Table of Contents
INTRODUCTION 10
WHAT IS NEW AND WHAT HAS CHANGED IN THE 2023 EUROPEAN SOCIETY OF HYPERTENSION ARTERIAL HYPERTENSION GUIDELINES? 12
1. Methodology and definition of evidence 14
1.1 Methodology of evidence grading 14
1.2 Level of evidence 14
2. PRINCIPLES OF HYPERTENSION PATHOPHYSIOLOGY 16
3. DEFINITION OF HYPERTENSION AND BP CLASSIFICATION 18
3.1 Definition of hypertension 18
3.2 Classification of hypertension 19
3.3 Prevalence of hypertension 20
3.4 BP relationship with risk of cerebral, cardiovascular and kidney events 20
3.5 Hypertension and total CV risk assessment 21
3.6 Screening versus case finding in the detection of hypertension 24
3.7 Confirming the diagnosis of hypertension 25
4. BP MEASUREMENT AND MONITORING 26
4.1 Devices for blood pressure measurement 26
4.1.1 Standard cuff-based devices 26
4.1.2 Cuffless blood pressure measuring devices 27
4.1.3 Validation of blood pressure measuring devices 27
4.2 Standard office blood pressure measurement 28
4.3 Unattended office blood pressure measurement 30
4.4 Blood pressure during exercise 32
4.5 Blood pressure measurement in hospital 32
4.6 Central blood pressure 33
4.7 Home blood pressure monitoring 34
4.8 Ambulatory blood pressure monitoring 36
4.9 Clinical indications for HBPM and ABPM 39
4.10 Blood pressure variability 41
5. PATIENT WORK-UP 42
5.1 Personal and medical history 42
5.2 Physical examination 44
5.3 Routine clinical chemistry investigations 45
5.4 Other investigations in hypertension 45
5.4.1 Electrocardiogram 45
5.4.2 Kidney ultrasound 46
5.4.3 Selected biomarkers and genetic markers 46
5.4.3.1 Lipoprotein (a) 46
5.4.3.2 Cardiac biomarkers 46
5.4.3.3 Kidney markers 47
5.4.3.4 Genetic markers 47
5.5 Assessment of hypertension-mediated organ damage 48
5.5.1 HMOD in the heart 49
5.5.1.1 Left ventricular mass and geometry 50
5.5.1.2 Transthoracic echocardiography 50
5.5.1.3 Cardiac magnetic resonance 51
5.5.1.4 Computed tomography of the heart 52
5.5.2 HMOD in the arteries 52
5.5.2.1 Carotid artery IMT and plaques 52
5.5.2.2 Pulse wave velocity 53
5.5.2.3 Ankle–brachial index 55
5.5.3 HMOD in the kidney 55
5.5.4 HMOD in the brain 56
5.5.5 HMOD in the eye 58
5.6 Using HMOD to help stratify risk in hypertensive patients 60
5.7 When to refer a patient to a specialist or for hospital-based care 62
6. SECONDARY HYPERTENSION 63
6.1 Genetic causes of secondary hypertension 67
7. LIFESTYLE INTERVENTIONS 69
7.1 Relevance of lifestyle changes 69
7.2 Weight reduction 70
7.3 Restriction of sodium intake 70
7.4 Augmentation of dietary potassium intake 71
7.5 Increase levels of daily physical activity and regular exercise 72
7.6 Moderation of alcohol intake 73
7.7 Smoking cessation 74
7.8 Other dietary interventions 75
7.9 Improve stress management 75
7.10 Exposure to noise and air pollution 76
8. BENEFITS OF ANTIHYPERTENSIVE TREATMENT 77
9. ANTIHYPERTENSIVE DRUG TREATMENT INITIATION 79
9.1 Should treatment initiation be based on total CV risk? 79
9.2 Office BP thresholds for initiation of drug treatment 79
9.3 Should BP-lowering treatment be initiated in patients with office BP <140/90 mmHg? 81
9.4 Drug treatment initiation in older people 82
10. OFFICE BP TARGETS FOR TREATMENT 85
10.1 Office BP targets in the general hypertensive population 85
10.2 Office versus home and ambulatory BP targets 87
10.3 Timing of BP control and time in therapeutic range 88
10.4 Residual risk 88
10.5 Challenges associated with evidence on BP targets 89
11. ANTIHYPERTENSIVE DRUGS AND TREATMENT 92
11.1 Blockers of the renin–angiotensin system 96
11.1.1 Angiotensin-converting-enzyme inhibitors 96
11.1.2 Angiotensin receptor blockers 96
11.1.3 Renin inhibitors 96
11.1.4 Combination of RAS inhibitors 97
11.2 Calcium channel blockers 97
11.2.1 Dihydropyridine CCBs 97
11.2.2 Nondihydropyridine CCBs 97
11.3 Diuretics 97
11.3.1 Thiazide and Thiazide-like diuretics 97
11.3.2 Loop diuretics 99
11.3.3 Potassium-sparing diuretics 99
11.4 Mineralocorticoid receptor antagonists 99
11.5 Beta-blockers 100
11.6 Alpha-1 blockers 102
11.7 Centrally acting drugs 103
11.8 Vasodilators 103
11.9 Angiotensin receptor-neprilysin inhibitor 103
11.10 Antihypertensive drug combinations 104
11.10.1 Impact on hypertension drug treatment strategy 104
11.10.2 Drug combinations 106
11.10.3 Rationale for initial two-drug combination therapy 110
11.10.4 Up-titration of treatment to three-drug combination 112
11.10.5 Rationale for single-pill combination therapy 112
11.10.6 The quadpill concept 113
11.10.7 The polypill concept 114
11.10.8 Choice of drug combinations for initiation of treatment 115
11.10.9 Tolerability and side effects of drugs 115
11.10.10 Prescribing of antihypertensive drugs 116
11.10.10.1 Standard drug administration 116
11.10.10.2 Partial treatment reduction or complete withdrawal 117
11.10.10.3 Antihypertensive drugs and cancer risk 118
11.10.11 Concomitant medications 119
11.10.11.1 LDL-cholesterol lowering 119
11.10.11.2 Antiplatelet therapy 121
12. TRUE RESISTANT HYPERTENSION 122
12.1 Definition, prevalence, pathophysiology and cardiovascular risk 122
12.2 Diagnostic work-up 123
12.3 Optimizing lifestyle interventions and ongoing drug therapy 125
12.4 Fourth and subsequent lines of antihypertensive therapy 126
13. DEVICE-BASED TREATMENT OF HYPERTENSION 131
13.1 Renal denervation 131
13.1.1 Clinical evidence of the BP-lowering effect of RDN 131
13.1.2 Off-medications studies 132
13.1.3 On-medications studies 132
13.1.4 Safety 133
13.1.5 Durability 134
13.1.6 Application 134
13.2 Carotid baroreceptor stimulation 136
13.3. Other device-based treatments 136
14. SPECIFIC HYPERTENSION PHENOTYPES 137
14.1 Sustained hypertension and true normotension 137
14.2 White-coat hypertension 138
14.3 Masked hypertension 139
14.4 White-coat uncontrolled hypertension and masked uncontrolled hypertension 141
14.5 Isolated systolic hypertension of the young 142
14.6 Isolated systolic hypertension in older persons 144
14.7 Isolated diastolic hypertension 146
14.8 Night-time hypertension and dipping 147
14.9 Orthostatic hypertension and hypotension 149
14.10 Baroreflex failure and efferent autonomic failure 150
15. HYPERTENSION IN DIFFERENT DEMOGRAPHIC SITUATIONS 152
15.1 Blood pressure in children, adolescents and transition period 152
15.1.1 Blood pressure measurements in children and adolescents 152
15.1.2 Hypertension in children and adolescents 153
15.1.3 Transition period to adulthood 154
15.2 Hypertension in young adults 155
15.3 Hypertension in older persons 156
15.3.1 Patients 65–79 years old 157
15.3.1.1 Threshold and target for drug treatment 157
15.3.1.2 Antihypertensive treatment strategies 158
15.3.1.3 Antihypertensive drugs 158
15.3.1.4 Monitoring the effects of treatment 159
15.3.2 Patients 80 years old or beyond 159
15.3.3 How to assess the level of frailty/functionality to better personalize therapeutic strategies 160
15.4 Sex and gender aspects in hypertension 163
15.4.1 Epidemiology and pathophysiology 163
15.4.2 Blood pressure and cardiovascular risk 164
15.4.3 Differences in clinical phenotypes 164
15.4.3.1 White-coat hypertension and masked hypertension 164
15.4.3.2 Hypertension-mediated organ damage 164
15.4.4 Sex differences in hypertension outcomes 165
15.4.5 Benefits of antihypertensive treatment and target blood pressure 166
15.4.6 Sex differences in hypertension management 167
15.4.7 Infertility treatments and hypertension in women 167
15.4.8. Oral contraceptive pills and hypertension 168
15.4.9 Hormone-replacement therapy and hypertension 169
15.4.10 Gender-affirming hormone therapy and hypertension 169
15.5 Hypertension and ethnicity 169
15.5.1 Nomenclature and relevance 169
15.5.2 Management 170
16. HYPERTENSION IN SPECIFIC SETTINGS 171
16.1 Hypertension disorders in pregnancy 171
16.1.1 Definition and classification of hypertension in pregnancy 173
16.1.2 Blood pressure measurement in pregnancy 174
16.1.3 Laboratory examinations in pregnancy 175
16.1.4 Prediction and prevention of preeclampsia 175
16.1.5 Lifestyle interventions 176
16.1.6 Clinical management of hypertension in pregnancy 176
16.1.6.1 Mild preexisting essential hypertension 176
16.1.6.2 Mild gestational hypertension 177
16.1.6.3 Preeclampsia 178
16.1.6.4 Severe hypertension 178
16.1.6.5 Preexisting secondary hypertension 179
16.1.7 Blood pressure during puerperium 180
16.1.8 Postpartum hypertension and breastfeeding 181
16.1.9 Risk of recurrence of hypertensive disorders in a subsequent pregnancy 181
16.1.10 Long-term cardiovascular consequences of hypertensive disorders in pregnancy 181
16.2 Hypertensive urgencies and emergencies 183
16.2.1 Definitions of hypertensive urgencies and emergencies 183
16.2.2 Hospital work-up, treatments and follow-up 185
16.2.3 Blood pressure in the emergency department 189
16.3 Perioperative hypertension and its management 190
17. HYPERTENSION IN ESTABLISHED CARDIOVASCULAR DISORDERS 192
17.1 Coronary artery disease 192
17.1.2 Treatment of hypertensive patients with coronary artery disease 193
17.2 Heart failure 195
17.2.1 Prevention of heart failure in hypertension 195
17.2.2 Heart failure with reduced ejection fraction 197
17.2.3 Heart failure with preserved ejection fraction 199
17.2.4 Overall management of heart failure and classification 200
17.3 Hypertension and atrial fibrillation 201
17.3.1 Blood pressure measurement in atrial fibrillation 201
17.3.2 Detection of atrial fibrillation 202
17.3.3 Prevention and treatment of atrial fibrillation in hypertension 202
17.3.4 Oral anticoagulation and BP control 204
17.4 Valvular heart disease 206
17.4.1 Aortic stenosis 206
17.4.2 Aortic regurgitation 207
17.4.3 Mitral regurgitation 207
17.5 Cerebrovascular disease and cognition 208
17.5.1 Management of elevated BP in acute stroke 208
17.5.1.1 Acute hemorrhagic stroke 208
17.5.1.2 Acute ischemic stroke 209
17.5.2 Management of elevated BP in patients with previous stroke or transient ischemic attack 210
17.5.3 Management of patients with cognitive dysfunction and dementia 211
17.6 Vascular disease 213
17.6.1 Lower extremity arterial disease 213
17.6.2 Aortic dilatation, aneurysm and dissection 214
18. HYPERTENSION AND DIABETES MELLITUS 215
18.1. Epidemiology and risk classification 215
18.2 Benefits of BP-lowering 216
18.3 Antihypertensive drug treatment 217
19. HYPERTENSION AND THE KIDNEY 219
19.1 Treatment of hypertension in CKD 219
19.1.1 Treatment BP targets 220
19.1.2 Antihypertensive drug treatment 222
19.1.3 Special therapeutic challenges 223
19.1.4 Use of additional drugs for cardiovascular and nephroprotection in CKD 224
19.2 Renovascular disease 227
19.3 Hypertension in patients with kidney transplantation 228
20. HYPERTENSION AND OTHER SELECTED COMORBIDITIES 231
20.1 Obesity 231
20.1.1 Antihypertensive pharmacotherapy in obesity 231
20.1.2 Role of nonpharmacological weight loss intervention 232
20.1.3 Role of weight loss medications 233
20.1.4 Role of bariatric surgery 234
20.2 Obstructive sleep apnea 235
20.3 Asthma 236
20.4 Obstructive pulmonary disease 237
20.5 Gout and uric acid 238
20.6 Immune-mediated inflammatory diseases 238
20.6.1 Rheumatoid arthritis 239
20.6.2 Psoriasic arthritis 239
20.6.3 Systemic lupus erythematosus 240
20.7 Glaucoma in hypertension 240
20.8 Hypertension oncology 242
20.8.1 Hypertension and its association with cancer 242
20.8.2 Hypertension induced by cancer treatments 243
20.8.2.1 Hypertension induced by VEGF inhibitors 243
20.8.2.2 Hypertension induced by other anticancer drugs 244
20.8.2.3 Hypertension induced by adjunctive therapies, radiotherapy or surgery 245
20.8.3 Management of hypertension in cancer patients 245
20.8.3.1 BP monitoring and general management before start of cancer treatment 245
20.8.3.2 General BP-lowering therapy and management during cancer therapy 247
20.8.3.3 Treatment of hypertension induced by VEGF inhbitors 248
20.8.4 Follow-up and management of hypertension in cancer survivors 250
20.9 COVID-19 and hypertension 250
20.9.1 COVID-19 and RAS inhibitors 251
20.9.2 COVID-19 lockdown and hypertension management 252
20.9.3 Vaccination against SARS-CoV-2 and hypertension 252
20.9.4 Long COVID-19 and hypertension 253
21. FOLLOW-UP 253
21.1 Importance of follow-up 253
21.2 Adherence 255
21.2.1 Definitions 255
21.2.2 Prevalence of nonadherence and associated burden 255
21.2.3 Methods to detect nonadherence to antihypertensive treatment 256
21.2.4 Etiology of nonadherence to antihypertensive treatment 257
21.2.5 When and how to screen for nonadherence 257
21.2.6 Management of nonadherence to antihypertensive treatment 258
21.3 Clinical inertia 259
21.4 Patient empowerment 261
21.5 Follow-up of low-risk hypertensive patients and deprescribing 262
21.6 Use of telemedicine and tele-health technologies 262
21.7 Challenges of long-term follow-up 263
21.8 Role of general physician, pharmacies and team-based care 263
21.9 Hypertension clinics 265
21.10 Health risks at workplace 265
21.11 Patient organizations 266
22. GAPS IN EVIDENCE AND FUTURE OPPORTUNITIES 268
23. REFERENCES 270
INTRODUCTION
The year 2023 marks the 20th anniversary of the hypertension guidelines of the European Society of Hypertension (ESH), which were published for the first time in 2003, following a proposal by Professor Alberto Zanchetti (Fig. 1 ). Professor Zanchetti thought that it was time for Europe to express its view on diagnostic and treatment aspects of this crucially important medical condition rather than referring, as in the past, to guidelines issued by the WHO, with or without the ISH or the scientific societies in the USA. He played a fundamental role in these first guidelines [1] [2] [3] [4] [5]
FIGURE 1:
Alberto Zanchetti.
These 2023 hypertension guidelines have also been prepared only by the ESH because the ESC did not want to continue the previous understanding with ESH to generate “Joint Guidelines” with the equalparticipation of ESH and ESC. The rules of these guidelines, however, are largely, although not entirely, the same as those that were followed in the previous guidelines. That is, in the 2023 guidelines: (i) the members of the Task Force have been appointed by the ESH, based on recognized scientific and clinical expertise in one or more areas covered by the guidelines as well as on the documented absence of relevant conflicts of interest; (ii) selected members were initially asked to write a section or sections of the guidelines related to her or his main scientific expertise, and a small Steering Committee was appointed to harmonize the material received; (iii) multiple revisions of the text were made by back and forth interactions between the Task Force members, with a final collective critical review of the text and (iv) the final manuscript has been sent to external reviewers and further revised according to their suggestions and criticism. Particular attention has been given to the scoring of the strength of the diagnostic and treatment recommendations, which have been graded according to criteria partly different from those used in previous guidelines, i.e. with consideration for the study design but also for the quality of the collected data (see Section 1). Because of the questionable scientific value of voting, disagreements on treatment recommendations have not been resolved that way but by consensus on a shared text. Conflicting evidence or interpretation of the data have been openly admitted.
The similarity of the present and past guidelines extends to the scientific principles on which the guidelines have been based. The 2023 guidelines have been developed after careful search for new studies in the hypertension and related areas. Furthermore, as in the past, RCTs have been assigned a top value while also mentioning their limits when appropriate. However, all other relevant sources of knowledge (from observational studies down to clinical cases) have been considered, and even mechanistic studies have not been ignored, given their relevance for diagnostic and treatment decisions in individual patients. Particular attention has been given to real-world studies, which play a growing role in hypertension research and provide knowledge in areas that cannot be addressed by RCTs. Like the previous guidelines, the 2023 guidelines (i) regard their value as educational, which explains why the text addresses the data justifying the recommendations and (ii) emphasize that their recommendations are not invariably prescriptive for individual patients because they are based on average data and address conditions or diseases in general. In individual patients, the most appropriate diagnostic and treatment decisions may differ from those expressed by the guidelines.
The 2023 guidelines (i) contain several conceptual elements of novelty originated by research performed after the 2018 guidelines; (ii) deal more in depth with topics that were only briefly considered in the past and (iii) extend to several conditions that were previously unaddressed by guidelines, although frequently coexisting with hypertension and leading to specific needs for medical management. Although mainly referring to hypertension in adults, they include for the first time essential recommendations on hypertension in children, adolescents and the transition to young hypertensive adult individuals; and (iv) include a detailed index of sections and subsections focused on specific issues that has been prepared to facilitate reading of these various and multiple aspects. Furthermore, while the text addresses the sometimes nonunivocal evidence provided by research on a given issue, each section offers, as is now usual for many guidelines, a simple final list of key statements and recommendations that translate research achievements into practical use. We hope that this structure will make the ESH guidelines useful not only to the practicing physicians but also to hypertension experts and investigators.
WHAT IS NEW AND WHAT HAS CHANGED IN THE 2023 EUROPEAN SOCIETY OF HYPERTENSION ARTERIAL HYPERTENSION GUIDELINES?
1. Modified and simplified criteria for evidence grading recommendations
2. Pathophysiological background of primary hypertension
3. Clinical BP measurements by different methods and in different settings and clinical conditions
4. Thorough description of office, ambulatory and home BP measurements and value in different demographic and clinical conditions
5. Upgrading of out-of-office BP measurements in hypertension management
6. New HMOD measurements and their clinical value in hypertension work-up
7. New CV risk factors and update on CV risk assessment
8. Update and comprehensive summary of secondary forms of hypertension
9. Update on lifestyle interventions
10. Update on threshold and targets for antihypertensive drug treatment, including their possible heterogeneity in demographic and clinical subgroups of patients
11. Confirmation of preferred use of RAS blockers, CCBs and Thiazide/Thiazide-like diuretics, and their various combinations for BP-lowering treatment. Inclusion of BBs among the major antihypertensive drugs
12. Update on available combination-based drug treatment strategies, including the quadpill and the polypill
13. Emphasis and update on the diagnosis and management of true resistant hypertension
14. Update on use and position of renal denervation for antihypertensive treatment
15. Impact of hypertension and its treatment on cognitive dysfunction and dementia
16. Management of hypertension in older people according to the frailty and functional level
17. Update on treatment of hypertension in HFrEF and HFpEF
18. New diagnostic approaches to diagnosis and treatment in hypertensive patients with AF
19. Update on treatment in CKD, including kidney transplantation
20. Update and novel treatment approaches to patients with type 2 diabetes
21. Epidemiology, diagnosis and treatment in different BP phenotypes
22. Diagnosis, treatment and follow-up of hypertension in demographic and clinical conditions not or only marginally addressed in previous guidelines:
a. Children/adolescents and transition to adulthood
b. Young patients
c. Sex-related differences
d. Pregnancy and puerperium
e. Peripheral artery disease
f. Aortic aneurism
g. Valvular heart disease
h. Treatment of hypertension in acute cerebrovascular diseases
i. Hypertensive emergencies/urgencies
j. Perioperative hypertension
k. Obesity
l. COVID-19
m. Chronic inflammatory diseases
n. Hypertension in oncology
o. Baroreflex failure and dysautonomia
p. Glaucoma
23. Detailed recommendations on patients’ follow-up strategies, including assessment and minimization of nonadher-ence and clinical inertia.
24. Mention of new potential approaches to the treatment of hypertension and containment of hypertension-related workload (tele-health, team-based treatment, role of pharmacists)
1. METHODOLOGY AND DEFINITION OF EVIDENCE
1.1 Methodology of evidence grading
The 2023 ESH guidelines aim to summarize the best available evidence for all aspects of hypertension management. The guidelines were developed by a Task Force of 59 experts form European countries, representing the areas of internal medicine, cardiology, nephrology, endocrinology, general medicine, geriatrics, pharmacology and epidemiology. Each topic was assigned to a small group of Task Force members responsible for reviewing and summarizing the available evidence within that topic. The ‘class of recommendation’ (CoR) and ‘level of evidence’ (LoE) for all recommendations were reviewed by an Evidence Grading Committee to make sure that they complied with the predefined criteria outlined in the following. Draft versions were reviewed by the Steering Committee, Task Force members and external reviewers. The final version was approved by all Task Force members.
In accordance with previous versions of the ESH guidelines, a similar system separating CoR and LoE was applied [3,4] [3,4] Fig. 2 ). Importantly, the CoR and LoE are independent of each other, e.g. strong recommendations may build on weak evidence if the assumed benefit of an intervention or a diagnostic procedure greatly outweighs the potential risks.
FIGURE 2:
Class of recommendation (CoR) and level of evidence (LoE). BP, blood pressure, CVD, cardiovascular disease, HMOD, hypertension mediated organ damage, RCT, randomized controlled trial. a Limitations affecting the level of evidence include (but may not be limited to) high risk of bias, inability to account for important confounding factors in observational studies, questionable external validity and uncertain effect estimates (confidence intervals including negligible effect).
1.2 Level of evidence
The 2023 ESH guidelines employ the same terminology as in the 2018 ESC/ESH guidelines but with updated criteria for assessing the LoE. This revision was influenced primarily by the recommendations from the GRADE working group [6,7] [7]
The most important difference compared with the previous guidelines is the priority given to patient-important CV outcomes, such as stroke, MI, HF, ESKD and CV or total mortality, acknowledging that the primary aim of antihypertensive treatment is to reduce the risk of clinical outcomes and not only BP. Although BP reduction is strongly associated with a reduction in clinical events, interventions affecting BP may also affect other physiological systems with beneficial or harmful effects, and the benefit/harm ratio cannot be firmly established without clinical outcome trials.
Furthermore, risk of bias and statistical precision were considered when assigning the LoE. This means that recom-mendations supported by well conducted RCTs with CV outcomes were assigned LoE A, whereas recommendations supported by trials with a similar design and with similar outcomes, were downgraded to LoE B or C if the risk of bias was judged as high, or if effect estimates were imprecise. Meta-analyses may contribute to any level of evidence depending on the type of studies included and the quality of the meta-analysis itself [8]
For diagnostic tests and procedures, we have adopted the strategy recommended by the GRADE working group, assessing the evidence for benefit on patient-important outcomes [9]
2. PRINCIPLES OF HYPERTENSION PATHOPHYSIOLOGY
Hypertension is divided into a primary (formerly and still also currently referred to as ‘essential’) and secondary forms. Secondary hypertension originates from specific causes and can be detected in only a small fraction of hypertensive patients (see Section 6). Primary hypertension covers the remaining large fraction of the hypertensive population, and its origin depends on the complex interaction between a genetic background, a large number of environmental factors [10–12] [13] [11,12] [14] [15–17] Fig. 3 , primary hypertension may be accompanied by alterations of the RAAS, central and peripheral autonomic cardiac and vascular regulation, the endothelin system and other systems controlling vascular function, including nitric oxide and natriuretic peptides [13,18–22] [23,24] [25,26] [26] [26] [10–13,18–22,27] [25,26] [13,28] [29] [13] [30] Fig. 3 , strong evidence for the existence of reciprocal influences between different CV control systems, as a result of which alteration of one system may favor or reinforce alterations of the other systems and vice versa [31]
FIGURE 3:
Mechanisms involved in BP regulation and the pathophysiology of hypertension.
