP was lower [201]. These findings have been supported by the results of a subgroup analysis of the Heart Outcomes Prevention Evaluation (HOPE)-3 trial, showing a significant 27% reduction in major cardiovascular outcomes in patients at intermediate cardiovascular risk and baseline SBP values in the grade 1 hypertensive range [i.e. >143.5 mmHg (mean 154 mmHg)] when SBP was lowered by drug treatment by a mean of 6 mmHg [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] or 80 years [213] in later trials. Chronological age is often a poor surrogate for biological age, with consideration of frailty and independence influencing the likely tolerability of BP-lowering medications. For the purposes of this guideline, the ‘old’ are defined as at least 65 years and the ‘very old’ as at least 80 years. The previous Guidelines [17] noted that all available evidence on cardiovascular event reduction by BP lowering in older patients was obtained in patients whose baseline SBP was at least 160 mmHg, and there is strong evidence that these patients should be offered BP-lowering drug treatment [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]. However, in most RCTs showing a protective effect of BP-lowering treatment in patients with an untreated baseline BP in the grade 1 hypertension range, older patients were well represented. This was further supported by the recent HOPE-3 trial, which showed beneficial effects of BP lowering on cardiovascular outcomes in patients, many with grade 1 hypertension (SBP >143 mmHg and mean BP = 154 mmHg), whose mean age was 66 years, and in whom only 22% had prior treatment of hypertension [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]. BP-lowering drugs should not be withdrawn on the basis of age alone. It is well established that BP-lowering treatment withdrawal leads to a marked increase in cardiovascular risk. This was exemplified in older patients by a recent subgroup analysis of the Hypertension in the Very Elderly Trial (HYVET) [213], reporting that in patients aged at least 80 years, cardiovascular risk reduction was greatest in those who continued treatment rather than in those whose treatment was discontinued [216]. As stated above, all of the above recommendations relate to relatively fit and independent older patients, because physically and mentally frail and institutionalized patients have been excluded in most RCTs of patients with hypertension [214]. Further details of the treatment of hypertension in older patients and very old patients is provided in Section 8.8.
7.2.4 Initiation of blood pressure-lowering drug treatment in patients with high-normal blood pressure
The previous (2013) Guidelines [17] recommended not to initiate antihypertensive treatment in people with high–normal BP and low–moderate cardiovascular risk. This recommendation is further supported by new evidence:
- In all RCTs (including SPRINT) [51] and meta-analyses [2] that have reported reduced major outcomes by lowering ‘baseline’ BP in the high–normal range, the ‘baseline’ BP was commonly measured on a background of antihypertensive treatment. Therefore, these studies do not provide evidence to support treatment initiation in patients without hypertension [8].
- The HOPE-3 trial [212], in which only 22% of the patients at intermediate cardiovascular risk had background antihypertensive treatment, showed that BP-lowering treatment did not reduce the risk of major cardiovascular events in patients with baseline SBP values in the high–normal range.
- 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]. In another analysis of trials including people with previous CAD and a mean baseline SBP of 138 mmHg, treatment was associated with reduced risk for major cardiovascular events (relative risk 0.90; 95% confidence interval 0.84–0.97), but was not associated with an increased survival (relative risk 0.98; 95% confidence interval 0.89–1.07) [201]. Thus, the benefit for treating people with high–normal BP appears marginal and, if present, appears to be restricted to those at very high cardiovascular risk and established CVD, especially CAD.
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] have shown that when BP-lowering data are stratified according to cardiovascular risk, the relative risk reductions do not differ across the various risk strata; not surprisingly, the absolute risk reduction is greater with increasing baseline cardiovascular risk. These data have been taken as support for the hypothesis that BP-lowering treatment should be based on cardiovascular risk and target those at greatest cardiovascular risk, irrespective of their BP [218]. However, it has recently been made that whereas patients at high or very high cardiovascular risk exhibit the greatest absolute reduction in cardiovascular outcomes with BP-lowering treatment, they also have the highest residual risk, which means failure of treatment to exert full protection [8]. It is the opinion of this Task Force that these data support earlier treatment of patients with SBP or DBP values more than 140/90 mmHg when their cardiovascular risk is still low–moderate, to prevent the accumulation of HMOD and a high incidence of late treatment failure (residual risk), which would otherwise occur if treatment was delayed by a purely cardiovascular risk-based approach. The most effective strategy to reduce risk is to prevent the development of high cardiovascular-risk situations with earlier intervention. The assessment of cardiovascular risk is at the core of the treatment strategy recommended by these Guidelines because of the frequent coexistence of multiple cardiovascular risk factors in hypertensive patients, and to inform the use of concomitant medications (e.g. statins, antiplatelet therapies, etc., see Section 9) to reduce cardiovascular risk. We conclude that, in general, the decision to use BP-lowering treatment should not be based solely on the level of cardiovascular risk because even in patients at the highest risk (with established CVD), when baseline BP is below 140/90 mmHg, the benefits of BP-lowering treatment are at best marginal and most evident in patients with CAD at the upper end of the high–normal BP range [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
FigureFIGURE 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] recommended an office BP treatment target of <140/90 mmHg, regardless of the number of comorbidities and level of cardiovascular risk. The Guidelines specifically stated that evidence from RCTs, meta-analyses, and post-hoc analysis of large-scale RCTs all showed no obvious incremental benefit of lowering BP to less than 130/80 mmHg. Since then, new information has emerged from post-hoc analyses of large outcome trials in patients at high cardiovascular risk [222–224], registries in patients with coronary disease, and, more importantly, new RCTs and meta-analyses of all available RCT evidence. In the post-hoc RCT analyses and registry data, compared with a target SBP of between 130 and 139 mmHg, lowering SBP to less than 130 mmHg was, in general, associated with no further benefit on major cardiovascular events, except perhaps for further reductions in the risk of stroke. A consistent finding was that reducing SBP to less than 120 mmHg increased the incidence of cardiovascular events and death.
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]. This outcome unquestionably provides strong support for the beneficial effects of more vs. less intensive BP-lowering treatment strategies in higher risk patients. However, this RCT does not clarify the optimal BP target because the method used for office BP measurement in SPRINT (unattended automatic measurement) had not been used in any previous RCTs that provide the evidence base for the treatment of hypertension [225]. This is because unattended automated office BP measurement results in lower BP values, relative to conventional office BP measurement, due to the absence of the white-coat effect [52,54]. Thus, it has been suggested that the BP values reported in SPRINT may correspond to conventional office SBPs in the 130–140 and 140–150 mmHg ranges in the more vs. less intensive BP-lowering groups, respectively.
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]. Lowering SBP to less than 140 mmHg reduced the relative risk of all major cardiovascular outcomes (including mortality); similar benefits were seen when SBP was lowered to less than 130 mmHg (average 126 mmHg). Importantly, the latter was also true when the achieved SBP in the comparator group was 130–139 mmHg. Stratification of RCTs for achieved DBP, to either 89–80 or less than 80 mmHg, also showed a reduction in all types of cardiovascular outcomes compared with higher DBP values [226].
The second meta-analysis, which also included the SPRINT trial [2], noted that every 10 mmHg reduction in SBP reduced the rate of major cardiovascular events and death for baseline SBP values more than 160 mmHg to baseline values between 130 and 139 mmHg, implying benefit at achieved SBP values of less than 130 mmHg. Furthermore, a benefit of a 10 mmHg reduction in SBP was also reported for patients with a baseline SBP of less than 130 mmHg, thereby achieving values less than 120 mmHg. However, there were far fewer patients in these subgroups, and this last set of data will have been heavily influenced by the unusually low BP values in the SPRINT trial, due to the method of BP measurement (see above). Importantly, this analysis showed consistent benefit from intensive BP lowering in patients at all levels of risk, including those with and without existing CVD, stroke, diabetes and CKD.
Finally, in the first meta-analysis [226], the incremental benefit of BP lowering on events progressively decreased as the target BP was lowered. Furthermore, an additional meta-analysis by the same group found that permanent treatment discontinuation because of treatment-related adverse effects was significantly higher in those targeted to lower BP values [227]. Therefore, advocating more intensive BP-lowering targets for all has to be viewed in the context of an increased risk of treatment discontinuation due to adverse events, which might offset, in part or completely, the limited incremental reduction in cardiovascular risk.
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 is a major missed opportunity for CVD prevention in millions of people across the world.
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], but because these patients tend to be younger, previous RCTs have had inadequate power to study cardiovascular outcomes and to establish optimal BP targets.
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]. Most of these RCTs have shown that BP lowering to less than 140/85 mmHg is beneficial in patients with type 2 diabetes and hypertension. However, the results have been less clear about whether a lower BP target is associated with further benefits. The evidence can be summarized as follows:
- 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], other large meta-analyses have confirmed that in type 2 diabetes, lowering SBP to <140 mmHg is associated with reductions in all major cardiovascular events [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], except for the continuing incremental benefit on stroke.
- 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] trial in type 2 diabetes, after removing the interaction from the intensive glucose-lowering arm and thereby limiting the analysis to BP-lowering effects, showed an overall reduction in cardiovascular events with intensive SBP lowering to less than 130 mmHg [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]. More recently, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron – MR Controlled Evaluation (ADVANCE) trial [229], the benefits on cardiovascular outcomes were observed at diastolic pressures of 75 mmHg. This is consistent with evidence from the meta-analyses cited above, that it is safe and effective to lower DBP to less than 80 mmHg in patients with type 2 diabetes.
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], and lower if tolerated. In older patients (aged ≥65 years) the SBP target range should be 130–140 mmHg [213] if tolerated. SBP should not be lowered to less than 120 mmHg and DBP should be lowered to less than 80 mmHg. Attention should also be given to the consistency of BP control, because visit-to-visit BP variability is associated with increased cardiovascular and renal disease risk. Furthermore, cardiovascular protection has been found to be greater when BP control is accompanied by fewer visit-to-visit BP variations [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]. More recent evidence supports a lower SBP target for older patients (≥65 years):
- 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]. It has been noted above that the BP measurement technique used in SPRINT generated lower values than those provided by the conventional office BP measurement [225,242]. Consequently, the SBP of 124 mmHg achieved in the intensively treated older patients in the SPRINT trial most probably reflects a conventional office SBP range of 130–139 mmHg.
- 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 whom the difference between office BP and ambulatory BP values diminishes and becomes negligible at an SBP of approximately 120 mmHg.
- 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]. Effective lifestyle changes may be sufficient to delay or prevent the need for drug therapy in patients with grade 1 hypertension. They can also augment the effects of BP-lowering therapy, but they should never delay the initiation of drug therapy in patients with HMOD or at a high level of cardiovascular risk. A major drawback of lifestyle modification is the poor persistence over time [245,246]. The recommended lifestyle measures that have been shown to reduce BP are salt restriction, moderation of alcohol consumption, high consumption of vegetables and fruits, weight reduction and maintaining an ideal body weight, and regular physical activity [17]. In addition, tobacco smoking has an acute prolonged pressor effect that may raise daytime ambulatory BP, but smoking cessation and other lifestyle measures are also important beyond BP (i.e. for CVD and cancer prevention) [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]. Conversely, sodium restriction has been shown to have a BP-lowering effect in many trials. A recent meta-analysis of these trials showed that a reduction of 1.75 g sodium per day (4.4 g salt per day) was associated with a mean 4.2/2.1 mmHg reduction in SBP/DBP, with a more pronounced effect (−5.4/−2.8 mmHg) in people with hypertension [248]. The beneficial effect of a reduced sodium intake on BP tends to diminish with time, in part due to poor dietary persistence. The BP-lowering effect of sodium restriction is greater in black people, in older patients, and in patients with diabetes, metabolic syndrome, or CKD [249]. In people with treated hypertension, effective sodium restriction may reduce the number or dose of BP-lowering drugs that are necessary to control BP [250,251].
The effect of reduced dietary sodium on cardiovascular events remains unclear [252–255]. Prospective cohort studies have reported an overall increased risk of mortality and cardiovascular events on high sodium intake. However, they also reported that reducing sodium intake below a certain level (about 3 g of sodium per day) further reduced BP, but paradoxically was associated with an increased risk of all-cause and cardiovascular mortalities in both the general population and in hypertensive people, suggesting a J-curve phenomenon [256]. The mechanism of this apparent increased risk at low sodium intake is not well understood and might be confounded by reverse causality. There is no evidence from epidemiological studies that very low sodium intake may cause harm [257]. Although a few trials and meta-analyses suggest that reducing salt intake from high to moderate is accompanied by a lower risk of cardiovascular events [254,255,258], to date, no prospective RCT has provided definitive evidence about the optimal sodium intake to minimize cardiovascular events and mortality. Increased potassium intake is associated with BP reduction and may have a protective effect, thereby modifying the association between sodium intake, BP and CVD [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]. The Prevention and Treatment of Hypertension Study (PATHS) investigated the effects of alcohol reduction on BP; the intervention group had a modest 1.2/0.7 mmHg lower BP than the control group at the end of the 6-month period [260]. A Mendelian randomization meta-analysis of 56 epidemiological studies suggested that reduction of alcohol consumption, even for light–moderate drinkers, might be beneficial for cardiovascular health [261]. Hypertensive men who drink alcohol should be advised to limit their consumption to 14 and women to 8 units per week (1 unit is equal to 125 ml of wine or 250 ml of beer). Alcohol-free days during the week and avoidance of binge drinking [35] are also advised.
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]. The Mediterranean diet includes many of these nutrients and foods, with a moderate consumption of alcohol (mostly wine with meals). A number of studies and meta-analyses [262–265] have shown that the Mediterranean diet is associated with a reduction in cardiovascular events and all-cause mortality. An RCT in high-risk individuals on the Mediterranean diet over 5 years showed a 29% cardiovascular risk reduction compared with a low-fat control diet, and a 39% reduction in stroke [265]. The Mediterranean diet also significantly reduced ambulatory BP, blood glucose, and lipid levels [266]. The diet should be accompanied by other lifestyle changes such as physical exercise and weight loss [35].
With regard to coffee consumption, caffeine has been shown to have an acute pressor effect [267]. Nevertheless, coffee consumption is associated with cardiovascular benefits, as highlighted by a recent systematic review of prospective cohort studies including more than 1 million participants and 36 352 cardiovascular events [267]. Moreover, green or black tea consumption may also have a small but significant BP-lowering effect [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]. In a meta-analysis, the mean SBP and DBP reductions associated with an average weight loss of 5.1 kg were 4.4 and 3.6 mmHg, respectively [271]. Both overweight and obesity are associated with an increased risk of cardiovascular death and all-cause mortality. Weight reduction is recommended in overweight and obese hypertensive patients for control of metabolic risk factors, but weight stabilization may be a reasonable goal for many. The Prospective Studies Collaboration [272] concluded that mortality was lowest at a BMI of approximately 22.5–25 kg/m2, whereas a more recent meta-analysis concluded that mortality was lowest in subjects with overweight [273,274]. Although the optimal BMI is unclear, maintenance of a healthy body weight (BMI of approximately 20–25 kg/m2 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]. Weight loss can also improve the efficacy of antihypertensive medications and the cardiovascular risk profile. Weight loss should employ a multidisciplinary approach that includes dietary advice, regular exercise, and motivational counselling [35,275]. Furthermore, short-term results are often not maintained over the long-term. Weight loss can also be promoted by antiobesity drugs and, to a greater degree, bariatric surgery, which appears to decrease cardiovascular risk in severely obese patients. Further details are available in a recent document of the ESH and the European Association for the Study of Obesity [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]. Endurance training, but not other types of training, reduces BP more in hypertensive participants (8.3/5.2 mmHg). Regular physical activity of lower intensity and duration lowers BP less than moderate-intensity or high-intensity training, but is associated with at least a 15% decrease in mortality in cohort studies [278,279]. This evidence suggests that hypertensive patients should be advised to participate in at least 30 min of moderate-intensity dynamic aerobic exercise (walking, jogging, cycling or swimming) on 5–7 days/week. Performance of resistance exercises on 2–3 days/week can also be advised. For additional benefit in healthy adults, a gradual increase in aerobic physical activity to 300 min a week of moderate intensity or 150 min a week of vigorous-intensity aerobic physical activity, or an equivalent combination thereof, is recommended [35]. The impact of isometric exercises on BP and cardiovascular risk is less well established [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]. There is also evidence suggesting ill-health effects of passive smoking [282]. Studies using ABPM have shown that both normotensive subjects and untreated hypertensive smokers present higher daily BP values than nonsmokers [283]. No chronic effect of smoking has been reported for office BP [284], which is not lowered by smoking cessation. Smoking is second only to BP in contributing risk to the global burden of disease, and smoking cessation is probably the single most effective lifestyle measure for the prevention of CVD, including stroke, myocardial infarction, and PAD [285,286]. Therefore, the history of tobacco use should be established at each patient visit and hypertensive smokers should be counselled regarding smoking cessation.
Brief advice from a physician has a small but significant effect of 1–3% over and above the unassisted 12-month quit rate [287]. This can be improved by the use of pharmacological measures, with varenicline and combination nicotine replacement therapy being superior to bupropion or single nicotine replacement therapy [288]. In comparison with placebo, nicotine replacement therapy or treatment with buproprion doubles the chance of quitting, while varenicline or combination nicotine replacement therapy triples the chance of quitting. Combining behavioural support with pharmacotherapy increases the chance of success by 70–100% compared with brief advice alone [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]. These meta-analyses have reported cause-specific differences on outcomes between some drugs (e.g. less stroke prevention with beta-blockers, and less heart failure prevention with CCBs); however, overall, major cardiovascular outcomes and mortality were similar with treatment based on initial therapy with all five major classes of treatment. These Guidelines thus recommend that the same five major classes of drugs should form the basis of antihypertensive therapy. There are compelling or possible contraindications for each class of drug (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] as each other and other major drug classes on major cardiovascular events and mortality outcomes [2,292]. ARBs are associated with significantly lower treatment discontinuation rates for adverse events than those of all other antihypertensive therapies [297], and similar rates to placebo [294]. ACE inhibitors and ARBs should not be combined for the treatment of hypertension because there is no added benefit on outcomes and an excess of renal adverse events [298,299]. Dual combination of RAS blockers also led to the premature cessation of another trial due to adverse events [291], when a renin inhibitor, aliskiren, was combined with either an ACE inhibitor or an ARB in people with diabetes. This result halted further research into the clinical utility of aliskiren for BP treatment.
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]. A recent meta-analysis shows that RAS blockers are the only antihypertensive agents for which evidence is available of a reduced risk of end-stage renal disease [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]. Both drugs reduce incident AF, which may be related to improved left ventricular function and more effective left ventricular structural regression [292]. ACE inhibitors and ARBs are also indicated postmyocardial infarction and in patients with chronic HFrEF, which are frequent complications of hypertension.
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]. CCBs have a greater effect on stroke reduction than expected for the BP reduction achieved, but may also be less effective at preventing HFrEF [2,292]. However, in antihypertensive treatment trials, emergent heart failure is the event considered. Though clinically a very relevant event, it is a difficult endpoint to quantify precisely, either because symptoms and signs are relatively nonspecific or because oedema due to CCBs may result in misdiagnosis. Comparison with diuretics may also be difficult because fluid loss may mask signs and symptoms of incipient heart failure rather than preventing it. CCBs have also been compared with other antihypertensive agents in HMOD-based trials, and are reported to be more effective than beta-blockers in slowing the progression of carotid atherosclerosis, and in reducing LVH and proteinuria [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]. Diuretics also appear to be more effective than other drug classes in preventing heart failure [292]. There has been debate about whether thiazide-like diuretics such as chlorthalidone and indapamide should be given preference over classical thiazide diuretics (e.g. hydrochlorothiazide and bendrofluazide), but their superiority on outcomes has never been tested in head-to-head RCTs. Chlorthalidone and indapamide have been used in a number of RCTs showing cardiovascular benefits, and these agents are more potent per milligram than hydrochlorothiazide in lowering BP, with a longer duration of action compared with hydrochlorothiazide and no evidence of a greater incidence of side effects [301]. Lower dose thiazide-like diuretics (typical of modern antihypertensive treatment regimens) also have more evidence from RCTs demonstrating reductions in cardiovascular events and mortality, when compared with lower dose thiazide diuretics [302]. That said, hydrochlorothiazide, alone or in combination with a potassium-sparing agent, has also been used in BP-lowering RCTs, with positive results [303]. A recent meta-analysis of placebo-controlled studies based on thiazides, chlorthalidone and indapamide reported similar effects on cardiovascular outcomes of the three types of diuretics [300]. Therefore, in the absence of evidence from direct comparator trials and recognizing that many of the approved single-pill combinations (SPCs) are based on hydrochlorothiazide (see below), we recommend that thiazides, chlorthalidone, and indapamide can all be considered suitable antihypertensive agents. Both thiazide and thiazide-like diuretics can reduce serum potassium and have a side effect profile that is less favourable than RAS blockers, which may account for their association with a higher rate of treatment discontinuation [293,300]. They also exhibit dysmetabolic effects that increase insulin resistance and the risk of new-onset diabetes. Potassium may attenuate these effects [304], and a recent study has shown that the adverse effect of thiazides on glucose metabolism may be reduced by the addition of a potassium-sparing diuretic [305]. Both thiazides and thiazide-like agents are less effective antihypertensive agents in patients with a reduced GFR (eGFR <45 ml/min) and become ineffective when the eGFR is less than 30 ml/min. In such circumstances, loop diuretics such as furosemide (or torasemide) should replace thiazides and thiazide-like diuretics to achieve an antihypertensive effect.
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]. When compared with other BP-lowering drugs, beta-blockers are usually equivalent in preventing major cardiovascular events, except for less effective prevention of stroke, which has been a consistent finding [1,2,217]. It is possible that the difference originated from small differences in achieved BP (including central SBP [108] between different drug treatments), to which cerebrovascular events may be especially sensitive. RCTs based on HMOD have also indicated that beta-blockers are somewhat less effective than RAS blockers and CCBs in preventing or regressing LVH, carotid IMT, aortic stiffness, and small artery remodelling [17]. In addition, a mortality benefit in postmyocardial infarction is uncertain in patients without left ventricular dysfunction [306]. Beta-blockers, as well as diuretics, and particularly their combination, are also associated with increased risk of new-onset diabetes in predisposed subjects (mostly those with the metabolic syndrome). They also exhibit a somewhat less favourable side effect profile than that of RAS blockers, with a higher rate of treatment discontinuation when assessed in real-life conditions [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], including less adverse effects on sexual function. Bisoprolol, carvedilol and nebivolol have been shown to improve outcomes in RCTs in heart failure [136]; however, there are no RCTs reporting patient outcomes with these beta-blockers in hypertensive patients.
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], and was more effective than placebo but less effective than spironolactone at lowering BP in resistant hypertension in the Prevention And Treatment of Hypertension With Algorithm-based therapY-2 (PATHWAY-2) study [310]. Alpha-blockers may also be required in specific indications (e.g. the treatment of symptomatic prostatic hypertrophy). Antihypertensive drugs, other than the major classes already discussed above, are no longer recommended for the routine treatment of hypertension, and are primarily reserved for add-on therapy in rare cases of drug-resistant hypertension where all other treatment options have failed.
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]. This failure to achieve BP control in most hypertensive patients, despite numerous iterations of previous Guidelines, suggests that these treatment strategies are not working and that a different approach is needed. This Task Force believes that one of the most important issues to address in these Guidelines is ‘how do we improve BP control in treated patients?’. This has become an even more pressing matter because, based on new evidence, current Guidelines are recommending more stringent BP targets (on-treatment values of ≤130/80 mmHg in the general population and ≤140/90 mmHg in older hypertensive people), which will make the achievement of BP control even more challenging.
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] contributes to suboptimal BP control, with many patients remaining on monotherapy and/or suboptimal doses, despite inadequate BP control [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]. Poor adherence has also been shown to be associated with increased cardiovascular risk in various studies [313] (see Section 10).
- 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]. Nonadherence was usually less than 10% with a single pill, rising to 20% with two pills, 40% with three pills, and very high rates of partial or complete nonadherence in patients receiving five or more pills [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] or CCB–ACE inhibitor combination [318], with both regimens being superior to a beta-blocker–diuretic combination in reducing cardiovascular outcomes. However, in six other trials (with seven comparisons), beta-blockers followed by diuretics or diuretics followed by beta-blockers were not associated with a significantly different risk of any cardiovascular outcome [233,234,316,319–321], and the beta-blocker diuretic combination was significantly more effective than placebo in three trials [322–324]. It should be mentioned that the beta-blocker–diuretic combination may result in more cases of new-onset diabetes in susceptible individuals compared with other combinations [325]. A rarely used combination of thiazide and potassium-sparing diuretic (amiloride) has also been shown to be equivalent to CCB-based treatment [310,326], and was recently reported to be associated with fewer metabolic adverse effects compared with thiazide alone (less hypokalaemia and glucose intolerance) [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]. This finding was not confirmed in the Combination of OLMesartan and a CCB or diuretic in Japanese older hypertensive patients (COLM)[328] and Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trials [329], which reported no significant differences in cardiovascular events when a RAS blocker-CCB combination was compared with a RAS blocker–thiazide diuretic combination, but both of these trials had insufficient statistical power.