3. DEFINITION OF HYPERTENSION AND BP CLASSIFICATION
3.1 Definition of hypertension
According to the previous 2018 European and current international guidelines [32–34] [35] [36] [4]
3.2 Classification of hypertension
The classification of office BP and definition of hypertension grades also remain the same from previous guidelines (Table 1 ).
TABLE 1 - Classification of office BP and definitions of hypertension grades
Category
Systolic (mmHg)
Diastolic (mmHg)
Optimal
<120
and
<80
Normal
120–129
and
80–84
High-normal
130–139
and/or
85–89
Grade 1 hypertension
140–159
and/or
90–99
Grade 2 hypertension
160–179
and/or
100–109
Grade 3 hypertension
≥180
and/or
≥110
Isolated systolic hypertensiona
≥140
and
<90
Isolated diastolic hypertensiona
<140
and
≥90
The BP category is defined by the highest level of BP, whether systolic or diastolic.
a Isolated systolic or diastolic hypertension is graded 1, 2 or 3 according to SBP and DBP values in the ranges indicated. The same classification is used for adolescents ≥16 years old (see Section 15.1).
In addition to grades of hypertension, which are based on BP values, we also distinguish stages of hypertension as follows:
Stage 1: Uncomplicated hypertension (i.e. without HMOD or established CVD, but including CKD stage 1 and 2)
Stage 2: Presence of HMOD or CKD stage 3 or diabetes.
Stage 3: Established CVD or CKD stages 4 or 5.
Definition of BP categories, hypertension grades and stages according to office BP
3.3 Prevalence of hypertension
Hypertension is the most prevalent CV disorder in the world and according to the WHO, it affects 1.28 billion adults aged 30–79 years worldwide, two-thirds living in low-income and middle-income countries. In 2019, the global age-standardized average prevalence of hypertension in adults aged 30– 79 years was reported to be 34% in men and 32% in women [37] [37] [38,39] [40] [38]
3.4 BP relationship with risk of cerebral, cardiovascular and kidney events
There is a continuous relationship between the increase in BP and the risk of stroke, CAD, HF and development and progression of CKD. This applies to all ages and ethnic groups [41] [35] [42] [43] [44,45]
3.5 Hypertension and total CV risk assessment
Hypertension is often associated with other risk factors, including dyslipidemia, impaired glucose tolerance and type 2 diabetes, which further increase CV risk [46,47] Table 2 . Special risk factors apply to women, e.g. hypertension disorders in pregnancy and early-onset menopause [48,49] [1] [4] Fig. 4 ) as a separate condition that impacts on CV risk, regardless of the concomitance of HMOD, CVD or CKD. Only diabetic patients with well controlled, short-standing duration of the disease (less than 10 years), no evidence of HMOD and no additional CV risk factors are categorized as at moderate risk [33]
TABLE 2 - Factors that influence CV risk in patients with hypertension
Parameter for risk stratification, which are included in SCORE2 and SCORE2-OP
Sex (men >women)
Age
Level of SBPa
Smoking – current or past history
Non-HDL cholesterol
Established and suggested novel factors
Family or parental history of early onset hypertension
Personal history of malignant hypertension
Family history of premature CVD (men aged <55 years; women aged <65 years)
Heart rate (resting values >80 bpm)
Low birth weight
Sedentary lifestyle
Overweight or Obesity
Diabetes
Uric acid
Lp(a)
Adverse outcomes of pregnancy (recurrent pregnancy loss, preterm delivery, hypertensive disorders, gestational diabetes)
Early-onset menopause
Frailty
Psychosocial and socioeconomic factors
Migration
Environmental exposure to air pollution or noise
Additional clinical conditions or comorbidities
True resistant hypertension
Sleep disorders (including OSA)
COPD
Gout
Chronic inflammatory diseases
Nonalcoholic fatty liver disease (NASH)
Chronic infections (including long COVID-19)
Migraine
Depressive syndromes
Erectile dysfunction
Hypertension-mediated organ damage (HMOD)
Increased large artery stiffness:
ECG LVH (Sokolow–Lyon index >35 mm, or R in aVL ≥11 mm; Cornell voltage-duration product (+6 mm in women) >2440 mm∗ ms, or Cornell voltage >28 mm in men or >20 mm in women)
Echocardiographic LVH (LV mass index: men >50 g/m2.7 ; women >47 g/m2.7 (m = height in meters); indexation for BSA may be used in normal-weight patients: >115 g/m2 in men and >95/m2 in women
Moderate increase of albuminuria 30–300 mg/24 h or elevated ACR (preferably in morning spot urine) 30–300 mg/g
CKD stage 3 with eGFR 30–59 ml/min/1.73 m2
Ankle–brachial index <0.9
Advanced retinopathy: hemorrhages or exudates, papilledema
Established cardiovascular and kidney disease
Cerebrovascular disease: ischemic stroke, cerebral hemorrhage, TIA
Coronary artery disease: myocardial infarction, angina, myocardial revascularization
Presence of hemodynamically significant atheromatous plaque (stenosis) on imaging
Heart failure, including heart failure with preserved ejection fraction
Peripheral artery disease
Atrial fibrillation
Severe albuminuria > 300 mg/24 h or ACR (preferably in morning urine) >300 mg/g
CKD stage 4 and 5, eGFR < 30 mL/min/1.73m2
CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LV, left ventricle; OSA, obstructive sleep apnea.
a DBP is not included in the SCORE2/SCORE2-OP tool to estimate CV risk.
FIGURE 4:
Cardiovascular risk according to grade and stage of hypertension.
Estimation of total CV risk is recommended in each hypertensive patient because of its relevance for hypertension management. Computerized methods have been developed for estimating total CV risk, i.e. the likelihood of developing a CV event, usually within the following 10 years. Many risk stratification systems are based on the Framingham study, estimating the 10-year risk for both fatal and nonfatal CAD by SBP and the presence of other risk factors [50] [51] [52,53] [54] [54] [55] [56]
Estimating a person's 10-year CV risk by SCORE2 and SCORE2-OP is done by first selecting the correct country group and its corresponding risk stratification table [33] Table 2 ). DBP is not included in the SCORE2/ SCORE2-OP tool, which is a weakness. Overall risk should be stratified in all patients as shown in Fig. 4 . Risk stratification is particularly important in individuals with a high-normal BP or grade 1 hypertension, in whom it may influence the decision of whether or how fast to initiate BP-lowering drug treatment. In patients with grade 2 and 3 hypertension, drug treatment should be used regardless of the CV risk level, but risk stratification is nevertheless important for several treatment aspects and FU strategies. The disadvantage of this and other approaches to CV risk quantification is that the estimated risk is usually low in younger adults, particularly in young women who may be stratified as being at low risk even if they have more than one risk factor. Indeed the SCORE2 system does not even provide risk estimations for adult women and men younger than 40 years. By contrast, most older men are considered at high risk, despite being at little increased risk relative to their peers. For young adults, it may be more useful to estimate lifetime risk of CVD and potential CVD-free life-years gained through risk factor optimization [57] [1]
Risk assessment in hypertension with SCORE2 and SCORE2-OP
3.6 Screening versus case finding in the detection of hypertension
Because of the high prevalence of hypertension in the general population and its major role as a cause of death and morbidity, its detection is crucially important for public health. Studies performed in different countries have almost universally shown that a considerable fraction of hypertensive individuals is unaware of their condition, with an adverse reflection on the number of patients undergoing treatment and achieving BP control [37] [58] [59] [60] [60] [59] [61]
Screening for hypertension
3.7 Confirming the diagnosis of hypertension
Because of the variability of BP, an elevation of office BP (SBP 140 mmHg or DBP 90 mmHg) should be confirmed by at least two to three visits, unless the BP values recorded during the first visit are markedly elevated (grade 3 hypertension) or CV risk is high, including the presence of HMOD. Although available evidence has some diagnostic limitations and, in clinical practice, collecting ABPM or HBPM data on a large scale may be difficult, out-of-office BP measurements are a source of important clinical information. Therefore, ABPM, HBPM or data from both methods should be collected whenever feasible when office BP is elevated, to confirm the diagnosis of hypertension and identify specific BP phenotypes. ABPM and/or HBPM can be especially important when office BP data from different visits provide variable results. These issues are addressed in detail Section in 4.
4. BP MEASUREMENT AND MONITORING
4.1 Devices for blood pressure measurement
4.1.1 Standard cuff-based devices
The accurate determination of BP is the cornerstone for the diagnosis and management of hypertension [62] [63–65] [66,67] Table 3 .
TABLE 3 - Noninvasive arm cuff BP measuring devices
a
Manual auscultatory devices
Automated electronic devices
• Mercury sphygmomanometer
• Automated oscillometric (also wrist cuff devices)
a Cuffless BP devices are currently not recommended for clinical use.
The manual auscultatory BP measurement using a mercury or mercury-free sphygmomanometer is still the gold standard method for validation studies testing the accuracy of novel BP measurement technology [62] [66] [62] [62] [62] [62]
4.1.2 Cuffless blood pressure measuring devices
All cuff BP measurement methods have limitations, mainly because they provide snapshot BP values in static conditions and ignore the dynamic nature of BP, i.e. its variability in response to different daily challenges and activities [68,69] [68,70] [68,71] [68,71] [68,72] [68] [73] [68,74] [68]
4.1.3 Validation of blood pressure measuring devices
In the last 30 years, several scientific societies and associations have developed validation protocols for the evaluation of the accuracy of BP measuring devices [75] [76] [72] [72]
Unfortunately, validation for accuracy is not mandatory prior to the distribution of BP devices in the market [75,77] [62,78] [62] www.stridebp.org https://bihsoc.org/bp-monitors/ www.hochdruckliga.de/betroffene/blutdruckmessgeraete-mit-pruefsiegel www.validatebp.org www.hypertension.ca/bpdevices www.jpnsh.jp/com_ac_wg1.html [62]
Periodic calibration is necessary, particularly for aneroid devices, whereas for electronic devices, the performance of the BP measurement algorithm is not affected by use, and what is mainly needed is maintenance of the device parts (e.g. cuffs, tubes or connections). Checking for maintenance is advisable once a year for professional office and ambulatory BP devices and less frequently for home devices [72,79]
Devices for BP measurement
4.2 Standard office blood pressure measurement
Conventional or standard OBPM is the most well studied method for assessing BP and the one by which the diagnosis of hypertension, BP classification, the role of BP as a CV risk factor, the protective effect of antihypertensive treatment and the BP thresholds and targets of therapeutic interventions have been established [4,62,80] [4,62,81]
Despite its widespread long time adoption, use of OBPM is often poorly standardized, leading to inaccurate BP estimations, which often consists of an overestimation of BP and overdiagnosis and overtreatment of hypertension [4,62,81] [82] [62] [83] [62,72] [84] [62]
Additional important requirements for the proper use of OBPM are the following. One, diagnosis of hypertension should not be based on a single office visit, unless office BP indicates grade 3 hypertension (180/110 mmHg) or the patient is at high or very high risk based on the presence of HMOD or CVD [62] Fig. 4 ). In the vast majority of patients, an accurate evaluation of office BP requires at least two to three office visits at 1– 4-week intervals (depending on the BP level and CV risk) using the average of the last two out of three readings per visit [62,85–89] [62] [90] [62,91]
Office BP measurements
4.3 Unattended office blood pressure measurement
Unattended OBPM performed automatically (three or more readings) without the medical staff being present in the examination room (patient alone) favors a standardized office BP evaluation by ensuring a quiet environment, multiple BP readings and no talking [62,92] [93] [92,94,95] [96] [97] [92,98]
For these reasons, attended OBPM using an automated device and a standardized protocol (triplicate measurements in appropriate conditions and position) appears to be the most reasonable and practical BP measurement recommendation for clinical practice.
4.4 Blood pressure during exercise
BP increases during dynamic and static exercise, and the increase is more pronounced for SBP than for DBP [99] [100] [100] [101] [101] [100]
4.5 Blood pressure measurement in hospital
Because the mercury sphygmomanometer has been banned, mercury-free professional automated BP measurement devices such as digital electronic and hybrid devices (which combine some of the features of both electronic and auscultatory devices) should be used in hospital wards. Multiparametric monitors that measure BP, pulse oximetry, temperature and pulse rate are becoming increasingly popular. Some professional monitors offer a high-speed measurement mode that measures BP in less than 30 s, and others may offer the possibility to determine SBP in a very fast mode [102] [102] [103] [104] [105]
Automatic oscillometric measurements may also be considered a reasonably good alternative to intra-arterial measurements in ICUs, the resuscitation area or during surgery [106] [107] [108] [109] [110] [106]
4.6 Central blood pressure
Central (aortic) BP can be assessed noninvasively from peripheral BP waveforms, using tonometry or cuff-based devices and dedicated algorithms [111] [112,113] [114] [115] [116] [117,118] [119] [111] [119,120] [121]
4.7 Home blood pressure monitoring
HBPM provides multiple BP readings away from the office, in the usual environment of each individual [62,122] [62,122] [123,124] [125–128] [129,130] [131] [62,122,132–134] [135] [122,135–137] [138,139]
HBPM should be performed using automated upper arm cuff devices validated according to an established protocol (www.stridebp.org [62,122] [62,122] [62,122] [140,141] [142–145] [146]
Home BP values should be collected before planned office visits or whenever a clinically significant change in BP is suspected. Ideally, home BP should be monitored for 7 days and never for less than 3 days, with duplicate measurements (1 min apart) in the morning (before drug intake if treated) and the evening [62,122,147,148] [62,122,147,148] Fig. 5 ). HBPM helps to improve persistence of BP control during long-term treatment [149]
FIGURE 5:
Recommendations for BP measurements in the office and at home. Adapted
[62] .
a Use an automated electronic (oscillometric) device, which is validated according to an established protocol (
www.stridebp.org ). A device that takes triplicate readings automatically is preferred.
b The selection of an appropriate cuff size is crucial for accurate BP measurement and depends on the arm circumference of each individual – a smaller than required cuff overestimates BP and a larger underestimates BP. Using automated electronic devices select cuff size according to the device's instructions. At the initial visit, measure BP in both arms.
c Measure in the morning and the evening for 3–7 days. Use the average of all readings excluding the first day.
d Strong data linking OBP with CVD. Used in most observational and interventional outcome trials in hypertension.
Limitations of HBPM are that it requires patient training, is often performed by inaccurate devices, can induce anxiety and lead to overly frequent measurements that may be followed by treatment modifications by the patient [122] [122] [70,150] [151]
Home BP monitoring (HBPM)
4.8 Ambulatory blood pressure monitoring
Although patients have to remain immobile at the time of the BP measurements, ABPM provides multiple BP readings in conditions that reflect the usual environment, including daily activities and sleep [62] [128,152–154] [155] [134,156,157] [158,159] [160] [62] [154] [140,141]
ABPM is performed using fully automated devices programmed to record BP automatically at preselected intervals for 24 h in a usual workday [62,161] [62] [62,162] [163,164] Table 4 ).
TABLE 4 - Definitions of hypertension according to the correspondence of home and ambulatory BP values with office BP
Method
SBP (mmHg)
DBP (mmHg)
Office BPa
≥140
and/or
≥90
Ambulatory BP
Awake mean
≥135
and/or
≥85
Asleep mean
≥120
and/or
≥70
24 h mean
≥130
and/or
≥80
Home BP mean
≥135
and/or
≥85
a Refers to standard office BP measurements (not unattended measurements). Data compare the averages from cohorts of untreated and treated individuals. Given the low correlation between office and out-of-office BP values, individuals can have considerable discrepancies from the averages.
Additional indices derived from ABPM recordings have been considered, and some were found to have an independent prognostic value, including indices of BP variability [165–168] [156] [169–171] [165]
Ambulatory BP monitoring (ABPM)
4.9 Clinical indications for HBPM and ABPM
HBPM and ABPM share several clinical indications (Table 5 ). Both HBPM and ABPM can identify WCH and MH and should be considered when, based on OBPM, the odds of one or the other condition is higher, i.e. in patients with grade 1 hypertension for WCH and with high-normal BP for MH [62]
TABLE 5 - Clinical indications for home and ambulatory BP monitoring
Conditions in which white-coat hypertension is more common, e.g.:
• Grade I hypertension on office BP measurement
Conditions in which masked hypertension is more common, e.g.:
• High-normal office BP
In treated individuals:
• Confirmation of uncontrolled and true resistant hypertension
Suspected postural or postprandial hypotension in treated patients
Exaggerated BP response to exercise
Considerable variability in office BP measurements
Specific indications for ABPM rather than HBPM:
• Assessment of nocturnal BP and dipping status (e.g. sleep apnea, CKD, diabetes, endocrine hypertension, or autonomic dysfunction)
Specific indications for HBPM rather than ABPM:
• Long-term follow-up of treated individuals to improve adherence with treatment and hypertension control
Indications for repeat out-of-office BP evaluation (same or alternative method – HBPM/ABPM)
• Confirmation of white-coat hypertension or masked hypertension in untreated or treated individuals
BP, blood pressure; CKD, chronic kidney disease; CV, cardiovascular; HMOD, Hypertension-mediated organ damage.
There are also selective indications for ABPM or HBPM. ABPM should be performed when postural or postprandial hypotension is suspected, which is more frequently observed in older patients, diabetic patients, patients with dysautonomia, and patients developing anxiety with self-BP measurements or patients who are unable to perform and correctly report the results of the procedure. HBPM may be indicated in patients reporting discomfort or sleep problems with ABPM as well for checking long-term BP control during treatment. On the other hand, and despite technological advancement on HBPM, ABPM remains the best approach to characterize nocturnal BP phenotypes, i.e. the dipping status, which is frequently altered in conditions such as diabetes, OSA, obesity and CKD, with a prognostic reflection that extends to the general population. Nevertheless, it is important to know that different dipping patterns and other BP phenotypes based on office and out-of-office BP measurements have a limited reproducibility [172–174] [172,173]
In conclusion, despite the technological and clinical advances obtained in the last decades, use of out-of-office BP monitoring still faces some unanswered questions. The most important questions are (i) whether the improved prognostic ability associated with addition of out-of-office to office BP is substantial or modest, in particular when OBPM is appropriately measured [129,130] [4,62] [4,62,122,161] [159] [175]
4.10 Blood pressure variability
Old studies on ambulatory intra-arterial BP monitoring have shown that BP is highly variable during the day and to a lesser extent during the night [176,177] [69] [177] [178] [157,167,179,180] [157,167,179,180] [181] [166,182] [183–185] [186–188] [189] [190,191] [192]
5. PATIENT WORK-UP
The work-up required to obtain the information that is necessary in patients with suspected or established hypertension has been accurately described by previous guidelines [4] Tables 6–8 ).
TABLE 6 - Medical and family history
a
Personal history
• Time of the first diagnosis of hypertension, including records of any previous medical screening, hospitalization
• Stable or rapidly increasing BP
• Recordings of current and past BP values by self BP measurements
• Current/past antihypertensive medications including their effectiveness and intolerance
• Adherence to therapy
• Previous hypertension in pregnancy/preeclampsia
Risk factors a
• Family history of hypertension, CVD, stroke or kidney disease
• Smoking history
• Dietary history, alcohol consumption
• Lack of physical exercise/sedentary lifestyle
• Weight gain or loss in the past
• History of erectile dysfunction
• Sleep history, snoring, sleep apnea (information also from partner)
• Distress or eustress with job or at home (subjective stress level)
• Long-term cancer survivor
History and symptoms of HMOD, CVD, stroke and kidney disease
• Brain and eyes: headache, vertigo, syncope, impaired vision, TIA, sensory or motor deficit, stroke, carotid revascularization, cognitive impairment, memory loss, dementia (in older people)
• Heart: chest pain, shortness of breath, edema, myocardial infarction, coronary revascularization, syncope, history of palpitations, arrhythmias (especially AF), heart failure
• Kidney: thirst, polyuria, nocturia, hematuria, urinary tract infections
• Peripheral arteries: cold extremities, intermittent claudication, pain-free walking distance, pain at rest, ulcer or necrosis, peripheral revascularization
• Patient or family history of CKD (e.g. polycystic kidney disease)
History of possible secondary hypertension
• Young onset of grade 2 or 3 hypertension (<40 years), or sudden development of hypertension or rapidly worsening BP in older patients
• History of repetitive renal/urinary tract disease
• Repetitive episodes of sweating, headache, anxiety or palpitations, suggestive of pheochromocytoma
• History of spontaneous or diuretic-provoked hypokalemia, episodes of muscle weakness and tetany (hyperaldosteronism)
• Symptoms suggestive of thyroid disease or hyperparathyroidism
• History of or current pregnancy, postmenopausal status and oral contraceptive use or hormonal substitution
Drug treatments or use (other than antihypertensive drugs)
• Recreational drug/substance abuse, concurrent therapies including nonprescription drugs, e.g. glucocorticoids, NSAIDs/COX-2 inhibitors, paracetamol (acetaminophen), immunosuppressive drugs, anticancer drugs, nasal vasoconstrictors
a Additional factors to be considered are listed in
Table 2 (see Section 3.5).
TABLE 7 - Comprehensive physical examination for hypertension
a
Body habitus
• Weight and height measured on a calibrated scale, with calculation of BMI
• Waist circumference
Signs of hypertension-mediated organ damage
• Neurological examination and cognitive status
• Fundoscopic examination for hypertensive retinopathy in emergencies
• Auscultation of heart and carotid arteries
• Palpation of carotid and peripheral arteries
• Ankle–brachial index
Signs of secondary hypertension (Section 6)
• Skin inspection: cafe-au-lait patches of neurofibromatosis (pheochromocytoma)
• Kidney palpation for signs of renal enlargement in polycystic kidney disease
• Auscultation of heart and renal arteries for murmurs or bruits indicative of aortic coarctation, or renovascular hypertension
• Signs of Cushing's disease or acromegaly
• Signs of thyroid disease
a Can be adapted according to the clinical circumstance.
TABLE 8 - Selected standard laboratory tests for work-up of hypertensive patients
a
• Hemoglobin and/or hematocrit
• Fasting blood glucose and HbA1c
• Blood lipids: total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides
• Blood potassium and sodium
• Blood uric acid
• Blood creatinine (and/or cystatin C) for estimating GFR with eGFRa formulas
• Blood calcium
• Urine analysis (first voided urine in the morning), multicomponent dipstick test in all patients, urinary albumin/creatinine ratio, microscopic examination in selected patients
eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
a Can be adapted according to the clinical circumstance.
5.1 Personal and medical history
5.2 Physical examination
5.3 Routine clinical chemistry investigations
5.4 Other investigations in hypertension
5.4.1 Electrocardiogram
A 12-lead ECG is part of the routine diagnostic evaluation in all hypertensive patients. LVH represents an important and typical HMOD, which increases markedly with long-standing hypertension and its severity [193] Table 9 ). The presence of strain (ST-T depression in lateral anterior leads) is the most serious sign of LVH on ECG [194] [195] [196]
TABLE 9 - Assessment of hypertension-mediated organ damage (HMOD)
a
Basic screening tests for HMOD recommended for all hypertensive patients
Aim
12 lead ECG
Measure HR and AV conduction, detect cardiac arrhythmias, myocardial ischemia and infarction, screen for LVH
Urine albumin : creatinine ratio (UACR)
Detect and classify CKD
Serum creatinine and eGFR
Detect and classify CKD
Extended screening for HMOD
Echocardiography
Evaluate structure and function of the ventricles and left atrium, detect valvular disease, aortic root diameter and ascending aortic aneurysm
cfPWV or baPWV
Evaluate aortic/large artery stiffness
Carotid artery ultrasound
Determine carotid intima-media thickness, plaque and stenosis
Coronary artery calcium scan
Determine the presence and extent of coronary calcium to predict CAD events
Abdominal aorta ultrasound
Screen for aortic aneurysm
Kidney ultrasound
Evaluate size and structure of kidney, detect renovascular disease, determine RRI (by spectral doppler ultrasonography)
Spectral doppler ultrasonography
Diagnosis of renovascular disease and determination of RRI
ABI
Screen for LEAD
Retina microvasculature
Detect microvascular changes
Cognitive function testing (MMSE, MoCA)
Screen for early stages of dementia
Brain imaging (CT, MRI)
Detect structural brain damage
a Can be adapted according to the clinical circumstance.
5.4.2 Kidney ultrasound
Due to its low cost and widespread availability, ultrasound imaging of the kidney is commonly used for information on renal morphology (kidney size and structure, roughness, adiposity, kidney stones) and, when contrast-enhanced perfusion is added, microstructure, stiffness, inflammation, edema and abscesses [197] [198]
5.4.3 Selected biomarkers and genetic markers
5.4.3.1 Lipoprotein (a)
Epidemiological and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and CV outcomes in different ethnicities [199–201]
5.4.3.2 Cardiac biomarkers
A large number of studies indicate that both high-sensitivity troponins (hs-cTnT and hs-cTnI) and natriuretic peptides (BNP and NT-proBNP) are able to detect individuals that are at higher CV risk.