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]. These are much less widely available as SPCs and do not include blockade of the RAS, which may be desirable in many patient groups.
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]. Furthermore, the combination of medications targeting multiple mechanisms, such as blocking the RAS as well as inducing vasodilatation and/or diuresis, reduces the heterogeneity of the BP response to initial treatment and provides a steeper dose response than is observed with escalating doses of monotherapy [342]. Finally, two-drug combinations as initial therapy have been shown to be safe and well tolerated, with no or only a small increase in the risk of hypotensive episodes [341], even when given to patients with grade 1 hypertension [343], in which adverse events leading to treatment discontinuation are infrequent [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]. Furthermore, there is evidence from the more general hypertensive population that, compared with patients on initial monotherapy, those who start treatment with a two-drug combination exhibit more frequent BP control after 1 year [341,345]. This is probably because initial combination treatment is associated with a better long-term adherence to the prescribed treatment regimen [346] and because initial two-drug administration prevents therapeutic inertia (i.e. reluctance or failure to upgrade treatment from one to more drugs when BP is uncontrolled) [347]. Studies from very large hypertension cohorts in usual care have shown that initial combination treatment results in reduced treatment discontinuation and a lower risk of cardiovascular events than initial monotherapy followed by the traditional stepped-care approach [312,346]. The usual-care settings for these studies may be especially relevant to study the true impact of treatment strategies on adherence and therapeutic inertia, because this can be difficult to replicate in a conventional RCT in which the motivation of the clinical staff and patients, and the monitoring of treatment, are very different from usual care. In this regard, the outcome of these real-life studies of the impact of initial combination therapy on adherence, BP control, and cardiovascular outcomes may be especially relevant [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]. In patients with high–normal BP and a high cardiovascular risk or in frail older patients, treatment initiation with monotherapy may be appropriate in the former because only a small BP reduction may be required to achieve the BP target, and in the latter because in older patients baroreflex sensitivity is frequently impaired and the risk of hypotension is greater.
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]. For patients whose BP is not controlled by two-drug combination therapy, the logical option is to increase treatment to three-drug combination therapy: usually a RAS blocker, a CCB, and a diuretic. Studies suggest that a three-drug combination should control BP in more than 80% of patients [349,350]. This rate of BP control is much greater than the current rate of BP control across Europe in treated hypertensive patients. We do not recommend three-drug combinations as initial therapy.
7.5.2.4 Rationale for single-pill combination therapy as usual therapy for hypertension
The 2013 ESH/ESC Guidelines [17] favoured the use of combinations of two antihypertensive drugs in a single pill, because reducing the number of pills to be taken daily improves adherence and increases the rate of BP control [346,351]. This recommendation is endorsed by the current Guidelines. It is further supported by data from recent studies using various methods to assess adherence to treatment, including the quantification of antihypertensive drugs in urine and blood [352,353], and estimates such as pill counting or prescription refills, which, although indirect, allow the measurement of adherence on a prolonged basis, thereby accounting for its time-variable nature [347,354]. These studies have unequivocally shown a direct inverse relationship between the number of pills and the likelihood of adherence. This approach is now facilitated by the availability of several SPCs with a range of dosages, which eliminates the often-stated disadvantage of SPC therapy (i.e. the inability to increase the dose of one drug independently of the other). It is also convenient that the most widely available SPCs mirror the major drug class combinations recommended by these Guidelines. The major advantage of an SPC as the usual therapeutic approach for hypertension is that patients can progress from 1, 2, or 3 drug treatments while remaining on a simple treatment regimen with a single pill throughout, increasing the likelihood of adherence to therapy and achieving BP control. Such an approach has the potential to double BP control rates in treated patients from the present low level of 40%. Although, at present, the availability of two-drug SPCs is largely limited to a RAS blocker with either a CCB or diuretic, it would be desirable to see the development of an expanded range of low-cost SPCs in different drug formulations, tailored to different clinical requirements.
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]. Furthermore, studies performed in the setting of secondary prevention, particularly in patients with a previous myocardial infarction, have shown that use of the polypill is accompanied by a better adherence to treatment compared with separate medications [356]. The ESC Guidelines for the management of myocardial infarction suggest that the use of the polypill may be considered to improve long-term adherence to prescribed therapy (class IIb, level B) [353]. No data are available for primary prevention in patients with hypertension. Nevertheless, the advantage of treatment simplification and adherence suggests that use of the polypill may be considered in patients with hypertension as substitution therapy, when the need and effectiveness of each polypill component has been previously established by their administration in separate tablets [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] or another additional diuretic therapy [higher-dose amiloride 10–20 mg daily [357], higher dose thiazide or thiazide-like diuretics, loop diuretics in patients with significant renal impairment (eGFR <45 ml/min/m2), 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. aCKD is defined as an eGFR <60 ml/min/1.72 m2 with or without proteinuria. bUse 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. cCaution: 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.
aConsider an angiotensin receptor/neprilysin inhibitor instead of ACEi or ARB per ESC Heart Failure Guidelines
[136].
bDiuretic refers to thiazide/thiazide-like diuretic. Consider a loop diuretic as an alternative in patients with oedema.
cMRA (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; CHA2DS2-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]. A second-generation unilateral device has been developed to improve safety and sustained efficacy. A propensity score-matched comparison of the first-generation and second-generation systems revealed that BP at 12 months post-implantation was similar, with a better safety profile for the second-generation device [359]. However, no RCT is currently available with this second-generation device. Another consideration is that implantation is costly and requires a complex surgical intervention. This has led to the development of an endovascular carotid baroreflex amplification device using a dedicated stent-like device designed to stretch the carotid bulb and increase baroreflex stimulation. Preliminary data in humans have shown evidence of BP-lowering efficacy of this new approach [360], but data from ongoing RCTs are needed to definitively understand its longer-term efficacy and safety.
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], the increased sympathetic tone to the kidney and other organs in hypertensive patients [361], and the pressor effect of renal afferent fibres documented in experimental animals [362]. Catheter-based renal denervation using radiofrequency, ultrasound, or perivascular injection of neurotoxic agents such as alcohol has been introduced as a minimally invasive treatment option for patients with resistant hypertension [363]. However, the clinical evidence in support of renal denervation as an effective BP-lowering technique is conflicting. Several observational studies and national and international registries [364] support the BP-lowering efficacy of renal denervation originally reported in the Symplicity HTN-1 and HTN-2 trials [365]. A reduction in sympathetic activity following renal denervation has also been observed [366]. However, two RCTs with a sham procedure control [367,368] failed to document the superiority of renal denervation compared with the sham procedure in reducing BP, but did confirm the safety of the procedure. Another RCT, the Renal Denervation for Hypertension (DENERHTN) trial [369], showed the superiority of renal denervation in combination with optimized pharmacotherapy compared with pharmacotherapy alone. The PRAGUE-15 study [370] documented similar effects between renal denervation and optimized pharmacotherapy (mainly by adding spironolactone) with respect to BP-lowering efficacy; however, the latter was associated with more side effects and high discontinuation rates. Beyond resistant hypertension, interim data in the first 80 patients treated with renal denervation but with no background antihypertensive therapy showed a modest effect of renal denervation vs. sham control on 24 h ambulatory BP after 3 months [366]. This study is ongoing.
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]. There is evidence indicating that isolated systolic hypertension, characterized by increased aortic stiffness, is associated with a limited response to renal denervation [372,373] and baroreceptor stimulation (see above). Except for rare problems related to the catheterization procedure (access site complications, vessel dissection, etc.), no major complications or deterioration of renal function have been reported.
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]. Device deployment can be verified and is reversible, resulting in the diversion of arterial blood (0.8–1 l/min) into the venous circuit with immediate, verifiable reductions in BP [374,375]. The BP-lowering effect of arteriovenous anastomosis was first observed in a study of patients with chronic obstructive pulmonary disease (COPD), in whom a moderate improvement in the 6 min walking test was shown [376]. In the ROX CONTROL HTN trial, patients with resistant hypertension were randomized to receive either standard care or insertion of an arteriovenous coupler in combination with standard care [377]. At 6 months, office and ambulatory BP were significantly reduced in the coupler group compared with the control group. Some important safety aspects need to be considered. Ipsilateral venous stenosis, which needed venoplasty and/or stenting, occurred in 29% of patients. There were no reports of right heart failure or high-output cardiac failure after device implantation over the short-term, but longer follow-up is clearly needed [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]. Stimulation of the carotid body drives sympathetic tone, resulting in an increase in BP and minute ventilation. Surgical resection of the carotid body is associated with reductions in BP [380] and sympathetic overactivity in patients with heart failure [381]. Devices for endovascular carotid body modification by ultrasound-guided ablation have been developed and are currently under investigation.
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] (see Section 10).
- 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] or atherosclerotic renal artery stenosis, particularly in older patients or patients with CKD. Poor adherence to treatment should be considered, but its identification may be challenging in routine clinical practice [387]. Some methods are easy to use but of limited value (e.g. standardized questionnaires), whereas others, such as drug screening of urine or blood, show considerable promise but are not yet widely available [388]. Other methods include the measurement of BP after directly observed treatment intake [389], which has been used in clinical trials [390] but may be more difficult to implement in routine clinical practice.
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] (spironolactone up to 50 mg/day), as shown in the PATHWAY 2 study [357] and supported by other studies and their meta-analysis [392–394]. Not all patients will be able to tolerate spironolactone due to antiandrogenic side effects resulting in breast tenderness or gynaecomastia (in 6%), impotence in men, and menstrual irregularities in women. Moreover, the efficacy and safety of spironolactone for the treatment of resistant hypertension has not yet been established in patients with significant renal impairment. As such, the use of spironolactone for resistant hypertension should usually be restricted to patients with an eGFR at least 45 ml/min and a plasma potassium concentration of ≤4.5 mmol/l. Moreover, electrolytes and eGFR should be monitored soon after initiation and at least annually thereafter. On theoretical grounds, alternative additional diuretic therapy to spironolactone (when it is not tolerated due to androgen-like side effects) could include the MRA eplerenone (50–100 mg/day). Amiloride (10–20 mg/day) has recently been shown to be as effective as spironolactone 25–50 mg daily) in reducing BP in the PATHWAY2 study [357]. It is emphasized that the same cautions about the use of these agents should be considered in patients with reduced eGFR and baseline potassium levels more than 4.5 mmol/l. The PATHWAY-2 study also evaluated bisoprolol (5–10 mg/day) or doxazosin modified release (4–8 mg/day) as alternatives to spironolactone. Neither was as effective as spironolactone, but they did reduce BP significantly vs. placebo when added to background treatment in resistant hypertension [310]. Thus, bisoprolol and doxazosin have an evidence base for the treatment of resistant hypertension when spironolactone is contraindicated or not tolerated. Direct vasodilators, such as hydralazine or minoxidil, are infrequently used because they may cause severe fluid retention and tachycardia.
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] of people with hypertension. Screening all hypertensive patients for secondary hypertension is not feasible or cost-effective; however, there are some general patient characteristics that suggest those more likely to have secondary hypertension and in whom screening should be considered after confirming that BP is elevated with ABPM (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]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]. They are rare but important causes of secondary hypertension because identifying the cause can point to a specific drug treatment (Table 29) [194,195]. Common features of these genetic disorders are that they usually present with hypertension in children, adolescents, or young adults, and most monogenic disorders induce hypertension by increasing the renal tubular reabsorption of sodium. Thus, they are usually associated with a suppressed plasma renin concentration (PRC) or plasma renin activity (PRA), which is unusual in younger patients and especially those treated with antihypertensive medications (e.g. RAS blockers, CCBs, or diuretics), that would be expected to increase PRC or PRA. Thus, the finding of a suppressed PRC or PRA, especially while taking these drugs, should raise the suspicion of secondary hypertension due a salt-retaining state. Importantly, beta-blockers in particular, but also nonsteroidal anti-inflammatory drugs, alpha-methyl dopa, or clonidine, suppress PRC and PRA. These drugs should be discontinued (if clinically feasible) for at least 2 weeks before measuring PRC or PRA.
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]. The rate and magnitude of an increase in BP may be at least as important as the absolute level of BP in determining the magnitude of organ injury [399]. Typical presentations of a hypertension emergency are:
- 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], acute heart failure, and acute deterioration in renal function. The hallmark of this condition is small artery fibrinoid necrosis in the kidney, retina, and brain. The term ‘malignant’ reflects the very poor prognosis for this condition if untreated [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]. Whilst these patients require BP reduction, they do not usually require admission to hospital, and BP reduction is best achieved with oral medication according to the drug treatment algorithm presented in 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] are shown in Table 31 and an expanded range of possible drug choices [398] is shown in 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], but these patients remain at high risk [408,409] and should be screened for secondary hypertension (see Section 8.2). After discharge from hospital, when BP has reached a safe and stable level on oral therapy, we recommend frequent, at least monthly, visits in a specialized setting until the optimal target BP is achieved and long-term specialist follow-up thereafter.
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]. It is recommended that people with white-coat hypertension should have an accurate assessment of their cardiovascular risk profile, including a search for HMOD. Office and out-of-office BP (both home and ambulatory BP) should be measured frequently, for example no less than every 2 years. Treatment should consider lifestyle changes to reduce the elevated cardiovascular risk [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]. Whether these BP changes lead to cardiovascular protection has not been investigated with adequately powered outcome studies and remains unknown. However, it should be considered that people with white-coat hypertension have inevitably been well represented in trials documenting the protective effect of antihypertensive drugs [415], particularly those addressing conditions in which white-coat hypertension is more common, such as grade 1 hypertension or hypertension in older patients. In a recent subanalysis of the HYVET trial of the very old with hypertension, white-coat hypertension was reported to account for 55% of the trial population [416]. Thus, antihypertensive drug treatment cannot definitively be excluded for patients with white-coat hypertension and may be considered, in particular, in white-coat hypertensive people with a higher cardiovascular risk profile, such as those with HMOD, an uncertain out-of-office BP normality pattern (i.e. ambulatory but not home BP normality or vice versa), or a persistent office BP elevation at repeated visits [417–420]. No cardiovascular risk excess has been reported in patients in whom white-coat hypertension results from treatment-dependant normalization of out-of-office BP only [418,421]. Thus, whether this condition benefits from an uptitration of the existing drug treatment regimen (to also achieve office BP normalization) remains to be determined.
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]. The challenge is how to diagnose masked hypertension, because most hypertension screening programmes use office BP measurement, which is normal in these people. Masked hypertension is commoner in younger rather than older individuals, and in those with an office BP in the borderline hypertension range (i.e. 130–139/80–89 mmHg). It is uncommon in people whose office BP is less than 130/80 mmHg. Masked hypertension is associated with progression to sustained office hypertension, increased frequency of developing type 2 diabetes, and the presence of HMOD. The long-term risk of fatal and nonfatal cardiovascular events approaches that of patients with sustained hypertension [68,81,93,95,423]. Patients with masked hypertension should have an accurate initial assessment of their cardiovascular risk profile. Cardiovascular risk factors (including organ damage and ideally both home and ambulatory BP) should then be periodically monitored. Factors contributing to the out-of-office BP elevation (e.g. smoking) should be discouraged and lifestyle interventions implemented to improve out-of-office BP levels. The impact of antihypertensive drug treatment on cardiovascular outcomes in people with masked hypertension has never been studied. Nevertheless, treatment with BP-lowering medication should be considered because these patients are at high cardiovascular risk, often have HMOD, and the adverse prognostic importance of out-of-office BP elevations has been well documented [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]. Registry-based studies in Spain have suggested that MUCH occurs in as many as 30% of treated hypertensive patients [84], and is more common with comorbidities such as diabetes and CKD and in those at highest risk. Moreover, MUCH was more commonly due to poorly controlled nocturnal rather than daytime pressures on ABPM. Presently, no data are available from outcome trials for patients with MUCH; however, mindful of their high cardiovascular risk, treatment uptitration should be considered to ensure that that both office and out-of-office BP are controlled [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]. There is a greater likelihood of detecting secondary hypertension in younger patients (<50 years), where the prevalence of secondary hypertension may be as high as 10% and should be considered, especially in those with more severe hypertension (see Section 3).
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]. There is little doubt that treating stage 1 hypertension in older patients, even those at low–moderate-risk, reduces cardiovascular morbidity and mortality [425]. Moreover, long-term epidemiological studies have demonstrated a clear relationship between BP and longer-term risk of cardiovascular events and mortality in young adults with a BP more than 130/80 mmHg [424,426]. Furthermore, earlier treatment [23] can prevent more severe hypertension [427] and the development of HMOD, which may not be completely reversible with later treatment. Thus, despite the absence of RCT evidence demonstrating the benefits of antihypertensive treatment in younger adults with uncomplicated grade 1 hypertension, treatment with BP-lowering drugs may be considered prudent. If a decision is taken not to offer treatment or treatment is declined, lifestyle advice should be prescribed, and longer-term follow-up is essential as BP will invariably rise. In younger patients with hypertension treated with BP-lowering medication, office BP should be reduced to at least 130/80 mmHg if treatment is well tolerated. Other interventions, for example statins or antiplatelet therapy, should also be considered for higher-risk patients (see Section 7.2.5).
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]. It is unclear whether isolated systolic hypertension in the context of a normal aortic pressure is benign. A recent examination of prospective data from the Chicago Heart Association Detection Project found that young men with isolated systolic hypertension had a cardiovascular risk similar to that of individuals with high–normal BP and that isolated systolic hypertension in the young was closely associated with smoking [429]. On the basis of current evidence, these young individuals should receive recommendations on lifestyle modification (particularly cessation of smoking); whether they should receive drug treatment is unclear, but they do require longer-term follow-up as many will develop sustained hypertension [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] (see Section 7). Moreover, treatment has been found to be generally well tolerated. However, older patients are more likely to have comorbidities such as renal impairment, atherosclerotic vascular disease, and postural hypotension, which may be worsened by BP-lowering drugs. Older patients also frequently take other medications, which may negatively interact with those used to achieve BP control. A further important caveat is that RCTs have not included very frail patients, dependent patients, and patients with postural hypotension. It is thus uncertain whether, and to what extent, such patients would benefit from BP-lowering treatment in the context of their comorbidities and reduced life expectancy. Thus, in older hypertensive patients, treatment presents more difficulties than in younger people, because the decision to treat hypertension must take into account the patient's clinical condition, concomitant treatments, and frailty. That said, age alone must never be a barrier to treatment because high BP is an important risk factor even at the most advanced ages. Furthermore, a recent study of a cohort of older patients from the general population (thus including those with frailty) has shown that better adherence to antihypertensive treatment was associated with a reduced risk of cardiovascular events and mortality, even when age was more than 85 years (mean 90 years) [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]. Renal function should be frequently assessed to detect possible increases in serum creatinine and reductions in eGFR as a result of BP-related reductions in renal perfusion. When treated, BP should be lowered to a systolic value of 130–139 mmHg and a diastolic value of less than 80 mmHg if tolerated. Treated SBP values of less than 130 mmHg should be avoided. A key emphasis in treating older patients, and especially the very old, is to carefully monitor for any adverse effects or tolerability problems associated with BP-lowering treatment, keeping in mind that adverse effects can be more frequent than reported in RCTs, in which specific medical expertise and close patient supervision may minimize adverse effects and tolerability problems.
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]. This suggests that the benefit of treatment is not limited to fit and independent older patients; however, to what extent BP-lowering treatment benefits the very frail [214] and institutionalized patients remains to be determined.
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], and is classified as mild (140–159/90–109 mmHg) or severe (≥160/110 mmHg), in contrast to the conventional hypertension grading.
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]. The only cure for preeclampsia is delivery. As proteinuria may be a late manifestation of preeclampsia, it should be suspected when de-novo hypertension is accompanied by headache, visual disturbances, abdominal pain, or abnormal laboratory tests, specifically low platelets and/or abnormal liver function.
- 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]. ABPM is superior to office BP measurement for the prediction of pregnancy outcome [440]. ABPM devices recommended for use in pregnancy are more accurate than those used for office measurement or HBPM. ABPM helps avoid unnecessary treatment of white-coat hypertension, and is useful in the management of high-risk pregnant women with hypertension and those with diabetic or hypertensive nephropathy.
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]. High risk of preeclampsia includes any of the following:
- 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]. A further study suggested that tighter vs. less tight control of BP in pregnancy showed no difference in the risk of adverse perinatal outcomes and overall serious maternal complications. However, secondary analysis suggested that tighter control of BP may reduce the risk of developing more severe hypertension and preeclampsia [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] have recommended initiating drug treatment:
- 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] considers an SBP of at least 170 mmHg or DBP of at least 110 mmHg an emergency in a pregnant woman, who should be immediately admitted to hospital for treatment. The selection of the antihypertensive drug and its route of administration depends on the expected time of delivery. Pharmacological treatment with i.v. labetalol, oral methyldopa, or CCB should be initiated. Intravenous hydralazine is no longer the drug of choice as it is associated with more perinatal adverse effects than other drugs [451]. However, hydralazine is still used when other treatment regimens fail to achieve adequate BP control. Intravenous urapidil can also be considered.
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]. Intravenous magnesium sulfate is recommended for the prevention of eclampsia and treatment of seizures. The consensus is to lower BP to less than 160/105 mmHg to prevent acute hypertensive complications in the mother. Both labetalol and nicardipine have shown to be safe and effective for the treatment of severe preeclampsia if i.v. BP-lowering therapy is necessary [452]. In both cases, monitoring of foetal heart rate is necessary. To prevent foetal bradycardia, the cumulative dose of labetalol should not exceed 800 mg/24 h. Intravenous sodium nitroprusside is contraindicated in pregnancy because of an increased risk of foetal cyanide poisoning. The drug of choice when preeclampsia is associated with pulmonary oedema is nitroglycerin (glyceryl trinitrate), given as an i.v. infusion of 5 μg/min, and gradually increased every 3–5 min to a maximum dose of 100 μg/min.
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]. Lifestyle modifications are indicated to avoid complications in subsequent pregnancies and to reduce maternal cardiovascular risk in the future. Therefore, annual visits to a primary care physician to check BP and metabolic factors are recommended for these patients.
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]. BP usually decreases promptly following cessation of these pills; consequently, BP should be monitored before and during oral contraceptive pill treatment. The rise in BP appears to be related to the oestrogen content and may be less likely with the progestogen-only oral contraceptive pill. Older studies have demonstrated a relationship between the oral contraceptive pill and venous thrombosis and venous thromboembolism, and, to a lesser extent, myocardial infarction (especially with concomitant smoking history) and stroke [458]. More recent studies with newer-generation oral contraceptive pills have reported conflicting results. Thus, the use of oral contraceptives should consider the risks and benefits for the individual patient. Changes in BP should be carefully evaluated with follow-up readings [459]. Concomitant cardiovascular risk factors (e.g. smoking history) should be assessed and oral contraceptive pill use is not recommended if BP is elevated. In such patients, alternative forms of contraception should be offered. Discontinuation of combined oestrogen–progestin oral contraceptives in women with hypertension may improve their BP control [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]. Although hormone-replacement therapy contains oestrogens, there is no convincing evidence that significant rises in BP will occur in otherwise normotensive menopausal women due to this therapy, or that BP will increase further due to hormone-replacement therapy in menopausal hypertensive women [462]. Hormone-replacement therapy and selective oestrogen receptor modulators should not be used for primary or secondary prevention of CVD. In summary, current evidence suggests that the use of hormone-replacement therapy is not associated with an increase in BP. Moreover, it is not contraindicated in women with hypertension, and women with hypertension may be prescribed hormone-replacement therapy as long as BP levels can be controlled by antihypertensive medication.
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], similarly to that reported for the USA [464]. As for the European white population, the black European population is heterogenous in nature [463], although in almost all European countries the largest ethnic group originates from the Sub-Saharan African region [463]. Hypertension epidemiology, diagnosis, and treatment have been thoroughly studied in black (i.e. Afro-American) US patients [464], in contrast to the much scarcer database available for European black people, and thus we extrapolate from US data. However, this extrapolation requires some caution as differences between the North American and the European black population exist, especially with regard to socioeconomic status, cardiovascular risk [465,466], and the response to antihypertensive drug treatment [467]. BP-related HMOD, as well as cardiovascular and renal complications, are more common and severe in black patients compared with age-matched white patients at any BP level [464]. Black hypertensive patients exhibit a similar proportional reduction of cardiovascular and renal events in response to BP-lowering treatment as white patients, with somewhat different treatment modalities. However, to achieve an effective BP reduction and BP control, salt restriction is particularly important in black patients, in whom it may lead to greater BP falls and more favourably impact on the effectiveness of BP-lowering drug treatment [468]. Hypertensive black patients also show a reduced antihypertensive response to RAS-blocker monotherapy, whereas they usually respond more effectively to thiazide or thiazide-like diuretics and CCBs [316,469,470], which in black patients may be combined with each other or with a RAS blocker, making the latter more effective. Angioedema appears more common with ACE inhibitors in black patients, which may favour the preferred use of ARBs in this population. Despite some progress in recent years, data on hypertension prevalence, management, and control in European black patients (and in other immigrant populations such as European individuals from South Asia) are still scarce [463,471], which makes this field an important area for future research. There is no evidence that the BP response to treatment in other ethnic groups differs from that reported in the general population in Europe.
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]. Recording 24 h ABPM in apparently normotensive people with diabetes may be a useful diagnostic procedure, especially in those with HMOD. Substantial evidence supports the benefits of BP reduction in people with diabetes to reduce major macrovascular and microvascular complications of diabetes, as well as reducing mortality. Proven benefits of BP-lowering treatment in diabetes also include a significant reduction in the rate of end-stage renal disease [231,235], retinopathy [1], and albuminuria [1]. Diabetic neuropathy has never been included as an outcome in RCTs of BP-lowering treatment.
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]. Initiation of antihypertensive drug therapy is recommended when the office BP is more than 140/90 mmHg. Alongside lifestyle interventions, treatment should usually be initiated with a two-drug combination of an ACE inhibitor or ARB with a CCB or thiazide/thiazide-like diuretic, and treatment escalated according to the recommended treatment algorithm (see Section 7). This approach ensures that the treatment strategy includes an ACE inhibitor or ARB, which has been shown to reduce albuminuria and the appearance or progression of diabetic nephropathy more effectively than other drug classes [235]. Combination of an ACE inhibitor with an ARB is contraindicated because it is accompanied by an excess of renal adverse events [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], and that this occurs even when people are treated with antihypertensive drugs. This may help improve BP control (see below), which is especially difficult in diabetes [477], and may reduce the progression of CKD [478–481] (see also Section 8.12).
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]. However, a more recent and larger meta-analysis has shown a significant reduction in all-cause mortality following BP reduction in patients with CKD [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]. However, there are also studies in which treatment that was less effective at reducing albuminuria was more effective at reducing cardiovascular events [175] and vice versa [176,291]. Thus, whether reducing albuminuria per se is a proxy for CVD prevention remains unresolved.
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]. Loop diuretics should replace thiazide diuretics when the estimated GFR is less than 30 ml/min/1.73 m2.
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]. In contrast, in patients with a proteinuria less than 1 g/day, the lowest risk of developing CKD (not cardiovascular risk) was obtained with an SBP of less than 140 mmHg [487]. Another systematic review failed to demonstrate that a BP target of less than 130/80 mmHg improved clinical outcomes more than a target of less than 140/90 mmHg in nondiabetic CKD [488]. In a large retrospective cohort containing 398 419 treated hypertensive patients (30% with diabetes), the nadir SBP and DBP for the lowest risk of end-stage renal disease and mortality were 137 and 71 mmHg, respectively, with a clear increase in mortality risk at SBP less than 120 mmHg [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]. Patients with hypertension and COPD are at particularly high cardiovascular risk [490,491]. Both conditions share similar environmental risks and, in addition, hypoxia may exacerbate the risk [490,491]. Treatment of COPD with anticholinergic agents and long-acting beta-2 adrenoceptor agonists may adversely affect the cardiovascular system (increase heart rate and BP). The presence of COPD also has an impact on the selection of antihypertensive drugs, which should consider their effects on pulmonary function. Concern has been predominantly directed to the use of beta-blockers, although there is evidence that in COPD these drugs maintain their cardiovascular-protective effects [492,493]. Beta-blockers may negatively affect the reduced basal lung function in patients with COPD, diminish the effectiveness of emergency beta-agonist administration, reduce the benefit of long-acting beta-agonist treatment, and make the discrimination of asthma and COPD more difficult. That said, when tolerated, the use of cardiac beta1-selective beta-blockers in patients with COPD has proven to be safe in different settings, including hypertension [494]. It should also be noted that diuretics may decrease the plasma level of potassium (in addition to the hypokalaemic effects of glucocorticoids and beta2-adrenoceptor agonists), worsen carbon dioxide retention (including metabolic alkalosis-related hypoxia in hypoventilated patients), increase haematocrit, and deteriorate mucus secretion in bronchi. Therefore, in general, diuretics are not recommended for widespread use in hypertensive patients with COPD [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]. Another registry-based study of over 1 million patients showed that ischaemic heart disease (angina and myocardial infarction) accounted for most (43%) of the CVD-free years of life lost due to hypertension from the age of 30 years [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]. A similar risk reduction has been reported by others with more intensive BP control [496]. The benefits of reducing cardiac events are also evident in high-risk groups, such as those with diabetes [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]. A recent analysis [501] of 22 672 patients with stable CAD who were treated for hypertension found that, after a median follow-up of 5.0 years, an SBP of at least 140 mmHg and a DBP of at least 80 mmHg were each associated with increased risk of cardiovascular events. An SBP of less than 120 mmHg was also associated with increased risk, as was a DBP of less than 70 mmHg. Similar findings were also reported from another analysis of RCT data evaluating the relationships between achieved BP and risks of cardiovascular outcomes [222]. Whether a J-curve phenomenon exists in patients with CAD who have been revascularized remains uncertain. Other analyses do not support the existence of a J-curve, even in hypertensive patients at increased cardiovascular risk [239]. For example, in patients with CAD and initially free from congestive heart failure enrolled in ONTARGET, a BP reduction from baseline over the examined BP range had little effect on the risk of myocardial infarction and predicted a lower risk of stroke [502]. Thus, a target BP of approximately less than 130/80 mmHg in patients with CAD appears safe and can be recommended, but achieving a BP less than 120/80 mmHg is not recommended.
In hypertensive patients with CAD, beta-blockers and RAS blockers may improve outcomes in postmyocardial infarction [503]. In patients with symptomatic angina, beta-blockers and calcium antagonists are the preferred components of the drug treatment strategy.
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], and most patients with heart failure will have a history of hypertension. This may be a consequence of CAD, which results in HFrEF. Hypertension also causes LVH, which impairs left ventricular relaxation (so-called diastolic dysfunction) and is a potent predictor of heart failure, even when left ventricular systolic function is normal and there is no preceding myocardial infarction (HFpEF). Hypertension-dependent fibrosis and structural alteration of large and small arteries (microvascular disease) also contribute.
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]. This has been observed using diuretics, beta-blockers, ACE inhibitors, or ARBs, with CCBs being less effective in comparative trials [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]. The magnitude of LVH regression is associated with baseline left ventricular mass, duration of therapy, the SBP reduction [505,506], and the drugs used, with ARBs, ACE inhibitors, and CBBs causing more effective LVH regression than beta-blockers [173] or diuretics.
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]. ACE inhibitors, ARBs, beta-blockers, and MRAs (e.g. spironolactone and epleronone) are all effective in improving clinical outcome in patients with established HFrEF, whereas for diuretics, evidence is limited to symptomatic improvement. If further BP lowering is required, a dihydropyridine CCB may be considered. Sacubutril/valsartan lowers BP has also been shown to improve outcomes in patients with HFrEF, and is indicated for the treatment of HFrEF as an alternative to ACE inhibitors or ARBs [507]. Nondihydropiridine CCBs (diltiazem and verapamil), alpha-blockers, and centrally acting agents, such as moxonidine, should not be used.
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]. Results from an RCT suggested that immediate BP lowering (within 6 h) to less than 140/90 mmHg did not show benefit on the primary outcome of disability or death at 3 months, but might reduce haematoma expansion and improve functional recovery, and was generally safe [511]. A subsequent RCT, in which SBP was immediately reduced (<4.5 h) from a mean of 200 mmHg to two different target intervals (140–170 vs. 110–139 mmHg), showed that more intensive BP lowering had no benefit on the same primary outcome and was associated with more renal adverse events [512]. Thus, we do not recommend treatment to immediately lower BP in patients with acute intracerebral haemorrhage. One possible caveat to this recommendation is patients with acute intracerebral haemorrhage and very severe hypertension (SBP ≥220 mmHg), for whom there are much fewer data. A meta-analysis [513] and secondary outcome data from one RCT [511] have suggested a possible benefit on functional recovery at 3 months, and that acute lowering of SBP to less than 180 mmHg in these patients might be beneficial. Thus, careful lowering of BP via i.v. infusion may be considered in patients with markedly elevated BP (SBP ≥220 mmHg).
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]. In patients receiving i.v. thrombolysis, BP should be lowered and maintained at less than 180/105 mmHg for at least the first 24 h after thrombolysis. The benefit of acute BP lowering in patients with acute ischaemic stroke who do not receive thrombolysis is uncertain. A meta-analysis suggested that BP lowering early after acute ischaemic stroke had a neutral effect on the prevention of death or dependency [516,517]. In such patients with markedly elevated SBP or DBP (i.e. ≥220 or ≥120 mmHg, respectively), clinical judgement should define whether to intervene with drug therapy, in which case a reasonable goal may be to lower BP by 15%, with close monitoring, during the first 24 h after stroke onset [516,518–520]. Patients with acute ischaemic stroke and a BP lower than this in the first 72 h after stroke do not seem to benefit from the introduction or reintroduction of BP-lowering medication [516,521]. For stable patients who remain hypertensive (≥140/90 mmHg) more than 3 days after an acute ischaemic stroke, initiation or reintroduction of BP-lowering medication should be considered [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]. No evidence is yet available that recurrent stroke is prevented by initiating therapy when BP is in the high–normal range. We recommend resumption of BP-lowering therapy several days after stroke, or immediately after TIA, for previously treated or untreated patients with hypertension, for prevention of both recurrent stroke and other cardiovascular events.
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] in patients with a recent lacunar stroke, which suggested an SBP target of less than 130 mmHg [525], and other studies [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] and meta-analyses suggest that beta-blockers are less effective at stroke prevention than other classes of antihypertensive agents [2,528]. Although the beta-blocker in these studies was atenolol, there are no data with more modern beta-blockers with regards to stroke prevention in hypertension. Thus, optimal antihypertensive treatment for stroke prevention should not include beta-blockers unless there is a compelling indication for their use, mindful of the fact that the most common recurrent event after stroke is a further stroke rather than myocardial infarction [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]. However, evidence on the beneficial effects of BP lowering on cognitive decline is scant and conflicting. A meta-analysis [534] of 12 studies investigating the impact of different antihypertensive drugs on dementia and cognitive function concluded that BP lowering reduced the incidence and risk of cognitive impairment and dementia by 9%. One study showed that achieving better BP control over 4 years reduced the progression of cerebral white matter lesions and the decrease in global cognitive performance [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], which should be considered a manifestation of hypertensive heart disease [539]. Even high–normal BP is associated with incident AF [540,541], and hypertension is the most prevalent concomitant condition in AF patients. AF adds to the risk of stroke and heart failure. AF necessitates stroke prevention with oral anticoagulation, with monitoring of the associated risks and prevention of bleeding [542].
Most patients show a high ventricular rate with AF [542] and, in such patients, beta-blockers or nondihydropyridine calcium antagonists (e.g. diltiazem and verapamil) are recommended as antihypertensive agents. Nondihydropyridine CCBs should be avoided in patients with reduced left ventricular systolic function and may precipitate heart failure in some patients. Beta-blockers are often indicated in these patients, and may need to be combined with digoxin to gain rate control [542].
In RCTs of hypertensive patients with LVH and/or high cardiovascular risk [543,544], RAS blockers have been shown to reduce first occurrence of AF, compared with beta-blockers or CCBs, consistent with similar effects of RAS blockers in patients with heart failure [545–547]. RAS blockers do not prevent recurrence of paroxysmal or persistent AF [548–550]. In patients with heart failure, beta-blockers [551] and MRAs [552] may also prevent AF. The preventive effect of RAS blockers against the development of AF is indirectly supported by a general practice database in the UK, with approximately 5 million patient records, which has reported that ACE inhibitors, ARBs, and beta-blockers are associated with a lower risk of AF compared with CCBs [553]. Hence, RAS blockers should be considered as part of the antihypertensive treatment strategy in hypertensive patients with a high risk of AF (e.g. LVH), to prevent incident AF.
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], hypertension does substantially increase the risk of intracerebral haemorrhage when oral anticoagulants are used, and efforts should be directed towards achieving a BP goal of less than 130/80 mmHg in patients receiving oral anticoagulants. Detailed information on hypertension and oral anticoagulants has been published recently [526,536]. Anticoagulants should be used to reduce the risk of stroke in most AF patients with hypertension, including those with AF in whom hypertension is the single additional stroke risk factor [554,555]. BP control is important to minimize the risks of AF-related stroke and oral anticoagulant-related bleeding. Until more data are available, BP values in AF patients taking oral anticoagulants should be at least less than 140 mmHg for SBP and less than 90 mmHg for DBP. Oral anticoagulants should be used with caution in patients with persistent uncontrolled hypertension (SBP ≥180 mmHg and/or DBP ≥100 mmHg), and urgent efforts to control BP should be made.
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], and ACE inhibitors more than diuretics [557]. However, the relevance of these findings is unclear because most patients receive combinations of treatment and the progression or treatment-induced changes in carotid IMT are poorly predictive of future cardiovascular events [184,558]. Patients with carotid plaques are at high risk of atheroembolic stroke and cardiovascular events, and BP lowering should be complemented by lifestyle advice and treatment with statins and antiplatelet therapy. A common conundrum faced by clinicians is the hypertensive patient with a tight carotid stenosis, especially when bilateral. No study has addressed this scenario and therefore advice is necessarily pragmatic, and we recommend a more cautious approach to BP lowering, initiating with monotherapy and carefully monitoring for adverse effects.
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] and meta-analyses [560,561] suggest that ACE inhibitors and ARBs may reduce PWV beyond the effect of BP lowering on a long-term basis. Whether RAS blockers are more effective than other antihypertensive drugs in this regard has not been demonstrated. Moreover, whether any long-term reduction in aortic stiffness [562] translates into a reduction in cardiovascular events beyond the impact of BP lowering alone [563] has not been demonstrated.
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], and these patients are at very high cardiovascular risk [190]. BP control is an important part of the cardiovascular risk-reduction strategy in these patients. Beta-blockers have not been shown to worsen the symptoms of claudication in two meta-analyses [565,566]. Thus, beta-blockers remain a treatment option in hypertensive patients with LEAD when there is a specific indication for their use. When critical limb ischaemia is present, BP reduction should be instituted slowly as it may worsen ischaemia. In patients with LEAD, antihypertensive treatment should be complemented by lifestyle changes and especially smoking cessation, as well as statin and antiplatelet therapy [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]. In patients with Marfan syndrome, prophylactic use of ACE inhibitors, ARBs, or beta-blockers seems to be able to reduce either the progression of the aortic dilation or the occurrence of complications [568–570]. However, there is no evidence for the specific efficacy of these treatments in aortic disease of other aetiologies.
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] and is probably exacerbated by hypertension. Beyond aortic dilation and aneurysm formation, bicuspid aortic valve disease is also a risk factor for dissection and rupture [572]. Thus, BP should be tightly controlled in patients with bicuspid aortic valve disease and targeted ≤130/80 mmHg if tolerated. There is popular misconception that BP-lowering treatment has deleterious effects in patients with aortic stenosis and hypertension, when in fact it is well tolerated even in patients with severe aortic stenosis. Moreover, vasodilating drugs (including RAS blockers) also appear to be well tolerated. Thus, treatment of hypertension should be considered in these patients [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]. A large meta-analysis of prospective cohort studies has provided strong evidence that in men, erectile dysfunction (i.e. inadequate penile erection) is a significant independent risk factor for cardiovascular events and mortality [575], which means that it may be viewed as an early marker of vascular damage [576]. Sexual dysfunction may be triggered or aggravated by treatment with thiazide or thiazide-like diuretics, conventional beta-blockers, or centrally acting agents (e.g. clonidine), while ACE inhibitors, ARBs, CCBs, or vasodilating beta-blockers may have neutral or even beneficial effects [574,577]. Phosphodiesterase-5 inhibitors are effective against erectile dysfunction in patients with hypertension. They should be given only in the absence of nitrate administration, but prescription also appears to be safe in patients with multidrug BP-lowering treatment [578], with some caution if treatment includes alpha-blockers [577]. However, it seems prudent for unstable patients with high cardiovascular risk or severe uncontrolled hypertension to defer sexual activity until their condition is stabilized and treatment for erectile dysfunction can be initiated [575]. Overall, studies on the effects of hypertension and antihypertensive therapy on female sexual dysfunction are limited, and the situation is thus less clear than in men [577,579], although in a recent cross-sectional analysis among middle-aged and older treated hypertensive women in the SPRINT trial, neither BP values nor antihypertensive medication was associated with sexual dysfunction [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]. This can be due to the high prevalence of hypertension at an age in which cancer is also common. However, it is also due to the pressor effect of two groups of widely used anticancer drugs, the inhibitors of the vascular endothelial growth factor signalling pathway (bevacizumab, sorafenib, sunitinib, and pazopanib) and the proteasome inhibitors (carfilzomib). While the former group of drugs inhibits the production of nitric oxide in the arterial wall, the latter reduces the vasodilator response to acetylcholine, favouring vasoconstriction and vasospasm [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]. After the first cycle is completed and BP values appear to be stable, BP can be measured at the time of the routine clinical evaluations or assessed by HBPM. Patients developing hypertension (≥140/90 mmHg), or showing an increase in DBP ≥20 mmHg compared with pretreatment values, should initiate or optimize antihypertensive therapy, for which RAS blockers and CCBs may be considered the preferred drugs, and a RAS blocker-CCB combination is a frequently needed strategy. CCBs should only be of the dihydropiridine type, because diltiazem and verapamil block the CYP3A4 isoenzyme, which is involved in the metabolic pathway of sorafenib, increasing the drug's levels and leading to potential toxicity [583]. Although anticancer therapy takes an obvious priority, its temporary discontinuation may be considered when BP values are exceedingly high despite multidrug treatment, in the presence of severe hypertension-generated symptoms, or when there is a cardiovascular event requiring an immediate effective BP control [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]. ESC Guidelines have been issued for the assessment of cardiovascular variables, risk, and disease management of patients undergoing noncardiac surgery [586]. While a BP elevation is per se not a strong risk factor for cardiovascular complications in noncardiac surgery, overall cardiovascular risk assessment, including the search for HMOD, is important in treated and untreated hypertensive patients, and mandatory when a BP elevation is newly detected [537,586]. Postponing necessary surgery is usually not warranted in patients with grade 1 or 2 hypertension, whereas in those with an SBP at least 180 mmHg and/or DBP at least 110 mmHg, deferring the intervention until BP is reduced or controlled is advisable, except for emergency situations. What seems to be also important is to avoid large perioperative BP fluctuations [537,586]. This approach is supported by the findings from a recent RCT that has shown that in patients undergoing abdominal surgery, an individualized intraoperative treatment strategy, which kept BP values within a 10% difference from the preoperative office SBP, resulted in reduced risk of postoperative organ dysfunction [587]. There is no clear evidence in favour or against one vs. another antihypertensive treatment mode in patients undergoing noncardiac surgery, and thus the general drug treatment algorithms apply to these patients as well [588,589]. However, the perioperative use of beta-blockers has been the object of controversy for many years, and the concern has recently been revived by meta-analyses showing some increase in the risk of hypotension, stroke, and mortality in patients on perioperative beta-blockers vs. placebo [586,588,589]. Continuation of beta-blockers is nevertheless recommended in hypertensive patients on chronic beta-blocker treatment [586] in whom their abrupt discontinuation may lead to BP or heart rate rebounds [537]. This may also occur with the abrupt discontinuation of central agents such as clonidine. More recently, the question has been raised whether RAS blockers should be discontinued before surgery to reduce the risk of intraoperative hypotension [586,590]. Preoperative discontinuation of these drugs has also been supported by a recent international prospective cohort study, in a heterogenous group of patients, in which withholding ACE inhibitors or ARBs 24 h before noncardiac surgery was associated with a significant reduction in cardiovascular events and mortality 30 days after the intervention [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]. The benefit of adding a statin to antihypertensive treatment was well established in the ASCOT-Lipid Lowering Arm study [596] and further studies, as summarized in previous European Guidelines [16,35]. The beneficial effect of statin administration to patients without previous cardiovascular events [targeting an LDL-C value of less than 3.0 mmol/l (115 mg/dl)] has been strengthened by the findings from the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) [597] and HOPE-3 studies [343,598], showing that lowering LDL-C in patients with baseline values less than 3.4 mmol/l (130 mg/dl) reduced the incidence of cardiovascular events by between 44 and 24%. This justifies the use of statins in hypertensive patients who have moderate–high cardiovascular risk [599].
As detailed in the recent ESC/EAS Guidelines [599], when overt CVD is present and the cardiovascular risk is very high, statins should be administered to achieve LDL-C levels of less than 1.8 mmol/l (70 mg/dl) or a reduction of at least 50% if the baseline LDL-C is between 1.8 and 3.5 mmol/l (70 and 135 mg/dl) [600–602]. In patients at high cardiovascular risk, an LDL-C goal of less than 2.6 mmol/l (100 mg/dl) or a reduction of at least 50% if the baseline LDL-C is between 2.6 and 5.2 mmol/l (100 and 200 mg/dl) is recommended [602]. Beneficial effects of statin therapy have also been shown in patients with a previous stroke with LDL-C targets less than 2.6 mmol/l (100 mg/dl) [525]. Whether they also benefit from a target of less than 1.8 mmol/l (70 mg/dl) is open to future research. The summary of the available evidence suggests that many patients with hypertension would benefit from statin therapy.
9.2 Antiplatelet therapy and anticoagulant therapy
The most common complications of hypertension are related to thrombosis [603]. Hypertension predisposes to a prothrombotic state [603], and also predisposes to LEAD, heart failure, or AF, which are common conditions associated with thromboembolism, whether systemic or venous.
Antiplatelet and anticoagulant therapy use in patients with hypertension was addressed in a Cochrane systematic review [604], which included four randomized trials with a combined total of 44 012 patients. The authors concluded that overall acetylsalicylic acid (aspirin) did not reduce stroke or cardiovascular events compared with placebo in primary prevention patients with elevated BP and no previous CVD [604]. For secondary prevention, antiplatelet therapy in patients with elevated BP was reported as causing an absolute reduction in vascular events of 4.1% compared with placebo [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]. In anticoagulated patients, uncontrolled hypertension is one of the independent risk factors for intracranial haemorrhage and major bleeding [605]. In such patients, attention to modifiable bleeding risk factors should be made during all patient contacts. Bleeding risk assessment with clinical risk scores such as the HAS-BLED [Hypertension, Abnormal renal/liver function (1 point each), Stroke, Bleeding history or predisposition, Labile INR, Older (>65), Drugs/alcohol concomitantly (1 point each)] score, includes uncontrolled hypertension (defined as SBP >160 mmHg) as one of the risk factors for bleeding [606]; these should be used to ‘flag up’ patients at particularly high risk (e.g. HAS-BLED ≥3) for more regular review and follow-up [607].
In summary, aspirin is not recommended for primary prevention in hypertensive patients without CVD [35]. For secondary prevention, the benefit of antiplatelet therapy in patients with hypertension may be greater than the harm [35,604]. Ticlopidine, clopidogrel, and newer antiplatelet agents such as prasugrel and ticagrelor have not been sufficiently evaluated in patients with high BP.
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]. More data are required with respect to the capacity of glucagon-like peptide 1 agonists and dipeptidyl peptidase 4 inhibitors to prevent heart failure.
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] and canagliflozin [476] have demonstrated a reduction in heart failure and total and cardiovascular mortality, and a protective effect on renal function. Several mechanisms may account for these effects, and increased sodium excretion and improvements in tubuloglomerular balance reducing hyperfiltration are suggested mechanisms for the observed cardiovascular and renal protection, respectively.