Studies suggest that on top of their role in the diagnosis and management of several cardiac conditions including asymptomatic LV dysfunction [202] [203] [204] [205]
5.4.3.3 Kidney markers
Cystatin C, a 13-kDa cysteine proteinase inhibitor protein, is produced by all nucleated cells at a steady rate and is freely filtered by the kidney with near-complete reabsorption and catabolism in the proximal tubule, and thus no significant urinary excretion [206] [207] [208,209]
Available kidney tubule biomarkers can be grouped into those that reflect tubule cell injury (kidney injury molecule 1, epidermal growth factor, monocyte chemoattractant protein one) and those that reflect tubule cell dysfunction (a 1-microglobulin and uromodulin). These biomarkers provide new opportunities to monitor the response to treatments in CKD patients [210] [211,212]
5.4.3.4 Genetic markers
A positive family history is a frequent feature of hypertensive patients, with hypertension heritability estimates that vary between 35 and 50% in most studies. Rare monogenic forms of hypertension belong to secondary forms of hypertension (see Section 6) [12] [213] [214] [215]
5.5 Assessment of hypertension-mediated organ damage
HMOD refers to structural or functional changes in large and small arteries or end-organs (brain, heart, kidney and eyes), caused by elevated BP and is a marker of preclinical or asymptomatic CV or kidney disease [4] [216] [217] [4,218,219] [220] [220] Table 9 .
5.5.1 HMOD in the heart
In hypertension, the heart is directly exposed to an increased load with consequent development of several structural and functional alterations, which are asymptomatic at an early stage but represent a potent risk factor for subsequent CV events, such as HFpEF or HFrEF, AF, CAD, sudden death and also stroke. Preclinical or asymptomatic hypertensive heart disease includes LVH, LV geometric changes, impaired diastolic and systolic function, LA enlargement and greater incidence of arrhythmias. In clinical practice, most or all parameters indicating hypertensive heart disease should be evaluated in a comprehensive examination, using the ECG and available imaging techniques.
5.5.1.1 Left ventricular mass and geometry
As mentioned above, LVH, as detected by two-dimensional transthoracic echocardiography (2D-TE) is a more sensitive marker of LVH than ECG. It is also a major predictor of morbidity and mortality in both hypertensive patients and the general population [221–223] [224,225] [226] [227] [227] [220] [194,228–230] Table 10 ).
TABLE 10 - Advantages and disadvantages of methods to assess LVH in clinical practice
ECG
ECHO
3D ECHO
CMR
Sensitivity ++
+++
++++
++++
Specificity +++
+++
++++
++++
Reproducibility ++++
+++
++++
++++
Prognostic significance ++++
++++
+
++++
Availability ++++
+++
++
++
Cost +
++
++
++++
When LVH is detected, it is recommended to follow patients, preferably by echocardiography for monitoring the evolution of LVH and other structural and functional modifications of the heart, the goal being LVH regression. This may take years, cannot always be achieved, and is less achievable in women, and patients with diabetes, obesity and African American ethnicity [231]
5.5.1.2 Transthoracic echocardiography
2D-TE represents the first and most widely used imaging technique to assess LVH. Image quality is the most important factor for reliable measurements. Use of artificial intelligence has been reported to provide a more accurate measurement of cardiac structural and functional alterations [232] [221,229,230] [216] [233] [230,234] [235] [236,237]
5.5.1.3 Cardiac magnetic resonance
Cardiac magnetic resonance is the gold standard for quantification of cardiac structure and function in clinical studies. An important application of cardiac magnetic resonance is tissue characterization, using late gadolinium enhancement [238] [239] [240]
Left atrial and aortic root dimensions. LA dilatation is usually a response to increased LV filling pressure and is independently associated with adverse CV events and greater incidence of AF [241,242] [243]
Left ventricular diastolic dysfunction. LV diastolic dysfunction is usually the first manifestation of cardiac damage, even before the development of LVH. LV diastolic dysfunction can be detected as an alteration of transmitral inflow pattern (E /A ratio) at Echo-doppler examinations. Initial LV abnormal relaxation may progress to increased LV filling pressure, which may be detected using additional parameters, such as tissue doppler of mitral annulus (e ’ velocity) and estimated pulmonary pressures (tricuspid regurgitation retrograde velocity) [244] [245] [246]
5.5.1.4 Computed tomography of the heart
Computed tomography may be used in hypertensive patients to obtain noninvasive coronary angiography, mainly to exclude coronary artery disease, when signs and symptoms are atypical, and the results of other cardiological examinations (i.e. exercise ECG, perfusion scintigraphy, stress echocardiography) are ambiguous.
Coronary artery calcium scanning offers the possibility to detect coronary atherosclerosis in its early stages. Coronary artery calcium is identified by noncontrast cardiac-gated multislice computed tomography of the heart, which is a rapid test using low radiation (<1 mSv) that can be performed at low cost by any modern multidetector computed tomography scanner. Coronary artery calcium is increased in individuals with high BP, predicts the risk of new-onset hypertension, and is also a predictor of CV events in patients with and without hypertension [247,248] [249,250]
5.5.2 HMOD in the arteries
5.5.2.1 Carotid artery IMT and plaques
Carotid intima– media thickness, combines the thickness of the intimal and medial layer of the carotid artery, is quantified by carotid ultrasound, and can be considered a marker for the early stage of atherosclerosis [251] [218] [252,253] [254] [255,256] [257] m m/year reduction of carotid IMT progression resulted in a significant 9% reduction of the risk of CV outcomes. However, separately analyzed cIMT changes by antihypertensive treatment did not show a significant relationship with CV events, and this was also the case for the separately analyzed cIMT changes with lipid lowering and antidiabetic treatment. The presence of a carotid plaque can be defined by an IMT 1.5 mm, or by a focal increase in thickness of 0.5 mm or 50% of the surrounding carotid IMT value [258] [252,253] [259] [260]
5.5.2.2 Pulse wave velocity
Increase in large artery stiffness is the most important pathophysiological determinant of age-related increase of SBP and reduction of DBP (and thus of ISH or predominant systolic hypertension) and increase in pulse pressure in the old population [261] [262] [263–265] [266] [267] [268,269] [270] [271] [272] [273,274]
A large body of evidence exists that assessment of large artery stiffness, using cfPWV or baPWV, can be clinically useful in hypertensive patients. Evidence from the Framingham and European studies has shown that increase of arterial stiffness is highly prevalent in the hypertensive population [254,275,276] [277,278] [263] [279] [264] [280] [281] [282] [283,284] [33,285] [286] [287]
5.5.2.3 Ankle– brachial index
ABI is the ratio between SBP in ankle and brachial SBP. Measurements are made with the patient supine, using a continuous wave Doppler, a BP sphygmomanometer (preferentially) or an automated oscillometric device [275] [288]
5.5.3 HMOD in the kidney
Hypertension is the second most important cause of CKD after diabetes and can also be the consequence of a primary kidney disease. Deterioration of kidney function can be detected by routine laboratory testing, using widely available equations for estimation of GFR (eGFR) based on serum creatinine [289] [290,291] [289] [289]
A lower eGFR and a higher amount of albuminuria, indicating loss of kidney function and kidney damage, are both independent and additive predictors of increased CV risk and progression of kidney disease [291,292] [33]
On the other hand, whether treatment-induced changes in eGFR and ACR are predictive of kidney and CV outcomes is still under discussion. Short-term effects of eGFR and albuminuria by pharmacological intervention, either an increase or a decrease, may be mixed up with long-term reductions of eGFR and albuminuria. Treatment-associated long-term changes of eGFR have shown a relationship with kidney failure and CV events, whereas treatment effects on proteinuria or albuminuria have been inconsistently related with mortality. In the ONTARGET study, change of albuminuria after 2 years was assessed in more than 20 000 patients at high CV risk, and change of albuminuria was related to total mortality, CV events and kidney outcomes in both diabetic and nondiabetic patients [293] [294,295] [289] [296] [297] [298,299]
5.5.4 HMOD in the brain
Hypertension is a major risk factor, not only for acute cerebrovascular events such as ischemic stroke, intracranial hemorrhage and TIA, but also for chronic and asymptomatic or oligosymptomatic brain damage, which may ultimately lead to dementia. In particular, long-standing arterial hypertension is known to exert a cumulative effect on cerebrovascular damage, including atherosclerosis, white matter lesions, silent brain infarcts, microinfarcts, microbleeds and brain atrophy [300] [301]
Hypertension causes pathological alterations in cerebral microvessels that damage microvascular structure, network architecture and function, and contribute to the genesis of cerebral microbleeds and lacunar infarcts. The latter are small infarcts, 2–20 mm in diameter, in the deep cerebral white matter, basal ganglia or pons that are presumed to result from the occlusion of a single, small perforating artery supplying the subcortical areas of the brain. In addition, white matter lesions, i.e. areas of abnormal myelination in the brain, that are best visualized as hyperintensities on T2-weighted and fluid-attenuated inversion recovery (FLAIR) MRI sequences, develop in hypertension [302,303] [303,304]
In hypertension, aortic stiffening leads to increased propagation of high BP pulsatility to the high flow–low impedance cerebral circulation [305] [306,307] [308] [309] [310] [311] [300] [312] [276] [300,304] [300] [300]
5.5.5 HMOD in the eye
The classification of hypertensive retinopathy is based on fundoscopy, which permits the detection of retinal lesions such as hemorrhages, microaneurysms, hard exudates and cotton wool spots (grade 3), papilledema and/or macula edema (grade 4). These alterations are indicative of severe retinopathy and are specific, reproducible and predictive of all-cause mortality [313] [314] [315] [316]
Retinal arterioles may represent a useful indicator of the remodeling of the microcirculation in other vascular beds of hypertensive patients. In recent years, Scanning Laser Doppler and Adaptive Optics have been increasingly used to estimate the wall-to-lumen ratio of retinal arterioles [317] [318] [319] Table 11 ).
TABLE 11 - Criteria to define HMOD
Measurement
Parameter
Abnormality threshold
ECG
LVH
SV1 + RV5 (Sokolow–Lyon)
>35 mm
R wave aVL
≥11 mm
SV3 + RaVL (Cornell voltage)
>28 mm (M), >20 mm (W)
LVH
Cornell voltage (+6 mm in W) × QRS duration
>2440 mm s
ECHO
LVH
LVM/BSA (g/m2 )
>115 (M), >95 (W)
LVM/height (g/m2.7 )
>50 (M), >47 (W)
RWT
LV conc. Remodeling
≥0.43
LV chamber size
LVDDiam/height
>3.4 (M), >3.3 (W) cm/m
LV diastolic dysfunction
e′ velocity septal<7 cm/s
e′ velocity lateral<10 cm/s
LV filling pressure
E /e′ average ratio>14
LAV/BSA
>34 ml/m2
LAV/height2
>18.5 (M) or >16.5 (W) ml/m2
LV systolic dysfunction
GLS
<20%
Kidney
Function
eGFR
<60 ml/min/1.73 m2
Albuminuria
UACR
>30 mg/g
Renal resistive index
RRI
>0.7
Large artery stiffness
Pulse pressure
Brachial PP (>60 years)
≥60 mmHg
Pulse wave velocity
baPWV (in people 60–70 years)
>18 m/s
cfPWV (in people 50–60 years)
>10 m/s
Carotid atherosclerosis
Plaque
IMT ≥1.5 mm, or focal increase in thickness ≥0.5 mm, or 50% of surrounding IMT
IMT
>0.9 mm
Coronary atherosclerosis
CAC
Age-specific and sex-specific reference value
LEAD
ABI
<0.9
Eye
KWB score
Grade III (hemorrhages, microaneurysms, hard exudates and cotton wool spots) and grade IV (papilledema and/or macula edema)
Microvascular changes
Wall-to-lumen ratio
no established reference value
ABI, ankle–brachial index; ACR, albumin : creatinine ratio; baPWV, brachial–ankle pulse wave velocity; BSA, body surface area; CAC, coronary artery calcium; cfPWV, carotid–femoral pulse wave velocity; DDim, diastolic dimension; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; GLS, global longitudinal strain; IMT, intima–media thickness; KWB, Keith–Wagener–Barker; LAV, left atrial volume; LEAD, lower extremity artery disease; LVH, left ventricular hypertrophy; LVM, left ventricular mass; M, men; RWT, relative wall thickness; w, women.
5.6 Using HMOD to help stratify risk in hypertensive patients
Assessment of HMOD should be performed at the time when thediagnosis of hypertension has been confirmed in orderto fine-tune the CV and kidney risk stratification. The data may influence the decision to initiate or intensify drug treatment. However, assessment of HMOD is also relevant during FU, as it can help physicians to evaluate the efficacy of therapy. A reduction in a previous HMOD may indicate the success of the therapy while, by contrast, the persistence/increment of HMOD may be a clue to review the prescribed treatment, with lack of adherence being a predominant reason. Likewise, the absence of HMOD at the time of initial evaluation should be monitored in the future, as new development of HMOD usually indicates a higher risk. As a consequence, repetition of HMOD assessment should be a main aspect of the FU (see Section 21).
As reported above, HMOD assessment may play a role in stratifying the risk of patients with hypertension. In this regard, LVH [216,221] [277] [320] [253,321] [252] [322] [322] [252] [276] [224,225] [277] [320] [253] [322] [288]
In post hoc analyses, BP treatment-induced regression of some (but not all) manifestations of HMOD has been associated with a reduction in CV risk, thereby providing additional information on the effectiveness of treatment in individual patients. This has been best illustrated for the treatment-induced regression of LVH measured by either ECG or echocardiography [229,323] [324,325] [326–329] [330,331] [257] [332] [287] [333] [334]
Guidance on use and repetition of HMOD with time needs to consider several factors, such as the ability of the HMOD marker to be modified by treatment, the reproducibility of the changes, the time necessary to detect them, their prognostic value and the costs. The characteristics of the most frequent HMOD are shown in Fig. 6 .
FIGURE 6:
Characteristics of the most frequent markers of HMOD in hypertension.a Using modern adaptive optics technology.
5.7 When to refer a patient to a specialist or for hospital-based care
Although most patients with hypertension are managed in the primary care setting, in some circumstances, a hospital-based evaluation and treatment may be required, keeping in mind that out-of-office or office-based care of hypertensive patients also depends on the healthcare organization of a given country (Table 12 ).
TABLE 12 - When to refer a hypertensive patient to a specialist or to hospital
• Patients in whom secondary hypertension is suspected
• Young patients (<40 years) with grade 2 or 3 hypertension in whom secondary hypertension should be excluded
• Patients with sudden onset or aggravation of hypertension when BP was previously normal
• Patients with treatment-resistant hypertension
• Need of more detailed assessment of HMOD, which might influence treatment decision
• Requirement of more in-depth specialist evaluation from the referring doctor
• Hypertensive emergencies (inpatient care will usually be needed)
6. SECONDARY HYPERTENSION
Secondary forms of hypertension account for only a small fraction of the overall hypertension prevalence, which is largely due to primary hypertension. However, their true prevalence is not precisely known, because available data may be confounded by the selection bias of the studies reported in the literature, the number of undiagnosed cases and the varying definition of secondary forms of hypertension. Hence, the classification of OSA, a phenotype more frequently observed in obese patients, as a secondary form of hypertension is questioned by many experts. Nevertheless, despite their limited prevalence, detection and management of secondary forms of hypertension is of utmost importance, because these forms often carry a high or very-high risk of morbidity and mortality and can possibly be cured by timely treatment of their cause [335] Table 13 ). Although secondary forms of hypertension are particularly frequent in younger patients (<40 years) with an elevated BP, some forms (such as atherosclerotic renovascular disease) are more common at an older age (Fig. 7 ).
TABLE 13 - Patient characteristics that should raise the suspicion of secondary hypertension
Younger patients (<40 years) with grade 2 or 3 hypertension or hypertension of any grade in childhood
Sudden onset of hypertension in individuals with previously documented normotension
Acute worsening of BP control in patients with previously well controlled by treatment
True resistant hypertension hypertension
Hypertensive emergency
Severe (grade 3) or malignant hypertension
Severe and/or extensive HMOD, particularly if disproportionate for the duration and severity of the BP elevation
Clinical or biochemical features suggestive of endocrine causes of hypertension
Clinical features suggestive of atherosclerotic renovascular disease or fibromuscular dysplasia
Clinical features suggestive of obstructive sleep apnea
Severe hypertension in pregnancy (>160/110 mmHg) or acute worsening of BP control in pregnant women with preexisting hypertension
FIGURE 7:
Incidence of selected forms of secondary hypertension according to age.
Screening all hypertensive patients for secondary hypertension is not feasible or cost-effective. However, secondary forms of hypertension frequently show clinical findings that suggest their presence and even their specific nature. More common causes of secondary hypertension are primary aldosteronism, renal parenchymal disease and renovascular disease, while Cushing syndrome, phaeochromocytoma and paraganglioma, or coarctation of the aorta are less frequently observed. The different types of secondary hypertension show different age distributions (Fig. 7 ).
Diagnostic suspicion (Table 13 ) should prompt immediate referral to specialized hypertension centers where the appropriate diagnostic tests and subsequent treatments can be performed [213,336–341] [213,338–341] Figs. 8a–e .
FIGURE 8:
A Atherosclerotic renovascular disease (ARVD). (a) The prevalence of ARVD differs considerably between studied populations – in a population-based cohort >65 years of age, ARVD (defined as >60% stenosis) was identified in 6.8%. Among hypertensives, the prevalence of ARVD is probably around 1% in patients with mild hypertension, but may be as high as 14%–24% in patients with severe or resistant hypertension. (b) In view of the frequent association with atherosclerotic lesions in other arterial beds, a cardiovascular work-up should be considered. (c) Medical management of ARVD should aim to reduction of CV risk and protection of kidney function; hypertension control is a prominent goal. With regard to antihypertensive treatment, an ACEi or an ARB are considered as first-line option (contraindicated in bilateral renal artery stenosis or stenosis in a solitary kidney). (d) Observational data showed that renal artery stenting in addition to medical therapy is associated with renal and CV benefits in patients presenting with high-risk ARVD phenotypes, e.g. resistant hypertension, recurrent pulmonary edema, heart failure and deterioration of kidney function.
FIGURE 8:
B Fibromuscular Dysplasia (FMD). (a) FMD occurs predominantly in young or middle-aged women. However it may be diagnosed at any age, both in women and men. Renal FMD is the second cause of renovascular hypertension after atherosclerotic renal artery stenosis. (b) Two subtypes of FMD have been described: multifocal FMD (80–90% of cases) and focal FMD (10–20% of cases). The characteristic lesion of multifocal FMD is the “string of beads”, characterized by alternating areas of stenosis and dilatation in the mid and distal portions of the artery. Focal FMD is characterized by focal stenosis of variable length, which may occur in any part of the artery and requires exclusion of atherosclerosis, inflammatory or genetic arteriopathies. (c) In a meta-analysis, the rate of cure of hypertension after angioplasty was 36% (range 14–85%) but may be much higher in younger patients with recent onset hypertension. Angioplasty deserves also to be considered in patients with renal FMD and resistant hypertension. (d) Stent kinking and fracture have been reported in the setting of renal FMD. Accordingly, stenting is usually not recommended in renal FMD and reserved for treatment of flow-limiting per-procedural dissection or in case of renal artery aneurysm. (e) In over 50% of cases, patients with renal FMD have lesions in one or more other arterial beds (multivessel FMD). Patients with FMD also often have arterial dissections, aneurysms or marked arterial tortuosity. For these reasons, it is recommended to perform at least once a life-time head to pelvis angio-CT or if contraindicated MR-angiography in all patients with FMD.
FIGURE 8:
C Primary aldosteronism (PA). (a) Depends on the population screened – ranges from 3.2% to 12.7% in primary practice and from 1% to 30% in referral centers; prevalence increases with the severity of hypertension to 20%. (b) PA prevalence in patients with adrenal incidentaloma ranges from 1.6% to 4.3%. (c) ARR requires at least normalization of plasma potassium and interruption of existing treatment with spironolactone and BBs. (d) Overall, seated SIT appears reliable and less complicated than FST and SLT. CCT may be a good alternative in patients at risk of potential fluid overload (patients with kidney failure or HF). (e) Although the majority of PA cases are sporadic, up to 5% of patients may have a familial form of the disease. Genetic testing should be performed in all patients with early onset PA (i.e. <20 years of age), irrespective of the severity of the clinical phenotype, and in patients with a family history of PA. (f) Steroidal MRAs are the treatment of choice for PA in patients with bilateral adrenal disease or unilateral disease that cannot be surgically treated.
FIGURE 8:
D Pheochromocytoma and paraganglioma (PPGL). (a) Varying from 0.2% to 0.6% in hypertensive patients to less than 0.05% in the general population. (b) These symptoms are most commonly reported whereas other (pallor, tremor, nausea, panic/anxiety) occur at a much lower frequency. (c) Routine genetic testing is recommended in all PPGL. The most frequently involved genes include SDHB, SDHD, VHL, RET and NF1. PPGL in patients with a known SDHB mutation do carry higher malignant potential and so require close FU with regular imaging and biochemical screening. (d) Presurgical medical preparation using an alpha-1 receptor blocker (doxazosin or phenoxybenzamine) as first choice is always required for preventing life-threatening perioperative cardiovascular complications. (e) All patients operated for a PPGL should be followed up annually for at least 10 years. The first FU should be at 2–6 weeks after surgery to verify completeness of surgical resection.
FIGURE 8:
E Cushing's syndrome. (a) In specific populations including patients with difficult to control hypertension or type 2 diabetes. The incidence in the general population is 0.7-2.4 per million per year. (b) In case of abnormal initial result of a first screening test, positivity of at least one of the remaining screening tests is required to establish the diagnosis.
6.1 Genetic causes of secondary hypertension
Several rare monogenic forms of hypertension have been described, in which mutations in specific genes, mostly coding for proteins involved in sodium tubular reabsorption or steroid metabolism account for the pathogenesis of hypertension (Table 14 ). An exception is represented by familial autosomal dominant hypertension with brachydactyly, in which the pathogenetic mechanism resides inside the vascular smooth muscle cells [342] [12] Fig. 8 ).
TABLE 14 - Rare genetic causes of secondary hypertension
[343]
Condition
Phenotype
Mechanism and Treatment
Liddle syndrome
Hypokalemia, metabolic alkalosis, low PRA or PRC, low PAC
Increased renal tubular ENaC activity; responds to treatment with amiloride
Apparent mineralocorticoid excess
Hypokalemia, metabolic alkalosis, low PRA or PRC, low PAC
Decreased 11β-hydroxysteroid dehydrogenase isoenzyme 2; responds to spironolactone
Gordon syndrome
Hyperkaliemia, metabolic acidosis, low PRA or PRC, low/normal PAC
Overactivity of the sodium-chloride cotransporter; responds to thiazides
Geller syndrome
Pregnancy-exacerbated hypertension, low PRA or PRC, low PAC
Agonist effect of progesterone on the mineralocorticoid receptor (which is constitutively active); responds to amiloride, spironolactone activates instead of blocking the receptor
Glucocorticoid-remediable aldosteronism (familial hyperaldosteronism type 1)
Hypokalemia, metabolic alkalosis, low PRA or PRC, increased PAC
Chimeric CYP11B1/CYP11B2 gene; responds to glucocorticoids
Familial hyperaldosteronism type 2
Hypokalemia, metabolic alkalosis, low PRA or PRC, increased PAC
Increased activity of CLCN2 chloride channel; responds to steroidal MRA
Familial hyperaldosteronism type 3
Hypokalemia, metabolic alkalosis, low PRA or PRC, increased PAC
Loss of selectivity of KCNJ5 potassium channel; patients who do not respond to steroidal MRA require bilateral adrenalectomy
Familial hyperaldosteronism type 4
Hypokalemia, metabolic alkalosis, low PRA or PRC, increased PAC
Increased activity of CACNA1H calcium channel; responds to steroidal MRA
PASNA syndrome (primary aldosteronism, seizures and neurological abnormalities)
Hypokalemia, metabolic alkalosis, low PRA or PRC, increased PAC; neurological defects coexists
Increased activity of CACNA1D calcium channel; responds to steroidal MRA and CCB
11beta-hydroxylase deficiency
Hypokalemia, metabolic alkalosis, low PRA or PRC, low PAC, virilization of female individuals
Reduced activity of 11β-hydroxylase with increase of DOC and androgens; responds to glucocorticoids
17alpha-hydroxylase deficiency
Hypokalemia, metabolic alkalosis, low PRA or PRC, low PAC, pseudohermaphroditism in male individuals
Reduced activity of 17α-hydroxylase with increase of DOC and reduction of androgens; responds to glucocorticoids
Autosomal dominant hypertension with brachydactyly [342]
Brachydactyly type E (BDE), short stature, severe hypertension (salt-independent, age-dependent), high risk of death from stroke before age 50
PDE3A mutations upregulated the cAMP-hydrolytic activity that results in lower cAMP levels in vascular smooth muscle cells
7. LIFESTYLE INTERVENTIONS
7.1 Relevance of lifestyle changes
The adoption of a heart-healthy lifestyle is a fundamentally important approach to prevent or delay the onset of hypertension, reduce the elevated BP values and lower the associated increase of CV risk [4,344] [345] [346–349] [349] [350,351] [352] [353–355] [356–359] [360–362]
The Achilles’ heel of treatment strategies based on or inclusive of nonpharmacological interventions is the low persistence of the prescribed measures. This is in part the result of the difficulty of permanently adhering to lifestyles that may interfere with working or home habits and needs. Some lifestyle measures also have a cost, which may not be reimbursed by healthcare providers. After prescribing to their hypertensive patients lifestyle changes that can help or achieve BP control, physicians should establish a FU program that allows to check whether there is adherence to the prescribed measures and whether the therapeutic goal is achieved. This will minimize the risk of the patient continuing with an uncontrolled BP for a prolonged time.