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]. Depending on the local organization of health resources, many of the later visits may be performed by nonphysician health workers such as nurses [611]. For stable patients, HBPM and electronic communication with the physician may also provide an acceptable alternative to reduce the frequency of visits [60,612,613]. It is nevertheless advisable to assess risk factors and asymptomatic organ damage at least every 2 years.
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] (see Section 4). Thus, even when untreated, they should be scheduled for regular follow-up (at least annual visits) to measure office and out-of-office BP, as well as to check the cardiovascular risk profile. At annual visits, recommendations on lifestyle changes, which represent the appropriate treatment in many of these patients, should be reinforced.
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]. Nonadherence to antihypertensive therapy correlates with higher risk of cardiovascular events [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]. Studies based on the detection of antihypertensive medications in blood or urine have shown that low adherence to the prescribed medications can affect or less 50% of patients with apparently resistant hypertension [352,624], and that poor adherence is strongly and inversely correlated with the number of pills prescribed. Early recognition of a lack of adherence might reduce the number of costly investigations and procedures (including interventional treatment), and avoid the prescription of unnecessary drugs [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], those giving adherence feedback to patients, self-monitoring of BP [64] using pill boxes and other special packaging, and motivational interviewing. Increasing the integration among healthcare providers with the involvement of pharmacists and nurses increases drug adherence. Using multiple components has a greater effect on adherence, as the effect size of each intervention is generally modest. Recent data suggest that adherence to treatment may also be improved with the use of telemetry for transmission of recorded home values, maintaining contact between patients and physicians, and studies are ongoing [627].
Prescription of an appropriate therapeutic regimen is crucial [389]. This might be achieved through: possible drug-related adverse events, using long-acting drugs that require once daily dosage [628,629], avoiding complex dosing schedules, using SPCs whenever possible, and taking into consideration the effect of treatment on a patient's budget.
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.
REFERENCES
1. Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis.
JAMA 2015; 313:603–615.
2. Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis.
Lancet 2016; 387:957–967.
3. Forouzanfar MH, Liu P, Roth GA, Ng M, Biryukov S, Marczak L, et al. Global burden of hypertension and systolic blood pressure of at least 110 to 115 mm Hg, 1990–2015.
JAMA 2017; 317:165–182.
4. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.
Lancet 2002; 360:1903–1913.
5. NCD Risk Factor CollaborationWorldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19.1 million participants.
Lancet 2017; 389:37–55.
6. O’Donnell MJ, Chin SL, Rangarajan S, Xavier D, Liu L, Zhang H, et al. INTERSTROKE InvestigatorsGlobal and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study.
Lancet 2016; 388:761–775.
7. Rapsomaniki E, Timmis A, George J, Pujades-Rodriguez M, Shah AD, Denaxas S, et al. Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1.25 million people.
Lancet 2014; 383:1899–1911.
8. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension. 1. Overview, meta-analyses, and meta-regression analyses of randomized trials.
J Hypertens 2014; 32:2285–2295.
9. Tsai WC, Wu HY, Peng YS, Yang JY, Chen HY, Chiu YL, et al. Association of intensive blood pressure control and kidney disease progression in nondiabetic patients with chronic kidney disease: a systematic review and meta-analysis.
JAMA Intern Med 2017; 177:792–799.
10. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, et al. INTERHEART Study InvestigatorsEffect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.
Lancet 2004; 364:937–952.
11. Banegas JR, Lopez-Garcia E, Dallongeville J, Guallar E, Halcox JP, Borghi C, et al. Achievement of treatment goals for primary prevention of cardiovascular disease in clinical practice across Europe: the EURIKA study.
Eur Heart J 2011; 32:2143–2152.
12. Chow CK, Teo KK, Rangarajan S, Islam S, Gupta R, Avezum A, et al. PURE Study InvestigatorsPrevalence, awareness, treatment, and control of hypertension in rural and urban communities in high-, middle-, and low-income countries.
JAMA 2013; 310:959–968.
13. Falaschetti E, Mindell J, Knott C, Poulter N. Hypertension management in England: a serial cross-sectional study from 1994 to 2011.
Lancet 2014; 383:1912–1919.
14. Tocci G, Agabiti Rosei E, Ambrosioni E, Borghi C, Ferri C, Ferrucci A, et al. Blood pressure control in Italy: analysis of clinical data from 2005–2011 surveys on hypertension.
J Hypertens 2012; 30:1065–1074.
15. European Society of Hypertension-European Society of Cardiology Guidelines Committee2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension.
J Hypertens 2003; 21:1011–1053.
16. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. 2007 Guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
J Hypertens 2007; 25:1105–1187.
17. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
Eur Heart J 2013; 34:2159–2219.
18. Lurbe E, Agabiti Rosei E, Cruickshank JK, Dominiczak A, Erdine S, Hirth A, et al. 2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents.
J Hypertens 2016; 34:1887–1920.
19. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data.
Lancet 2005; 365:217–223.
20. Lip GYH, Coca A, Kahan T, Boriani G, Manolis AS, Olsen MH, et al. Hypertension and cardiac arrhythmias: executive summary of a consensus document from the European Heart Rhythm Association (EHRA) and ESC Council on Hypertension, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia (SOLEACE).
Eur Heart J Cardiovasc Pharmacother 2017; 3:235–250.
21. Gottesman RF, Albert MS, Alonso A, Coker LH, Coresh J, Davis SM, et al. Associations between midlife vascular risk factors and 25-year incident dementia in the Atherosclerosis Risk in Communities (ARIC) cohort.
JAMA Neurol 2017; 74:1246–1254.
22. Rovio SP, Pahkala K, Nevalainen J, Juonala M, Salo P, Kahonen M, et al. Cardiovascular risk factors from childhood and midlife cognitive performance: the Young Finns study.
J Am Coll Cardiol 2017; 69:2279–2289.
23. Vishram JK, Borglykke A, Andreasen AH, Jeppesen J, Ibsen H, Jorgensen T, et al. MORGAM ProjectImpact of age on the importance of systolic and diastolic blood pressures for stroke risk: the MOnica, Risk, Genetics, Archiving, and Monograph (MORGAM) project.
Hypertension 2012; 60:1117–1123.
24. Brown DW, Giles WH, Greenlund KJ. Blood pressure parameters and risk of fatal stroke, NHANES II mortality study.
Am J Hypertens 2007; 20:338–341.
25. Lawes CM, Rodgers A, Bennett DA, Parag V, Suh I, Ueshima H, MacMahon S. Asia Pacific Cohort Studies CollaborationBlood pressure and cardiovascular disease in the Asia Pacific region.
J Hypertens 2003; 21:707–716.
26. Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Is pulse pressure useful in predicting risk for coronary heart disease? The Framingham heart study.
Circulation 1999; 100:354–360.
27. Williams B, Lindholm LH, Sever P. Systolic pressure is all that matters.
Lancet 2008; 371:2219–2221.
28. Domanski M, Mitchell G, Pfeffer M, Neaton JD, Norman J, Svendsen K, et al. MRFIT Research GroupPulse pressure and cardiovascular disease-related mortality: follow-up study of the Multiple Risk Factor Intervention Trial (MRFIT).
JAMA 2002; 287:2677–2683.
29. Franklin SS, Lopez VA, Wong ND, Mitchell GF, Larson MG, Vasan RS, Levy D. Single versus combined blood pressure components and risk for cardiovascular disease: the Framingham Heart Study.
Circulation 2009; 119:243–250.
30. Bhatt DL, Steg PG, Ohman EM, Hirsch AT, Ikeda Y, Mas JL, et al. REACH Registry InvestigatorsInternational prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis.
JAMA 2006; 295:180–189.
31. Mancia G, Facchetti R, Bombelli M, Polo Friz H, Grassi G, Giannattasio C, Sega R. Relationship of office, home, and ambulatory blood pressure to blood glucose and lipid variables in the PAMELA population.
Hypertension 2005; 45:1072–1077.
32. Berry JD, Dyer A, Cai X, Garside DB, Ning H, Thomas A, et al. Lifetime risks of cardiovascular disease.
N Engl J Med 2012; 366:321–329.
33. Aktas MK, Ozduran V, Pothier CE, Lang R, Lauer MS. Global risk scores and exercise testing for predicting all-cause mortality in a preventive medicine program.
JAMA 2004; 292:1462–1468.
34. Cooney MT, Dudina AL, Graham IM. Value and limitations of existing scores for the assessment of cardiovascular risk: a review for clinicians.
J Am Coll Cardiol 2009; 54:1209–1227.
35. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. ESC Scientific Document Group2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR).
Eur Heart J 2016; 37:2315–2381.
36. Borghi C, Agabiti Rosei E, Bardin T, Dawson J, Dominiczak A, Kielstein JT, et al. Serum uric acid and the risk of cardiovascular and renal disease.
J Hypertens 2015; 33:1729–1741. discussion 1741.
37. van Dis I, Geleijnse JM, Boer JM, Kromhout D, Boshuizen H, Grobbee DE, et al. Effect of including nonfatal events in cardiovascular risk estimation, illustrated with data from The Netherlands.
Eur J Prev Cardiol 2014; 21:377–383.
38. Cuspidi C, Ambrosioni E, Mancia G, Pessina AC, Trimarco B, Zanchetti A. Role of echocardiography and carotid ultrasonography in stratifying risk in patients with essential hypertension: the Assessment of Prognostic Risk Observational Survey.
J Hypertens 2002; 20:1307–1314.
39. Roman MJ, Pickering TG, Schwartz JE, Pini R, Devereux RB. Association of carotid atherosclerosis and left ventricular hypertrophy.
J Am Coll Cardiol 1995; 25:83–90.
40. Cuspidi C, Valerio C, Sala C, Esposito A, Masaidi M, Negri F, et al. Prevalence and correlates of multiple organ damage in a never-treated hypertensive population: role of ambulatory blood pressure.
Blood Press Monit 2008; 13:7–13.
41. Pontremoli R, Ravera M, Bezante GP, Viazzi F, Nicolella C, Berruti V, et al. Left ventricular geometry and function in patients with essential hypertension and microalbuminuria.
J Hypertens 1999; 17:993–1000.
42. Sehestedt T, Jeppesen J, Hansen TW, Wachtell K, Ibsen H, Torp-Pedersen C, et al. Risk prediction is improved by adding markers of subclinical organ damage to SCORE.
Eur Heart J 2010; 31:883–891.
43. Perrone-Filardi P, Coca A, Galderisi M, Paolillo S, Alpendurada F, de Simone G, et al. Noninvasive cardiovascular imaging for evaluating subclinical target organ damage in hypertensive patients: a consensus article from the European Association of Cardiovascular Imaging, the European Society of Cardiology Council on Hypertension and the European Society of Hypertension.
J Hypertens 2017; 35:1727–1741.
44. Stergiou GS, Alpert B, Mieke S, Asmar R, Atkins N, Eckert S, et al. A universal standard for the validation of blood pressure measuring devices: Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Collaboration Statement.
J Hypertens 2018; 36:472–478.
45. Clark CE, Taylor RS, Shore AC, Ukoumunne OC, Campbell JL. Association of a difference in systolic blood pressure between arms with vascular disease and mortality: a systematic review and meta-analysis.
Lancet 2012; 379:905–914.
46. Fagard RH, De Cort P. Orthostatic hypotension is a more robust predictor of cardiovascular events than nighttime reverse dipping in elderly.
Hypertension 2010; 56:56–61.
47. Julius S, Palatini P, Kjeldsen SE, Zanchetti A, Weber MA, McInnes GT, et al. Usefulness of heart rate to predict cardiac events in treated patients with high-risk systemic hypertension.
Am J Cardiol 2012; 109:685–692.
48. Myers MG. A short history of automated office blood pressure – 15 years to SPRINT.
J Clin Hypertens (Greenwich) 2016; 18:721–724.
49. Parati G, Pomidossi G, Casadei R, Mancia G. Lack of alerting reactions to intermittent cuff inflations during noninvasive blood pressure monitoring.
Hypertension 1985; 7:597–601.
50. Myers MG, Godwin M, Dawes M, Kiss A, Tobe SW, Kaczorowski J. Measurement of blood pressure in the office: recognizing the problem and proposing the solution.
Hypertension 2010; 55:195–200.
51. Research Group SPRINT, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, et al. A randomized trial of intensive versus standard blood-pressure control.
N Engl J Med 2015; 373:2103–2116.
52. Filipovsky J, Seidlerova J, Kratochvil Z, Karnosova P, Hronova M, Mayer O Jr. Automated compared to manual office blood pressure and to home blood pressure in hypertensive patients.
Blood Press 2016; 25:228–234.
53. Myers MG, Kaczorowski J, Dolovich L, Tu K, Paterson JM. Cardiovascular risk in hypertension in relation to achieved blood pressure using automated office blood pressure measurement.
Hypertension 2016; 68:866–872.
54. Parati G, Stergiou G, O’Brien E, Asmar R, Beilin L, Bilo G, et al. European Society of Hypertension Working Group on Blood Pressure Monitoring and Cardiovascular VariabilityEuropean Society of Hypertension practice guidelines for ambulatory blood pressure monitoring.
J Hypertens 2014; 32:1359–1366.
55. Stergiou GS, Parati G, Vlachopoulos C, Achimastos A, Andreadis E, Asmar R, et al. Methodology and technology for peripheral and central blood pressure and blood pressure variability measurement: current status and future directions – Position statement of the European Society of Hypertension Working Group on blood pressure monitoring and cardiovascular variability.
J Hypertens 2016; 34:1665–1677.
56. O’Brien E, Parati G, Stergiou G, Asmar R, Beilin L, Bilo G, et al. European Society of Hypertension Working Group on Blood Pressure MEuropean Society of Hypertension position paper on ambulatory blood pressure monitoring.
J Hypertens 2013; 31:1731–1768.
57. Parati G, Stergiou GS, Asmar R, Bilo G, de Leeuw P, Imai Y, et al. European Society of Hypertension guidelines for blood pressure monitoring at home: a summary report of the Second International Consensus Conference on Home Blood Pressure Monitoring.
J Hypertens 2008; 26:1505–1526.
58. Bliziotis IA, Destounis A, Stergiou GS. Home versus ambulatory and office blood pressure in predicting target organ damage in hypertension: a systematic review and meta-analysis.
J Hypertens 2012; 30:1289–1299.
59. Ward AM, Takahashi O, Stevens R, Heneghan C. Home measurement of blood pressure and cardiovascular disease: systematic review and meta-analysis of prospective studies.
J Hypertens 2012; 30:449–456.
60. McManus RJ, Mant J, Bray EP, Holder R, Jones MI, Greenfield S, et al. Telemonitoring and self-management in the control of hypertension (TASMINH2): a randomised controlled trial.
Lancet 2010; 376:163–172.
61. McManus RJ, Mant J, Haque MS, Bray EP, Bryan S, Greenfield SM, et al. Effect of self-monitoring and medication self-titration on systolic blood pressure in hypertensive patients at high risk of cardiovascular disease: the TASMIN-SR randomized clinical trial.
JAMA 2014; 312:799–808.
62. Tucker KL, Sheppard JP, Stevens R, Bosworth HB, Bove A, Bray EP, et al. Self-monitoring of blood pressure in hypertension: a systematic review and individual patient data meta-analysis.
PLoS Med 2017; 14:e1002389.
63. Omboni S, Gazzola T, Carabelli G, Parati G. Clinical usefulness and cost effectiveness of home blood pressure telemonitoring: meta-analysis of randomized controlled studies.
J Hypertens 2013; 31:455–467. discussion 467–458.
64. Parati G, Omboni S. Role of home blood pressure telemonitoring in hypertension management: an update.
Blood Press Monit 2010; 15:285–295.
65. Gaborieau V, Delarche N, Gosse P. Ambulatory blood pressure monitoring versus self-measurement of blood pressure at home: correlation with target organ damage.
J Hypertens 2008; 26:1919–1927.
66. Clement DL, De Buyzere ML, De Bacquer DA, de Leeuw PW, Duprez DA, Fagard RH, et al. Office versus Ambulatory Pressure Study InvestigatorsPrognostic value of ambulatory blood-pressure recordings in patients with treated hypertension.
N Engl J Med 2003; 348:2407–2415.
67. Sega R, Facchetti R, Bombelli M, Cesana G, Corrao G, Grassi G, Mancia G. Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population: follow-up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study.
Circulation 2005; 111:1777–1783.
68. Banegas JR, Ruilope LM, de la Sierra A, Vinyoles E, Gorostidi M, de la Cruz JJ, et al. Relationship between clinic and ambulatory blood-pressure measurements and mortality.
N Engl J Med 2018; 378:1509–1520.
69. Investigators ABC-H, Roush GC, Fagard RH, Salles GF, Pierdomenico SD, Reboldi G, et al. Prognostic impact from clinic, daytime, and night-time systolic blood pressure in nine cohorts of 13,844 patients with hypertension.
J Hypertens 2014; 32:2332–2340. discussion 2340.
70. Fagard RH, Celis H, Thijs L, Staessen JA, Clement DL, De Buyzere ML, De Bacquer DA. Daytime and nighttime blood pressure as predictors of death and cause-specific cardiovascular events in hypertension.
Hypertension 2008; 51:55–61.
71. Parati G, Ochoa JE, Bilo G, Agarwal R, Covic A, Dekker FW, et al. European Renal and Cardiovascular Medicine Working Group of the European Renal Association-European Dialysis and Transplant AssociationHypertension in chronic kidney disease part 2: role of ambulatory and home blood pressure monitoring for assessing alterations in blood pressure variability and blood pressure profiles.
Hypertension 2016; 67:1102–1110.
72. Piper MA, Evans CV, Burda BU, Margolis KL, O’Connor E, Whitlock EP. Diagnostic and predictive accuracy of blood pressure screening methods with consideration of rescreening intervals: a systematic review for the U.S. Preventive Services Task Force.
Ann Intern Med 2015; 162:192–204.
73. Omboni S, Parati G, Palatini P, Vanasia A, Muiesan ML, Cuspidi C, Mancia G. Reproducibility and clinical value of nocturnal hypotension: prospective evidence from the SAMPLE study. Study on Ambulatory Monitoring of Pressure and Lisinopril Evaluation.
J Hypertens 1998; 16:733–738.
74. Mancia G, Verdecchia P. Clinical value of ambulatory blood pressure: evidence and limits.
Circ Res 2015; 116:1034–1045.
75. Salles GF, Reboldi G, Fagard RH, Cardoso CR, Pierdomenico SD, Verdecchia P, et al. ABC-H InvestigatorsPrognostic effect of the nocturnal blood pressure fall in hypertensive patients: the Ambulatory Blood pressure Collaboration in patients with Hypertension (ABC-H) meta-analysis.
Hypertension 2016; 67:693–700.
76. Mancia G. Short- and long-term blood pressure variability: present and future.
Hypertension 2012; 60:512–517.
77. Kario K, Pickering TG, Umeda Y, Hoshide S, Hoshide Y, Morinari M, et al. Morning surge in blood pressure as a predictor of silent and clinical cerebrovascular disease in elderly hypertensives: a prospective study.
Circulation 2003; 107:1401–1406.
78. Parati G, Schillaci G. What are the real determinants of the ambulatory arterial stiffness index?
J Hypertens 2012; 30:472–476.
79. Kikuya M, Ohkubo T, Metoki H, Asayama K, Hara A, Obara T, et al. Day-by-day variability of blood pressure and heart rate at home as a novel predictor of prognosis: the Ohasama study.
Hypertension 2008; 52:1045–1050.
80. Mancia G, Zanchetti A. White-coat hypertension: misnomers, misconceptions and misunderstandings. What should we do next?
J Hypertens 1996; 14:1049–1052.
81. Bobrie G, Clerson P, Menard J, Postel-Vinay N, Chatellier G, Plouin PF. Masked hypertension: a systematic review.
J Hypertens 2008; 26:1715–1725.
82. Mancia G, Bombelli M, Cuspidi C, Facchetti R, Grassi G. Cardiovascular risk associated with white-coat hypertension: pro side of the argument.
Hypertension 2017; 70:668–675.
83. Parati G, Omboni S, Staessen J, Thijs L, Fagard R, Ulian L, Mancia G. Limitations of the difference between clinic and daytime blood pressure as a surrogate measure of the ‘white-coat’ effect. Syst-Eur investigators.
J Hypertens 1998; 16:23–29.
84. Banegas JR, Ruilope LM, de la Sierra A, de la Cruz JJ, Gorostidi M, Segura J, et al. High prevalence of masked uncontrolled hypertension in people with treated hypertension.
Eur Heart J 2014; 35:3304–3312.
85. Huang Y, Huang W, Mai W, Cai X, An D, Liu Z, et al. White-coat hypertension is a risk factor for cardiovascular diseases and total mortality.
J Hypertens 2017; 35:677–688.
86. Briasoulis A, Androulakis E, Palla M, Papageorgiou N, Tousoulis D. White-coat hypertension and cardiovascular events: a meta-analysis.
J Hypertens 2016; 34:593–599.
87. Grassi G, Seravalle G, Trevano FQ, Dell’oro R, Bolla G, Cuspidi C, et al. Neurogenic abnormalities in masked hypertension.
Hypertension 2007; 50:537–542.
88. Mancia G. Clinical significance of white-coat hypertension.
J Hypertens 2016; 34:623–626.
89. Mancia G. White-coat hypertension: growing evidence in favour of its adverse prognostic significance.
J Hypertens 2017; 35:710–712.
90. Mancia G, Grassi G. The heterogeneous nature of white-coat hypertension.
J Am Coll Cardiol 2016; 68:2044–2046.
91. Asayama K, Li Y, Franklin SS, Thijs L, O’Brien E, Staessen JA. Cardiovascular risk associated with white-coat hypertension: con side of the argument.
Hypertension 2017; 70:676–682.
92. Lurbe E, Torro I, Alvarez V, Nawrot T, Paya R, Redon J, Staessen JA. Prevalence, persistence, and clinical significance of masked hypertension in youth.
Hypertension 2005; 45:493–498.
93. Mancia G, Facchetti R, Bombelli M, Grassi G, Sega R. Long-term risk of mortality associated with selective and combined elevation in office, home, and ambulatory blood pressure.
Hypertension 2006; 47:846–853.
94. Bobrie G, Chatellier G, Genes N, Clerson P, Vaur L, Vaisse B, et al. Cardiovascular prognosis of ‘masked hypertension’ detected by blood pressure self-measurement in elderly treated hypertensive patients.
JAMA 2004; 291:1342–1349.
95. Fagard RH, Cornelissen VA. Incidence of cardiovascular events in white-coat, masked and sustained hypertension versus true normotension: a meta-analysis.
J Hypertens 2007; 25:2193–2198.
96. Franklin SS, Thijs L, Li Y, Hansen TW, Boggia J, Liu Y, et al. Response to masked hypertension in untreated and treated patients with diabetes mellitus: attractive but questionable interpretations and response to Is masked hypertension related to diabetes mellitus?
Hypertension 2013; 62:e23–e25.
97. Lurbe E, Redon J, Kesani A, Pascual JM, Tacons J, Alvarez V, Batlle D. Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes.
New Engl J Med 2002; 347:797–805.
98. Lindholt JS, Sogaard R. Population screening and intervention for vascular disease in Danish men (VIVA): a randomised controlled trial.
Lancet 2017; 390:2256–2265.
99. Hodgkinson J, Mant J, Martin U, Guo B, Hobbs FD, Deeks JJ, et al. Relative effectiveness of clinic and home blood pressure monitoring compared with ambulatory blood pressure monitoring in diagnosis of hypertension: systematic review.
BMJ 2011; 342:d3621.
100. Vinyoles E, Felip A, Pujol E, de la Sierra A, Dura R, del Rey RH, et al. Clinical characteristics of isolated clinic hypertension.
J Hypertens 2008; 26:438–445.
101. McManus RJ, Mant J. Do differences in blood pressure between arms matter?
Lancet 2012; 379:872–873.
102. McManus RJ, Mant J, Franssen M, Nickless A, Schwartz C, Hodgkinson J, et al. Efficacy of self-monitored blood pressure, with or without telemonitoring, for titration of antihypertensive medication (TASMINH4): an unmasked randomised controlled trial.
Lancet 2018; 391:949–959.
103. Le VV, Mitiku T, Sungar G, Myers J, Froelicher V. The blood pressure response to dynamic exercise testing: a systematic review.
Prog Cardiovasc Dis 2008; 51:135–160.
104. Holmqvist L, Mortensen L, Kanckos C, Ljungman C, Mehlig K, Manhem K. Exercise blood pressure and the risk of future hypertension.
J Hum Hypertens 2012; 26:691–695.