7.2 Weight reduction
Being overweight or obese has been directly associated with hypertension [363,364] [349,365,366] [366] [366] [349] [367] [368] [366,369] [370] [371] [372] [373] [370] [370]
7.3 Restriction of sodium intake
There is strong evidence for an association between high sodium consumption and increased BP in the overall population [374,375] [376] [377,378] [378,379] [380] [381] [382]
Sodium and corresponding salt (NaCl) values are approximately:
Sodium (Na+ ) 2.0 g = 87 mmol Na+ = NaCl (salt) 5.0 g.
Moreover, meta-analysis of RCTs examining sodium intake reduction to as low as 800 mg/day showed a linear decrease in BP [352,378] [383] [384,385] [376,386,387] [353] [388,389] [390,391] [366] [392] [393] [393]
7.4 Augmentation of dietary potassium intake
Dietary potassium is associated with BP and hypertension [386] [355] [353,354,394] [395] [395] [392] [355] [394]
7.5 Increase levels of daily physical activity and regular exercise
The acute pressor effect of dynamic and isometric exercise does not contraindicate regular exercise on a chronic basis. Large epidemiological studies, which allowed for age and other confounding factors, have yielded consistent evidence of an inverse relation between the incidence of hypertension and habitual levels of physical activity, assessed by means of questionnaires or sometimes an interview [396,397] [396] [346,356,359,398] [356,357,399,400] [358,401] [402–404] [399,405] [406,407] [399,408] [409] [357] [410] [411–413] [398,401] [414] [415–419] [415,418]
7.6 Moderation of alcohol intake
Large-scale observational studies report a strong positive linear association between alcohol consumption and BP [420,421] [4] [422] [423,424] [425] [425,426] [427] [360] [360] [428] [429] [430]
7.7 Smoking cessation
Tobacco smoking is the single largest preventable cause of death and is known to significantly increase the risk of CVD [431,432] [433] [434] [433] [435] [436] [437] [438] [438] [439] [440] [441,442] [440,441,443] [444] [442]
7.8 Other dietary interventions
Diet is an important modifier of vascular health and BP, and it has been shown that targeting the whole diet has synergistic and cumulative effects on BP beyond individual foods and nutrients. The most well established dietary interventions for the reduction in BP are the DASH diet [366] [445–447] [347,366] [351] [347,366] [448] [449] [448] [450,451] [452] [453] [454]
7.9 Improve stress management
Stress and anxiety are associated with an increased risk of hypertension and CV events [455,456] [456] [456–459] [366,460] [461,462] [366] [366]
7.10 Exposure to noise and air pollution
Exposure to environmental noise and air pollution are two major risk factors that exert a negative impact on CV health, particularly in urbanized settings. Both factors are environmental stressors that have been identified as risk factors for increases in BP, incident hypertension and also HMOD, including vascular stiffness [463] [464]
Lifestyle interventions
8. BENEFITS OF ANTIHYPERTENSIVE TREATMENT
Although improvement or correction of inappropriate lifestyle patterns can lower BP and reduce total CV risk [465] [466–468] [466,467,469] [468] [470,471] [472] [473] [474–477] [478,479] [480–483]
9. ANTIHYPERTENSIVE DRUG TREATMENT INITIATION
9.1 Should treatment initiation be based on total CV risk?
A recent meta-analysis of RCTs reported that BP reduction was beneficial across almost the entire BP range [484] [485,486] [80]
The above data and considerations support earlier in-life treatment of hypertension as well as treatment implementation also when CV risk is still low-to-moderate. Although total CV risk provides clinically important information and should always be quantified, the data also support the decision to start antihypertensive drug treatment based on office BP level according to the values mentioned in the subsequent sections.
9.2 Office BP thresholds for initiation of drug treatment
All guidelines agree that patients with grade 2 or 3 hypertension should be offered antihypertensive drug treatment alongside lifestyle interventions [4,32,487,488] [489] [486] [472,490,491] [472,491] [490] [492] Fig. 9 ). However, in patients with grade 1 hypertension in its lower BP range, no HMOD and a low CV risk, the possibility may be considered to start treatment with lifestyle changes only (see Section 7). The duration of a lifestyle-based intervention alone can be of several months (e.g. 3 to 6 months) and will depend on the level of BP within the grade 1 range (closer to 140 mmHg SBP), the opportunities for the implementation of lifestyle changes and the perceived adherence to the lifestyle regimen, all related to the likelihood of achieving BP control. If BP control is not achieved within a few months of a lifestyle-based approach, drug treatment will be necessary.
FIGURE 9:
Diagnosis by office BP and initial management of hypertension.
Office BP thresholds for drug treatment initiation
9.3 Should BP-lowering treatment be initiated in patients with office BP <140/90 mmHg?
Previous guidelines [4] [466] [97] [492] n =21 128 patients) no effect of BP-lowering treatment on any CV outcomes [493] [484] [36] [494,495]
The decision regarding treatment may be different in patients with a high-normal BP and a very high CV risk. In a meta-analysis of 10 RCTs or RCT subgroups that included individuals with established CVD (mainly myocardial infarction) and an untreated high-normal BP (26 863 patients), a few mmHg SBP reduction was accompanied by a reduced risk of stroke, although not of any other CV event [493] [472]
9.4 Drug treatment initiation in older people
The present guidelines rely on the definition of older patients as those aged ≥ 60 or 65 years [489] [5] et al. [489] [489] [492] [496] [145,497,498] [144] [497,498] [499] [500,501]
Evidence on the BP threshold for treatment is much more scant for patients aged ≥ 80 years in whom the beneficial effect of SBP reduction has been documented in only one specifically designed outcome trial, HYVET [502] [503]
A final important recommendation is that in patients under well tolerated treatment, who reach 80 years of age, treatment should be continued, because there is evidence that in hypertensive octogenarians, discontinuation of chronically used BP-lowering drugs is associated with a rebound increase of outcomes. In the HYVET trial, about two-thirds of the overall 3845 patients were on antihypertensive drugs at randomization to either active treatment or placebo [495]
The present guidelines strongly support the concept that age should be no barrier to antihypertensive drug treatment, as further emphasized in the section specifically devoted to hypertension in old people. However, they also recognize that evidence on antihypertensive treatment in the old patients has limitations that go beyond the need for more evidence on the most appropriate BP threshold for treatment. One limitation is that in HYVET, the patient age was close to 80 years (mean 83 years) [502] [504–511] [512,513]
10. OFFICE BP TARGETS FOR TREATMENT
10.1 Office BP targets in the general hypertensive population
Based on RCTs, as well as their meta-analyses and post hoc analyses, the 2018 ESC/ESH guidelines recommended that the first objective of antihypertensive treatment should be to lower BP to <140/90 mmHg in all patients. If drug treatment is well tolerated, treated BP values should be targeted to 130/80 mmHg or lower, with the caveat that in some clinical conditions (e.g. CKD), the evidence for this lower BP target was uncertain. It was additionally recommended that treatment should never target BP values to <120/70 mmHg because of the lack of consistent evidence that this has an incremental protective effect, the risk of introducing harm and the increased risk of side effects, leading to treatment discontinuation and a rebound increase in events. In a large population study from northern Italy, discontinuation of antihypertensive drugs for several months was associated with an almost 40% increase of hospitalization for CAD, stroke and HF compared with patients continuing treatment [514] [496] [484] [515] [515] [97] [516] [517] [484] [36]
Thus, information on SBP and DBP targets for drug treatment still substantially rely on the two large meta-analyses of RCTs referred to in the 2018 ESC/ESH guidelines [466,518] [489] [4]
However, despite the smaller incremental benefit, an effort should be made to reach a SBP range of 120– 129 mmHg, but only if treatment is well tolerated to avoid the risk of treatment discontinuation because of adverse events, which might offset, in part or completely, the incremental reduction in CV outcomes. Attention should also be given to the fact that evidence on the advantages of a lower BP target are not available or unequivocal in a number of clinically important subgroups of patients. These issues will be discussed in the sections on special conditions.
10.2 Office versus home and ambulatory BP targets
A crucial gap in hypertension research is that no outcome-based RCT has ever used HBPM or ABPM to guide treatment of hypertension. One attempt to address this issue was made more than 20 years ago by a small RCT in which the number of CV events registered during a several-year FU did not differ significantly between treatments based on ABPM versus office BP, although their overall number (n = 25) did not make the data conclusive [519] [520] [128,521] [522]
10.3 Timing of BP control and time in therapeutic range
RCTs have usually defined the achieved BP target as the mean BP value during the treatment period. However, it is now clear that this oversimplifies the relationship between BP reduction and outcomes. Post hoc or secondary analyses of several RCTs such as VALUE have shown that in high-risk patients achieving an earlier BP control (within 6 months [523] [524] [183,185,525] [191] [190]
10.4 Residual risk
Although substantially reducing hypertension-related outcomes, effective antihypertensive treatment does not return the CV risk of treated hypertensive patients to the level of normotensive people when matched for age, sex and ethnicity. In other words, even when treatment achieves the target BP value that is believed to maximize CV protection, CV risk is not normalized, the excess risk being referred to as ‘residual risk’ [526–528] [528,529] [485] [530–532] [180] [188] [189]
10.5 Challenges associated with evidence on BP targets
For guidelines, recommending the BP targets to reach with treatment is a difficult task. First, recommendations on optimal (i.e. most protective) target BP values may vary between different guidelines, and often also within guidelines at a few-year intervals, despite little concomitant increase in available evidence. This is due to the limited consistency of the available data, an example of which is that the incremental benefit of lowering SBP to <130 mmHg shown by some RCTs and meta-analyses does not clearly emerge from other major trials. Second, as mentioned by the present guidelines (Sections on special conditions), evidence on optimal BP targets is not always univocal or equally strong for all clinical hypertensive subgroups. An example can be offered by people with LVH, quite a common condition in hypertensive patients. A real-life study from a large Korean population has reported a lower risk of CV outcomes in hypertensive patients with ECG-LVH in whom SBP was reduced to <130 or even <120 mmHg compared with higher on-treatment values [533] [534] [524] [535,536] [537] [538] Fig. 10 ).
FIGURE 10:
Office BP targets in the general adult hypertensive population.a The first objective of antihypertensive treatment should be to lower BP to <140/80 mmHg in most patients, because this accounts for the major portion of the protective effect of BP-lowering.a If drug treatment is well tolerated, treated SBP values should be targeted to 130 mmHg or lower in most patients up to 79 years old.a Despite the smaller incremental benefit, an effort should be made to reach a BP range of 120–129/70–79 mmHg in patients up to 79 years old, but only if treatment is well tolerated. Evidence on the advantages of this lower BP target range is not available or unequivocal in a number of clinically important subgroups of patients (e.g. patients with LVH, CKD, or ISH). These issues are discussed in the sections on special conditions (see Sections 17 to 20).a In patients at least 80 years old who are not frail, the first objective of antihypertensive treatment is to lower BP below 150 mmHg. However, a SBP target range between 130-139 mmHg may be considered, if well tolerated.a In very frail patients, treatment targets should be individualized.
Office BP targets for drug treatment
11. ANTIHYPERTENSIVE DRUGS AND TREATMENT
In the 2018 ESC/ESH guidelines [4]
1. A proven ability to reduce BP as monotherapy.
2. Evidence from RCTs that they reduce morbidity and mortality.
3. A favorable tolerability and safety profile.
Based on RCTs and their meta-analyses [539–541] [539]
Moreover, mention is made of new drug classes, such as SGLT2 inhibitors (SGLT2is) and nonsteroidal MRAs, which have become available and exhibit BP-lowering effects. These effects may be less pronounced than those of classical antihypertensive drugs [542] [543–547] [548] Fig. 11 .
FIGURE 11:
Drug classes for BP-lowering therapy. (a) Use of Diuretics: Consider transition to Loop Diuretic if eGFR is between 30 to 45 ml/min/1.73 m2 . If eGFR <30 ml/min/1.73 m2 use Loop Diuretic. (b) Non-DHP CCB should not be combined with BB. (c) BB should be used as guideline directed medical therapy in respective indications or considered in several other conditions (Table 16). Start with dual combination therapy including a RAS-blocker (either ACEi or ARB) plus a T/TL Diuretic or a CCB is recommended (thick blue lines). Triple therapy includes a combination of the three classes as indicated by the blue lines.
Compelling or possible contraindications for the selection of drug classes are summarized in Table 15 .
TABLE 15 - Compelling contraindications and conditions requiring cautious use of BP-lowering drugs
Drug class
Contraindications
Cautious use
ACEi
• Pregnancy
• Women of child-bearing potential without reliable contraception
ARB
• Pregnancy
• Women of child-bearing potential without reliable contraception
Beta-blocker
• Severe asthma
• Asthma
DHP-CCB
• Tachyarrhythmia
Non-DHP-CCB (verapamil, diltiazem)
• Any high-grade sino-atrial or AV block
• Constipation
Thiazide/Thiazide-like diuretics
• Hyponatremia
• Gout
MRA
• Severe hyperkalemia (e.g. potassium >5.5 mmol/l)2
• Co-medications susceptible to significant drug interactions mediated by P-gp or CYP3A4 for eplerenone
11.1 Blockers of the renin–angiotensin system (RAS)
11.1.1 Angiotensin-converting-enzyme inhibitors
ACEis are among the most widely used classes of antihypertensive drugs. Because of their earlier availability and, thus, their earlier evaluation against placebo in outcome-based RCTs, knowledge about ACEis is based on a large amount of RCT data, particularly in patients with HF, CAD and at high CV risk [549–551] [550,551] [552,553] [554] [514]
11.1.2 Angiotensin receptor blockers
ARBs have a similar antihypertensive efficacy and protective effect as ACEis [554–556] [514]
11.1.3 Renin inhibitors
The renin inhibitor aliskiren is a potent, long-acting antihypertensive drug when prescribed alone or in combination with a diuretic or a CCB [557] [558]
11.1.4 Combination of RAS inhibitors
ACEis, ARBs or aliskiren should not be combined because no added benefit on CV outcomes has been shown by dual RAS inhibition [559] [560] [559] [561]
11.2 Calcium channel blockers
CCBs represent a heterogeneous class of drugs that can be divided into vascular-selective dihydropyridine (DHP) and non-DHP-CCBs. CCBs are widely used for the treatment of hypertension, and they are particularly effective in patients of African descent as well as in the general older population.
11.2.1 Dihydropyridine CCBs
Most RCTs demonstrating their benefits on outcomes have used DHP– CCBs, especially amlodipine [539]
11.2.2 Nondihydropyridine CCBs
Diltiazem and verapamil are not vascular-selective CCBs, but they are also efficacious in reducing BP. A smaller number of RCTs have compared non-DHP-CCBs with other drugs, while meta-analyses evaluating DHP and non-DHP-CCBs versus other drugs have not shown substantial differences in effectiveness [539] [562] [563,564]
11.3 Diuretics
11.3.1 Thiazide/Thiazide-like
The effectiveness of Thiazide/Thiazide-like diuretics in preventing CV morbidity and mortality has been shown in RCTs and meta-analyses [539–541,565] [566] [567] [539] [568] [569] [570] n = 6756) or hydrochlorothiazide continuation (n = 6767). Patients on treatment with hydrochlorothiazide 25 or 50 mg were converted to 12.5 or 25 mg chlorthalidone, respectively. No difference in CV outcomes between the two drugs was found, except for patients with a prior stroke in whom there was a greater benefit with chlorthalidone. Despite some limitations (in the last study, very few patients were on hydrochlorothiazide monotherapy at baseline, which means that the results could have been affected by concomitant medications and adherence to their use), the above-mentioned recent observations justify the recommendation of the present guidelines to still consider Thiazide/Thiazide-like diuretics both as suitable antihypertensive agents and as similarly effective in CV prevention. Both Thiazide/Thiazide-like can lower serum potassium and have a side-effect profile that is less favorable than RAS blockers. This may account for their higher rate of treatment discontinuation. Depending on the dose, they may also increase insulin resistance and, hence, the risk of new-onset diabetes. Potassium plays an important role in the metabolic effects of Thiazide/Thiazide-like, and evidence is available that these effects are reduced by the combination of Thiazide/Thiazide-like with a potassium-sparing diuretic [571,572] [573] 2 ) when added to the therapy of these conditions, which often includes a loop diuretic (60% of the patients) (see Section 12).
11.3.2 Loop diuretics
Thiazide/Thiazide-like are considered less effective antihypertensive agents in patients with a reduced GFR (eGFR <30 ml/min/1.73 m2 ). Consequently, while loop diuretics (furosemide, bumetanide, torasemide/torsemide) are usually not indicated in the treatment of uncomplicated hypertension, they are recommended in patients with CKD stage 4 and 5 (eGFR below 30 ml/min/1.73 m2 ) and in patients with severe fluid overload/retention, e.g. in patients with HF or nephrotic syndrome. Recently, furosemide and torsemide were found to be equally effective on mortality, independently of ejection fraction in a RCT comprising 2859 HF patients receiving one drug or the other at discharge from hospital [574] [573]
11.3.3 Potassium-sparing diuretics
Amiloride is an agent that directly inhibits epithelial sodium channels at the luminal side of the late distal tubule and collecting duct. Hence, it is used as potassium-sparing diuretic in edematous states and for potassium conservation in combination with Thiazide or loop diuretics in hypertension or HF [575] [571] [576] P < 0.0001) [576] [577] [578]
11.4 Mineralocorticoid receptor antagonists
The steroidal MRAs spironolactone and eplerenone are established treatments in HFrEF based on outcome-based RCTs, but no outcome trial has been carried out in hypertension. Lack of outcome data and the risk of MRA-induced hyperkalemia and other side effects have restricted the use of MRA in the treatment of hypertension, except in specific conditions such as hyperaldosteronism or resistant hypertension. In resistant hypertension, a meta-analysis of 12 RCTs (1655 patients) [579] [580] [581] [545–547] [582] [582] [545]
11.5 Beta-blockers
RCTs and meta-analyses have demonstrated that when compared with placebo, first-generation and second-generation BBs like propranolol, atenolol and metoprolol significantly reduce the risk of stroke, HF and major CV events in hypertensive patients. When compared with other BP-lowering drugs, BBs were almost equivalent in preventing major CV events, except for a less effective prevention of stroke [539–541,583,584] [514] [4,32,488] [585,586] [587] [588] [589,590]
A recent pragmatic review scrutinized the use of BBs in medical treatments [591] Table 16 ). In addition, concerns about the impact of BBs on psychological health should not affect their use in clinical practice, because a recent systematic review and meta-analysis of psychiatric adverse events during BB therapy indicated that BB use was not adversely associated with depression and most other psychiatric adverse events [592] [593] [594–596] [597,598] [599]
TABLE 16 - Selected diseases and conditions for the use of BBs in patients with hypertension
[591]
Selected indications with guideline directed medical therapy for BBs
Chronic coronary syndromes, antiischemic therapy
Postmyocardial infarction: arrhythmias, angina, known incomplete re-vascularization, HF
Acute coronary syndrome
HFrEF and HFpEF if coronary disease (ischemia), arrhythmias and tachycardia
Atrial fibrillation: prevention, rhythm control, heart rate control
Women with child-bearing potential/planning pregnancy
Hypertension disorders in pregnancy
Selected other conditions in which therapy with BBs can be favourable
Hypertension with elevated resting heart rate >80 bpm
Emergency, urgency and parenteral administration
Perioperative hypertension
Major noncardiac surgery
Excessive pressor response to exercise and stress
Hyperkinetic heart syndrome
Postural orthostatic tachycardia syndrome
Orthostatic hypertension
OSA
Peripheral arterial disease with claudication
COPD
Portal hypertension, cirrhosis-related esophageal varices and recurrent variceal bleeding
Glaucoma
Thyrotoxicosis, hyperthyroidism
Hyperparathyroidism in uremia
Migraine headache
Essential tremor
Performance anxiety and anxiety disorders
Psychiatric disorders (posttraumatic stress)
11.6 Alpha-1 blockers
Treatment with the alpha-1 blocker doxazosin was equally effective as chlorthalidone in preventing the primary endpoint in ALLHAT [566] [600] [580] [601] [602]
11.7 Centrally acting drugs
In recent decades, centrally active drugs have been less frequently used, principally because of the lack of evidence by outcome RCTs and/or their poorer tolerability relative to the newer major classes of drugs. Thus, older compounds such as reserpine, alpha-methyldopa, clonidine, moxonidine or rilmenidine are no longer recommended for the routine treatment of hypertension and are primarily reserved for add-on therapy in the rare cases of resistant hypertension where other treatment options have failed or for specific conditions such as the use of methyldopa in pregnancy. It is worth noting that a recent study demonstrated a significant BP-lowering effect of clonidine in resistant hypertension that was similar to that of spironolactone [603]
11.8 Vasodilators
Vasodilators are a heterogeneous group of drugs, which exert a direct relaxing effect on vascular smooth muscle cells, thereby reducing BP via vasodilation and reduction of systemic vascular resistance. Powerful vasodilators, such as hydralazine and minoxidil were occasionally used in the past, but they have been now virtually abandoned because of their association with serious side effects. Side effects include marked baroreflex activation with tachycardia and increased activity of the sympathetic nervous system and activation of the RAS system resulting in tachycardia and fluid retention. Hydralazine may be occasionally considered in resistant hypertension that is unresponsive to multiple attempts to control BP, always in combination with BBs and diuretics to limit its side effects. A serious specific side effect for minoxidil is hirsutism. Nitrates and nitroprussiate also relax vascular smooth muscle cells and can lower BP. Intravenous nitroprussiate has a very efficacious and well controllable BP-lowering effect and is, therefore, used to manage hypertension emergencies (see Section 16.2).
11.9 Angiotensin receptor-neprilysin inhibitor (ARNI)
ARNI is a chemical combination of the ARB valsartan and the neprilysin inhibitor sacubitril, which simultaneously blocks the effects of angiotensin II at the AT-1 receptor (by valsartan) and inhibits the degradation of natriuretic peptides, thus promoting peripheral vasodilatation (by sacubitril) [604] [605] [604]
11.10 Antihypertensive drug combinations
11.10.1 Impact on hypertension drug treatment strategy
Guidelines have generated a variety of different strategies to initiate and increase BP-lowering medications in order to control an elevated BP. Before 2018, guidelines largely focused on the stepped care approach, initiating treatment with a variety of different monotherapies and then sequentially adding other drugs, until BP control was achieved. Starting with a two-drug combination was proposed only for patients with marked BP elevations and/or a high/very-high CV risk. Despite this, BP control rates have remained poor in Europe and worldwide. Failure to achieve BP control in most hypertensive patients, despite numerous iterations of guidelines, suggested that, whatever the reasons, the step care treatment strategy was not sufficiently effective and that a different approach was needed. The new strategy elaborated by the 2018 ESC/ESH guidelines was based on the following main considerations:
1. Efficacy of pharmacological therapies. Evidence from RCTs investigating BP responses to antihypertensive drugs demonstrates that BP control can be achieved in most patients and that no more than 5– 10% of these patients exhibit resistance to the selected treatment regimen [606]
2. Physician or treatment inertia. Evidence suggests that medical inertia, i.e. failure to adequately intensify or up-titrate treatment, contributes to failure or delay of treatment initiation but exerts an important adverse role also on suboptimal BP control with many patients remaining on monotherapy and/or suboptimal drug doses [607,608] [609] [609] [608] [610]
3. Patient adherence to treatment. Evidence is accumulating that adherence to treatment is a fundamental factor to consider. Studies using urine or blood assays for the presence or absence of medication have shown that low or partial adherence to treatment is frequent, in particular, among patients with an uncontrolled BP [611] [476,612] [478,479,613]
4. Insufficient use of combination treatment. BP is a multiregulated variable depending on many pathophysiological pathways. Therefore, monotherapy is likely to be inadequate or insufficient to control BP in most patients, and combinations of drugs, working through different mechanisms, are necessary to achieve BP targets in most people with hypertension [608,614] [615]
5. Complexity of current treatment strategies. There is also evidence that adherence to treatment is adversely affected by the complexity of the prescribed treatment regimen [479,616]
The above considerations suggest that the most effective evidence-based treatment strategy to improve BP control would be one that:
1. encourages the use of combination treatment in most patients, especially in the context of lower BP targets
2. promotes the use of simplified single-pill-based combination therapies to support long-term persistence to treatment
3. Recommends initial combination treatment in most hypertensive patients, as evidence is available that compared to monotherapy, initial combination treatment bypasses the problem of inertial monotherapy [608] [617–619] [617,620] [612,621–623]
These are the main reasons why the 2018 ESC/ESH guidelines recommended a new simple and pragmatic treatment algorithm applicable to most patients, with the use of SPC therapy as first-line initial therapy. Exceptions are frail and very old patients, because of the impairment of the baroreflex and greater risk of hypotension, and very high-risk patients with high-normal BP, in whom the small BP reduction associated with monotherapy may allow to reach the BP target. For the same reason, initial monotherapy may also be considered in grade 1 hypertensive patients at low risk with a BP only modestly elevated above the BP threshold for drug treatment.