105. Parati G, Agostoni P, Basnyat B, Bilo G, Brugger H, Coca A, et al. Clinical recommendations for high altitude exposure of individuals with preexisting cardiovascular conditions.
Eur Heart J 2018; 39:1546–1554.
106. Picone DS, Schultz MG, Otahal P, Aakhus S, Al-Jumaily AM, Black JA, et al. Accuracy of cuff-measured blood pressure: systematic reviews and meta-analyses.
J Am Coll Cardiol 2017; 70:572–586.
107. Herbert A, Cruickshank JK, Laurent S, Boutouyrie P. Establishing reference values for central blood pressure and its amplification in a general healthy population and according to cardiovascular risk factors.
Eur Heart J 2014; 35:3122–3133.
108. Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, et al. CAFE Investigators, Anglo-Scandinavian Cardiac Outcomes Trial Investigators, CAFE Steering Committee and Writing CommitteeDifferential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study.
Circulation 2006; 113:1213–1225.
109. Vlachopoulos C, Aznaouridis K, O’Rourke MF, Safar ME, Baou K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with central haemodynamics: a systematic review and meta-analysis.
Eur Heart J 2010; 31:1865–1871.
110. Lurbe E, Redon J. Isolated systolic hypertension in young people is not spurious and should be treated: con side of the argument.
Hypertension 2016; 68:276–280.
111. McEniery CM, Franklin SS, Cockcroft JR, Wilkinson IB. Isolated systolic hypertension in young people is not spurious and should be treated: pro side of the argument.
Hypertension 2016; 68:269–275.
112. Devereux RB, Alderman MH. Role of preclinical cardiovascular disease in the evolution from risk factor exposure to development of morbid events.
Circulation 1993; 88:1444–1455.
113. Cordero A, Morillas P, Bertomeu-Gonzalez V, Quiles J, Mazon P, Guindo J, et al. Prevalence of Peripheral Arterial Disease in Patients with Acute Coronary Syndrome InvestigatorsClustering of target organ damage increases mortality after acute coronary syndromes in patients with arterial hypertension.
J Hum Hypertens 2011; 25:600–607.
114. Greve SV, Blicher MK, Sehestedt T, Gram-Kampmann EM, Rasmussen S, Vishram JK, Olsen MH. Effective risk stratification in patients with moderate cardiovascular risk using albuminuria and atherosclerotic plaques in the carotid arteries.
J Hypertens 2015; 33:1563–1570.
115. de Simone G, Devereux RB, Izzo R, Girfoglio D, Lee ET, Howard BV, Roman MJ. Lack of reduction of left ventricular mass in treated hypertension: the strong heart study.
J Am Heart Assoc 2013; 2:e000144.
116. Lonnebakken MT, Izzo R, Mancusi C, Gerdts E, Losi MA, Canciello G, et al. Left ventricular hypertrophy regression during antihypertensive treatment in an outpatient clinic (the Campania Salute Network).
J Am Heart Assoc 2017; 6:e004152.
117. Volpe M, Battistoni A, Tocci G, Agabiti Rosei E, Catapano AL, Coppo R, et al. Cardiovascular risk assessment beyond systemic coronary risk estimation: a role for organ damage markers.
J Hypertens 2012; 30:1056–1064.
118. Bacharova L, Schocken D, Estes EH, Strauss D. The role of ECG in the diagnosis of left ventricular hypertrophy.
Curr Cardiol Rev 2014; 10:257–261.
119. Pahor M, Guralnik JM, Ambrosius WT, Blair S, Bonds DE, Church TS, et al. Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE study randomized clinical trial.
JAMA 2014; 311:2387–2396.
120. Lehtonen AO, Puukka P, Varis J, Porthan K, Tikkanen JT, Nieminen MS, et al. Prevalence and prognosis of ECG abnormalities in normotensive and hypertensive individuals.
J Hypertens 2016; 34:959–966.
121. Okin PM, Devereux RB, Jern S, Kjeldsen SE, Julius S, Nieminen MS, et al. LIFE Study InvestigatorsRegression of electrocardiographic left ventricular hypertrophy during antihypertensive treatment and the prediction of major cardiovascular events.
JAMA 2004; 292:2343–2349.
122. Okin PM, Oikarinen L, Viitasalo M, Toivonen L, Kjeldsen SE, Nieminen MS, et al. LIFE Study InvestigatorsPrognostic value of changes in the electrocardiographic strain pattern during antihypertensive treatment: the Losartan Intervention for End-Point Reduction in Hypertension Study (LIFE).
Circulation 2009; 119:1883–1891.
123. de Simone G, Izzo R, Chinali M, De Marco M, Casalnuovo G, Rozza F, et al. Does information on systolic and diastolic function improve prediction of a cardiovascular event by left ventricular hypertrophy in arterial hypertension?
Hypertension 2010; 56:99–104.
124. Bombelli M, Facchetti R, Cuspidi C, Villa P, Dozio D, Brambilla G, et al. Prognostic significance of left atrial enlargement in a general population: results of the PAMELA study.
Hypertension 2014; 64:1205–1211.
125. Devereux RB, Wachtell K, Gerdts E, Boman K, Nieminen MS, Papademetriou V, et al. Prognostic significance of left ventricular mass change during treatment of hypertension.
JAMA 2004; 292:2350–2356.
126. de Simone G, Izzo R, Aurigemma GP, De Marco M, Rozza F, Trimarco V, et al. Cardiovascular risk in relation to a new classification of hypertensive left ventricular geometric abnormalities.
J Hypertens 2015; 33:745–754. discussion 754.
127. Marwick TH, Gillebert TC, Aurigemma G, Chirinos J, Derumeaux G, Galderisi M, et al. Recommendations on the use of echocardiography in adult hypertension: a report from the European Association of Cardiovascular Imaging (EACVI) and the American Society of Echocardiography (ASE).
Eur Heart J Cardiovasc Imaging 2015; 16:577–605.
128. Gerdts E, Wachtell K, Omvik P, Otterstad JE, Oikarinen L, Boman K, et al. Left atrial size and risk of major cardiovascular events during antihypertensive treatment: losartan intervention for endpoint reduction in hypertension trial.
Hypertension 2007; 49:311–316.
129. Muiesan ML, Salvetti M, Monteduro C, Bonzi B, Paini A, Viola S, et al. Left ventricular concentric geometry during treatment adversely affects cardiovascular prognosis in hypertensive patients.
Hypertension 2004; 43:731–738.
130. Takeuchi M, Nishikage T, Mor-Avi V, Sugeng L, Weinert L, Nakai H, et al. Measurement of left ventricular mass by real-time three-dimensional echocardiography: validation against magnetic resonance and comparison with two-dimensional and m-mode measurements.
J Am Soc Echocardiogr 2008; 21:1001–1005.
131. Stanton T, Jenkins C, Haluska BA, Marwick TH. Association of outcome with left ventricular parameters measured by two-dimensional and three-dimensional echocardiography in patients at high cardiovascular risk.
J Am Soc Echocardiogr 2014; 27:65–73.
132. Codella NC, Lee HY, Fieno DS, Chen DW, Hurtado-Rua S, Kochar M, et al. Improved left ventricular mass quantification with partial voxel interpolation: in vivo and necropsy validation of a novel cardiac MRI segmentation algorithm.
Circ Cardiovasc Imaging 2012; 5:137–146.
133. Weinsaft JW, Cham MD, Janik M, Min JK, Henschke CI, Yankelevitz DF, Devereux RB. Left ventricular papillary muscles and trabeculae are significant determinants of cardiac MRI volumetric measurements: effects on clinical standards in patients with advanced systolic dysfunction.
Int J Cardiol 2008; 126:359–365.
134. Perrone-Filardi P, Coca A, Galderisi M, Paolillo S, Alpendurada F, de Simone G, et al. Noninvasive cardiovascular imaging for evaluating subclinical target organ damage in hypertensive patients: a consensus paper from the European Association of Cardiovascular Imaging (EACVI), the European Society of Cardiology Council on Hypertension, and the European Society of Hypertension (ESH).
Eur Heart J Cardiovasc Imaging 2017; 18:945–960.
135. de Simone G, Kitzman DW, Chinali M, Oberman A, Hopkins PN, Rao DC, et al. Left ventricular concentric geometry is associated with impaired relaxation in hypertension: the HyperGEN study.
Eur Heart J 2005; 26:1039–1045.
136. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
Eur Heart J 2016; 37:2129–2200.
137. Yaghi S, Moon YP, Mora-McLaughlin C, Willey JZ, Cheung K, Di Tullio MR, et al. Left atrial enlargement and stroke recurrence: the Northern Manhattan Stroke Study.
Stroke 2015; 46:1488–1493.
138. Losi MA, Izzo R, De Marco M, Canciello G, Rapacciuolo A, Trimarco V, et al. Cardiovascular ultrasound exploration contributes to predict incident atrial fibrillation in arterial hypertension: the Campania Salute Network.
Int J Cardiol 2015; 199:290–295.
139. Douglas PS. The left atrium: a biomarker of chronic diastolic dysfunction and cardiovascular disease risk.
J Am Coll Cardiol 2003; 42:1206–1207.
140. Kuznetsova T, Haddad F, Tikhonoff V, Kloch-Badelek M, Ryabikov A, Knez J, et al. European Project On Genes in Hypertension InvestigatorsImpact and pitfalls of scaling of left ventricular and atrial structure in population-based studies.
J Hypertens 2016; 34:1186–1194.
141. Evangelista A, Flachskampf FA, Erbel R, Antonini-Canterin F, Vlachopoulos C, Rocchi G, et al. European Association of Echocardiography, Document Reviewers: Pepi M, Breithardt OA, Plonska-Gosciniak EEchocardiography in aortic diseases: EAE recommendations for clinical practice.
Eur J Echocardiogr 2010; 11:645–658.
142. Nambi V, Chambless L, Folsom AR, He M, Hu Y, Mosley T, et al. Carotid intima-media thickness and presence or absence of plaque improves prediction of coronary heart disease risk: the ARIC (Atherosclerosis Risk In Communities) study.
J Am Coll Cardiol 2010; 55:1600–1607.
143. Vlachopoulos C, Xaplanteris P, Aboyans V, Brodmann M, Cifkova R, Cosentino F, et al. The role of vascular biomarkers for primary and secondary prevention. A position paper from the European Society of Cardiology Working Group on peripheral circulation: endorsed by the Association for Research into Arterial Structure and Physiology (ARTERY) Society.
Atherosclerosis 2015; 241:507–532.
144. Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Desvarieux M, et al. Advisory Board of the 3rd Watching the Risk Symposium 2004, 13th European Stroke ConferenceMannheim intima-media thickness consensus.
Cerebrovasc Dis 2004; 18:346–349.
145. Inaba Y, Chen JA, Bergmann SR. Carotid plaque, compared with carotid intima-media thickness, more accurately predicts coronary artery disease events: a meta-analysis.
Atherosclerosis 2012; 220:128–133.
146. Zanchetti A, Hennig M, Hollweck R, Bond G, Tang R, Cuspidi C, et al. Baseline values but not treatment-induced changes in carotid intima-media thickness predict incident cardiovascular events in treated hypertensive patients: findings in the European Lacidipine Study on Atherosclerosis (ELSA).
Circulation 2009; 120:1084–1090.
147. Polak JF, Pencina MJ, Pencina KM, O’Donnell CJ, Wolf PA, D’Agostino RB Sr. Carotid-wall intima-media thickness and cardiovascular events.
N Engl J Med 2011; 365:213–221.
148. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, et al. European Network for Non invasive Investigation of Large Arteries. Expert consensus document on arterial stiffness: methodological issues and clinical applications.
Eur Heart J 2006; 27:2588–2605.
149. Van Bortel LM, Laurent S, Boutouyrie P, Chowienczyk P, Cruickshank JK, De Backer T, et al. Artery Society, European Society of Hypertension Working Group on Vascular Structure and Function, European Network for Noninvasive Investigation of Large ArteriesExpert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity.
J Hypertens 2012; 30:445–448.
150. Reference Values for Arterial Stiffness Collaboration. Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: ‘establishing normal and reference values’.
Eur Heart J 2010; 31:2338–2350.
151. Ben-Shlomo Y, Spears M, Boustred C, May M, Anderson SG, Benjamin EJ, et al. Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects.
J Am Coll Cardiol 2014; 63:636–646.
152. Feringa HH, Bax JJ, van Waning VH, Boersma E, Elhendy A, Schouten O, et al. The long-term prognostic value of the resting and postexercise ankle-brachial index.
Arch Intern Med 2006; 166:529–535.
153. Fowkes FG, Murray GD, Butcher I, Heald CL, Lee RJ, Chambless LE, et al. Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.
JAMA 2008; 300:197–208.
154. De Buyzere ML, Clement DL. Management of hypertension in peripheral arterial disease.
Prog Cardiovasc Dis 2008; 50:238–263.
155. Clase CM, Barzilay J, Gao P, Smyth A, Schmieder RE, Tobe S, et al. Acute change in glomerular filtration rate with inhibition of the renin-angiotensin system does not predict subsequent renal and cardiovascular outcomes.
Kidney Int 2017; 91:683–690.
156. Schmidt M, Mansfield KE, Bhaskaran K, Nitsch D, Sørensen HT, Smeeth L, Tomlinson LA. Serum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study.
BMJ 2017; 356:j791.
157. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF III, Feldman HI, et al. A new equation to estimate glomerular filtration rate.
Ann Intern Med 2009; 150:604–612.
158. Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, et al. HOPE Study InvestigatorsAlbuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals.
JAMA 2001; 286:421–426.
159. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work GroupKDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.
Kidney Int 2013; 3:1–150.
160. McTaggart MP, Newall RG, Hirst JA, Bankhead CR, Lamb EJ, Roberts NW, Price CP. Diagnostic accuracy of point-of-care tests for detecting albuminuria: a systematic review and meta-analysis.
Ann Intern Med 2014; 160:550–557.
161. Breslin DJ, Gifford RW Jr, Fairbairn JF 2nd, Kearns TP. Prognostic importance of ophthalmoscopic findings in essential hypertension.
JAMA 1966; 195:335–338.
162. Frant R, Groen J. Prognosis of vascular hypertension; a 9 year follow-up study of 418 cases.
Arch Intern Med (Chic) 1950; 85:727–750.
163. Sairenchi T, Iso H, Yamagishi K, Irie F, Okubo Y, Gunji J, et al. Mild retinopathy is a risk factor for cardiovascular mortality in Japanese with and without hypertension: the Ibaraki Prefectural Health Study.
Circulation 2011; 124:2502–2511.
164. Dimmitt SB, West JN, Eames SM, Gibson JM, Gosling P, Littler WA. Usefulness of ophthalmoscopy in mild to moderate hypertension.
Lancet 1989; 1:1103–1106.
165. Muiesan ML, Salvetti M, Di Castelnuovo A, Paini A, Assanelli D, Costanzo S, et al. Moli-sani Study InvestigatorsObesity and ECG left ventricular hypertrophy.
J Hypertens 2017; 35:162–169.
166. Longstreth WT Jr, Manolio TA, Arnold A, Burke GL, Bryan N, Jungreis CA, et al. Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study.
Stroke 1996; 27:1274–1282.
167. Vermeer SE, Longstreth WT Jr, Koudstaal PJ. Silent brain infarcts: a systematic review.
Lancet Neurol 2007; 6:611–619.
168. Iadecola C, Yaffe K, Biller J, Bratzke LC, Faraci FM, Gorelick PB, et al. American Heart Association Council on Hypertension, Council on Clinical Cardiology, Council on Cardiovascular Disease in the Young, Council on Cardiovascular and Stroke Nursing, Council on Quality of Care and Outcomes Research, Stroke CouncilImpact of hypertension on cognitive function: a scientific statement from the American Heart Association.
Hypertension 2016; 68:e67–e94.
169. Kearney-Schwartz A, Rossignol P, Bracard S, Felblinger J, Fay R, Boivin JM, et al. Vascular structure and function is correlated to cognitive performance and white matter hyperintensities in older hypertensive patients with subjective memory complaints.
Stroke 2009; 40:1229–1236.
170. Tsoi KK, Chan JY, Hirai HW, Wong SY, Kwok TC. Cognitive tests to detect dementia: a systematic review and meta-analysis.
JAMA Intern Med 2015; 175:1450–1458.
171. Kato Y, Suzuki S, Uejima T, Semba H, Yamashita T. Variable prognostic value of blood pressure response to exercise.
J Cardiol 2018; 71:31–35.
172. Bang CN, Devereux RB, Okin PM. Regression of electrocardiographic left ventricular hypertrophy or strain is associated with lower incidence of cardiovascular morbidity and mortality in hypertensive patients independent of blood pressure reduction – A LIFE review.
J Electrocardiol 2014; 47:630–635.
173. Fagard RH, Celis H, Thijs L, Wouters S. Regression of left ventricular mass by antihypertensive treatment: a meta-analysis of randomized comparative studies.
Hypertension 2009; 54:1084–1091.
174. Ibsen H, Olsen MH, Wachtell K, Borch-Johnsen K, Lindholm LH, Mogensen CE, et al. Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study.
Hypertension 2005; 45:198–202.
175. Bakris GL, Sarafidis PA, Weir MR, Dahlof B, Pitt B, Jamerson K, et al. ACCOMPLISH Trial InvestigatorsRenal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial.
Lancet 2010; 375:1173–1181.
176. Haller H, Ito S, Izzo JL Jr, Januszewicz A, Katayama S, Menne J, et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes.
N Engl J Med 2011; 364:907–917.
177. Holtkamp FA, de Zeeuw D, de Graeff PA, Laverman GD, Berl T, Remuzzi G, et al. Albuminuria and blood pressure, independent targets for cardioprotective therapy in patients with diabetes and nephropathy: a post hoc analysis of the combined RENAAL and IDNT trials.
Eur Heart J 2011; 32:1493–1499.
178. Inker LA, Levey AS, Pandya K, Stoycheff N, Okparavero A, Greene T. Early change in proteinuria as a surrogate end point for kidney disease progression: an individual patient meta-analysis.
Am J Kidney Dis 2014; 64:74–85.
179. de Galan BE, Perkovic V, Ninomiya T, Pillai A, Patel A, Cass A, et al. Lowering blood pressure reduces renal events in type 2 diabetes.
J Am Soc Nephrol 2009; 20:883–892.
180. Ninomiya T, Perkovic V, de Galan BE, Zoungas S, Pillai A, Jardine M, et al. ADVANCE Collaborative GroupAlbuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes.
J Am Soc Nephrol 2009; 20:1813–1821.
181. Chowdhury EK, Langham RG, Ademi Z, Owen A, Krum H, Wing LM, et al. Rate of change in renal function and mortality in elderly treated hypertensive patients.
Clin J Am Soc Nephrol 2015; 10:1154–1161.
182. Matsushita K, Selvin E, Bash LD, Franceschini N, Astor BC, Coresh J. Change in estimated GFR associates with coronary heart disease and mortality.
J Am Soc Nephrol 2009; 20:2617–2624.
183. Costanzo P, Perrone-Filardi P, Vassallo E, Paolillo S, Cesarano P, Brevetti G, Chiariello M. Does carotid intima-media thickness regression predict reduction of cardiovascular events? A meta-analysis of 41 randomized trials.
J Am Coll Cardiol 2010; 56:2006–2020.
184. Wang JG, Staessen JA, Li Y, Van Bortel LM, Nawrot T, Fagard R, et al. Carotid intima-media thickness and antihypertensive treatment: a meta-analysis of randomized controlled trials.
Stroke 2006; 37:1933–1940.
185. Izzo R, Losi MA, Stabile E, Lonnebakken MT, Canciello G, Esposito G, et al. Development of left ventricular hypertrophy in treated hypertensive outpatients: the Campania Salute Network.
Hypertension 2017; 69:136–142.
186. Schmieder RE, Mann JF, Schumacher H, Gao P, Mancia G, Weber MA, et al. ONTARGET InvestigatorsChanges in albuminuria predict mortality and morbidity in patients with vascular disease.
J Am Soc Nephrol 2011; 22:1353–1364.
187. Verdecchia P, Dagenais G, Healey J, Gao P, Dans AL, Chazova I, et al. Blood pressure and other determinants of new-onset atrial fibrillation in patients at high cardiovascular risk in the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease studies.
J Hypertens 2012; 30:1004–1014.
188. Criqui MH, Ninomiya JK, Wingard DL, Ji M, Fronek A. Progression of peripheral arterial disease predicts cardiovascular disease morbidity and mortality.
J Am Coll Cardiol 2008; 52:1736–1742.
189. Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients.
Hypertension 2001; 37:1236–1241.
190. Aboyans V, Ricco JB, Bartelink MEL, Bjorck M, Brodmann M, Cohnert T, et al. 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries. Endorsed by: the European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS).
Eur Heart J 2017; 39:763–816.
191. Fagard R, Brguljan J, Staessen J, Thijs L, Derom C, Thomis M, Vlietinck R. Heritability of conventional and ambulatory blood pressures. A study in twins.
Hypertension 1995; 26:919–924.
192. Luft FC. Twins in cardiovascular genetic research.
Hypertension 2001; 37:350–356.
193. Warren HR, Evangelou E, Cabrera CP, Gao H, Ren M, Mifsud B, et al. International Consortium of Blood Pressure 1000G Analyses, Bios Consortium, Lifelines Cohort Study, Understanding Society Scientific Group, CHD Exome+ Consortium, ExomeBP Consortium, T2D Genes Consortium, GoT2DGenes Consortium, Cohorts for Heart and Ageing Research in Genome Epidemiology (CHARGE), Consortium BE, International Genomics of Blood Pressure Consortium, Group UBCCBWGenome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk.
Nat Genet 2017; 49:403–415.
194. Burrello J, Monticone S, Buffolo F, Tetti M, Veglio F, Williams TA, Mulatero P. Is there a role for genomics in the management of hypertension?
Int J Mol Sci 2017; 18:1131.
195. Dominiczak A, Delles C, Padmanabhan S. Genomics and precision medicine for clinicians and scientists in hypertension.
Hypertension 2017; 69:e10–e13.
196. Zennaro MC, Boulkroun S, Fernandes-Rosa F. An update on novel mechanisms of primary aldosteronism.
J Endocrinol 2015; 224:R63–R77.
197. Favier J, Amar L, Gimenez-Roqueplo AP. Paraganglioma and phaeochromocytoma: from genetics to personalized medicine.
Nat Rev Endocrinol 2015; 11:101–111.
198. Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, et al. Endocrine SocietyPheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.
J Clin Endocrinol Metab 2014; 99:1915–1942.
199. Toledo RA, Burnichon N, Cascon A, Benn DE, Bayley JP, et al. NGS in PPGL (NGSnPPGL) Study GroupConsensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas.
Nat Rev Endocrinol 2017; 13:233–247.
200. Plouin PF, Amar L, Dekkers OM, Fassnacht M, Gimenez-Roqueplo AP, Lenders JW, et al. Guideline Working GroupEuropean Society of Endocrinology Clinical Practice Guideline for long-term follow-up of patients operated on for a phaeochromocytoma or a paraganglioma.
Eur J Endocrinol 2016; 174:G1–G10.
201. Brunstrom M, Carlberg B. Association of blood pressure lowering with mortality and cardiovascular disease across blood pressure levels: a systematic review and meta-analysis.
JAMA Intern Med 2018; 178:28–36.
202. Collins R, MacMahon S. Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease.
Br Med Bull 1994; 50:272–298.
203. Lv J, Ehteshami P, Sarnak MJ, Tighiouart H, Jun M, Ninomiya T, et al. Effects of intensive blood pressure lowering on the progression of chronic kidney disease: a systematic review and meta-analysis.
CMAJ 2013; 185:949–957.
204. Chalmers J, Woodward M, Borghi C, Manolis A, Mancia G. Strategies to meet the need for long-term data.
J Hypertens 2016; 34:1473–1479.
205. Cirillo M, Terradura-Vagnarelli O, Mancini M, Menotti A, Zanchetti A, Laurenzi M. Cohort profile: the Gubbio Population Study.
Int J Epidemiol 2014; 43:713–720.
206. Sytkowski PA, D’Agostino RB, Belanger AJ, Kannel WB. Secular trends in long-term sustained hypertension, long-term treatment, and cardiovascular mortality. The Framingham Heart Study 1950 to 1990.
Circulation 1996; 93:697–703.
207. Zoungas S, Chalmers J, Neal B, Billot L, Li Q, Hirakawa Y, et al. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes.
N Engl J Med 2014; 371:1392–1406.
208. Kjeldsen S, Feldman RD, Lisheng L, Mourad JJ, Chiang CE, Zhang W, et al. Updated national and international hypertension guidelines: a review of current recommendations.
Drugs 2014; 74:2033–2051.
209. Diao D, Wright JM, Cundiff DK, Gueyffier F. Pharmacotherapy for mild hypertension.
Cochrane Database Syst Rev 2012; 8:CD006742.
210. Zanchetti A, Grassi G, Mancia G. When should antihypertensive drug treatment be initiated and to what levels should systolic blood pressure be lowered? A critical reappraisal.
J Hypertens 2009; 27:923–934.
211. Sundstrom J, Arima H, Jackson R, Turnbull F, Rahimi K, Chalmers J, et al. Blood Pressure-Lowering Treatment Trialists’ CollaborationEffects of blood pressure reduction in mild hypertension: a systematic review and meta-analysis.
Ann Intern Med 2015; 162:184–191.
212. Lonn EM, Bosch J, Lopez-Jaramillo P, Zhu J, Liu L, Pais P, et al. HOPE-3 InvestigatorsBlood-pressure lowering in intermediate-risk persons without cardiovascular disease.
N Engl J Med 2016; 374:2009–2020.
213. Beckett N, Peters R, Leonetti G, Duggan J, Fagard R, Thijs L, et al. HYVET Study GroupSubgroup and per-protocol analyses from the Hypertension in the Very Elderly Trial.
J Hypertens 2014; 32:1478–1487.
214. Benetos A, Bulpitt CJ, Petrovic M, Ungar A, Agabiti Rosei E, Cherubini A, et al. An expert opinion from the European Society of Hypertension-European Union Geriatric Medicine Society Working Group on the management of hypertension in very old, frail subjects.
Hypertension 2016; 67:820–825.
215. Williamson JD, Supiano MA, Applegate WB, Berlowitz DR, Campbell RC, Chertow GM, et al. SPRINT Research GroupIntensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trial.
JAMA 2016; 315:2673–2682.
216. Carlberg B. What do we know about the risks of stopping antihypertensive treatment?
J Hypertens 2014; 32:1400–1401.
217. Thomopoulos C, Parati G, Zanchetti A. Effects of blood-pressure-lowering treatment on outcome incidence. 12. Effects in individuals with high-normal and normal blood pressure: overview and meta-analyses of randomized trials.
J Hypertens 2017; 35:2150–2160.
218. Sundstrom J, Arima H, Woodward M, Jackson R, Karmali K, Lloyd-Jones D, et al. Blood Pressure-Lowering Treatment Trialists’ CollaborationBlood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data.
Lancet 2014; 384:591–598.
219. Lim GB. Hypertension: low sodium and DASH diet to lower blood pressure.
Nat Rev Cardiol 2018; 15:68.
220. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al. HYVET Study GroupTreatment of hypertension in patients 80 years of age or older.
N Engl J Med 2008; 358:1887–1898.
221. Mancia G, Laurent S, Agabiti Rosei E, Ambrosioni E, Burnier M, Caulfield MJ, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document.
J Hypertens 2009; 27:2121–2158.
222. Bohm M, Schumacher H, Teo KK, Lonn EM, Mahfoud F, Mann JFE, et al. Achieved blood pressure and cardiovascular outcomes in high-risk patients: results from ONTARGET and TRANSCEND trials.
Lancet 2017; 389:2226–2237.
223. Kjeldsen SE, Berge E, Bangalore S, Messerli FH, Mancia G, Holzhauer B, et al. No evidence for a J-shaped curve in treated hypertensive patients with increased cardiovascular risk: The VALUE trial.
Blood Press 2016; 25:83–92.
224. Mancia G, Kjeldsen SE, Zappe DH, Holzhauer B, Hua TA, Zanchetti A, et al. Cardiovascular outcomes at different on-treatment blood pressures in the hypertensive patients of the VALUE trial.
Eur Heart J 2016; 37:955–964.
225. Kjeldsen SE, Lund-Johansen P, Nilsson PM, Mancia G. Unattended blood pressure measurements in the systolic blood pressure intervention trial: implications for entry and achieved blood pressure values compared with other trials.
Hypertension 2016; 67:808–812.
226. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension: 7. Effects of more vs. less intensive blood pressure lowering and different achieved blood pressure levels – updated overview and meta-analyses of randomized trials.
J Hypertens 2016; 34:613–622.
227. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering treatment in hypertension: 8. Outcome reductions vs. discontinuations because of adverse drug events – meta-analyses of randomized trials.
J Hypertens 2016; 34:1451–1463.
228. Tarnow L, Rossing P, Jensen C, Hansen BV, Parving HH. Long-term renoprotective effect of nisoldipine and lisinopril in type 1 diabetic patients with diabetic nephropathy.
Diabetes Care 2000; 23:1725–1730.
229. Patel A, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, et al. ADVANCE Collaborative GroupEffects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial.
Lancet 2007; 370:829–840.
230. Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, Cutler JA, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus.
N Engl J Med 2010; 362:1575–1585.
231. Brunstrom M, Carlberg B. Effect of antihypertensive treatment at different blood pressure levels in patients with diabetes mellitus: systematic review and meta-analyses.
BMJ 2016; 352:i717.
232. Bangalore S, Kumar S, Lobach I, Messerli FH. Blood pressure targets in subjects with type 2 diabetes mellitus/impaired fasting glucose: observations from traditional and bayesian random-effects meta-analyses of randomized trials.
Circulation 2011; 123:2799–2810. 9 p following 2810.
233. Black HR, Elliott WJ, Grandits G, Grambsch P, Lucente T, White WB, et al. CONVINCE Research GroupPrincipal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial.
JAMA 2003; 289:2073–2082.
234. Steptoe A, Breeze E, Banks J, Nazroo J. Cohort profile: the English longitudinal study of ageing.
Int J Epidemiol 2013; 42:1640–1648.
235. Thomopoulos C, Parati G, Zanchetti A. Effects of blood-pressure-lowering treatment on outcome incidence in hypertension: 10 – Should blood pressure management differ in hypertensive patients with and without diabetes mellitus? Overview and meta-analyses of randomized trials.
J Hypertens 2017; 35:922–944.
236. Margolis KL, O’Connor PJ, Morgan TM, Buse JB, Cohen RM, Cushman WC, et al. Outcomes of combined cardiovascular risk factor management strategies in type 2 diabetes: the ACCORD randomized trial.
Diabetes Care 2014; 37:1721–1728.
237. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group.
Lancet 1998; 351:1755–1762.
238. UK Prospective Diabetes Study GroupTight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38.
BMJ 1998; 317:703–713.
239. Mancia G, Messerli F, Bakris G, Zhou Q, Champion A, Pepine CJ. Blood pressure control and improved cardiovascular outcomes in the International Verapamil SR-Trandolapril Study.
Hypertension 2007; 50:299–305.
240. Rothwell PM, Howard SC, Dolan E, O’Brien E, Dobson JE, Dahlof B, et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension.
Lancet 2010; 375:895–905.
241. Mancia G, Schumacher H, Bohm M, Redon J, Schmieder RE, Verdecchia P, et al. Relative and combined prognostic importance of on-treatment mean and visit-to-visit blood pressure variability in ONTARGET and TRANSCEND patients.
Hypertension 2017; 70:938–948.
242. Parati G, Ochoa JE, Bilo G, Zanchetti A. SPRINT blood pressure: sprinting back to Smirk's basal blood pressure?
Hypertension 2017; 69:15–19.
243. Mancia G, Parati G, Bilo G, Gao P, Fagard R, Redon J, et al. Ambulatory blood pressure values in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET).
Hypertension 2012; 60:1400–1406.
244. Odden MC, McClure LA, Sawaya BP, White CL, Peralta CA, Field TS, et al. Achieved blood pressure and outcomes in the Secondary Prevention of Small Subcortical Strokes Trial.
Hypertension 2016; 67:63–69.
245. Stevens VJ, Obarzanek E, Cook NR, Lee IM, Appel LJ, Smith West D, et al. Trials for the Hypertension Prevention Research GLong-term weight loss and changes in blood pressure: results of the Trials of Hypertension Prevention, phase II.
Ann Intern Med 2001; 134:1–11.
246. Whelton PK, Appel LJ, Espeland MA, Applegate WB, Ettinger WH Jr, Kostis JB, et al. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). TONE Collaborative Research Group.
JAMA 1998; 279:839–846.
247. Elliott P, Stamler J, Nichols R, Dyer AR, Stamler R, Kesteloot H, Marmot M. Intersalt revisited: further analyses of 24 h sodium excretion and blood pressure within and across populations. Intersalt Cooperative Research Group.
BMJ 1996; 312:1249–1253.
248. He FJ, Li J, Macgregor GA. Effect of longer-term modest salt reduction on blood pressure.
Cochrane Database Syst Rev 2013; 4:CD004937.
249. Suckling RJ, He FJ, Markandu ND, MacGregor GA. Modest salt reduction lowers blood pressure and albumin excretion in impaired glucose tolerance and type 2 diabetes mellitus: a randomized double-blind trial.
Hypertension 2016; 67:1189–1195.
250. Graudal NA, Hubeck-Graudal T, Jurgens G. Effects of low-sodium diet vs. high-sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride (Cochrane Review).
Am J Hypertens 2012; 25:1–15.
251. He FJ, MacGregor GA. How far should salt intake be reduced?
Hypertension 2003; 42:1093–1099.
252. Bibbins-Domingo K, Chertow GM, Coxson PG, Moran A, Lightwood JM, Pletcher MJ, Goldman L. Projected effect of dietary salt reductions on future cardiovascular disease.
N Engl J Med 2010; 362:590–599.
253. He FJ, Burnier M, Macgregor GA. Nutrition in cardiovascular disease: salt in hypertension and heart failure.
Eur Heart J 2011; 32:3073–3080.
254. He FJ, MacGregor GA. Salt reduction lowers cardiovascular risk: meta-analysis of outcome trials.
Lancet 2011; 378:380–382.
255. Taylor RS, Ashton KE, Moxham T, Hooper L, Ebrahim S. Reduced dietary salt for the prevention of cardiovascular disease: a meta-analysis of randomized controlled trials (Cochrane review).
Am J Hypertens 2011; 24:843–853.
256. Mente A, O’Donnell M, Rangarajan S, Dagenais G, Lear S, McQueen M, et al. Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension: a pooled analysis of data from four studies.
Lancet 2016; 388:465–475.
257. Binia A, Jaeger J, Hu Y, Singh A, Zimmermann D. Daily potassium intake and sodium-to-potassium ratio in the reduction of blood pressure: a meta-analysis of randomized controlled trials.
J Hypertens 2015; 33:1509–1520.
258. Aburto NJ, Ziolkovska A, Hooper L, Elliott P, Cappuccio FP, Meerpohl JJ. Effect of lower sodium intake on health: systematic review and meta-analyses.
BMJ 2013; 346:f1326.
259. O’Donnell M, Mente A, Rangarajan S, McQueen MJ, Wang X, Liu L, et al. PURE InvestigatorsUrinary sodium and potassium excretion, mortality, and cardiovascular events.
N Engl J Med 2014; 371:612–623.
260. Cushman WC, Cutler JA, Hanna E, Bingham SF, Follmann D, Harford T, et al. Prevention and Treatment of Hypertension Study (PATHS): effects of an alcohol treatment program on blood pressure.
Arch Intern Med 1998; 158:1197–1207.
261. Holmes MV, Dale CE, Zuccolo L, Silverwood RJ, Guo Y, Ye Z, et al. InterAct ConsortiumAssociation between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data.
BMJ 2014; 349:g4164.
262. Dickinson HO, Mason JM, Nicolson DJ, Campbell F, Beyer FR, Cook JV, et al. Lifestyle interventions to reduce raised blood pressure: a systematic review of randomized controlled trials.
J Hypertens 2006; 24:215–233.
263. Mente A, de Koning L, Shannon HS, Anand SS. A systematic review of the evidence supporting a causal link between dietary factors and coronary heart disease.
Arch Intern Med 2009; 169:659–669.
264. Sofi F, Abbate R, Gensini GF, Casini A. Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis.
Am J Clin Nutr 2010; 92:1189–1196.
265. Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, Aros F, et al. PREDIMED Study InvestigatorsPrimary prevention of cardiovascular disease with a Mediterranean diet.
N Engl J Med 2013; 368:1279–1290.
266. Domenech M, Roman P, Lapetra J, Garcia de la Corte FJ, Sala-Vila A, de la Torre R, et al. Mediterranean diet reduces 24-h ambulatory blood pressure, blood glucose, and lipids: one-year randomized, clinical trial.
Hypertension 2014; 64:69–76.
267. Ding M, Bhupathiraju SN, Satija A, van Dam RM, Hu FB. Long-term coffee consumption and risk of cardiovascular disease: a systematic review and a dose-response meta-analysis of prospective cohort studies.
Circulation 2014; 129:643–659.
268. Li G, Zhang Y, Thabane L, Mbuagbaw L, Liu A, Levine MA, Holbrook A. Effect of green tea supplementation on blood pressure among overweight and obese adults: a systematic review and meta-analysis.
J Hypertens 2015; 33:243–254.
269. Greyling A, Ras RT, Zock PL, Lorenz M, Hopman MT, Thijssen DH, Draijer R. The effect of black tea on blood pressure: a systematic review with meta-analysis of randomized controlled trials.
PLoS One 2014; 9:e103247.
270. Hall JE, do Carmo JM, da Silva AA, Wang Z, Hall ME. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms.
Circ Res 2015; 116:991–1006.
271. Neter JE, Stam BE, Kok FJ, Grobbee DE, Geleijnse JM. Influence of weight reduction on blood pressure: a meta-analysis of randomized controlled trials.
Hypertension 2003; 42:878–884.
272. Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, Halsey J, et al. Prospective Studies CollaborationBody-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies.
Lancet 2009; 373:1083–1096.
273. Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis.
JAMA 2013; 309:71–82.
274. Di Angelantonio E, Bhupathiraju Sh N, Wormser D, Gao P, Kaptoge S, Berrington de Gonzalez A, et al. Global BMI Mortality CollaborationBody-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents.
Lancet 2016; 388:776–786.
275. Jebb SA, Ahern AL, Olson AD, Aston LM, Holzapfel C, Stoll J, et al. Primary care referral to a commercial provider for weight loss treatment versus standard care: a randomised controlled trial.
Lancet 2011; 378:1485–1492.
276. Jordan J, Yumuk V, Schlaich M, Nilsson PM, Zahorska-Markiewicz B, Grassi G, et al. Joint statement of the European Association for the Study of Obesity and the European Society of Hypertension: obesity and difficult to treat arterial hypertension.
J Hypertens 2012; 30:1047–1055.
277. Cornelissen VA, Smart NA. Exercise training for blood pressure: a systematic review and meta-analysis.
J Am Heart Assoc 2013; 2:e004473.
278. Leitzmann MF, Park Y, Blair A, Ballard-Barbash R, Mouw T, Hollenbeck AR, Schatzkin A. Physical activity recommendations and decreased risk of mortality.
Arch Intern Med 2007; 167:2453–2460.
279. Rossi A, Dikareva A, Bacon SL, Daskalopoulou SS. The impact of physical activity on mortality in patients with high blood pressure: a systematic review.
J Hypertens 2012; 30:1277–1288.
280. Mann SJ, James GD, Wang RS, Pickering TG. Elevation of ambulatory systolic blood pressure in hypertensive smokers. A case-control study.
JAMA 1991; 265:2226–2228.
281. Kotseva K, Wood D, De Bacquer D, De Backer G, Ryden L, Jennings C, et al. EUROASPIRE IV: A European Society of Cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 European countries.
Eur J Prev Cardiol 2016; 23:636–648.
282. Yarlioglues M, Kaya MG, Ardic I, Calapkorur B, Dogdu O, Akpek M, et al. Acute effects of passive smoking on blood pressure and heart rate in healthy females.
Blood Press Monit 2010; 15:251–256.
283. Groppelli A, Giorgi DM, Omboni S, Parati G, Mancia G. Persistent blood pressure increase induced by heavy smoking.
J Hypertens 1992; 10:495–499.
284. Primatesta P, Falaschetti E, Gupta S, Marmot MG, Poulter NR. Association between smoking and blood pressure: evidence from the health survey for England.
Hypertension 2001; 37:187–193.
285. Doll R, Peto R, Wheatley K, Gray R, Sutherland I. Mortality in relation to smoking: 40 years’ observations on male British doctors.
BMJ 1994; 309:901–911.
286. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010.
Lancet 2012; 380:2224–2260.
287. Stead LF, Buitrago D, Preciado N, Sanchez G, Hartmann-Boyce J, Lancaster T. Physician advice for smoking cessation.
Cochrane Database Syst Rev 2013; 5:CD000165.
288. Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis.
Cochrane Database Syst Rev 2013; 5:CD009329.
289. Stead LF, Koilpillai P, Fanshawe TR, Lancaster T. Combined pharmacotherapy and behavioural interventions for smoking cessation.
Cochrane Database Syst Rev 2016; 3:CD008286.
290. Berrington de Gonzalez A, Hartge P, Cerhan JR, Flint AJ, Hannan L, MacInnis RJ, et al. Body-mass index and mortality among 1.46 million white adults.
N Engl J Med 2010; 363:2211–2219.
291. Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, et al. ALTITUDE InvestigatorsCardiorenal end points in a trial of aliskiren for type 2 diabetes.
N Engl J Med 2012; 367:2204–2213.
292. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure-lowering on outcome incidence in hypertension: 5. Head-to-head comparisons of various classes of antihypertensive drugs – overview and meta-analyses.
J Hypertens 2015; 33:1321–1341.
293. Corrao G, Zambon A, Parodi A, Poluzzi E, Baldi I, Merlino L, et al. Discontinuation of and changes in drug therapy for hypertension among newly-treated patients: a population-based study in Italy.
J Hypertens 2008; 26:819–824.
294. Thomopoulos C, Parati G, Zanchetti A. Effects of blood-pressure-lowering treatment in hypertension: 9. Discontinuations for adverse events attributed to different classes of antihypertensive drugs: meta-analyses of randomized trials.
J Hypertens 2016; 34:1921–1932.
295. Volpe M, Mancia G, Trimarco B. Angiotensin II receptor blockers and myocardial infarction: deeds and misdeeds.
J Hypertens 2005; 23:2113–2118.
296. Reboldi G, Angeli F, Cavallini C, Gentile G, Mancia G, Verdecchia P. Comparison between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk of myocardial infarction, stroke and death: a meta-analysis.
J Hypertens 2008; 26:1282–1289.
297. Kronish IM, Woodward M, Sergie Z, Ogedegbe G, Falzon L, Mann DM. Meta-analysis: impact of drug class on adherence to antihypertensives.
Circulation 2011; 123:1611–1621.
298. Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, et al. VA NEPHRON-D InvestigatorsCombined angiotensin inhibition for the treatment of diabetic nephropathy.
N Engl J Med 2013; 369:1892–1903.
299. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al. ONTARGET InvestigatorsTelmisartan, ramipril, or both in patients at high risk for vascular events.
N Engl J Med 2008; 358:1547–1559.
300. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension: 4. Effects of various classes of antihypertensive drugs – overview and meta-analyses.
J Hypertens 2015; 33:195–211.
301. Roush GC, Ernst ME, Kostis JB, Tandon S, Sica DA. Head-to-head comparisons of hydrochlorothiazide with indapamide and chlorthalidone: antihypertensive and metabolic effects.
Hypertension 2015; 65:1041–1046.
302. Olde Engberink RH, Frenkel WJ, van den Bogaard B, Brewster LM, Vogt L, van den Born BJ. Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality: systematic review and meta-analysis.
Hypertension 2015; 65:1033–1040.
303. Zanchetti A, Mancia G. Strategies for antihypertensive treatment decisions: how to assess benefits?
J Hypertens 1997; 15:215–216.
304. Zillich AJ, Garg J, Basu S, Bakris GL, Carter BL. Thiazide diuretics, potassium, and the development of diabetes: a quantitative review.
Hypertension 2006; 48:219–224.
305. Brown MJ, Williams B, Morant SV, Webb DJ, Caulfield MJ, Cruickshank JK, et al. Effect of amiloride, or amiloride plus hydrochlorothiazide, versus hydrochlorothiazide on glucose tolerance and blood pressure (PATHWAY-3): a parallel-group, double-blind randomised phase 4 trial.
Lancet Diabetes Endocrinol 2016; 4:136–147.
306. Dondo TB, Hall M, West RM, Jernberg T, Lindahl B, Bueno H, et al. Beta-blockers and mortality after acute myocardial infarction in patients without heart failure or ventricular dysfunction.
J Am Coll Cardiol 2017; 69:2710–2720.
307. Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli FH, Phillips RA, et al. GEMINI InvestigatorsMetabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial.
JAMA 2004; 292:2227–2236.
308. Ayers K, Byrne LM, DeMatteo A, Brown NJ. Differential effects of nebivolol and metoprolol on insulin sensitivity and plasminogen activator inhibitor in the metabolic syndrome.
Hypertension 2012; 59:893–898.
309. Chapman N, Chang CL, Dahlof B, Sever PS, Wedel H, Poulter NR. Effect of doxazosin gastrointestinal therapeutic system as third-line antihypertensive therapy on blood pressure and lipids in the Anglo-Scandinavian Cardiac Outcomes Trial.
Circulation 2008; 118:42–48.
310. Williams B, MacDonald TM, Morant S, Webb DJ, Sever P, McInnes G, et al. British Hypertension Society's PATHWAY Studies GroupSpironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial.
Lancet 2015; 386:2059–2068.
311. Wang YR, Alexander GC, Stafford RS. Outpatient hypertension treatment, treatment intensification, and control in Western Europe and the United States.
Arch Intern Med 2007; 167:141–147.
312. Corrao G, Parodi A, Nicotra F, Zambon A, Merlino L, Cesana G, Mancia G. Better compliance to antihypertensive medications reduces cardiovascular risk.
J Hypertens 2011; 29:610–618.
313. Tiffe T, Wagner M, Rucker V, Morbach C, Gelbrich G, Stork S, Heuschmann PU. Control of cardiovascular risk factors and its determinants in the general population – findings from the STAAB cohort study.
BMC Cardiovasc Disord 2017; 17:276.
314. Mensah GA, Bakris G. Treatment and control of high blood pressure in adults.
Cardiol Clin 2010; 28:609–622.
315. Gupta P, Patel P, Strauch B, Lai FY, Akbarov A, Gulsin GS, et al. Biochemical screening for nonadherence is associated with blood pressure reduction and improvement in adherence.
Hypertension 2017; 70:1042–1048.
316. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research GroupMajor outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
JAMA 2002; 288:2981–2997.
317. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al. LIFE Study GroupCardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol.
Lancet 2002; 359:995–1003.
318. Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al. ASCOT InvestigatorsPrevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial.
Lancet 2005; 366:895–906.
319. McKavanagh P, Lusk L, Ball PA, Verghis RM, Agus AM, Trinick TR, et al. A comparison of cardiac computerized tomography and exercise stress electrocardiogram test for the investigation of stable chest pain: the clinical results of the CAPP randomized prospective trial.
Eur Heart J Cardiovasc Imaging 2015; 16:441–448.
320. Hedner T. Progress report on the Nordic diltiazem study (NORDIL): an outcome study in hypertensive patients.
Blood Press 1999; 8:296–299.
321. Elgendy IY, Bavry AA, Gong Y, Handberg EM, Cooper-DeHoff RM, Pepine CJ. Long-term mortality in hypertensive patients with coronary artery disease: results from the US cohort of the International Verapamil (SR)/Trandolapril Study.
Hypertension 2016; 68:1110–1114.
322. Coope J, Warrender TS. Randomised trial of treatment of hypertension in elderly patients in primary care.
Br Med J (Clin Res Ed) 1986; 293:1145–1151.
323. SHEP Cooperative Research GroupPrevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP).
JAMA 1991; 265:3255–3264.
324. Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension).
Lancet 1991; 338:1281–1285.
325. Mancia G, Grassi G, Zanchetti A. New-onset diabetes and antihypertensive drugs.
J Hypertens 2006; 24:3–10.
326. Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia G, Rosenthal T, Ruilope LM. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT).
Lancet 2000; 356:366–372.
327. Jamerson K, Weber MA, Bakris GL, Dahlof B, Pitt B, Shi V, et al. ACCOMPLISH Trial InvestigatorsBenazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients.
N Engl J Med 2008; 359:2417–2428.
328. Ogihara T, Saruta T, Rakugi H, Saito I, Shimamoto K, Matsuoka H, et al. COLM InvestigatorsCombination therapy of hypertension in the elderly: a subgroup analysis of the Combination of OLMesartan and a calcium channel blocker or diuretic in Japanese elderly hypertensive patients trial.