11.10.2 Drug combinations
Among the large number of RCTs of antihypertensive therapy, only a few have directly compared two different drug combinations, with systematic use of the two combinations in both arms. In most trials, treatment was initiated using monotherapy in either arm and another drug (and frequently more than one drug) was added, usually in a nonrandomized fashion, according to a prespecified treatment algorithm. In a few trials, such as ALLHAT [566] Table 17 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 CV events.
TABLE 17 - Major drug combinations used in trials of antihypertensive treatment in a stepped approach or as a randomized combination
Trial
Comparator
Type of patients
SBP difference (mmHg)
Outcomes (change in relative risk)
ACEi and diuretic combination
PROGRESS [629]
Placebo
Previous stroke or TIA
−9
–28% strokes (P <0.001)
ADVANCE [630]
Placebo
Diabetes
−5.6
–9% micro/macrovasc. events (P = 0.04)
HYVET [502]
Placebo
Hypertensive; ≥80 years
−15
–34% CV events (P < 0.001)
ARB and diuretic combination
SCOPE [631]
Diuretic + placebo
Hypertensive; ≥70 years
−3.2
–28% nonfatal strokes (P = 0.04)
HOPE-3 [492]
Placebo
Patients at intermediate CV risk without CV disease (38% hypertensive patients)
−6
NS overall difference in CV events but
ARB and CCB
OSCAR [632]
ARB
Older, high-risk hypertensive patients
−2.4
NS overall difference in CV events -31% events, patients with CV disease (P=0.02)
CCB and diuretic combination
FEVER [633]
Diuretic + placebo
Hypertensive
−4
–27% CV events (P < 0.001)
ACEi and CCB combination
Syst-Eur [498]
Placebo
Older with ISH
−10
–31% CV events (P < 0.001)
Syst-China [145]
Placebo
Older with ISH
−9
–37% CV events (P < 0.004)
BB and diuretic combination
Coope and Warrender [634]
Placebo
Older hypertensive
−18
–42% strokes (P < 0.03)
SHEP [635]
Placebo
Older with ISH
−13
–36% strokes (P < 0.001)
STOP-Hypertension [636]
Placebo
Older hypertensive
−23
–40% CV events (P = 0.003)
STOP-Hypertension 2 [637]
ACEi or conv. antiHT
Hypertensive
0
NS difference in CV events
Combination of two RAS blockers/ACEi + ARB or RAS blocker + renin inhibitor
ONTARGET [638]
ACE inhibitor or ARB
High-risk patients
More renal events
ALTITUDE [561]
ACE inhibitor or ARB
High-risk diabetic patients
More renal events
Combinations versus placebo or monotherapy
In trials comparing different regimens [624] Table 18 ), 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 or a CCB/ACEi combination, with both regimens being superior to a BB (atenolol)/diuretic combination in reducing CV outcomes [600,625] [626] [626] [627,628]
TABLE 18 - Major drug combinations used in trials of antihypertensive treatment in a stepped approach or
as a randomized combination
Trial
Comparator
Type of patients
SBP diff (mmHg)
Outcomes (change in relative risk)
ACE inhibitor and diuretic combination
CAPPP [639]
BB + diuretic
Hypertensive
+3
+5% CV events (NS)
ACCOMPLISH [626]
ACE inhibitor + CCB
Hypertensive with risk factors
+1
+21% CV events (P < 0.001)
ARB and diuretic combination
LIFE [640]
BB + diuretic
Hypertensive with LVH
−1
–26% stroke (P < 0.001)
Calcium channel blocker and diuretic combination
ELSA [641]
BB + diuretic
Hypertensive
0
NS difference in CV events
CONVINCE [642]
BB + diuretic
Hypertensive with risk factors
0
NS difference in CV events
VALUE [524]
ARB + diuretic
High-risk hypertensive
−2.2
–3% CV events (P = NS)
COPE [627]
CCB + BB
Hypertensive
+0.7
NS difference in CV events or stroke
CREOLE [643]
ACEi+CA
Black Hypertensives uncontrolled
−0.14
No outcome data; CCB+D and ACE+CCB superior to ACEi+D in BP control
ACE inhibitor and CCB combination
NORDIL [644]
BB + diuretic
Hypertensive
+3
NS difference in CV events
INVEST [645]
BB + diuretic
Hypertensive with CAD
0
NS difference in CV events
ASCOT [600]
BB + diuretic
Hypertensive with risk factors
−3
–16% CV events (P < 0.001)
ACCOMPLISH [626]
ACE inhibitor + diuretic
Hypertensive with risk factors
−1
–21% CV events (P < 0.001)
Beta-blocker and diuretic combination
CAPPP [639]
ACE inhibitor + diuretic
Hypertensive
−3
–5% CV events (P = NS)
LIFE [640]
ARB + diuretic
Hypertensive with LVH
+1
+26% stroke (P < 0.001)
ALLHAT [566]
ACE inhibitor + BB
Hypertensive with risk factors
−2
NS difference in CV events
ALLHAT [566]
CCB + BB
Hypertensive with risk factors
−1
NS difference in CV events
CONVINCE [642]
CCB + diuretic
Hypertensive with risk factors
0
NS difference in CV events
NORDIL [644]
ACE inhibitor + CCB
Hypertensive
−3
NS difference in CV events
INVEST [645]
ACE inhibitor + CCB
Hypertensive with CAD
0
NS difference in CV events
ASCOT [600]
ACE inhibitor + CCB
Hypertensive with risk factors
+3
+16% CV events (P < 0.001)
Beta-blocker and CCB combination
COPE [627]
ARB+CCB
Hypertensive
+0.8
NS difference in CV events or stroke
ARB and CCB combination
COPE [627]
CCB + diuretic
Hypertensive
−0.7
NS difference in CV events or stroke
COPE [627]
CCB + BB
Hypertensive
−0.8
NS difference in CV events or stroke
COLM [628]
ARB + diuretic
Older hypertensive
0
NS difference in CV events
Combinations versus other combinations.
Based on the results of outcome RCTs, recent meta-analyses and evidence of BP-lowering effectiveness, all five major drug classes can in principle be combined with one another, except for ACEis and ARBs (see Section 11.10). However, we recommend that treatment of hypertension should be preferentially based on combinations of an ACEi or an ARB with CCB or a Thiazide/Thiazide-like diuretic. These combinations are now widely available in a single pill and in a range of doses, facilitating flexible prescribing and up-titration from lower to higher doses. They also (i) limit potential adverse effects associated with diuretic or CCB monotherapy, i.e. reduce the risk of hypokalemia due to diuretics, or the prevalence of peripheral edema due to CCBs and (ii) ensure that the RAS is inhibited as part of the treatment strategy, which is important for many patient groups (patients with diabetes, LVH, CKD with or without proteinuria etc.). Other combinations, such as CCB or BB plus a diuretic, also have RCT-based evidence supporting their use, as mentioned by the 2018 ESC/ESH guidelines. In addition, they can be the preferred combinations in a number of conditions. In black patients in sub-Saharan Africa, amlodipine plus either hydrochlorothiazide or perindopril was more effective than perindopril plus hydrochlorothiazide at lowering BP [643]
11.10.3 Rationale for initial two-drug combination therapy
As discussed above and with the emphasis in the present guidelines on achieving a BP target of <130/80 mmHg in most patients, the majority of patients will require combination therapy. Although no RCT has ever compared major CV outcomes between initial combination therapy and monotherapy, multiple arguments support combination of two antihypertensive drugs as the initial treatment step. One, initial combination therapy is invariably more effective at BP-lowering than monotherapy, and indeed even low-dose combination therapy is usually more effective than maximal dose monotherapy. Furthermore, the combination of medications targeting multiple mechanisms (i) reduces the heterogeneity of the BP response to initial treatment and (ii) provides a steeper dose– response effect than that observed with escalating doses of monotherapy and (iii) is safe and well tolerated, with no or only a small increase in the risk of hypotensive episodes, even when given to patients with grade 1 hypertension. Two, initial two-drug combination is associated with a faster BP reduction compared with monotherapy, and observational evidence suggests that the time taken to achieve BP control is an important determinant of clinical outcomes, especially in high-risk patients, with a shorter time to control associated with lower risk risk [646] [620] [608,617] [619] [608,622,623,647] [648]
General recommendations for antihypertensive drug treatment
11.10.4 Up-titration of treatment to three-drug combination
Evidence from RCTs shows that two-drug combination therapy will control BP in approximately half to two-thirds of patients [649] [32] [650]
11.10.5 Rationale for single-pill combination therapy
The 2013 and 2018 ESH/ESC guidelines [3,4] [479,616,621,647] [647] [651] [647,651–653]
11.10.6 The quadpill concept
Another innovative therapeutic approach to increase BP control while improving tolerability is to use combinations of low or even ultralow doses of the recommended antihypertensive drugs. With this approach, the ability to effectively reduce an elevated BP appears to be maintained while most side effects are avoided. A proof-of-concept study and a systematic review of quarter-dose BP-lowering drugs was reported in 2017 [654,655] n = 4721 participants) of one drug at quarter-dose and 6 trials (n = 312) of two drugs at quarter-dose against placebo. The pooled placebo-corrected SBP/DBP-lowering effects were, respectively, 5/2 mmHg and 7/5 mmHg with no reported side effects. The BP-lowering effect was even greater when quarter-doses of four drugs, i.e. quadpill, were used. These preliminary data have been supported by a phase 3 study by the same authors, in which 591 patients were randomized to the quadpill or to full-dose monotherapy with an ARB. BP changes were assessed at 12 weeks and 12 months. The BP control rate was greater in the quadpill group at both time points. Studies in broader populations are needed, and more information is required on a number of issues such as the strategy to adopt when side effects occur or hypotension develops using the quadpill approach.
11.10.7 The polypill concept
Polypills consist of SPCs of one or two antihypertensive agents and a statin with or without low-dose acetyl salicylic acid (aspirin) [656] [479,612,657–659] [660] [656] [660] [656] [661,662] [663] [662] [4,664]
11.10.8 Choice of drug combinations for initiation of treatment
Reflecting on the evidence discussed above and recognizing the need to avoid or minimize the factors contributing to poor BP control in treated hypertensive patients, the following few simple and pragmatic recommendations for the treatment of hypertension can be listed (Figs. 11 and 12 ):
1. In most patients, treatment should be initiated with an SPC of two drugs to improve the speed, efficiency and predictability of BP control.
2. Although several two-drug combinations can be used, the preferred two-drug combinations should be an RAS blocker with a CCB or a Thiazide/Thiazide-like diuretic.
3. A BB can be used at any step of combination with any drug from the other major drug classes as GDMT or in several other conditions (Table 16 ).
4. Initial monotherapy is recommended for very-high-risk patients with a high-normal BP as well as (for cautionary reasons) for very old and frail patients. It may also be considered in low-risk patients with stage 1 hypertension whose SBP is more modestly elevated (<150 mmHg).
5. An SPC comprising an RAS blocker CCB Thiazide/Thiazide-like diuretic, should be used if two-drug combinations do not achieve BP control (at the maximum tolerated doses) and a BB is not indicated.
6. Regardless the initial treatment choice, ultimately most patients should be on combination treatment, using SPC whenever possible.
FIGURE 12:
General BP-lowering strategy in patients with hypertension.a Use of Diuretics:–Consider transition to Loop Diuretic if eGFR is between 30 to 45 ml/min/1.73 m2 –If eGFR <30 ml/min/1.73 m2 use Loop Diureticb BB should be used as guideline directed medical therapy in respective indications or considered in several other conditions (Table 16)c Controlled below 140/90 mmHgd When SBP is ≥140mmHg or DBP is ≥90 mmHg provided that:–maximum recommended and tolerated doses of a three-drug combination comprising a RAS blocker (either an ACEi or an ARB), a CCB and a Thiazide/Thiazide-like diuretic were used–adequate BP control has been confirmed by ABPM or by HBPM if ABPM is not feasible–various causes of pseudo-resistant hypertension (especially poor medication adherence) and secondary hypertension have been excluded (see Section 12).
11.10.9 Tolerability and side effects of drugs
All antihypertensive drugs can elicit side effects, which can be modest or, in some instances, serious, leading to treatment discontinuation. Side effects play a major role for treatment nonadherence and discontinuation [665] [666,667] [665]
11.10.10 Prescribing of antihypertensive drugs
11.10.10.1 Standard drug administration
The primary goal of antihypertensive treatment is to provide BP control over the 24 h period (short-term) and to maintain this control over time (long-term). To achieve this goal, clinicians must consider (1) the half-lives and dose of the used drugs, as well as their interactions with the concomitantly used drugs (pharmacokinetics), (2) the mechanism of action of the drugs (pharmacodynamics) and (3) patient characteristics that might influence absorption, metabolism or elimination of the drug [668] [479,612,657,659,669] [670] [670] [180]
Most of the available evidence on the outcome benefit of BP-lowering therapy has come from RCTs using morning dosing of the drugs. However, recent evidence that night-time hypertension is not rare as well as that a nondipping profile may have adverse prognostic consequences [671] [671,672] [671,672] [673] [670] [670] P < 0.0001). However, there was no significant difference in the primary outcome (hospitalization for major CV events and vascular death) between the evening-dosing and the morning-dosing groups. Thus, data do not support preferential use of antihypertensive drugs at bedtime, which is, however, also not harmful. Based on TIME, patients have a choice as to when to take their medication, while physicians may consider bedtime dosing in patients with documented high night-time BP [674] [670,674,675]
11.10.10.2 Partial treatment reduction or complete withdrawal
Complete withdrawal of antihypertensive drug therapy, because of side effects or other reasons, is accompanied by a more or less rapid return of BP to the pretreatment elevated values [676] [676] [494,677,678] [676,679] [676] Table 19 ).
TABLE 19 - Withdrawal of BP-lowering drugs
Drug class
Effects of abrupt withdrawal
CCBs
• Risk of angina
BBs
• Risk of angina and other complications in CAD patients
Centrally acting agents
• Sympathetic overactivity (nervousness, tachycardia, headache, agitation and nausea for 36–72 h after drug cessation)
Diuretics
• Fluid retention, edema, HF decompensation
11.10.10.3 Antihypertensive drugs and cancer risk
Whether hypertension “per se” or treatment with antihypertensive drugs may influence the risk of cancer has been a matter of debate for many years [680–682] [683,684] [681,685] [681] [686] [687] [688] [689] [690]
11.10.11 Concomitant medications
11.10.11.1 LDL-cholesterol lowering
Hypertension and dyslipidemia are highly prevalent in the general population and often coexist, contributing to CV risk in an additive way [531] [691] [33] [33] [33]
The ASCOT trial [692] [693] [694] [695,696] [697] [692,695] [691] [698] [699]
In isolated triglyceridemia, statin therapyshould be the initial drug class of choice to reduce CV risk, and maybe considered if triglyceride levels are 2.3 mmol/l (200 mg/dl), especially in diabetic patients. Treatment with fenofibrate has been suggested to provide additional benefit, proportional to its effect on non-HDL-cholesterol [691,694] [700,701]
On the antihypertensive treatment side, BBs and diuretics may be regarded as less preferable in difficult-to-treat dyslipidemia because of their modest dyslipidemic effects, more evident in combination treatment. However, their ability to reduce CV risk through BP-lowering greatly outweighs their metabolic downsides, and they should be used to control BP if necessary.
Recommendations for LDL-cholesterol-lowering therapy in hypertension
11.10.11.2 Antiplatelet therapy
Common complications of hypertension are related to atherothrombotic diseases, i.e. CAD, ischemic stroke, and LEAD [702] [703] [704] n = 41 695 patients; and two trials in secondary prevention, n = 19 320 patients) investigated the effects of antiplatelet agents and anticoagulants in hypertension. Four studies compared low-dose aspirin versus placebo and found no evidence of a difference in all-cause or CV mortality. However, aspirin treatment reduced the risk of all nonfatal CV events, albeit increasing the risk of major bleedings. The authors conclude that there is currently no evidence that antiplatelet therapy has a protective effect on hypertensive patients in the setting of primary prevention. The same conclusion had been reached more than 25 years ago in the HOT trial in which, however, some protective effect of low-dose aspirin was shown in a subgroup of patients with no previous CV events but with a high CV risk due to advanced kidney disease [705]
The benefits and harms of the newer drugs, i.e. clopidogrel, prasugrel and ticagrelor, have not been sufficiently studied in clinical trials on patients with hypertension.
Recommendations of antiplatelet therapy in hypertension
12. TRUE RESISTANT HYPERTENSION
12.1 Definition, prevalence, pathophysiology and cardiovascular risk
In the 2018 Guidelines, hypertension was defined as resistant to treatment when appropriate lifestyle measures and treatment with optimal or best tolerated doses of three or more drugs (a Thiazide/Thiazide-like diuretic, an RAS blocker and a CCB) fail to lower office BP to <140/90 mmHg [4] Fig. 13 ).
FIGURE 13:
Characteristics of true resistant hypertension. RAAS, renin – angiotensin aldosterone system.
The prevalence of resistant hypertension has been difficult to quantify because of its dependence on a number of factors: the clinical setting (e.g. general population, tertiary referral center, clinical trial), (ii) the classes and optimal doses of the antihypertensive drugs used, (iii) the exclusion or retention of patients not adhering to treatment, (iv) the method of BP measurement and (v) the definition of the target BP value representing BP control [606,706,707] [708] [709] [707,710,711] [712–715] [580,716,717] [718] [719] [720] [721–723] [724] [725] [726,727] Fig. 13 ).
12.2 Diagnostic work-up
The diagnostic work-up should rule out pseudoresistant hypertension and, once true resistant hypertension is identified, characterize the patient's clinical status by history, physical examination and laboratory and imaging analysis for the assessment of risk factors and HMOD (see Section 5.5). Exclusion of pseudoresistant hypertension requires (i) the demonstration of an elevated ABPM; (ii) the exclusion of an origin of the BP elevation from inaccurate BP measurement, e.g. the spurious BP increase associated with marked brachial artery calcification, especially in older patients or in patients with advanced CKD; (iii) the exclusion of a secondary cause of hypertension (see Section 6) or (iv) the exclusion of poor adherence to the prescribed treatment regimen (see Section 21). The prevalence of secondary hypertension, especially primary aldosteronism [728] [716] [729–733]
Poor adherence to antihypertensive drug treatment is common in hypertension [479] [616] [479,612,616,657,659,669] [616] [616,659] [734] [616] Table 20 ). Careful evaluation of the drugs taken by patients is made easier by use of standardized questionnaires [735]
TABLE 20 - Medications and other substances that may increase BP
Medication/substance
Proposed mechanism
Comments
NSAIDs
Inhibition of COX-1 and 2 decreasing PG I2 and E2 synthesis with subsequent reduction in urinary Na excretion and an increased systemic vascular resistance.
Mild, dose-dependent increase in BP. Increased risk with age, preexisting hypertension, salt-sensitive patients, patients with renovascular hypertension.
Paracetamol (acetaminophen)
Presumably via inhibition of cyclooxygenases and reduced production of prostaglandins.
Increased relative risk of 1.34 of hypertension with almost daily paracetamol use.
Estrogens and progestins
Increased renin synthesis (by estrogens) leading to RAS activation and subsequent Na+ and water retention.
Mild, sustained increase in BP (6/3 mmHg increase with high doses of estrogen >50 μg of estrogen and 1–4 μg progestin) but can be severe, common in premenopausal women, cause hypertension in 5% of women.
Glucocorticoids
Enhanced Na+ reabsorption and fluid retention via stimulation of mineralocorticoid receptors.
Dose-dependent, low doses have less effect on BP, more common in older patients, or with a family history of primary hypertension.
Calcineurin inhibitors
Reduced NO production, ET-1 overproduction, systemic and renal vasoconstriction, renal Na+ retention.
Dose-dependent, mild-to-moderate increase in BP. Severe hypertension has been reported. Increased risk with preexisting hypertension, elevated creatinine levels and maintenance therapy with corticosteroids. See Section 20.8.2
Antidepressants
Increased noradrenaline release causing adrenergic activation and increased SNS activity.
Dose-dependent, mild (2/1 mmHg) increase in BP.
Nasal decongestants
Vasoconstriction due to stimulation of alpha-1 receptors on vascular smooth muscles.
Dose-dependent, sustained increase in BP.
Erythropoietin-stimulating agents
Increased thromboxane, reduced prostacyclin levels and activation of the local RAS.
Dose-dependent, mild increase in BP, increased risk with preexisting hypertension, or when the initial hematocrit level is low. See Section 20.8.2
Stimulants
VEGF inhibitors
Decreased NO production via VEGFR-2 antagonism and stimulation of ET-1 receptors promoting vasoconstriction.
A class effect. The incidence of hypertension is dose-related, risk is increased by preexisting hypertension, old age and overweight. See Section 20.8.2.
Substances of abuse
Increased release and inhibited reuptake of monoamine neurotransmitters with subsequent SNS activation.
Cocaine induces both acute and chronic increases in BP.
Herbal products
Chronic excessive liquorice use mimics hyperaldosteronism by stimulating the mineralocorticoid receptor and inhibiting cortisol metabolism.
Licorice: Dose-dependent, sustained increase in BP characterized by hypokalemia, metabolic alkalosis and suppressed plasma renin activity and aldosterone levels
Diet pills
Increased levels of norepinephrine with subsequent activation of noradrenergic transmission
Mild increase in BP.
12.3 Optimizing lifestyle changes and ongoing drug therapy
Effective treatment of true resistant hypertension should combine (i) lifestyle changes (particularly reduction of sodium and alcohol intake, implementation of regular physical activity and weight loss in overweight or obese patients) (ii) discontinuation of interfering substances, (iii) rationalization of current treatment and (iv) the sequential addition of antihypertensive drugs to the existing triple therapy.
Replacing current drugs with a more rational and possibly simpler treatment regimen is based on use of combination therapies that are appropriate to a patient‘s age, ethnicity, compelling indications for certain drug classes, comorbidities and risk of drug– drug interactions. Drugs should be used at the maximal tolerated doses and SPCs should be preferred when available to reduce pill burden and improve adherence to treatment [617] [573] 2 ) and poorly controlled hypertension, showed an about 10 mmHg 24 h SBP reduction with chlortalidone versus placebo, and the BP-lowering effect was particularly evident in patients already on loop diuretics [736] [737] [737]
12.4 Fourth and subsequent lines of antihypertensive therapy
In patients with true resistant hypertension, the fourth line treatment should include the MRA spironolactone, based on the evidence of its efficacy in the PATHWAY-2 trial [580] [579] Fig. 14 ). A secondary analysis of the TOPCAT trial has shown beneficial effects of spironolactone also in patients with HFpEF [738] [193] [739] [740] [741] [742] [711] [743] [576] [742] [744] [717]
FIGURE 14:
BP-lowering strategy in true resistant hypertension according to renal function. (a) When SBP is ≥140mmHg or DBP is ≥90 mmHg provided that: maximum recommended and tolerated doses of a three-drug combination comprising a RAS blocker (either an ACEi or an ARB), a CCB and a T/TL Diuretic were used, adequate BP control has been confirmed by ABPM or by HBPM if ABPM is not feasible, various causes of pseudo-resistant hypertension (especially poor medication adherence) and secondary hypertension have been excluded (see Section 12). (b) Use of Diuretics: Use T/TL Diuretic if eGFR >45 ml/min/1.73 m2 . Consider transition to Loop Diuretic if eGFR is between 30 to 45 ml/min/1.73 m2 . Use loop Diuretic if eGFR <30 ml/min/1.73 m2 . (c) MRA contraindicated. (d) Caution if eGFR <45 ml/min/1.73 m2 or serum potassium >4.5 mmol/l. (e) Should be used earlier at any step as guideline directed medical therapy in respective indications or considered in several other conditions (Table 16).
When spironolactone and other MRAs are not tolerated or contraindicated (i.e. in CKD stage 4, eGFR <30 ml/min), bisoprolol (5– 10 mg/day), doxazosin extended release (4– 8 mg/day) or a centrally acting agent such as the alpha-adrenergic receptor agonists (clonidine, 0.1– 0.3 mg twice a day) [603] [580] [603] [718] [718] [743,745,746] [191,747] 2 , in whom BP control cannot be achieved or serious side effects cannot be avoided with antihypertensive medications [743,748]
It is important to emphasize that in resistant hypertension, dedicated trials such as the PATHWAY-2 [580] [603] [749] [750] n = 350), BBs (n = 2869) and alpha-1 blockers (n = 5420) [751] [751]
Treatment of true resistant hypertension includes the patients’ frequent comorbidities, for which additional treatment options may apply. Hence, for patients with OSA, continuous CPAP may be of moderate benefit [752,753] [754] [755] [756,757] [758] [759] [760] [761] [762] [763] [605]
Given the association with multiple comorbidities and the need for multiple and complex drug therapeutic regimens, we recommend to address patients with true resistant hypertension to a hypertension specialist or, if necessary, to a hypertension specialist center. A dedicated tertiary BP clinic can be useful to perform the necessary diagnostic steps, optimize the multidrug treatment regimen, reduce the likelihood of drug-related adverse effects and increase adherence to treatment. Patients should receive a dedicated program of FU.
True resistant hypertension
13. DEVICE-BASED TREATMENT OF HYPERTENSION
13.1 Renal denervation (RDN)
Increased activity of the SNS (Fig. 3 ) is one of the important factors in the pathophysiology of hypertension, especially in obesity, OSA and CKD [764] 1 -adrenergic receptor activation at the level of the juxta-glomerular cells, decrease renal perfusion and GFR, increase tubular reabsorption of sodium and induce a rightward shift of the BP-natriuresis curve. Conversely, increased afferent sensory nerve signaling to the central nervous system in response to kidney ischemia, injury or inflammatory, fibrotic processes and other alterations of the tissue environment leads to reflex sympathetic activation, with peripheral vasoconstriction, increased BP and aggravation of HMOD [765–768] [720] [769] [770–772] [773] [774]
13.1.1 Clinical Evidence of the BP-lowering effect of RDN
Proof-of-concept human studies applying radiofrequency energy, high frequency unfocused ultrasound energy and perivascular injection of alcohol found substantial decreases in BP in patients with uncontrolled, treatment-resistant hypertension [748,769,775] [776] [777] [778]
To categorize the scientific quality of published RCTs, the following quality criteria were applied: (i) sham-controlled, multicenter trial, (ii) adequate blinding of patients and outcome assessors, (iii) ambulatory BP change as the primary outcome, (iv) study completion as planned and (v) use of advanced RDN systems [748,769] [748,769] [779] [748,769]
13.1.2 Off-medications studies
Patients with uncontrolled office and 24 h ABPM in the absence of antihypertensive drugs, with suitable renal artery anatomy, and eGFR 40 to 45 ml/min/1.73 m2 were investigated in four of the nine RCTs. In the SPYRAL HTN-Off MED Proof-of-Concept Study, radiofrequency-based RDN decreased 24 h SBP (primary objective) by 5.0 mmHg (P = 0.041) compared with the sham procedure [780] P < 0.001)] [746] P = 0.001) versus a sham procedure [745] P < 0.001)] [781]
13.1.3 On-medications studies
In the SPYRAL HTN-ON Med study in 80 patients with uncontrolled office BP and 24 h ABPM on one to three antihypertensive drugs, radiofrequency-RDN was associated with a greater BP reduction than sham procedure at 6 months (between-group difference of 7.0 mmHg, P = 0.0059), while antihypertensive therapy was unchanged [782] P = 0.022) [743]
Published meta-analyses including RCTs of high, medium and even low scientific quality showed variable results, albeit data from RCTs showed consistent 24 h BP reduction ranging from 3.9 to 7.0 mmHg SBP and from -3.7 to -6.9 mmHg DBP after RDN. Remaining gaps in knowledge concern a more precise definition of the prevailing magnitude of BP reduction after RDN, an issue that might be fruitfully addressed by individual patient-level meta-analysis [769] [783] [784] [748,769]
13.1.4 Safety
The main concerns regarding the safety of RDN is potential damage to the arterial endothelium, intima and media by the applied energy, renal artery dissection, contrast-induced nephropathy in the short-term, occurrence of de-novo renal artery stenosis and eGFR loss in the long-term [748,769] [743,745,746,778,780–782,785] 2 . A meta-analysis of 50 trials comprising 10 249 patient-years of data estimated a 0.20 annual incidence of renal artery stenting following RDN, which is similar to the reported natural incidence of renal artery stenosis in hypertension [786] [787] [747] [748,769]
13.1.5 Durability
Long-term data are available from sham-controlled RCTs, although unblinding of both patients and physicians generally took place after 6 and 12 months, respectively, and antihypertensive medications were added, changed or stopped by primary care physicians. Based on the analysis of patients enrolled in the Global Simplicity Registry (n = 2652 patients) [747] [788] [789] [790,791] [792]
13.1.6 Application
Endovascular RDN with radiofrequency energy or high frequency unfocused ultrasound energy represents a treatment option, that is additive or alternative to increasing medication in patients with uncontrolled resistant hypertension confirmed by ABPM after excluding secondary causes of hypertension [748,769] [748,769] [80,793] [793] [191] [80]
RDN should be performed only in experienced and specialized centers that have established a multidisciplinary team with a structured pathway for evaluating hypertensive patients [748,769] [748,769] [794] [794]
Use of renal denervation
13.2 Carotid baroreceptor stimulation
Stretch-sensitive baroreceptors located in the carotid sinus and the aortic arch are involved in short-term and long-term BP regulation. Carotid baroreceptor external stimulation via a pacemaker-like device or baroreflex neuromodulation by endovascular deployment of a self-expanding nitinol implant in the carotid artery has been investigated for treatment of resistant hypertension [795] [796,797] [797] [798] [798] [799] [800]
13.3. Other device-based treatments
The creation of a fixed-diameter iliac arteriovenous anastomosis with a catheter-based device (ROX coupler; ROX Medical) was investigated in resistant hypertension to lower peripheral vascular resistance [795] [801]
The Moderato system (BackBeat Cardiac Neuromodulation Therapy, Orchestra BioMed) is a dual-chamber, rate-responsive, implantable pulse generator that variably shortens and lengthens the atrioventricular interval [795] [802] [802] [803]
14. SPECIFIC HYPERTENSION PHENOTYPES
14.1 Sustained hypertension and true normotension
Use of out-of-office BP measurements by HBPM and/or ABPM allows identifying BP phenotypes that were unknown when BP measurements were limited to office BP. One phenotype is termed sustained hypertension and consists of an elevation of both office and out-of-office BP. Another is true normotension, which is characterized by office and out-of-office BP normality. These phenotypes may refer not only to untreated but also to treated individuals, where they indicate extended office and out-of-office BP control or no control of all these BP values. Available studies have defined out-office BP normality or elevation by either HBPM or ABPM and, at present, only the PAMELA study (a study based on a population sample from northern Italy) provides office BP, ABPM and HBPM in each individual, although with a restricted protocol for home BP measurements [142] [159]
14.2 White-coat hypertension
WCH refers to the untreated condition in which BP is elevated in the office but is normal when measured by ABPM, HBPM or both [4] [804,805] [806,807] [62] [95]
There has been much debate in the literature about whether WCH should be considered an innocent condition. HMOD is less prevalent in WCH than in sustained hypertension, and several studies have shown that this is the case also for the risk of CV events [62] [808] [809] [217] [217,810–814] [815–818] [814] [814] [819,820] [821]
White-coat hypertension (WCH)
14.3 Masked hypertension
MH refers to untreated patients in whom the BP is normal in the office but elevated when measured by HBPM or ABPM [822] [62] [822,823] [824,825] [824] [826] [822] [815,826–828] [812,829] [830,831] [822,832–834] [822,832,833] [835] [836] [62]
Masked hypertension (MH)
14.4 White-coat uncontrolled hypertension (WUCH) and masked uncontrolled hypertension (MUCH)
Originally referred to untreated patients, WCH and MH now also include patients on antihypertensive treatment, defined as (i) WUCH (white-coat uncontrolled hypertension), i.e. BP control by treatment during the 24 h but not in the office and MUCH (masked uncontrolled hypertension), i.e. BP control by treatment in the office but not outside the office. Although patients with WUCH have shown greater large artery stiffness than those with controlled BP [837] [133,838] [133] [811] [133] [839] [840] [841] [842] [832,833] [843] [172,844] [172] [824,845] [846] [845,847]
White-coat uncontrolled hypertension (WUCH) and masked uncontrolled hypertension (MUCH)
14.5 Isolated systolic hypertension of the young
ISHY, defined as an SBP 140 mmHg and a DBP <90 mmHg, is present not only in older persons but also in young and very young individuals (ISHY), more commonly in male individuals [121] [121,848] [849] [848] [850] [121] [851,852] [853] [121,851,852] [854,855] [856] [855,857] [858] [121] [859]
Isolated systolic hypertension in the young (ISHY)
14.6 Isolated systolic hypertension in older persons
In older people, several functional and structural abnormalities including endothelial dysfunction, vascular remodeling and fibrosis cause an increase in stiffness of large elastic arteries. The increased size of the forward pressure wave together with the earlier arterial wave reflection from the peripheral to the large arteries lead to an increase of SBP and pulse pressure [860] [861,862] [863] [864,865] [860,866] [867] [868] [869]
Diagnosis of ISH is particularly challenging in old individuals because of the high BP variability that characterizes this condition and the frequent occurrence of a pronounced white-coat effect at office BP measurement [860] [498,635,870] [502] [871] [860,866]
Target SBP and DBP values in older patients with hypertension have been an issue of intense debate. In dedicated RCTs, documenting the protective effect of antihypertensive treatment in ISH, on-treatment SBP remained in the 140–150 mmHg range [145,497,498] [144] [499] [500] [872]
Nevertheless, in ISH patients, a marked decrease in DBP should be avoided, because the risk reduction obtained by lowering SBP may be jeopardized by the increased risk arising from an excessive decrease of DBP, as recently suggested by the SPRINT study [873]
To prevent organ hypoperfusion, DBP should not be reduced below 70 mmHg by drug treatment, although compliance with this recommendation is often difficult as a large number of ISH patients already have a DBP <70 mmHg [874] [874] [497]
14.7 Isolated diastolic hypertension
Isolated diastolic hypertension (IDH) is a hypertension phenotype characterized by an SBP <140 mmHg and a DBP >90 mmHg. In the general adult population, IDH prevalence has been reported to be between 2.5 and 7.8% [875,876] [877] [875] [875,878] [875] [875] [875,879] [880,881] [882–884] [885] [886] [887] [888]
Isolated diastolic hypertension (IDH)
14.8 Night-time hypertension and dipping
Night-time hypertension is defined as an average BP ≥ 120/70 mmHg recorded during the night hours with ABPM. In recent years, dedicated home BP devices have emerged as a new method for obtaining BP values during sleep, and they could be a practical alternative to ABPM [889,890] [150] [891] [892] [893] [890,893,894] [895,896] [897] [898] [62] [62,159,898] [898] [173,899] [732,900] [732,900] [671,672] [670] [901]
Night-time hypertension and BP phenotypes
14.9 Orthostatic hypertension and hypotension
BP should also be measured in the standing position at the first visit, and regularly at each visit in patients who are older, under antihypertensive treatment, have diabetes, or with specific causes or factors that may favor an orthostatic BP fall. At least two BP measurements should be taken 1 and 3 min after standing. Orthostatic hypotension is defined as a decline 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 CV events events [902,903] [831,902,904] [869,905] [831] [831] [906] [779]
14.10 Baroreflex failure and efferent autonomic failure
Arterial baroreceptors sense changes in vascular stretch resulting from BP fluctuations. The information is conveyed through afferent nerves to the brainstem and elicits counter-regulatory adjustments in sympathetic and parasympathetic efferent activity, thereby stabilizing BP. Given the importance of the baroreflex in BP control, damage to the afferent portion, the integrating brainstem centers and/or the efferent portion of the baroreflex results in severe BP abnormalities. Despite anatomical preservation of the aortic baroreflex arch, baroreflex failure occurs following bilateral damage to carotid baroreceptors or baroreflex afferent nerves [907–909] [909]
Clinically, baroreflex failure is characterized by extreme BP variability with dramatic hypertensive surges, hypotensive episodes and orthostatic hypotension in some but not all patients [907–909] [907–910] [909] [911]
The clinical presentation of autonomic failure is characterized by a variety of manifestations of loss of autonomic BP control, including posture-related BP abnormalities with orthostatic hypotension and, in many patients, supine hypertension [912] [913] [914] [915] [916] [916]
Baroreflex failure and autonomic failure
15. HYPERTENSION IN DIFFERENT DEMOGRAPHIC SITUATIONS
15.1 Blood pressure in children, adolescents and transition period
15.1.1 Blood pressure measurements in children and adolescents
There is a general consensus that starting from the age of 3 years (or earlier in children with risk factors for high BP), BP should be regularly measured [917–920] [917,921,922] [917,922] www.stridebp.org [62] [917,922] [62,917]
15.1.2 Hypertension in children and adolescents
In children and adolescents, BP increases with age and body size, making it impossible to use a single BP cutoff value to define hypertension. Hypertension in the age range of 1– 15 years is diagnosed when office BP values are found to be equal or above the 95th percentile of the normative BP distribution for age, sex and height percentile, persistently on at least three separate occasions [62,917,923] [62,917,919,924,925] [62,917] [62,917] [917,926] [927] [919,927] [917,928,929] [917,930,931] [917,930,931]
15.1.3 Transition period to adulthood
In hypertensive adolescents aged 16 years or older, the consensus is to shift to the diagnostic and treatment criteria largely similar to those used in adult hypertensive patients. That is, to (i) identify hypertension by office BP values ≥ 140 mmHg for SBP and/or ≥ 90 mmHg for DBP, (ii) pursue an office BP target of <130/80 mmHg aiming at <125/75 mmHg in the presence of HMOD or CKD [4] [932]
BP measurement in children and adolescents
15.2 Hypertension in young adults
Recent large-scale longitudinal studies have expanded knowledge on the relationship of high BP with nonfatal CV events and mortality [933,934] n = 5000, age <40 years) from the CARDIA study followed for about 19 years [935] [936] [43] [857] [484] [43] [55]
15.3 Hypertension in older persons
Hypertension is extremely frequent in older individuals, where it is accompanied by an increase in the risk of CV and kidney outcomes almost throughout the entire old age range. In old people, SBP is prognostically much more important than DBP, and ISH is the predominant hypertension phenotype, particularly above 70 years of age. Some studies have shown that in old people, a pulse pressure >65 mmHg could be an independent risk factor for CV morbidity and mortality[937] [937] [938] [939]
15.3.1 Patients 65–79 years old
15.3.1.1 Threshold and target for drug treatment
There is strong evidence from RCTs that in this age range, antihypertensive therapy significantly reduces CV morbidity as well as CV and all-cause mortality. In addition, antihypertensive treatment can generally be well tolerated [940,941] [4] [496] [503] [942] [4] [943] [144,145,489] [144,145,497,498] [499,500]
15.3.1.2 Antihypertensive treatment strategies
Treatment of older patients should make use of lifestyle interventions as in younger patients. However, in subjects 80 years or older the measures indicated for younger patients (see Section 7) may have to be adapted. Although overweight and obesity remain deleterious for CV and metabolic health, weight loss programs may lead to muscle mass loss, sarcopenia and malnutrition. Therefore, except for the case of severe obesity or with robust old people, weight loss is not recommended. Also, salt restriction may contribute to loss of appetite with deleterious effects on nutritional status and therefore should not be adopted, except in cases of very high salt consumption (e.g. NaCl >10 g day). In these patients, a particular effort should be devoted to the promotion of physical activity, adapted to the individual's capacity and cultural context. Collective physical activities (e.g. dance, tai-chi or walking) should be preferred to also promote social contacts and fight loneliness and social isolation in older people. In older patients (even those in healthy conditions) who experience drug-related side effects [944] [608] [945,946]
15.3.1.3 Antihypertensive drugs
In the absence of specific indications, there is no evidence of more pronounced long-term benefits or harms of any specific drug class. Therefore, any of the five major drug classes can be used. However, older patients may be more susceptible to side effects associated with BBs, most importantly fatigue or sleep-related disorders (unusual dreams or insomnia) [592] Table 16 ). However, in clinical practice there are many cardiac, vascular and non-CV conditions, for which BBs are indicated, and their prevalence is high in old people as well [591] [947]
15.3.1.4 Monitoring the effects of treatment
The search for orthostatic hypotension should be systematic in people aged 65– 79 years, even in the absence of symptoms. HBPM should be implemented and help to better define the usual BP values in the face of the higher SBP variability in this age group. These measurements can be proposed even in patients with mild-to-moderate dementia, including patients with Alzheimer disease and other neurocognitive disorders. ABPM can be useful, especially in patients with polypharmacy, to identify hypotensive episodes and obtain information on the presence and magnitude of the night-time BP reduction.
15.3.2 Patients 80 years old or beyond
There is only one outcome-based RCT in this age group, i.e. the HYVET trial [502] [948] [503] [512]
No RCTs are available in patients close to 90 years of age or beyond. Data on therapeutic strategies and BP targets are also missing in patients with documented severe loss of autonomy due to the fact that trials on antihypertensive therapy in older people target healthier individuals and exclude those with loss of autonomy and limited life expectancy [949,950] [504,505] [506,507,509–511,945] [38,945]
15.3.3 How to assess the level of frailty/functionality to better personalize therapeutic strategies
Tools that can be used by physicians, nurses or other healthcare professionals in daily practice need clinical validation, standardization, limited requirement of time to be completed (less than 15 min), no need of complicated/expensive specific devices and no requirement of specialized skills (except for a short course for a minimal theoretical education and practical training). The clinical frailty scale [951] Table 21 ). This tool should be employed before the initiation of treatment and repeated annually in order to monitor the evolution of a patient's functionality/autonomy and personalize the treatment strategies (Table 21 ) [38] [952] [953] [954]
TABLE 21 - Adapting BP-lowering strategies in patients older than 80 years according to their functional/autonomy status (adapted from
[38] )
Group 1
Group 2
Group 3
Characteristics
Fit
Slowed but autonomous for most activities
Severely dependent
Diagnosis
-ADL (Katz) ≥5/6
-Profile between Groups 1 and 3
-ADL (Katz) ≤2/6
Therapeutic strategy
- Initiate drug treatment if office SBP ≥160 mmHg
- Initiate drug treatment if office SBP ≥160mmHg
- Priorize therapeutic strategies according to comorbidities and polypharmacy issues
ADL [952] : Activities of Daily Living (Katz Index) scaled rated from 0 (completely dependent) to 6 (completely autonomous). This scale comprises 6 ADL: Bathing, Dressing, Toileting, Transferring, Feeding and Continence. For each ADL ‘0’ means that the person is unable to do it without assistance, 0.5 need of some assistance, 1 no need of any assistance.
MMSE [955] : Mini mental status evaluation. Score 0-30, 30 best, 0-10 severe dementia, 11-20 moderate dementia.
SPPB [956] : Short Physical Performance Battery. Combined test including a balance test, a gait speed test and a 5-time chair stand test. Each one of the 3 tests is scored from 0 to 4, 4 best. The total score is from 0 to 12, 0-6 high risk of falls, 10-12 low risk of falls.
Mini GDS [957] : Geriatric depression scale. 4 questions score 0 to 4 (classically score 3-4 indicates a high risk of depression).
MNA-SF [958] : Mini nutritional assessment short form. Six items, score 0-14 (0-10 possible malnutrition, 14 best).
Treatment strategies in older persons
15.4 Sex and gender aspects in hypertension
15.4.1 Epidemiology and pathophysiology
In hypertension, as in many other diseases, there are sex (a biological characteristic) and gender (a social construct) differences that have an important impact on its pathophysiology, epidemiology and clinical management. In 2019, the worldwide age-standardized prevalence of hypertension, defined by SBP 140 mmHg and/or DBP 90 mmHg, or taking medication for hypertension, was 32% in women and 34% in men [37] [37] [37,959] [959] [39] [37,39,959]
The differences exhibited by women in BP development over the life course and the age-related hypertension can be explained by differences of BP regulatory mechanisms in male and female individuals – most likely a combination of sex and gender-specific factors [37,959] [960] [37,960] [961] [962]
15.4.2 Blood pressure and cardiovascular risk
In the pooled data of the IDACO study, the absolute CV risk was lower in women than in men, while the increase in risk associated with 24 h and night-time BP was steeper in women than in men. The proportion of events potentially preventable by BP-lowering may, therefore, be greater in women [963] [964] [965]
15.4.3 Differences in clinical phenotypes
15.4.3.1 White-coat hypertension and masked hypertension
The IDACO study reported that WCH exponentially increased from individuals aged 18– 30 years to individuals aged 70 years, with limited differences between men and women (8.0 versus 6.1%; P = 0.0003). However, data from national and international registries consistently report a higher prevalence of WCH in women [966] [967] [968] [969]
15.4.3.2 Hypertension-mediated organ damage
Female and male patients develop HMOD, but differences in HMOD frequency, severity and reversibility occur according to sex [970] [971,972] [973] [974,975]
Regarding arterial stiffness, PWV decreases in women after puberty. Thereafter, both sexes experience an increase in arterial stiffness with age, with women showing a more rapid increase after menopause. Older women experience greater aortic stiffness and arterial pulsatility than their male counterparts, seemingly contributing to ISH, uncontrolled hypertension, HFpEF and aortic stenosis, all being more common in women [976] [977]
There is also evidence that the impact of hypertension on kidney function and disease progression may have a sex-dependent component [978] [979] [980]
15.4.4 Sex differences in hypertension outcomes
The development of CV outcomes in relation to hypertension is also influenced by gender. An important observation is that hypertension-related outcomes, e.g. myocardial infraction, HF, stroke and CVD, may occur at lower SBP levels in women [964] [531] [981] [982] [857,983] [983] [984] [985] [203,986–988] [960,976] [973,986] [989] [990,991] [964,992] [993,994]
15.4.5 Benefits of antihypertensive treatment and target blood pressure
Do women receive the same CV outcome benefits from antihypertensive treatment than men? Because of the global under-representation of women in trials, answering this question is difficult. Moreover, the statistical analyses of interventional trials commonly used a binary approach that does not appropriately capture the clinical specificities of men and women. Only few clinical trials in hypertension report treatment results stratified by sex. The NORDIL study showed similar treatment effects in both sexes [995] [996] [997] [998] [941] [97] [999] [1000]
15.4.6 Sex differences in hypertension management
Lifestyle modifications are important for nonpharmacological management of hypertension, and sex differences in their effects have been noted. In the DASH trial, dietary sodium restriction induced pronounced BP reductions only in female individuals. Regarding physical activity, a meta-analysis of 93 trials assessing the impact of a structured aerobic exercise therapy found that exercise induced a greater BP reduction in male than in female participants [357,1001] [1002] [1003] [1004] [1005] [1006] [1007] [1008] [669]
15.4.7 Infertility treatments and hypertension in women
Following any invasive assisted reproductive therapy, the risk ratios for gestational hypertension, preeclampsia and a combination of both, increase by 54% independently of the gestation order [1009] [1010]
15.4.8 Oral contraceptive pills and hypertension
Physicians counselling women with CV risk factors, including hypertension, should balance the potential risks of contraceptive methods against those of an unintended pregnancy. Older studies have demonstrated a relationship between the use of a combined estrogen– progestin oral contraceptive pill (mostly with a higher dose of estrogens), venous thromboembolism, and, to a lesser extent, myocardial infarction (especially with a concomitant smoking history) and stroke [1011,1012] [1012–1014] [1015–1017] [1018] [1019] [1020] [1021] [1022] [1021,1023] [1021] [1023]
15.4.9 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 [1024] [1025]
15.4.10 Gender-affirming hormone therapy and hypertension
According to the Global Health 50/50 definition, gender refers to the socially constructed norms that impose and determine roles, relationships, and positional power for all people across their lifetime [1026] [1027] [1028]
15.5 Hypertension and ethnicity
15.5.1 Nomenclature and relevance
Given the degree of African and Asian migration to Europe, attention to factors and differences in the management of hypertension related to ethnicity is mandatory. In the United States, the notion is consolidated that in African Americans, hypertension is more common, possibly more severe, more risky for CV and kidney events, and more difficult to control. A major research agenda to improve the hypertensive burden among African-Americans was proposed some years ago [1029] [1030,1031] [1032–1035] [1036,1037] [1038] [1038] [1039–1042] [1043–1045] [1046,1047] [1048] [1049] [1046,1050]
15.5.2 Management
Lifestyle modifications are vital for reducing BP and risk across the life-span in all hypertensive patients. Differences in BP response to antihypertensive drugs by ancestry have been associated with BP levels rather than ‘race’ [466] [1051] [1052] [1052,1053] [566,1054] [1052] [1048,1052] [1055]
To date, only the ACCOMPLISH trial (n = 11 506, mean age 68 years) has provided outcome data with initial combination therapy [626] n = 1414) versus only a 23% benefit in the total study population (N = 11 506).