Hypertens Res 2015; 38:89–96.
329. Matsuzaki M, Ogihara T, Umemoto S, Rakugi H, Matsuoka H, Shimada K, et al. Combination Therapy of Hypertension to Prevent Cardiovascular Events Trial GroupPrevention of cardiovascular events with calcium channel blocker-based combination therapies in patients with hypertension: a randomized controlled trial.
J Hypertens 2011; 29:1649–1659.
330. Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, et al. Group SSThe Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial.
J Hypertens 2003; 21:875–886.
331. Liu L, Zhang Y, Liu G, Li W, Zhang X, Zanchetti A, Group FS. The Felodipine Event Reduction (FEVER) Study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients.
J Hypertens 2005; 23:2157–2172.
332. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators.
Lancet 1997; 350:757–764.
333. Wang JG, Staessen JA, Gong L, Liu L. Chinese trial on isolated systolic hypertension in the elderly. Systolic Hypertension in China (Syst-China) Collaborative Group.
Arch Intern Med 2000; 160:211–220.
334. Hansson L, Lindholm LH, Ekbom T, Dahlof B, Lanke J, Schersten B, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study.
Lancet 1999; 354:1751–1756.
335. Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial.
Lancet 1999; 353:611–616.
336. Zanchetti A, Hennig M, Baurecht H, Tang R, Cuspidi C, Carugo S, Mancia G. Prevalence and incidence of the metabolic syndrome in the European Lacidipine Study on Atherosclerosis (ELSA) and its relation with carotid intima-media thickness.
J Hypertens 2007; 25:2463–2470.
337. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al. VALUE trial groupOutcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial.
Lancet 2004; 363:2022–2031.
338. PROGRESS Collaborative GroupRandomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack.
Lancet 2001; 358:1033–1041.
339. Hansson L, Hedner T, Lund-Johansen P, Kjeldsen SE, Lindholm LH, Syvertsen JO, et al. Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study.
Lancet 2000; 356:359–365.
340. Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli FH, et al. Investigators IA calcium antagonist vs a noncalcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial.
JAMA 2003; 290:2805–2816.
341. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials.
Am J Med 2009; 122:290–300.
342. MacDonald TM, Williams B, Webb DJ, Morant S, Caulfield M, Cruickshank JK, et al. British Hypertension Society Programme of Prevention And Treatment of Hypertension With Algorithm-based Therapy (PATHWAY)Combination therapy is superior to sequential monotherapy for the initial treatment of hypertension: a double-blind randomized controlled trial.
J Am Heart Assoc 2017; 6:e006986.
343. Yusuf S, Lonn E, Pais P, Bosch J, Lopez-Jaramillo P, Zhu J, et al. HOPE-3 InvestigatorsBlood-pressure and cholesterol lowering in persons without cardiovascular disease.
N Engl J Med 2016; 374:2032–2043.
344. Xu W, Goldberg SI, Shubina M, Turchin A. Optimal systolic blood pressure target, time to intensification, and time to follow-up in treatment of hypertension: population based retrospective cohort study.
BMJ 2015; 350:h158.
345. Egan BM, Bandyopadhyay D, Shaftman SR, Wagner CS, Zhao Y, Yu-Isenberg KS. Initial monotherapy and combination therapy and hypertension control the first year.
Hypertension 2012; 59:1124–1131.
346. Corrao G, Parodi A, Zambon A, Heiman F, Filippi A, Cricelli C, et al. Reduced discontinuation of antihypertensive treatment by two-drug combination as first step. Evidence from daily life practice.
J Hypertens 2010; 28:1584–1590.
347. Conn VS, Ruppar TM, Chase JA, Enriquez M, Cooper PS. Interventions to improve medication adherence in hypertensive patients: systematic review and meta-analysis.
Curr Hypertens Rep 2015; 17:94.
348. Mancia G, Rea F, Cuspidi C, Grassi G, Corrao G. Blood pressure control in hypertension. Pros and cons of available treatment strategies.
J Hypertens 2017; 35:225–233.
349. Weir MR, Hsueh WA, Nesbitt SD, Littlejohn TJ III, Graff A, Shojaee A, et al. A titrate-to-goal study of switching patients uncontrolled on antihypertensive monotherapy to fixed-dose combinations of amlodipine and olmesartan medoxomil ± hydrochlorothiazide.
J Clin Hypertens (Greenwich) 2011; 13:404–412.
350. Volpe M, Christian Rump L, Ammentorp B, Laeis P. Efficacy and safety of triple antihypertensive therapy with the olmesartan/amlodipine/hydrochlorothiazide combination.
Clin Drug Investig 2012; 32:649–664.
351. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis.
Hypertension 2010; 55:399–407.
352. Jung O, Gechter JL, Wunder C, Paulke A, Bartel C, Geiger H, Toennes SW. Resistant hypertension? Assessment of adherence by toxicological urine analysis.
J Hypertens 2013; 31:766–774.
353. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC).
Eur Heart J 2018; 39:119–177.
354. Gupta P, Patel P, Horne R, Buchanan H, Williams B, Tomaszewski M. How to screen for nonadherence to antihypertensive therapy.
Curr Hypertens Rep 2016; 18:89.
355. Coca A, Agabiti Rosei E, Cifkova R, Manolis AJ, Redon J, Mancia G. The polypill in cardiovascular prevention: evidence, limitations and perspective – position paper of the European Society of Hypertension.
J Hypertens 2017; 35:1546–1553.
356. Castellano JM, Sanz G, Penalvo JL, Bansilal S, Fernandez-Ortiz A, Alvarez L, et al. A polypill strategy to improve adherence: results from the FOCUS project.
J Am Coll Cardiol 2014; 64:2071–2082.
357. Williams B, MacDonald TM, Morant SV, Webb DJ, Sever P, McInnes GT, et al. ritish Hypertension Society programme of Prevention And Treatment of Hypertension With Algorithm based Therapy (PATHWAY) Study GroupEndocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies.
Lancet Diabetes Endocrinol 2018; 6:464–475.
358. Bisognano JD, Bakris G, Nadim MK, Sanchez L, Kroon AA, Schafer J, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial.
J Am Coll Cardiol 2011; 58:765–773.
359. Wachter R, Halbach M, Bakris GL, Bisognano JD, Haller H, Beige J, et al. An exploratory propensity score matched comparison of second-generation and first-generation baroreflex activation therapy systems.
J Am Soc Hypertens 2017; 11:81–91.
360. Spiering W, Williams B, Van der Heyden J, van Kleef M, Lo R, Versmissen J, et al. CALM-FIM_EUR InvestigatorsEndovascular baroreflex amplification for resistant hypertension: a safety and proof-of-principle clinical study.
Lancet 2017; 390:2655–2661.
361. DiBona GF. Physiology in perspective: the wisdom of the body. Neural control of the kidney.
Am J Physiol Regul Integr Comp Physiol 2005; 289:R633–R641.
362. Esler M. Sympathetic nervous system moves toward center stage in cardiovascular medicine: from Thomas Willis to resistant hypertension.
Hypertension 2014; 63:e25–e32.
363. Mahfoud F, Bohm M, Azizi M, Pathak A, Durand Zaleski I, Ewen S, et al. Proceedings from the European Clinical Consensus Conference for Renal Denervation: considerations on future clinical trial design.
Eur Heart J 2015; 36:2219–2227.
364. Bohm M, Mahfoud F, Ukena C, Hoppe UC, Narkiewicz K, Negoita M, et al. GSR InvestigatorsFirst report of the Global SYMPLICITY Registry on the effect of renal artery denervation in patients with uncontrolled hypertension.
Hypertension 2015; 65:766–774.
365. Krum H, Schlaich MP, Sobotka PA, Bohm M, Mahfoud F, Rocha-Singh K, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study.
Lancet 2014; 383:622–629.
366. Townsend RR, Mahfoud F, Kandzari DE, Kario K, Pocock S, Weber MA, et al. Spyral HTN-OFF Med trial investigatorsCatheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial.
Lancet 2017; 390:2160–2170.
367. Bhatt DL, Kandzari DE, O’Neill WW, D’Agostino R, Flack JM, Katzen BT, et al. for the Symplicity HTN-3 InvestigatorsA controlled trial of renal denervation for resistant hypertension.
N Engl J Med 2014; 370:1393–1401.
368. Mathiassen ON, Vase H, Bech JN, Christensen KL, Buus NH, Schroeder AP, et al. Renal denervation in treatment-resistant essential hypertension.
A randomized, SHAM-controlled, double-blinded 24-h blood pressure-based trial J Hypertens 2016; 34:1639–1647.
369. Azizi M, Sapoval M, Gosse P, Monge M, Bobrie G, Delsart P, et al. DENERHTN InvestigatorsOptimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial.
Lancet 2015; 385:1957–1965.
370. Rosa J, Widimsky P, Tousek P, Petrak O, Curila K, Waldauf P, et al. Randomized comparison of renal denervation versus intensified pharmacotherapy including spironolactone in true-resistant hypertension: six-month results from the Prague-15 study.
Hypertension 2015; 65:407–413.
371. Mahfoud F, Schmieder RE, Azizi M, Pathak A, Sievert H, Tsioufis C, et al. Proceedings from the 2nd European Clinical Consensus Conference for device-based therapies for hypertension: state of the art and considerations for the future.
Eur Heart J 2017; 38:3272–3281.
372. Ewen S, Ukena C, Linz D, Kindermann I, Cremers B, Laufs U, et al. Reduced effect of percutaneous renal denervation on blood pressure in patients with isolated systolic hypertension.
Hypertension 2015; 65:193–199.
373. Mahfoud F, Bakris G, Bhatt DL, Esler M, Ewen S, Fahy M, et al. Reduced blood pressure-lowering effect of catheter-based renal denervation in patients with isolated systolic hypertension: data from SYMPLICITY HTN-3 and the Global SYMPLICITY Registry.
Eur Heart J 2017; 38:93–100.
374. Burchell AE, Lobo MD, Sulke N, Sobotka PA, Paton JF. Arteriovenous anastomosis: is this the way to control hypertension?
Hypertension 2014; 64:6–12.
375. Ng FL, Saxena M, Mahfoud F, Pathak A, Lobo MD. Device-based therapy for hypertension.
Curr Hypertens Rep 2016; 18:61.
376. Faul J, Schoors D, Brouwers S, Scott B, Jerrentrup A, Galvin J, et al. Creation of an iliac arteriovenous shunt lowers blood pressure in chronic obstructive pulmonary disease patients with hypertension.
J Vasc Surg 2014; 59:1078–1083.
377. Lobo MD, Sobotka PA, Stanton A, Cockcroft JR, Sulke N, Dolan E, et al. ROX CONTROL HTN InvestigatorsCentral arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN study): a randomised controlled trial.
Lancet 2015; 385:1634–1641.
378. Ott C, Lobo MD, Sobotka PA, Mahfoud F, Stanton A, Cockcroft J, et al. Effect of arteriovenous anastomosis on blood pressure reduction in patients with isolated systolic hypertension compared with combined hypertension.
J Am Heart Assoc 2016; 5:e004234.
379. McBryde FD, Abdala AP, Hendy EB, Pijacka W, Marvar P, Moraes DJ, et al. The carotid body as a putative therapeutic target for the treatment of neurogenic hypertension.
Nat Commun 2013; 4:2395.
380. Narkiewicz K, Ratcliffe LE, Hart EC, Briant LJ, Chrostowska M, Wolf J, et al. Unilateral carotid body resection in resistant hypertension: a safety and feasibility trial.
JACC Basic Transl Sci 2016; 1:313–324.
381. Niewinski P, Janczak D, Rucinski A, Tubek S, Engelman ZJ, Piesiak P, et al. Carotid body resection for sympathetic modulation in systolic heart failure: results from first-in-man study.
Eur J Heart Fail 2017; 19:391–400.
382. Daugherty SL, Powers JD, Magid DJ, Tavel HM, Masoudi FA, Margolis KL, et al. Incidence and prognosis of resistant hypertension in hypertensive patients.
Circulation 2012; 125:1635–1642.
383. Myat A, Redwood SR, Qureshi AC, Spertus JA, Williams B. Resistant hypertension.
BMJ 2012; 345:e7473.
384. de la Sierra A, Banegas JR, Segura J, Gorostidi M, Ruilope LM. Ambulatory blood pressure monitoring and development of cardiovascular events in high-risk patients included in the Spanish ABPM registry: the CARDIORISC Event study.
J Hypertens 2012; 30:713–719.
385. Williams B. Resistant hypertension: an unmet treatment need.
Lancet 2009; 374:1396–1398.
386. Mantero F, Mattarello MJ, Albiger NM. Detecting and treating primary aldosteronism: primary aldosteronism.
Exp Clin Endocrinol Diabetes 2007; 115:171–174.
387. Fagard RH. Resistant hypertension.
Heart 2012; 98:254–261.
388. Laurent S, Schlaich M, Esler M. New drugs, procedures, and devices for hypertension.
Lancet 2012; 380:591–600.
389. Vrijens B, Vincze G, Kristanto P, Urquhart J, Burnier M. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories.
BMJ 2008; 336:1114–1117.
390. Bakris GL, Lindholm LH, Black HR, Krum H, Linas S, Linseman JV, et al. Divergent results using clinic and ambulatory blood pressures: report of a darusentan-resistant hypertension trial.
Hypertension 2010; 56:824–830.
391. Oxlund CS, Henriksen JE, Tarnow L, Schousboe K, Gram J, Jacobsen IA. Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial.
J Hypertens 2013; 31:2094–2102.
392. Liu L, Xu B, Ju Y. Addition of spironolactone in patients with resistant hypertension: a meta-analysis of randomized controlled trials.
Clin Exp Hypertens 2017; 39:257–263.
393. Zhao D, Liu H, Dong P, Zhao J. A meta-analysis of add-on use of spironolactone in patients with resistant hypertension.
Int J Cardiol 2017; 233:113–117.
394. Wang C, Xiong B, Huang J. Efficacy and safety of spironolactone in patients with resistant hypertension: a meta-analysis of randomised controlled trials.
Heart Lung Circ 2016; 25:1021–1030.
395. Pimenta E, Gaddam KK, Oparil S, Aban I, Husain S, Dell’Italia LJ, Calhoun DA. Effects of dietary sodium reduction on blood pressure in subjects with resistant hypertension: results from a randomized trial.
Hypertension 2009; 54:475–481.
396. Rimoldi SF, Scherrer U, Messerli FH. Secondary arterial hypertension: when, who, and how to screen?
Eur Heart J 2014; 35:1245–1254.
397. Grossman A, Messerli FH, Grossman E. Drug induced hypertension-An unappreciated cause of secondary hypertension.
Eur J Pharmacol 2015; 763:15–22.
398. van den Born BJ, et al. ESC Council on hypertension position document on the management of hypertensive emergencies.
Eur Heart J Cardiovasc Pharmacother 2018; Aug 25. doi: 10.1093/ehjcvp/pvy032. [Epub ahead of print].
399. Vaughan CJ, Delanty N. Hypertensive emergencies.
Lancet 2000; 356:411–417.
400. Chester EM, Agamanolis DP, Banker BQ, Victor M. Hypertensive encephalopathy: a clinicopathologic study of 20 cases.
Neurology 1978; 28:928–939.
401. van den Born BJ, Koopmans RP, Groeneveld JO, van Montfrans GA. Ethnic disparities in the incidence, presentation and complications of malignant hypertension.
J Hypertens 2006; 24:2299–2304.
402. Cremer A, Amraoui F, Lip GY, Morales E, Rubin S, Segura J, et al. From malignant hypertension to hypertension-MOD: a modern definition for an old but still dangerous emergency.
J Hum Hypertens 2016; 30:463–466.
403. Pinna G, Pascale C, Fornengo P, Arras S, Piras C, Panzarasa P, et al. Hospital admissions for hypertensive crisis in the emergency departments: a large multicenter Italian study.
PLoS One 2014; 9:e93542.
404. van den Born BJ, Lowenberg EC, van der Hoeven NV, de Laat B, Meijers JC, Levi M, van Montfrans GA. Endothelial dysfunction, platelet activation, thrombogenesis and fibrinolysis in patients with hypertensive crisis.
J Hypertens 2011; 29:922–927.
405. Grassi D, O’Flaherty M, Pellizzari M, Bendersky M, Rodriguez P, Turri D, et al. Hypertensive urgencies in the emergency department: evaluating blood pressure response to rest and to antihypertensive drugs with different profiles.
J Clin Hypertens (Greenwich) 2008; 10:662–667.
406. Perez MI, Musini VM. Pharmacological interventions for hypertensive emergencies: a Cochrane systematic review.
J Hum Hypertens 2008; 22:596–607.
407. Lane DA, Lip GY, Beevers DG. Improving survival of malignant hypertension patients over 40 years.
Am J Hypertens 2009; 22:1199–1204.
408. Amraoui F, Van Der Hoeven NV, Van Valkengoed IG, Vogt L, Van Den Born BJ. Mortality and cardiovascular risk in patients with a history of malignant hypertension: a case-control study.
J Clin Hypertens (Greenwich) 2014; 16:122–126.
409. Gonzalez R, Morales E, Segura J, Ruilope LM, Praga M. Long-term renal survival in malignant hypertension.
Nephrol Dial Transplant 2010; 25:3266–3272.
410. Cuspidi C, Rescaldani M, Tadic M, Sala C, Grassi G, Mancia G. White-coat hypertension, as defined by ambulatory blood pressure monitoring, and subclinical cardiac organ damage: a meta-analysis.
J Hypertens 2015; 33:24–32.
411. Mancia G, Bombelli M, Facchetti R, Madotto F, Quarti-Trevano F, Grassi G, Sega R. Increased long-term risk of new-onset diabetes mellitus in white-coat and masked hypertension.
J Hypertens 2009; 27:1672–1678.
412. Tientcheu D, Ayers C, Das SR, McGuire DK, de Lemos JA, Khera A, et al. Target organ complications and cardiovascular events associated with masked hypertension and white-coat hypertension: analysis from the Dallas Heart Study.
J Am Coll Cardiol 2015; 66:2159–2169.
413. Fagard RH, Staessen JA, Thijs L, Gasowski J, Bulpitt CJ, Clement D, et al. Response to antihypertensive therapy in older patients with sustained and nonsustained systolic hypertension. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators.
Circulation 2000; 102:1139–1144.
414. Mancia G, Facchetti R, Parati G, Zanchetti A. Effect of long-term antihypertensive treatment on white-coat hypertension.
Hypertension 2014; 64:1388–1398.
415. Staessen JA, Celis H, Thijs L, Fagard R, Amery AK. Efficacy of antihypertensive drugs given once a day: the calcium antagonists revisited.
J Hypertens Suppl 1994; 12:S107–S115.
416. Bulpitt CJ, Beckett NS, Peters R, Leonetti G, Gergova V, Fagard R, et al. Blood pressure control in the Hypertension in the Very Elderly Trial (HYVET).
J Hum Hypertens 2012; 26:157–163.
417. Franklin SS, Thijs L, Asayama K, Li Y, Hansen TW, Boggia J, et al. IDACO InvestigatorsThe cardiovascular risk of white-coat hypertension.
J Am Coll Cardiol 2016; 68:2033–2043.
418. Franklin SS, Thijs L, Hansen TW, Li Y, Boggia J, Kikuya M, et al. International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes InvestigatorsSignificance of white-coat hypertension in older persons with isolated systolic hypertension: a meta-analysis using the International Database on Ambulatory Blood Pressure Monitoring in Relation to Cardiovascular Outcomes population.
Hypertension 2012; 59:564–571.
419. Mancia G, Bombelli M, Brambilla G, Facchetti R, Sega R, Toso E, Grassi G. Long-term prognostic value of white coat hypertension: an insight from diagnostic use of both ambulatory and home blood pressure measurements.
Hypertension 2013; 62:168–174.
420. Mancia G, Facchetti R, Grassi G, Bombelli M. Adverse prognostic value of persistent office blood pressure elevation in white coat hypertension.
Hypertension 2015; 66:437–444.
421. Gorostidi M, Banegas JR, de la Sierra A, Vinyoles E, Segura J, Ruilope LM. Ambulatory blood pressure monitoring in daily clinical practice – the Spanish ABPM Registry experience.
Eur J Clin Invest 2016; 46:92–98.
422. Mancia G, Bombelli M, Facchetti R, Madotto F, Quarti-Trevano F, Polo Friz H, et al. Long-term risk of sustained hypertension in white-coat or masked hypertension.
Hypertension 2009; 54:226–232.
423. Ogedegbe G, Agyemang C, Ravenell JE. Masked hypertension: evidence of the need to treat.
Curr Hypertens Rep 2010; 12:349–355.
424. Sundstrom J, Neovius M, Tynelius P, Rasmussen F. Association of blood pressure in late adolescence with subsequent mortality: cohort study of Swedish male conscripts.
BMJ 2011; 342:d643.
425. Zanchetti A, Thomopoulos C, Parati G. Randomized controlled trials of blood pressure lowering in hypertension: a critical reappraisal.
Circ Res 2015; 116:1058–1073.
426. Williams B. High blood pressure in young people and premature death.
BMJ 2011; 342:d1104.
427. Julius S, Nesbitt SD, Egan BM, Weber MA, Michelson EL, Kaciroti N, et al. Trial of Preventing Hypertension Study InvestigatorsFeasibility of treating prehypertension with an angiotensin-receptor blocker.
N Engl J Med 2006; 354:1685–1697.
428. O’Rourke MF, Adji A. Guidelines on guidelines: focus on isolated systolic hypertension in youth.
J Hypertens 2013; 31:649–654.
429. Yano Y, Stamler J, Garside DB, Daviglus ML, Franklin SS, Carnethon MR, et al. Isolated systolic hypertension in young and middle-aged adults and 31-year risk for cardiovascular mortality: the Chicago Heart Association Detection Project in Industry study.
J Am Coll Cardiol 2015; 65:327–335.
430. Palatini P, Mormino P, Canali C, Santonastaso M, De Venuto G, Zanata G, Pessina AC. Factors affecting ambulatory blood pressure reproducibility. Results of the HARVEST Trial. Hypertension and Ambulatory Recording Venetia Study.
Hypertension 1994; 23:211–216.
431. Briasoulis A, Agarwal V, Tousoulis D, Stefanadis C. Effects of antihypertensive treatment in patients over 65 years of age: a meta-analysis of randomised controlled studies.
Heart 2014; 100:317–323.
432. Corrao G, Rea F, Monzio Compagnoni M, Merlino L, Mancia G. Protective effects of antihypertensive treatment in patients aged 85 years or older.
J Hypertens 2017; 35:1432–1441.
433. Corrao G, Mazzola P, Monzio Compagnoni M, Rea F, Merlino L, Annoni G, Mancia G. Antihypertensive medications, loop diuretics, and risk of hip fracture in the elderly: a population-based cohort study of 81,617 Italian patients newly treated between 2005 and 2009.
Drugs Aging 2015; 32:927–936.
434. Kjeldsen SE, Stenehjem A, Os I, Van de Borne P, Burnier M, Narkiewicz K, et al. Treatment of high blood pressure in elderly and octogenarians: European Society of Hypertension statement on blood pressure targets.
Blood Press 2016; 25:333–336.
435. ESC Committee for Practice GuidelinesGuidelines on the management of cardiovascular diseases during pregnancy 2018.
Eur Heart J 2018; Aug 25. doi: 10.1093/eurheartj/ehy340. [Epub ahead of print].
436. American College of Obstetricians Gynecologists Task Force on Hypertension in PregnancyHypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy.
Obstet Gynecol 2013; 122:1122–1131.
437. Lowe SA, Bowyer L, Lust K, McMahon LP, Morton MR, North RA, et al. The SOMANZ Guidelines for the management of hypertensive disorders of pregnancy 2014.
Aust N Z J Obstet Gynaecol 2015; 55:11–16.
438. Bartsch E, Medcalf KE, Park AL, Ray JG. Clinical risk factors for preeclampsia determined in early pregnancy: systematic review and meta-analysis of large cohort studies.
BMJ 2016; 353:i1753.
439. Blood Pressure Association. Blood Pressure UK.
http://www.bloodpressureuk.org (20 April 2018).
440. Penny JA, Halligan AW, Shennan AH, Lambert PC, Jones DR, de Swiet M, Taylor DJ. Automated, ambulatory, or conventional blood pressure measurement in pregnancy: which is the better predictor of severe hypertension?
Am J Obstet Gynecol 1998; 178:521–526.