The above limited evidence suggests that in hypertensive adults of African ancestry, antihypertensive treatment should be largely based on CCBs but also that CCB plus ACEi and CCB plus diuretic combinations can both effectively lower BP, with some suggestion of a greater CV protection by the former combination. A systemic review has shown no different response to antihypertensive drugs in south Asian patients with a relatively high CV risk [1052]
16. HYPERTENSION IN SPECIFIC SETTINGS
16.1 Hypertension disorders in pregnancy
Hypertension disorders affect almost 10% of pregnancies worldwide and are the major cause of maternal, fetal or neonatal morbidity and mortality [1056] [1057] Table 22 and addressed in detail below.
TABLE 22 - Classification of hypertensive disorders in pregnancy
A. Preexisting (chronic) hypertension
B. Gestational hypertension Transient gestational hypertension Preeclampsia is gestational hypertension accompanied by one or more of the following new-onset conditions at or after 20 weeks gestation:
C. Preexisting hypertension + superimposed preeclampsia
D. Antenatally unclassifiable hypertension
16.1.1 Definition and classification of hypertension in pregnancy
The definition of hypertension in pregnancy is based on office BP values, i.e. SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg [1057,1058] Table 1 ). HDPs are further classified according to the onset of hypertension in pregnancy. Hypertension known before pregnancy or present in the first 20 weeks can be distinguished as preexisting (chronic) hypertension (primary or secondary), WCH (elevated office and normal out-of-office BP), and MH (normal office and elevated out-of-office BP). Hypertension that develops de novo at or after 20 weeks of pregnancy is classified as gestational hypertension, transient gestational hypertension, or preeclampsia de novo or superimposed on preexisting hypertension. Prepregnancy or early first-trimester BP measurements should be available to avoid misclassification of hypertensive disorders in pregnancy. Early second-trimester BP measurements in women without previous BP measurements should be interpreted with caution because of the physiological second-trimester BP fall. However, women with hypertensive BP levels after 20 weeks and unknown BP levels before 20 weeks should be managed as those with gestational hypertension. In these women with prepartum pregnancy unclassifiable hypertension, BP reassessment 6 weeks postpartum will help to distinguish preexisting hypertension from gestational hypertension. Transient gestational hypertension (diagnosed at the clinic after 20 weeks) is characterized by BP normalization after consecutive BP measurements over several hours. However, almost 40% of women with transient gestational hypertension develop sustained gestational hypertension [1059]
The present guidelines adopt the broader definition of preeclampsia previously endorsed by the International Society for the Study of Hypertension in Pregnancy [1058]
Among women with preexisting hypertension, almost 25% will develop superimposed preeclampsia [1060]
16.1.2 Blood pressure measurement in pregnancy
During pregnancy, BP should be measured in the sitting position (or in the left lateral recumbent position during labor) with an appropriately sized arm cuff at heart level using the manual auscultatory method and Korotkoff phase V for DBP [1061] [1061] [1062] [1063] [1064]
16.1.3 Laboratory examinations in pregnancy
Basic laboratory investigations are recommended for monitoring pregnant hypertensive women, including urine analysis, blood count, hematocrit, liver enzymes, serum creatinine and serum uric acid (increased in clinically evident preeclampsia). Hyperuricemia in hypertensive pregnancies identifies women at increased risk of adverse maternal and fetal outcomes [1065] sine qua non’ criterion for the diagnosis of preeclampsia. Occasionally, proteinuria may anticipate a subsequent rise of BP in the natural course of preeclampsia. A dipstick test of at least 1+ should prompt evaluation of ACR in a single spot urine sample, and a value of less than 30 mg/g can reliably rule out proteinuria [1066,1067]
16.1.4 Prediction and prevention of preeclampsia
Women at high or moderate risk of preeclampsia should be advised to take 100–150 mg of aspirin daily (at bedtime), preferably before 16 weeks and ideally from weeks 11 to 14 until 36 weeks of gestation [1068–1071]
High risk of preeclampsia includes any of the following:
1. Hypertensive disorders during a previous pregnancy
2. Chronic hypertension
3. Chronic kidney disease
4. Type 1 or type 2 diabetes mellitus
5. Autoimmune diseases such as systemic lupus erythematosus or antiphospholipid syndrome
6. Assisted reproductive therapy in the current pregnancy
Moderate risk of preeclampsia includes two or more of the following risk factors:
1. Nulliparity
2. Age 40 years or older
3. Pregnancy interval of more than 10 years
4. BMI of 35 kg/m2 or more at the first visit
5. Family history of preeclampsia
6. Multifetal pregnancy
Beyond clinical and ultrasonographic parameters, several laboratory markers have been tested during early pregnancy for the prediction of preeclampsia:
1. Angiogenic factors [endoglin, PIGF, soluble fms-like tyrosine kinase-1 (sFlt-1) and sFlt-1/PIGF ratio]
2. Pregnancy-associated plasma protein A (PAPP-A) in association with clinical (e.g. BP, maternal risk factors) and ultrasonographic characteristics (e.g. uterine artery Doppler) [1072]
However, more studies are desirable to refine the role of the above markers separately or in combination with clinical characteristics for predicting preeclampsia. Although prospective evidence is limited [1073,1074] [1074]
16.1.5 Lifestyle interventions
Unless contraindicated, aerobic exercise (three to four times per week for 30– 60 min sessions until delivery) should be recommended in pregnant women to maintain ideal body weight and reduce adverse pregnancy outcomes, including hypertensive disorders [1075–1077] [1078] [1070]
16.1.6 Clinical management of hypertension in pregnancy
16.1.6.1 Mild preexisting essential hypertension
During the first trimester, all RAS blockers, i.e. ACEis, ARBs or direct renin inhibitors should be stopped. Clinicians should decide on an individual basis whether drug treatment during fetal organogenesis (until week 16) overcomes the risk of fetal drug effects because any drug may be potentially hazardous during the first trimester, including alpha-methyldopa [1079]
In the large CHIPS [1080] [1081] [1080] [1071,1080,1081] [1071] [1082]
16.1.6.2 Mild gestational hypertension
Although the CHIPS trial [1080]
16.1.6.3 Preeclampsia
All women with preeclampsia should be hospitalized and carefully monitored at first diagnosis. A diagnosis of preeclampsia at or after 37 weeks of gestation underscores the need for hypertension control and prompt delivery. Clinically stable women with preeclampsia before 37 weeks of gestation can be managed on an outpatient basis. However, despite optimal antihypertensive treatment, delivery is indicated even before 37 weeks, whenever hypertension remains severe. Delivery induction before 37 weeks is also recommended with (i) emerging maternal (neurological, hematological or CV) manifestations or (ii) a nonreassuring fetal status [1058]
The management of hypertension in preeclamptic women with mild or severe hypertension does not differ from women without preeclampsia (see above sections), although evidence is limited. Preeclampsia with severe features (severe hypertension with or without proteinuria, any hypertension grade with neurological, hematological, or cardiovascular complications, liver dysfunction or renal dysfunction) should be managed with MgSO4 infusion (and delivery) to prevent eclampsia. Infusion of MgSO4 for the 24 h postpartum seems reasonable for prevention purposes [1083] 4 remains the treatment of choice for eclamptic seizures. Hypertension control can be achieved by labetalol (unless contraindicated) alone or with the combination of labetalol, nifedipine extended-release and/or alpha-methyldopa.
16.1.6.4 Severe hypertension
In severe hypertension, hospitalization is mandatory to allow gradual BP reduction to <160/105 mmHg and exclude preeclampsia. Continuous cardiotocographic monitoring is also mandatory [1058] [1084] [1080] [1085]
16.1.6.5 Preexisting secondary hypertension
Women with known preexisting hypertension should receive preconception counseling, including ruling out secondary hypertension causes. Renal Doppler ultrasounds should be performed in all women with hypertension planning a pregnancy. In women diagnosed with fibromuscular dysplasia (FMD) before pregnancy, further evaluation of other vascular beds should be performed to exclude any additional arterial damage [340] [1086]
Women with primary aldosteronism should be discouraged from pregnancy because of the competitive antagonism of progesterone and aldosterone in excess at the level of the mineralocorticoid receptors [1087] [1088] [1087,1088]
Pheochromocytoma in pregnancy is one of the most life-threatening conditions for the mother and fetus. Although extraordinarily rare, with a frequency of 0.002% of all pregnancies, this disease is notorious for its devastating consequences [1089]
HDP are observed in almost half of pregnant women with CKD. Therefore, it is important to know the degree of CKD, level of eGFR or degree of proteinuria, before pregnancy rather than the underlying cause [1090] [1091] 2 and proteinuria of more than 1 g/day should be considered at very high risk for pregnancy and kidney outcomes, including kidney replacement therapy.
16.1.7 Blood pressure during puerperium
Postpartum hypertension is common during the first week. Also, in women with a normotensive pregnancy, a BP elevation during the first-day postpartum is usually associated with (i) the use of vasoactive drugs to favor uterine contraction (oxytocin, methergine), (ii) blood transfusions, (iii) the physiological uterine ‘auto-transfusion phenomenon’ or (iv) an excessive fluid intake. In women with preeclampsia, a reduced diuresis during 12– 36 h postpartum is observed because of a delayed fluid redistribution associated with a greater colloid osmotic pressure drop compared to a normal pregnancy [1092] [1093]
During puerperium, BP levels usually normalize within the first 6 weeks in women with gestational hypertension or preeclampsia. By contrast, women with preexisting hypertension or superimposed preeclampsia perpetuate elevated BP values beyond the 6 weeks of puerperium. A further unusual postpartum hypertension phenotype is the so-called ‘late postpartum hypertension’ phenotype, which appears 6 months after delivery and resolves several months later [1094] [1094,1095]
All antihypertensive agents used during pregnancy may be used during puerperium to achieve BP control. However, the use of ACEis in the postpartum period should be reserved for women with cardiorenal comorbidities and is, thus, not recommended in healthy women with hypertensive disorders during puerperium. Methyldopa should be used with caution because of the risk of postpartum depression.
16.1.8 Postpartum hypertension and breastfeeding
Antihypertensive drugs taken by the nursing mother are excreted into breast milk, mostly in very low concentrations. Proper information on prescribable drugs in breastfeeding women is important [1057,1096] [1096]
16.1.9 Risk of recurrence of hypertensive disorders in a subsequent pregnancy
Women experiencing hypertension in their first pregnancy are at increased risk of hypertension and hypertensive disorders in a subsequent pregnancy. The earlier the onset of hypertension in the first pregnancy, the higher the risk of recurrence in a subsequent pregnancy.
16.1.10 Long-term cardiovascular consequences of hypertensive disorders in pregnancy
Several registries [1097,1098] [1097,1098] [33,1099] [48,1100] [49] [1101] [33,1099]
Hypertension management in pregnancy
16.2 Hypertensive urgencies and emergencies
The proper management of patients who come to the Emergency Department for BP elevation faces a number of difficulties. A major challenge for the physician is to identify and discriminate the patients at immediate risk of CV or kidney complications from those in whom the BP elevation does not carry any immediate risk for health. While the former patients require immediate attention and treatment, the latter are in no need of hospitalization or even treatment. FU and treatment of patients after discharge from the Emergency Department is still poorly defined and often inadequate [1102,1103]
16.2.1 Definitions of hypertensive urgencies and emergencies
Hypertension emergencies are conditions in which severe hypertension (grade 3) is associated with acute symptomatic HMOD. Hypertension emergencies can be life-threatening and require immediate intervention to lower BP, usually with intravenous (i.v.) therapy [1103] [1103,1104]
1. Severe hypertension associated with conditions that need intensified BP management: acute stroke (hemorrhagic or ischemic/thromboembolic), aortic aneurysm or dissection, acute HF, acute coronary syndrome and kidney failure. These emergency conditions are compatible also with a relatively modest BP increase, which is sufficient to precipitate organ failure.
2. Hypertension caused by phaeochromocytoma or exogenous sympathomimetics substances (e.g. substance abuse). Ingestion of sympathomimetic drugs such as meta-amphetamine or cocaine may precipitate acute and severe BP increases that may result in hypertension emergencies when there is evidence of acute HMOD.
3. Severe forms of HDP, including preeclampsia/eclampsia with a HELLP syndrome (see Section 16.1) [1103]
Malignant hypertension with or without thrombotic microangiopathy or acute kidney failure is a hypertensive emergency characterized by small artery fibrinoid necrosis in the kidney, retina and brain. There might be also funduscopic changes (flame hemorrhages and papilledema), microangiopathy, disseminated intravascular coagulation, encephalopathy (15% of cases) or acute HF [1105] [1106] [1105,1107–1109] [1103,1105,1110] [4,1103,1104,1111,1112]
The term ‘hypertension urgency’ has been used to describe severe hypertension in patients in whom there is no evidence of acute HMOD [1102,1108–1110] [1102,1108–1110]
For patients with a suspected hypertension emergency, the diagnostic work-up is shown in Table 23 .
TABLE 23 - Diagnostic work-up of hypertension emergencies and urgencies
Common tests
Fundoscopy
ECG 12 leads
Hemoglobin, platelet count, fibrinogen, peripheral smear
Creatinine, eGFR, electrolytes, LDH, haptoglobin
UACR, urine microscopy for red blood cells, leucocytes and/or casts
Pregnancy test in women of child-bearing age
Specific tests
Troponin, (suspected HF and/or acute coronary syndrome) NT-proBNP
Chest X-ray or ultrasound (pulmonary congestion and fluid overload)
Echocardiography (heart failure, acute ischemia, aortic dissection)
CT angiography of thorax and/or abdomen in suspected aortic disease (aortic dissection)
CT or MRI brain (nervous system involvement)
Kidney ultrasound (renal impairment or suspected renal artery stenosis)
Urine drug collection (cocaine or methamphetamine use)
16.2.2 Hospital work-up, treatments and follow-up
Hypertensive emergencies, including BP 170/110 mmHg in a pregnant woman, should be hospitalized. Except for acute BP-lowering in stroke, there are no RCTs on the management of these conditions. It should first be established, which organs are affected to determine whether (i) they require any specific intervention other than BP-lowering and (ii) there is a precipitating cause for the acute rise in BP that might affect the treatment plan (e.g. pregnancy). Then a decision should be made on the timescale and magnitude of the BP-lowering as well as on the type of drug treatment that might be appropriate. Intravenous treatment with a drug that has a short half-life is ideal to allow careful titration of the BP response, keeping the patient in a close clinical area under continuous hemodynamic monitoring (Table 24 ). Rapid uncontrolled BP-lowering is not recommended [4] [1105] Table 25 , and further details can be found in dedicated publications [4,1103,1113]
TABLE 24 - Hypertensive emergencies requiring immediate BP-lowering with i.v. drug therapy
Clinical presentation
Timing and BP target
First-line treatment
Alternative
Malignant hypertension with or without acute renal failure
Several hours
Labetalola
Nitroprusside
Hypertensive encephalopathy
Immediately reduce MAP by 20–25%
Labetalola
Nitroprusside
Acute coronary event
Immediately reduce SBP to <140 mmHg
Nitroglycerinea
Urapidil
Acute cardiogenic pulmonary edema
Immediately reduce SBP to <140 mmHg
Nitroprusside or nitroglycerine (with loop diuretic)
Urapidil
Acute aortic dissection
Immediately reduce SBP to <120 mmHg and heart rate to <60 bpm
Esmolol AND nitroprusside or nitroglycerine or nicardipine
Labetalola or metoprolol
Eclampsia and severe preeclampsia/HELLP
Immediately reduce SBP to <160 mmHg and DBP to <105 mmHg
Labetalola or nicardipine and magnesium sulphate
Consider delivery
a Not available in several countries.
TABLE 25 - Drug types, dose and characteristics for treatment of hypertension emergencies
Drug
Onset of action
Duration of action
Dose
Contraindications
Adverse effects
Esmolol
1 min
10–30 min
0.5–1 mg/kg i.v. bolus; 50–300 μg/kg/min i.v. infusion
Second-degree or third-degree AV block, systolic heart failure, asthma, bradycardia
Bradycardia
Metoprolol
1–2 min
5–8 h
2.5–5 mg i.v. bolus over 2 min; may repeat every 5 min to a maximum dose of 15 mg
Second-degree or third-degree AV block, systolic heart failure, asthma, bradycardia
Bradycardia
Labetalola
5–10 min
3–6 h
10–20 mg i.v. bolus in 1 min; incremental doses ≥20 mg may be administered i.v. at 10 min intervals (max 80 mg) or 1–3 mg/min i.v. infusion until goal BP is reached
Second-degree or third-degree AV block; systolic heart failure, asthma, bradycardia
Bronchoconstriction, fetal bradycardia
Fenoldopam
5–15 min
30–60 min
0.1–0.3 μg/kg/min i.v. infusion, increase every 15 min with 0.1 μg/kg/min increments until goal BP is reached
Caution in glaucoma
Clevidipine
2 min
10 min
1–2 mg/h i.v. infusion, increase every 2 min with 2 mg/h until goal BP, then titrate by smaller increments every 5–10 min
Headache, reflex tachycardia
Nicardipine
5–15 min
4–6 h
5–15 mg/h i.v. infusion, starting dose 5 mg/h, increase every 15–30 min with 2.5 mg until goal BP, maximum 15 mg/h
Liver failure
Headache, reflex tachycardia
Nitroglycerine
1–5 min
5–10 min
5–200 μg/min i.v. infusion, 5 μg/min increase every 5 min
Headache, reflex tachycardia
Nitroprusside
Immediate
1–3 min
0.3–0.5 μg/kg/min i.v. infusion, increase by 0.5 μg/kg/min every 5 min until goal BP (maximum dose 10 μg/kg/min)
Liver/kidney failure (relative)
Cyanide intoxication
Enalaprilat
5–15 min
4–6 h
0.62–1.25 mg i.v. bolus given over 5 min every 6 h
History of angioedema
Urapidil
3–5 min
4–6 h
12.5–25 mg i.v. bolus;
Clonidine
30 min
4–6 h
0.2–0.5 μg/kg/min i.v.
Sedation, rebound hypertension
Phentolamine
1–2 min
10–30 min
1–5 mg i.v. bolus or continuous i.v. infusion at a rate of 0.5–20 μg/kg/min
Tachyarrhythmia, chest pain
a Not available in serveral countries.
Patients with hypertensive urgencies do not usually require hospitalization. However, they require BP reduction, which can be obtained by oral administration of antihypertensive drugs, aimed at lowering BP gradually over 24–48 h. Oral treatment may include reinstitution or intensification of previous treatment or starting new treatment. DHP-CCBs are suggested as first choice in an untreated patient as they have few or no contraindications and do not interfere with the diagnostic work-up for secondary hypertension. Sublingual, rapidly acting, administration of nifedipine should be avoided because the degree of BP decrease cannot be anticipated and may often be too fast and larger than desirable [4,1103] [1114] [1115]
The survival of patients with hypertension emergencies has improved strikingly over past decades [1105] [4,1105,1108–1112,1116] [4,1117,1118]
16.2.3 Blood pressure in the emergency department
BP measurements in the emergency department usually do not follow guidelines and may, thus, be inaccurate [4] [1119] [1120,1121] [1117] [95] [1114]
16.3 Perioperative hypertension and its management
Because of its high prevalence and association with age, hypertension is an extremely common condition in patients undergoing surgery, in several cases with no awareness of the high BP status by the patient. A BP elevation at the time of a surgical intervention is not an innocent association because severe hypertension has been found to be accompanied by an increased incidence of surgery-related complications, including bleeding [1122] [488,1123] [1124] [1125] [1126,1127] [1128]
Hypertension may occur during induction of anesthesia, the intubation maneuvers, the operation or in the early postanesthesia period. Induction of anesthesia generates pain and stress, and intubation evokes reflexes that may lead to cardiac and vascular sympathetic activation, increasing the odds of a rise in BP and heart rate as well as of excessive BP fluctuations and arrhythmias [1122] [1129]
Perioperative hypertension and its management
17. HYPERTENSION IN ESTABLISHED CARDIOVASCULAR DISORDERS
17.1 Coronary artery disease
Hypertension is one of the major risk factors for CAD in its various clinical aspects (myocardial infarction, angina pectoris, acute coronary syndrome and chronic coronary syndromes), together with other risk factors including smoking, dyslipidemia and type-2 diabetes [531,1130] [35,1131] [1132] [1133] [1134] [559] [493] [1135] [524,1136] [559,1136] [538,1133,1137–1140] [1139] [1141,1142] [1139] [534,537]
Prevention of coronary artery disease (CAD) in hypertension
17.1.2 Treatment of hypertensive patients with coronary artery disease
BBs, DHP-CCBs and nondihydropyridine CCBs are the preferred drugs for the treatment of hypertension in symptomatic CAD patients with angina, with a DHP-CCB and a BB in combination if needed. In patients with a recent myocardial infarction, BBs also improve prognosis [1143–1146] [1145,1147,1148] [598,1149] [1150,1151] Fig. 15 ).
FIGURE 15:
BP-lowering therapy in patients with hypertension and coronary artery disease.a Target heart rate below 80 beats per minute, if BBs are contraindicated or not tolerated consider use of non-DHP CCB at any step instead of DHP-CCB.
Treatment of hypertension in coronary artery disease (CAD)
17.2 Heart failure
17.2.1 Prevention of heart failure in hypertension
Prevention of HF received less attention than prevention of stroke and myocardial infarction until a review of the placebo-controlled RCTs in hypertension [1152] [1152] [228,229] [193] [193] [231] [228] [193] [1153]
A few RCTs have received special attention because of the HF findings. Their results, as well as those of large meta-analyses of RCTs [80,583] [566,1154,1155] [566,1154,1155] [600]
Prevention of heart failure in hypertension
17.2.2 Heart failure with reduced ejection fraction (HFrEF)
Hypertension is a major risk factor for HFrEF, against which antihypertensive treatment has a major protective effect. However, in patients with clinically manifest HFrEF, an elevated BP is an uncommon problem because the reduced cardiac output counterbalances or overrides the increase in systemic vascular resistance typical of hypertension, usually leading to a normal or reduced BP. According to outcome-based RCTs, four drug classes in combination therapy are recommended for treatment of HFrEF in current HF guidelines [1156,1157] Fig. 16 ). With the exception of SGLT2is, all these drugs are also recommended for the treatment of hypertension (Fig. 14 ). ACEis and BBs are part of the basic antihypertensive treatment strategy, while MRAs are recommended in patients with true resistant hypertension (see Section 12). Additionally, diuretics are recommended to manage fluid balance and reduce congestion, and are another antihypertensive treatment cornerstone. Thiazide/Thiazide-like diuretics are preferable if fluid retention is not a major problem or there is sufficient kidney function. Treatment with a loop-diuretic (furosemide, torsemide) is given to patients with severe fluid retention, in particular if they have suffered from pulmonary edema or have advanced CKD (eGFR <30 ml/min/1.73 m2 ). In the rare cases in which the above drugs in combination therapy at maximum tolerated doses are not sufficient to lower an elevated BP to control values (<130/80 mmHg), DHP-CCBs may offer an additional option because they have been shown to be safe when added to existing treatments in HFrEF and are indicated when HFrEF is associated with CAD and angina (see Section 17.1). However, in the last few years, use of ARNI (a compound that combines an ARB with the endopeptidase neprylisin inhibitor sacubitril) has made an uncontrolled BP in HFrEF even more unlikely, because this drug has a BP-lowering effect as shown in hypertensive patients [605]
FIGURE 16:
BP-lowering drugs in hypertension and heart failure. (a) Non-DHP CCB are not recommended in HFrEF and should not be combined with BB. (b) Use of Diuretics: Use T/TL Diuretic if eGFR >45 ml/min/1.73 m2 . Consider transition to Loop Diuretic if eGFR is between 30 to 45 ml/min/1.73 m2 . Use loop Diuretic if eGFR <30 ml/min/1.73 m2 or in patients with fluid retention/edema.
Treatment of hypertension in heart failure with reduced ejection fraction (HFrEF)
17.2.3 Heart failure with preserved ejection fraction (HFpEF)
HFpEF accounts for about half of all HF patients, and hypertension is by far the most frequent precursor of and comorbidity for this condition [193,1158] [193,1158] [193,1158] [466] [1159,1160] [1156] [762] [1161] [193,1156] Fig. 17 ).
FIGURE 17:
BP-lowering therapy in hypertension and HFpEF. (a) Use of Diuretics: Use T/TL Diuretic if eGFR >45 ml/min/1.73 m2 . Consider transition to Loop Diuretic if eGFR is between 30 to 45 ml/min/1.73 m2 . Use loop Diuretic if eGFR <30 ml/min/1.73 m2 or in patients with fluid retention/edema. (b) BB should be used as guideline directed medical therapy in respective indications or considered in several other conditions (Table 16) (c) Use SGLT2i according to approval.