441. Schmella MJ, Clifton RG, Althouse AD, Roberts JM. Uric acid determination in gestational hypertension: is it as effective a delineator of risk as proteinuria in high-risk women?
Reprod Sci 2015; 22:1212–1219.
442. Chappell LC, Shennan AH. Assessment of proteinuria in pregnancy.
BMJ 2008; 336:968–969.
443. Cnossen JS, Morris RK, ter Riet G, Mol BW, van der Post JA, Coomarasamy A, et al. Use of uterine artery Doppler ultrasonography to predict preeclampsia and intrauterine growth restriction: a systematic review and bivariable meta-analysis.
CMAJ 2008; 178:701–711.
444. Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennstrom M, et al. Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia.
N Engl J Med 2016; 374:13–22.
445. Rolnik DL, Wright D, Poon LC, O’Gorman N, Syngelaki A, de Paco Matallana C, et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia.
N Engl J Med 2017; 377:613–622.
446. Magee LA, von Dadelszen P, Singer J, Lee T, Rey E, Ross S, et al. CHIPS Study GroupThe CHIPS randomized controlled trial (Control of Hypertension in Pregnancy Study): is severe hypertension just an elevated blood pressure?
Hypertension 2016; 68:1153–1159.
447. Redman CW. Fetal outcome in trial of antihypertensive treatment in pregnancy.
Lancet 1976; 2:753–756.
448. Cockburn J, Moar VA, Ounsted M, Redman CW. Final report of study on hypertension during pregnancy: the effects of specific treatment on the growth and development of the children.
Lancet 1982; 1:647–649.
449. Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C, Cifkova R, Ferreira R, Foidart JM, et al. ESC Guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC).
Eur Heart J 2011; 32:3147–3197.
450. Abalos E, Duley L, Steyn DW. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy.
Cochrane Database Syst Rev 2014; 2:CD002252.
451. Magee LA, Cham C, Waterman EJ, Ohlsson A, von Dadelszen P. Hydralazine for treatment of severe hypertension in pregnancy: meta-analysis.
BMJ 2003; 327:955–960.
452. Duley L, Henderson-Smart DJ, Meher S. Drugs for treatment of very high blood pressure during pregnancy.
Cochrane Database Syst Rev 2006; 3:CD001449.
453. Koopmans CM, Bijlenga D, Groen H, Vijgen SM, Aarnoudse JG, Bekedam DJ, et al. Induction of labour versus expectant monitoring for gestational hypertension or mild preeclampsia after 36 weeks’ gestation (HYPITAT): a multicentre, open-label randomised controlled trial.
Lancet 2009; 374:979–988.
454. Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA. Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study.
Lancet 2005; 366:1797–1803.
455. Black MH, Zhou H, Sacks DA, Dublin S, Lawrence JM, Harrison TN, Reynolds K. Hypertensive disorders first identified in pregnancy increase risk for incident prehypertension and hypertension in the year after delivery.
J Hypertens 2016; 34:728–735.
456. Chasan-Taber L, Willett WC, Manson JE, Spiegelman D, Hunter DJ, Curhan G, et al. Prospective study of oral contraceptives and hypertension among women in the United States.
Circulation 1996; 94:483–489.
457. Dong W, Colhoun HM, Poulter NR. Blood pressure in women using oral contraceptives: results from the Health Survey for England 1994.
J Hypertens 1997; 15:1063–1068.
458. Gillum LA, Mamidipudi SK, Johnston SC. Ischemic stroke risk with oral contraceptives: a meta-analysis.
JAMA 2000; 284:72–78.
459. World Health Organization. Medical eligibility criteria for contraceptive use. Third edition, 2004.
http://apps.who.int/iris/bitstream/10665/42907/1/9241562668.pdf (date accessed June 28th 2018).
460. Lubianca JN, Moreira LB, Gus M, Fuchs FD. Stopping oral contraceptives: an effective blood pressure-lowering intervention in women with hypertension.
J Hum Hypertens 2005; 19:451–455.
461. Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ, Lloyd-Jones DM, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women-2011 update: a guideline from the American Heart Association.
J Am Coll Cardiol 2011; 57:1404–1423.
462. Issa Z, Seely EW, Rahme M, El-Hajj Fuleihan G. Effects of hormone therapy on blood pressure.
Menopause 2015; 22:456–468.
463. Modesti PA, Reboldi G, Cappuccio FP, Agyemang C, Remuzzi G, Rapi S, et al. Panethnic differences in blood pressure in Europe: a systematic review and meta-analysis.
PLoS One 2016; 11:e0147601.
464. Whelton PK, Einhorn PT, Muntner P, Appel LJ, Cushman WC, Diez Roux AV, et al. Research needs to improve hypertension treatment and control in African Americans.
Hypertension 2016; 68:1066–1072.
465. Kaufman JS, Cooper RS, McGee DL. Socioeconomic status and health in blacks and whites: the problem of residual confounding and the resiliency of race.
Epidemiology 1997; 8:621–628.
466. Agyemang C, van Oeffelen AA, Norredam M, Kappelle LJ, Klijn CJ, Bots ML, et al. Socioeconomic inequalities in stroke incidence among migrant groups: analysis of nationwide data.
Stroke 2014; 45:2397–2403.
467. Mehanna M, Gong Y, McDonough CW, Beitelshees AL, Gums JG, Chapman AB, et al. Blood pressure response to metoprolol and chlorthalidone in European and African Americans with hypertension.
J Clin Hypertens (Greenwich) 2017; 19:1301–1308.
468. Erlinger TP, Vollmer WM, Svetkey LP, Appel LJ. The potential impact of nonpharmacologic population-wide blood pressure reduction on coronary heart disease events: pronounced benefits in African-Americans and hypertensives.
Prev Med 2003; 37:327–333.
469. Wright JT Jr, Dunn JK, Cutler JA, Davis BR, Cushman WC, Ford CE, et al. ALLHAT Collaborative Research GroupOutcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril.
JAMA 2005; 293:1595–1608.
470. Wright JT Jr, Harris-Haywood S, Pressel S, Barzilay J, Baimbridge C, Bareis CJ, et al. Clinical outcomes by race in hypertensive patients with and without the metabolic syndrome: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
Arch Intern Med 2008; 168:207–217.
471. Agyemang C, Nyaaba G, Beune E, Meeks K, Owusu-Dabo E, Addo J, et al. Variations in hypertension awareness, treatment, and control among Ghanaian migrants living in Amsterdam, Berlin, London, and nonmigrant Ghanaians living in rural and urban Ghana – the RODAM study.
J Hypertens 2018; 36:169–177.
472. Wijkman M, Lanne T, Engvall J, Lindstrom T, Ostgren CJ, Nystrom FH. Masked nocturnal hypertension-a novel marker of risk in type 2 diabetes.
Diabetologia 2009; 52:1258–1264.
473. Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial.
Lancet 2008; 372:547–553.
474. Persson F, Lewis JB, Lewis EJ, Rossing P, Hollenberg NK, Parving HH. Aliskiren in combination with losartan reduces albuminuria independent of baseline blood pressure in patients with type 2 diabetes and nephropathy.
Clin J Am Soc Nephrol 2011; 6:1025–1031.
475. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. EMPA-REG OUTCOME InvestigatorsEmpagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
N Engl J Med 2015; 373:2117–2128.
476. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes.
N Engl J Med 2017; 377:644–657.
477. Mancia G, Schumacher H, Redon J, Verdecchia P, Schmieder R, Jennings G, et al. Blood pressure targets recommended by guidelines and incidence of cardiovascular and renal events in the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET).
Circulation 2011; 124:1727–1736.
478. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. EMPA-REG OUTCOME InvestigatorsEmpagliflozin and progression of kidney disease in type 2 diabetes.
N Engl J Med 2016; 375:323–334.
479. Mancia G, Cannon CP, Tikkanen I, Zeller C, Ley L, Woerle HJ, et al. Impact of empagliflozin on blood pressure in patients with type 2 diabetes mellitus and hypertension by background antihypertensive medication.
Hypertension 2016; 68:1355–1364.
480. Buse JB. Liraglutide and cardiovascular outcomes in type 2 diabetes.
N Engl J Med 2016; 375:1798–1799.
481. Bethel MA, Patel RA, Merrill P, Lokhnygina Y, Buse JB, Mentz RJ, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis.
Lancet Diabetes Endocrinol 2018; 6:105–113.
482. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension: 2. Effects at different baseline and achieved blood pressure levels-overview and meta-analyses of randomized trials.
J Hypertens 2014; 32:2296–2304.
483. Drawz PE, Alper AB, Anderson AH, Brecklin CS, Charleston J, Chen J, et al. Chronic Renal Insufficiency Cohort Study InvestigatorsMasked hypertension and elevated nighttime blood pressure in CKD: prevalence and association with target organ damage.
Clin J Am Soc Nephrol 2016; 11:642–652.
484. Rossignol P, Massy ZA, Azizi M, Bakris G, Ritz E, Covic A, et al. ERA-EDTA EURECA-m Working Group, Red de Investigacion Renal (REDINREN) Network, Cardiovascular and Renal Clinical Trialists (F-CRIN INI-CRCT) NetworkThe double challenge of resistant hypertension and chronic kidney disease.
Lancet 2015; 386:1588–1598.
485. Malhotra R, Nguyen HA, Benavente O, Mete M, Howard BV, Mant J, et al. Association between more intensive vs less intensive blood pressure lowering and risk of mortality in chronic kidney disease stages 3 to 5: a systematic review and meta-analysis.
JAMA Intern Med 2017; 177:1498–1505.
486. de Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy.
Circulation 2004; 110:921–927.
487. Jafar TH, Stark PC, Schmid CH, Landa M, Maschio G, de Jong PE, et al. AIPRD Study GroupProgression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level meta-analysis.
Ann Intern Med 2003; 139:244–252.
488. Upadhyay A, Earley A, Haynes SM, Uhlig K. Systematic review: blood pressure target in chronic kidney disease and proteinuria as an effect modifier.
Ann Intern Med 2011; 154:541–548.
489. Sim JJ, Shi J, Kovesdy CP, Kalantar-Zadeh K, Jacobsen SJ. Impact of achieved blood pressures on mortality risk and end-stage renal disease among a large, diverse hypertension population.
J Am Coll Cardiol 2014; 64:588–597.
490. Farsang CK, Kiss I, Tykarski A, Narkiewicz K. Treatment of hypertension in patients with chronic obstructive pulmonary disease (COPD).
European Society of Hypertension Scientific Newsletter 2016; 17:62.
491. Baker JG. Wilcox RG. beta-Blockers, heart disease and COPD: current controversies and uncertainties.
Thorax 2017; 72:271–276.
492. Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths.
Ann Intern Med 2006; 144:904–912.
493. Rutten FH, Zuithoff NP, Hak E, Grobbee DE, Hoes AW. Beta-blockers may reduce mortality and risk of exacerbations in patients with chronic obstructive pulmonary disease.
Arch Intern Med 2010; 170:880–887.
494. Coiro S, Girerd N, Rossignol P, Ferreira JP, Maggioni A, Pitt B, et al. Association of beta-blocker treatment with mortality following myocardial infarction in patients with chronic obstructive pulmonary disease and heart failure or left ventricular dysfunction: a propensity matched-cohort analysis from the High-Risk Myocardial Infarction Database Initiative.
Eur J Heart Fail 2017; 19:271–279.
495. Cazzola M, Noschese P, D’Amato G, Matera MG. The pharmacologic treatment of uncomplicated arterial hypertension in patients with airway dysfunction.
Chest 2002; 121:230–241.
496. Xie X, Atkins E, Lv J, Bennett A, Neal B, Ninomiya T, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis.
Lancet 2016; 387:435–443.
497. Bangalore S, Messerli FH, Wun C, Zuckerman AL, DeMicco D, Kostis JB, LaRosa JC. Treating to New Targets Steering Committee and Investigators. J-Curve revisited: an analysis of the Treating to New Targets (TNT) Trial.
J Am Coll Cardiol 2009; 53:A217.
498. Bangalore S, Qin J, Sloan S, Murphy SA, Cannon CP. PROVE IT-TIMI 22 Trial InvestigatorsWhat is the optimal blood pressure in patients after acute coronary syndromes?: relationship of blood pressure and cardiovascular events in the PRavastatin OR atorVastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction (PROVE IT-TIMI) 22 trial.
Circulation 2010; 122:2142–2151.
499. Messerli FH, Mancia G, Conti CR, Hewkin AC, Kupfer S, Champion A, et al. Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous?
Ann Intern Med 2006; 144:884–893.
500. Sleight P, Redon J, Verdecchia P, Mancia G, Gao P, Fagard R, et al. ONTARGET InvestigatorsPrognostic value of blood pressure in patients with high vascular risk in the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial study.
J Hypertens 2009; 27:1360–1369.
501. Vidal-Petiot E, Ford I, Greenlaw N, Ferrari R, Fox KM, Tardif JC, et al. CLARIFY InvestigatorsCardiovascular event rates and mortality according to achieved systolic and diastolic blood pressure in patients with stable coronary artery disease: an international cohort study.
Lancet 2016; 388:2142–2152.
502. Redon J, Mancia G, Sleight P, Schumacher H, Gao P, Pogue J, et al. ONTARGET InvestigatorsSafety and efficacy of low blood pressures among patients with diabetes: subgroup analyses from the ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial).
J Am Coll Cardiol 2012; 59:74–83.
503. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies.
BMJ 2009; 338:b1665.
504. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure-lowering treatment. 6. Prevention of heart failure and new-onset heart failure-meta-analyses of randomized trials.
J Hypertens 2016; 34:373–384.
505. Soliman EZ, Byington RP, Bigger JT, Evans G, Okin PM, Goff DC Jr, Chen H. Effect of intensive blood pressure lowering on left ventricular hypertrophy in patients with diabetes mellitus: action to control cardiovascular risk in diabetes blood pressure trial.
Hypertension 2015; 66:1123–1129.
506. Verdecchia P, Staessen JA, Angeli F, de Simone G, Achilli A, Ganau A, et al. Cardio-Sis InvestigatorsUsual versus tight control of systolic blood pressure in nondiabetic patients with hypertension (Cardio-Sis): an open-label randomised trial.
Lancet 2009; 374:525–533.
507. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure.
N Engl J Med 2014; 371:993–1004.
508. Manning LS, Mistri AK, Potter J, Rothwell PM, Robinson TG. Short-term blood pressure variability in acute stroke: post hoc analysis of the controlling hypertension and hypotension immediately post stroke and continue or stop poststroke antihypertensives collaborative study trials.
Stroke 2015; 46:1518–1524.
509. Rodriguez-Luna D, Pineiro S, Rubiera M, Ribo M, Coscojuela P, Pagola J, et al. Impact of blood pressure changes and course on hematoma growth in acute intracerebral hemorrhage.
Eur J Neurol 2013; 20:1277–1283.
510. Sakamoto Y, Koga M, Yamagami H, Okuda S, Okada Y, Kimura K, et al. Systolic blood pressure after intravenous antihypertensive treatment and clinical outcomes in hyperacute intracerebral hemorrhage: the stroke acute management with urgent risk-factor assessment and improvement-intracerebral hemorrhage study.
Stroke 2013; 44:1846–1851.
511. Anderson CS, Heeley E, Huang Y, Wang J, Stapf C, Delcourt C, et al. INTERACT2 InvestigatorsRapid blood-pressure lowering in patients with acute intracerebral hemorrhage.
N Engl J Med 2013; 368:2355–2365.
512. Qureshi AI, Palesch YY, Barsan WG, Hanley DF, Hsu CY, Martin RL, et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage.
N Engl J Med 2016; 375:1033–1043.
513. Tsivgoulis G, Katsanos AH, Butcher KS, Boviatsis E, Triantafyllou N, Rizos I, Alexandrov AV. Intensive blood pressure reduction in acute intracerebral hemorrhage: a meta-analysis.
Neurology 2014; 83:1523–1529.
514. Ahmed N, Wahlgren N, Brainin M, Castillo J, Ford GA, Kaste M, et al. Relationship of blood pressure, antihypertensive therapy, and outcome in ischemic stroke treated with intravenous thrombolysis: retrospective analysis from Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR).
Stroke 2009; 40:2442–2449.
515. Wu W, Huo X, Zhao X, Liao X, Wang C, Pan Y, et al. Relationship between blood pressure and outcomes in acute ischemic stroke patients administered lytic medication in the TIMS-China Study.
PLoS One 2016; 11:e0144260.
516. Lee M, Ovbiagele B, Hong KS, Wu YL, Lee JE, Rao NM, et al. Effect of blood pressure lowering in early ischemic stroke: meta-analysis.
Stroke 2015; 46:1883–1889.
517. Zhao R, Liu FD, Wang S, Peng JL, Tao XX, Zheng B, et al. Blood pressure reduction in the acute phase of an ischemic stroke does not improve short- or long-term dependency or mortality: a meta-analysis of current literature.
Medicine (Baltimore) 2015; 94:e896.
518. Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk BM, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
Stroke 2013; 44:870–947.
519. Sandset EC, Bath PM, Boysen G, Jatuzis D, Korv J, Luders S, et al. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial.
Lancet 2011; 377:741–750.
520. Sandset EC, Murray GD, Bath PM, Kjeldsen SE. Berge E; Scandinavian Candesartan Acute Stroke Trial (SCAST) Study Group. Relation between change in blood pressure in acute stroke and risk of early adverse events and poor outcome.
Stroke 2012; 43:2108–2114.
521. ENOS Trial InvestigatorsEfficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial.
Lancet 2015; 385:617–628.
522. Robinson TG, Potter JF, Ford GA, Bulpitt CJ, Chernova J, Jagger C, et al. Effects of antihypertensive treatment after acute stroke in the Continue or Stop Post-Stroke Antihypertensives Collaborative Study (COSSACS): a prospective, randomised, open, blinded-endpoint trial.
Lancet Neurol 2010; 9:767–775.
523. PATS Collaborating GroupPoststroke antihypertensive treatment study. A preliminary result.
Chin Med J (Engl) 1995; 108:710–717.
524. White CL, Szychowski JM, Pergola PE, Field TS, Talbert R, Lau H, et al. Secondary Prevention of Small Subcortical Strokes Study InvestigatorsCan blood pressure be lowered safely in older adults with lacunar stroke? The Secondary Prevention of Small Subcortical Strokes study experience.
J Am Geriatr Soc 2015; 63:722–729.
525. Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, et al. American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, Council on Peripheral Vascular DiseaseGuidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
Stroke 2014; 45:2160–2236.
526. Arima H, Chalmers J, Woodward M, Anderson C, Rodgers A, Davis S, et al. PROGRESS Collaborative GroupLower target blood pressures are safe and effective for the prevention of recurrent stroke: the PROGRESS trial.
J Hypertens 2006; 24:1201–1208.
527. Collier DJ, Poulter NR, Dahlof B, Sever PS, Wedel H, Buch J, Caulfield MJ. Impact of amlodipine-based therapy among older and younger patients in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA).
J Hypertens 2011; 29:583–591.
528. National Institute for Health and Clinical Excellence. Hypertension (CG127): clinical management of primary hypertension in adults.
www.nice.org.uk/guidance/CG127 (April 2018).
529. Vickrey BG, Rector TS, Wickstrom SL, Guzy PM, Sloss EM, Gorelick PB, et al. Occurrence of secondary ischemic events among persons with atherosclerotic vascular disease.
Stroke 2002; 33:901–906.
530. Emdin CA, Rothwell PM, Salimi-Khorshidi G, Kiran A, Conrad N, Callender T, et al. Blood pressure and risk of vascular dementia: evidence from a primary care registry and a cohort study of transient ischemic attack and stroke.
Stroke 2016; 47:1429–1435.
531. Ninomiya T, Ohara T, Hirakawa Y, Yoshida D, Doi Y, Hata J, et al. Midlife and late-life blood pressure and dementia in Japanese elderly: the Hisayama study.
Hypertension 2011; 58:22–28.
532. Sierra C, De La Sierra A, Salamero M, Sobrino J, Gomez-Angelats E, Coca A. Silent cerebral white matter lesions and cognitive function in middle-aged essential hypertensive patients.
Am J Hypertens 2004; 17:529–534.
533. Snyder HM, Corriveau RA, Craft S, Faber JE, Greenberg SM, Knopman D, et al. Vascular contributions to cognitive impairment and dementia including Alzheimer's disease.
Alzheimers Dement 2015; 11:710–717.
534. Levi Marpillat N, Macquin-Mavier I, Tropeano AI, Bachoud-Levi AC, Maison P. Antihypertensive classes, cognitive decline and incidence of dementia: a network meta-analysis.
J Hypertens 2013; 31:1073–1082.
535. Godin O, Tzourio C, Maillard P, Mazoyer B, Dufouil C. Antihypertensive treatment and change in blood pressure are associated with the progression of white matter lesion volumes: the Three-City (3C)-Dijon Magnetic Resonance Imaging Study.
Circulation 2011; 123:266–273.
536. Lip GYH, Coca A, Kahan T, Boriani G, Manolis AS, Olsen MH, et al. Hypertension and cardiac arrhythmias: a consensus document from the European Heart Rhythm Association (EHRA) and ESC Council on Hypertension, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS) and Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia (SOLEACE).
Europace 2017; 19:891–911.
537. Manolis A, Doumas M, Poulimenos L, Kallistratos M, Mancia G. The unappreciated importance of blood pressure in recent and older atrial fibrillation trials.
J Hypertens 2013; 31:2109–2117.
538. Laukkanen JA, Khan H, Kurl S, Willeit P, Karppi J, Ronkainen K, Di Angelantonio E. Left ventricular mass and the risk of sudden cardiac death: a population-based study.
J Am Heart Assoc 2014; 3:e001285.
539. Lip GY. Atrial fibrillation in patients with hypertension: trajectories of risk factors in yet another manifestation of hypertensive target organ damage.
Hypertension 2016; 68:544–545.
540. Conen D, Tedrow UB, Koplan BA, Glynn RJ, Buring JE, Albert CM. Influence of systolic and diastolic blood pressure on the risk of incident atrial fibrillation in women.
Circulation 2009; 119:2146–2152.
541. Grundvold I, Skretteberg PT, Liestol K, Erikssen G, Kjeldsen SE, Arnesen H, et al. Upper normal blood pressures predict incident atrial fibrillation in healthy middle-aged men: a 35-year follow-up study.
Hypertension 2012; 59:198–204.
542. Freedman B, Potpara TS, Lip GY. Stroke prevention in atrial fibrillation.
Lancet 2016; 388:806–817.
543. Schmieder RE, Kjeldsen SE, Julius S, McInnes GT, Zanchetti A, Hua TA. VALUE Trial GroupReduced incidence of new-onset atrial fibrillation with angiotensin II receptor blockade: the VALUE trial.
J Hypertens 2008; 26:403–411.
544. Wachtell K, Lehto M, Gerdts E, Olsen MH, Hornestam B, Dahlof B, et al. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: the Losartan Intervention For End Point Reduction in Hypertension (LIFE) study.
J Am Coll Cardiol 2005; 45:712–719.
545. Cohn JN, Tognoni G. Valsartan Heart Failure Trial InvestigatorsA randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.
N Engl J Med 2001; 345:1667–1675.
546. Ducharme A, Swedberg K, Pfeffer MA, Cohen-Solal A, Granger CB, Maggioni AP, et al. CHARM InvestigatorsPrevention of atrial fibrillation in patients with symptomatic chronic heart failure by candesartan in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program.
Am Heart J 2006; 152:86–92.
547. Vermes E, Tardif JC, Bourassa MG, Racine N, Levesque S, White M, et al. Enalapril decreases the incidence of atrial fibrillation in patients with left ventricular dysfunction: insight from the Studies Of Left Ventricular Dysfunction (SOLVD) trials.
Circulation 2003; 107:2926–2931.
548. Disertori M, Latini R, Barlera S, Franzosi MG, Staszewsky L, Maggioni AP, et al. GISSI-AF InvestigatorsValsartan for prevention of recurrent atrial fibrillation.
N Engl J Med 2009; 360:1606–1617.
549. Goette A, Schon N, Kirchhof P, Breithardt G, Fetsch T, Hausler KG, et al. Angiotensin II-antagonist in paroxysmal atrial fibrillation (ANTIPAF) trial.
Circ Arrhythm Electrophysiol 2012; 5:43–51.
550. Tveit A, Grundvold I, Olufsen M, Seljeflot I, Abdelnoor M, Arnesen H, Smith P. Candesartan in the prevention of relapsing atrial fibrillation.
Int J Cardiol 2007; 120:85–91.