Treatment of hypertension in heart failure with preserved ejection fraction (HFpEF)
17.2.4 Overall management of heart failure and classification
Optimal management of HF patients includes special care programs for both hospitalized patients and outpatients who can be managed in HF clinics, in which the problem of long-term drug adherence is also addressed [1162] [229] [193,1158]
17.3 Hypertension and atrial fibrillation
AF is by far the most common arrhythmia in adults, and both its persistent and paroxysmal (more or less frequent AF episodes of variable duration) phenotypes are associated not only with increased risk of stroke but also with an increase of overall CV morbidity and mortality, including the risk of developing HF [1163,1164] [1163–1165] [1166] [1163–1165] [1167] [1168,1169] [4,1163–1165] [1170] [1171] [1172]
17.3.1 Blood pressure measurement in atrial fibrillation
Accurate measurement of BP is important and challenging in patients with AF who are usually older and more frequently hypertensive than people without AF [1173] [1173] [4] [1173] [127,1174] [105,1174–1178] [1163,1164]
17.3.2 Detection of atrial fibrillation
Because the lifetime risk for development of AF in adults is high (one of three Europeans >50 years of age) [1165] [1176] [1176] [1179]
17.3.3 Prevention and treatment of atrial fibrillation in hypertension
Prevention and treatment strategies for AF do not substantially differ in patients with and without hypertension. BBs combine their BP-lowering effect with heart rate reduction in patients with hypertension and rapid AF, thereby helping to achieve heart rate control, which is central in AF management [1180] [1180] [1180]
Although several small studies suggest a moderate decrease of AF recurrence rate by BBs, the effect of these drugs on clinically relevant outcomes (stroke, systemic embolism or HF) remains to be established [1181] [1182–1185] [1186] [1187] [1188] [1186] [1189] [1190,1191] [1192]
Prevention of atrial fibrillation in hypertension
Treatment of hypertension in atrial fibrillation
17.3.4 Oral anticoagulation and BP control
In AF, the administration of anticoagulants has become mandatory if the risk of stroke is high and greater than the risk of major bleeding associated with these drugs [1163,1164] [1163,1164] [1193] [127,1194] [127] [1195] [1196] [1197,1198] [1199] [1170,1200,1201] [1202] Fig. 18 ) [1203,1204]
FIGURE 18:
BP-lowering therapy in hypertension and atrial fibrillation. (a) Target heart rate below 80 beats per minute, if BBs are contraindicated or not tolerated consider use of non-DHP CCB at any step instead of DHP-CCB.
Management of patients with hypertension and AF during oral anticoagulation
17.4 Valvular heart disease
The most common valve disorders of the heart are aortic stenosis (AS), aortic regurgitation (aortic insufficiency) and mitral regurgitation (mitral insufficiency). Detection is usually obtained by auscultation of murmur and subsequent echocardiography. In patients with progressive AS severity, ultimate treatment is open valve surgery or catheter-based valve replacement or repair. At a later stage, cardiac valve disease may be a component of the HF syndrome, and patients should receive HF treatment. Hypertension is common in patients with valvular heart diseases and particularly in patients with AS.
17.4.1 Aortic stenosis
AS is a degeneration of the aortic valve with fibrotic tissue and calcification. A bicuspid valve predisposes to this development. The pathophysiological mechanism is different from atherosclerosis with plaque formation in the intima of large arteries because intensive lipid-lowering treatment does not prevent worsening of aortic stenosis [1205] [1206–1208] [1206–1208]
17.4.2. Aortic regurgitation
Hypertension with aortic regurgitation (insufficiency) should be treated according to the general treatment guidelines until the valve disease needs surgery or catheter-based treatment, which usually takes place when a dilated left ventricle is detected by echocardiography. An RCT performed three decades ago showed that treatment with nifedipine could delay the time point for surgery [1209]
17.4.3 Mitral regurgitation
Numerous cardiac diseases may be associated with damage of the mitral valve and mitral regurgitation (insufficiency). Longstanding or severe hypertension may cause mild or even moderate-to-severe mitral regurgitation through dilatation of the left ventricle and thus stretching of the chorda tendineae, separation of the two mitral leaflets in systole and leakage of blood into the left atrium. This appears to be a sequence of events that is not rare, because in a British population study [1210]
Hypertension and cardiac valve disorders
17.5 Cerebrovascular disease and cognition
17.5.1 Management of elevated BP in acute stroke
17.5.1.1 Acute hemorrhagic stroke
In acute intracerebral hemorrhage, an increase of BP is common and associated with a greater risk of hematoma expansion, death and reduced chance of neurological recovery [1211,1212] [1213,1214] [1215] [1216] [1217]
In patients with acute intracranial hemorrhage and an SBP <220 mmHg, current evidence for initiation of BP-lowering treatment >6 h after onset of symptoms is not entirely univocal. Recently, an individual patient data meta-analysis of 16 studies (6221 participants) has shown that a moderate SBP reduction (12.1 mmHg achieved over several hours) reduced the hematoma expansion, although with no clear effect on the chance of clinical recovery. Therefore, slow and moderate BP reductions are preferable over intensive BP targets [1216,1218] [1219] [1213] [1220] Fig. 19 ).
FIGURE 19:
BP management in acute stroke. (a) Avoid absolute reductions of SBP >60 mmHg from initial SBP.
17.5.1.2 Acute ischemic stroke
The beneficial effects of BP reduction are even less clear in acute ischemic stroke. In most patients, initial BP values are high or very high and show a spontaneous progressive reduction during the first 48–72 h after stroke [1221] [1216,1222–1228] [1229] [1225,1227,1230] [1227,1231]
Patients with an acute ischemic stroke who have or will receive reperfusion interventions such as intravenous thrombolysis or mechanical thrombectomy are a special category, because observational studies have reported that these interventions increase the risk of intracerebral hemorrhage if BP is markedly elevated [1232,1233] [1234] [1235] [1236,1237] Fig. 19 ). For stable patients, who remain hypertensive (≥ 140/90 mmHg) more than 3 days after an acute ischemic stroke, initiation or reintroduction of BP-lowering medications should be considered [1238]
Management of blood pressure in acute stroke
17.5.2 Management of elevated BP in patients with previous stroke or transient ischemic attack
Placebo-controlled RCTs of antihypertensive treatment in clinically stable hypertensive patients (BP ≥ 140/90 mmHg) with a previous stroke or TIA [1239,1240] [1241] [1242] [466,1242–1249] [1250]
Prevention of stroke has been observed in large RCTs using different drug regimens. However, RCTs comparing different treatment regimens [625,1251] [466,583,584,1252] [584,625,1251] [625,1251] [625,1251,1253,1254] [1255–1257] Table 16 ).
17.5.3 Management of patients with cognitive dysfunction and dementia
In the last 25 years, the incidence of dementia has sizably increased, mainly because of the increase in population aging. Dementia is more frequent in women than in men and is the fifth most common cause of death in the world [1258] [1258,1259] [312,1260] [1261] [308,1262–1264] [300] [1265] [471,1266,1267]
The question if some antihypertensive drugs or strategies are better than others in preventing cognitive decline and dementia is still under debate. Several observational studies and data from international registries suggested that ARBs, DHP-CCBs and Thiazide/Thiazide-like diuretics may be better than ACEis, non-DHP-CCBs and BBs in reducing the progression of cognitive decline and the incidence of dementia [1268,1269] [1270] [1271]
17.6 Vascular disease
17.6.1 Lower extremity arterial disease
LEAD is often a manifestation of more widespread atherosclerosis and especially of atherosclerotic renal artery disease. Indeed, an association has been found between LEAD and an increased risk for multiple adverse outcomes including CAD, HF, aortic aneurysm and CKD [1272] [1273] [1272] [1274] [485] [1275] [1276,1277] [1278,1279] [1280] [1276] [1281] [1282] [1273]
17.6.2 Aortic dilatation, aneurysm and dissection
Hypertension can be associated with modest aortic root dilatation [1283] [1283] [1284] [1285] [1286] [1287] [1288] [1289]
Hypertension is an important risk factor for aortic dissection [1290] [1283] [1289] [1291]
Hypertension is also a risk factor for abdominal aortic aneurysm, and some studies suggest that special attention should be attributed to the DBP elevation [1274] [1292] [1293] [1294] [1295] [1296] [1297]
18. HYPERTENSION AND DIABETES MELLITUS
18.1. Epidemiology and risk classification
Hypertension is common in type 1 and much more in type 2 diabetes. Type 1 diabetes develops mostly in children, adolescents and individuals usually below 30 years and shows a prevalence of hypertension greater than that of nondiabetic individuals or the age-matched general population. Prevalence of hypertension varies in different studies, and in an old large Danish population study has been reported to be about 15% of type 1 diabetic patients [1298,1299] [1300] [1299] [1301] [37] [1302,1303] [1304] [1305] [1306] [538] [33]
18.2 Benefits of BP-lowering
Overwhelming evidence supports the benefits of BP reduction in people with hypertension and type 2 diabetes to reduce macrovascular events and mortality, as well as to prevent microvascular complications, such as nephropathy and retinopathy [1307–1309] [1308,1309] [1310] [1310] [1142] [1310,1311] [466,559,1308,1312] [1311] [538] [1313] [183,1314]
18.3 Antihypertensive drug treatment
The generally recommended strategy for antihypertensive drug treatment (see Section 11), i.e. starting with dual combination therapy and using drug combinations in the majority of the patients, is even more necessary for diabetic patients, considering the difficulties of BP control in diabetes and the importance to achieve BP targets in patients with high CV risk [184] [1315] [1316]
Newer antidiabetic agents, i.e. SGLT2is and GLP-1 RA have been shown to reduce macrovascular and microvascular complications in type 2 diabetes [1317] [1318] [1319–1321] [1322] [1319,1323,1324] [183] [184] [758] [582]
Treatment strategies in diabetes
19. HYPERTENSION AND THE KIDNEY
Hypertension is a strong independent risk factor for development of CKD and progression of CKD to ESKD [1325,1326] [1327,1328] [290] [1329–1331] 2 at any level of albuminuria or a UACR >30 mg/g at any level of eGFR persisting for more than 3 months. Serum creatinine, eGFR and UACR should be documented in all patients at the initial evaluation for hypertension if CKD is diagnosed, and repeated at least annually thereafter. A negative urinary dipstick test does not rule out albuminuria, because it cannot detect UACR levels in the lower range [296]
19.1 Treatment of hypertension in CKD
High BP is by far the most common modifiable factor for CKD progression [1332] [1325,1333–1336] [1326,1337] [1338,1339]
19.1.1 Treatment BP targets
Available evidence suggests that BP reduction with any type of the major antihypertensive drug classes can offer similar protection against major CV events (stroke, myocardial infarction or CV death) and all-cause death in individuals with CKD [1340] [1341,1342] [1325] [1343] [1344] [1345] [1346] [1347] [1348] [1347]
The results of the SPRINT study have little relevance to the question discussed above. SPRINT randomized 9361 hypertensive patients at increased CV risk to intensive (SBP <120 mmHg) or standard treatment (SBP <140 mmHg) [97] 2 , but very few patients had proteinuria because individuals with proteinuria >1 g/day or >1 g/g were excluded. Diabetes mellitus, i.e. the most common cause of ESKD, or prior stroke were also exclusion criteria. In the overall trial, the primary composite outcome (CV events as well as CV and total mortality) was significantly lower in the intensive-treatment group, but kidney outcomes did not differ between the two target groups. A sub-analysis of the SPRINT CKD subpopulation [1349]
No direct evidence is available to answer the question of the optimal target BP in patients with CKD and type 2 diabetes mellitus. Older studies, including UKPDS38 [1350] [1351] [1352] [1341] [1353] [1354] [1341] [1355] P = 0.21). However, after excluding patients with higher GFR and those undergoing intensive glycemic control, lowering BP to <130 mmHg decreased all-cause mortality (hazard ratio 0.79, 95% CI 0.63–1.00, P = 0.048) when compared with a standard target of <140 mm Hg [1356]
Taking these largely indirect findings together and considering that, at least after development of proteinuria, progression of kidney injury tends to follow the same course in different situations, it may be suggested that (i) the BP target for proteinuric nondiabetic CKD applies to patients with proteinuric diabetic kidney disease as well and (ii) for both patient categories, a target SBP of <130 mmHg and DBP <80 mmHg, if well tolerated, can be associated with protection against CKD progression in individuals with an albuminuria >30 mg/g. A similar target may be associated with a reduction in mortality in most patients with CKD. Particularly in patients with advanced CKD in stage 4 and 5, careful monitoring of eGFR is recommended as a further functional, but reversible, decline of GFR may occur on a lower BP.
An office SBP of <120 mmHg and DBP <70 mmHg cannot be recommended because of the absence of relevant evidence. However, these guidelines acknowledge that these recommendations have a number of limitations: (i) none of the trials comparing different BP targets included patients with diabetes and CKD, thus current evidence cannot be readily extrapolated to this subpopulation; (ii) MDRD and AASK trials randomized participants to different mean BP levels, which cannot be readily extrapolated to SBP and DBP values; (iii) MDRD and AASK trials recruited patient populations of a relatively young age (mean age 51.7 and 54.6 years, respectively), and thus, their findings cannot be readily extrapolated to older patients with CKD and (iv) even for the long-term observational analyses, the benefits associated with lower BP targets were mainly apparent in individuals with proteinuria.
19.1.2 Antihypertensive drug treatment
People with CKD should receive lifestyle interventions, as reported in Section 7, with special attention to sodium restriction, as low-sodium diet reduces protein excretion in proteinuric CKD [1357] 2 (CKD stages 3a). While in patients with an eGFR below 30 ml/min/1.73m2 , Thiazide/Thiazide-like diuretics should be generally replaced by loop diuretics, the transition from treatment with a Thiazide/Thiazide-like to a loop diuretic should be individualized in patients with eGFR values between 30 and 45 ml/min/ 1.73m2 . Clinical trials in people with diabetic [1358–1361] [1346,1362,1363] [561,1364] [1365] [1366] Fig. 20 ). Indeed, in a recent open-label trial in which patients with an eGFR were randomly assigned to either discontinuation or continuation of therapy with RAS inhibitors, discontinuation was not associated with a significant between-group difference in the long-term eGFR decline [1367]
FIGURE 20:
BP-lowering therapy in patients with hypertension and chronic kidney disease. (a) Transition from T/TL Diuretic to Loop Diuretic should be individualized in patients with eGFR < 45 ml/min/1.73 m2 . (b) Cautious start with low-dose. (c) Check for dose adjustment according to renal impairment for drugs with relevant renal excretion rate. (d) When SBP is ≥140mmHg or DBP is ≥90 mmHg provided that: maximum recommended and tolerated doses of a three-drug combination comprising a RAS blocker (either an ACEi or an ARB), a CCB and a T/TL Diuretic were used, adequate BP control has been confirmed by ABPM or by HBPM if ABPM is not feasible, various causes of pseudo-resistant hypertension (especially poor medication adherence) and secondary hypertension have been excluded (see Section 12). (e) Caution if eGFR <45 ml/min/1.73 m2 or serum potassium >4.5 mmol/l. (f) Should be used at any step as guideline directed medical therapy in respective indications or considered in several other conditions (Table 16). (g) SGLT2is and Finerenone should be used according to their approval for CKD treatment.
19.1.3 Special therapeutic challenges
CKD poses several additional difficult treatment problems. Firstly, the vasodilating effect of ACEis or ARBs on the efferent arteriole reduces intraglomerular pressure. This is frequently followed by eGFR reductions, on average 10–15% in the first weeks of treatment. A similar effect can be seen with large BP reductions by any antihypertensive agent. Thus, repeated monitoring of eGFR (as well as serum electrolytes, see the following) within the first 4– 8 weeks of treatment (depending on baseline kidney function) is important when treatment is initiated. Clinicians should not be alarmed by this early GFR reduction, but if the decline in GFR continues or becomes more severe (>30%), the RAS blocker should be stopped, and the patient should be investigated for the presence of renovascular disease. Secondly, use of RAS blockers in CKD patients further increases the risk of hyperkalemia [1368] [1369] [1370,1371] [1372–1374]
Novel potassium binders (patiromer and sodium zirconium cyclosilicate) were shown to normalize elevated serum potassium and chronically maintain normal serum potassium levels in CKD patients treated with ACEis, ARBs or spironolactone, with a good tolerability [1375,1376] [1377,1378] [1379,1380] [1361,1381] [1366] [326] [1357] 2 , Thiazide diuretics become less effective, because they cannot reach their tubular site of action because of competition for tubular secretion with other substances that accumulate in CKD [1382] [573] 2 , diuretic therapy should be modified and the dosing individualized, while in patients with CKD stage 4, eGFR <30 ml/min/1.73 m2 , Thiazide should be substituted with a loop diuretic. Within this class, torasemide might be preferred to furosemide because of its longer half-life, which allows a less frequent dosing scheme and a better adherence to treatment [1326] [1383,1384] [1385,1386] [1387] 2 or potassium above 4.5 ≥ mmol/l were excluded in this trial [580] 2 , BP was effectively reduced in both groups, but the rates of hyperkalemia (potassium 5.5 mmol/l) were at about 60 and 35%, respectively, at 12 weeks [740] Fig. 20 ).
19.1.4 Use of additional drugs for cardiovascular- and nephroprotection in CKD
In addition to achieving BP control with the agents described above, progression of CKD and risk of CV events and mortality can be reduced in CKD patients by two novel drug classes that also have some BP-lowering effects, although they are not approved as antihypertensive agents. SGLT2is were first introduced as oral hypoglycemic agents that reduce plasma glucose levels by inhibiting renal glucose reabsorption through the SGLT-2 transporters, located in the proximal convoluted tubule. Early clinical studies in patients with type 2 diabetes suggested that these agents can reduce office SBP/DBP by 3– 5/1– 2 mmHg in hypertensive patients [1388] [1389] [1390] [1388] [1391] [1392] [1318]
CV outcome trials with SGLT2i in patients with type 2 diabetes have included large proportions of patients with CKD, showing impressive and homogeneous reductions (around 40%) of composite kidney endpoints [544,1319,1393] [1394] [1320] [1395] 2 and any level of albuminuria or 45 to <90 ml/ min/1.73 m2 with a UACR of ≥ 200 mg/g)[1395] [1395] [1396,1397] [1398] [1398–1401] [1402–1404] [1405] [1406] [742,1405] [582] [1407] [545,546] [582] [546] [1408] [547] [1409] [1410] Fig. 20 ).
19.2 Renovascular disease
Renovascular hypertension represents one of the most common forms of secondary hypertension, with a reported prevalence of around 2– 5% of all hypertensive individuals and up to 30% of patients with secondary hypertension [1411,1412] [1413,1414] [1415] [1416] [1417,1418] [1419] [1416] [1420] [1421]
While revascularization with balloon angioplasty without stenting is the treatment of choice for patients with FMD and hemodynamically significant renal artery stenosis [340] [1422,1423] [1424–1426] [1414] [1421,1427] [1418,1422,1423]
19.3 Hypertension in patients with kidney transplantation
Kidney transplantation is considered the optimal choice for kidney replacement therapy in patients with ESKD because of improved survival and quality of life compared with dialysis. This survival benefit has been attributed to kidney function improvement and delayed progression of CVD [1428] [1429] [1430,1431] [1432] [1433] [1405,1434,1435] [1436] [1437] [1438,1439] [1435]
The pathogenesis of hypertension in kidney transplanted patients is multifactorial, involving traditional risk factors, factors related to CKD (most commonly impaired sodium handling and activation of RAS and SNS) and factors related to transplantation and its treatment [1440] [1440,1441] [1442,1443] [1440,1441] [1444]
BP targets for hypertension management in kidney transplanted patients are extrapolated from data in CKD populations, as there are no specific RCTs that have tested different BP targets on major clinical endpoints. Yet, a target SBP of <130 mmHg is considered as a reasonable target for kidney transplant patients. Lifestyle modifications should be adopted on the basis of general recommendations for CKD, and drug combinations between major antihypertensive agents should be employed in most patients. Special benefits by ACEis/ARBs are not clearly established, because available studies provide conflicting results [1405,1441] [1445] [1445] [1440] [1446]
Treatment strategies in patients with kidney disease
20. HYPERTENSION AND OTHER SELECTED COMORBIDITIES
20.1 Obesity
Obesity and arterial hypertension commonly occur in the same patients and often have type 2 diabetes has a third associated condition. Hypertensive obese patients may require more antihypertensive medications to have their BP controlled than nonobese individuals and are more likely to exhibit treatment-resistant hypertension [1447–1449]
20.1.1 Antihypertensive pharmacotherapy in obesity
When treating patients with obesity and hypertension, a sensible goal is to attain BP reduction without worsening obesity and associated metabolic risks. Although there is no evidence that BP targets differ between patients with and without obesity, achieving the target BP value is more difficult in the presence of obesity. For example, a retrospective analysis of the ALLHAT trial stratified patients according to BMI in normal weight (BMI <25 kg/m2 ), overweight (BMI 25– 29.9 kg/m2 ) and obese (BMI >30 kg/m2 ) groups [1450] [1450] [1451,1452] [1453] [1454–1456] [1450] [1457,1458] [21] [1459,1460] [1461] [1462,1463]
20.1.2 Role of nonpharmacological weight loss intervention
Strong evidence is available that in addition to improving metabolic risk factors, weight loss can have a beneficial effect on BP control [1464] [1465] [1466] [1467] [1468] [1469] [1470] [367] [1471,1472]
20.1.3 Role of weight loss medications
Very few currently available weight loss medications have been specifically tested in obese hypertensive patients, having BP reduction as the primary goal. Newer weight loss drugs that have been evaluated for CV protection in large-scale trials on overweight and obese type 2 diabetic patients have not been shown to improve CV outcomes in nondiabetic patients with overweight or obesity. Therefore, the role of such medications in managing BP in obese hypertensive patients is unclear. A recent meta-analysis has shown that not all medications that reduce body weight improve BP control in patients with hypertension [372] [1473] [1474,1475] [372,1476–1478] [1479] [1323] [1323] [1480] [1480,1481] 2 but less than 30 kg/m2 (overweight) and hypertension in addition to their approval in type 2 diabetes or obesity.
20.1.4 Role of bariatric surgery
Bariatric surgery comprises various procedures such as sleeve gastrectomy, Roux-en-Y gastric bypass or biliopancreatic diversion with the common goal of reducing body weight. Procedures differ in terms of weight reduction, adverse effects and weight-independent effects on gut hormones. The nonrandomized Swedish SOS study showed that weight reduction through bariatric surgery improves CV morbidity and mortality in men and in women with a BMI of at least 34 or 38 kg/m2 , respectively [1482] [1483] [1483–1485] [1486] [1487,1488] [1483] [1489] [1483] 2 has reported that compared with medical therapy, the Roux-en-Y gastric bypass surgery group required fewer antihypertensive medications to maintain BP below 140/90 mmHg for up to 3 years [1490] [760] [1489]
Hypertension management in obesity
20.2 Obstructive sleep apnea
Sleep disorders such as a reduction of sleep to <6 h per night [1491] [726] [1492] [1493] [1494] [1495] [1496] [1496] [1497] [1498] [753,1499,1500]
20.3 Asthma
Hypertension and asthma are common diseases frequently encountered together in the same patient. Epidemiological studies indicate an increased prevalence of hypertension in asthmatic patients compared with patients without asthma [1501] [1502] [1501] [1503,1504] [1503,1504] [1501,1503–1505] [1501,1506,1507]
Patients with hypertension and asthma constitute a subgroup of patients in whom treatment of either condition is more difficult and the risk of developing CV events is elevated [4,1501,1508] [1509] [1510] [1501,1508]
20.4 Obstructive pulmonary disease
Hypertension is the most common comorbidity in patients with COPD and both comorbidities are independently associated with increased risk of CV events [1511] [1511] [1511] [1512,1513] [4,1511] [1511] [4] [1514] Table 16 ).
20.5 Gout and uric acid
The prevalence of hypertension in patients with gout is twice as high compared with patients without gout (36 versus 17%), while hyperuricemia (with or without gout) can be found in more than one out of four hypertensive patients [1515,1516] [1517,1518] [1519] [1520] [1521] [1522–1524] [1525] [1526] [1522,1524] [1527,1528]
Antihypertensive drugs have a well known differential effect on serum uric acid. Serum uric acid level increases with the use of Thiazide/Thiazide-like and loop diuretics [1529] [1530] [1531] [1530] [1525]
20.6 Immune-mediated inflammatory diseases
Immune-mediated inflammatory diseases, including diseases such as rheumatoid arthritis, psoriasic arthritis or lupus erythematosus, are associated with an increased prevalence of hypertension that is often underdiagnosed and poorly controlled [1532–1534] [1533] [1525]
20.6.1 Rheumatoid arthritis
Rheumatoid arthritis is associated with an increased risk of CV disease [1535,1536] [1537] [1538] [1539] [1540] [1541] [1515] [1542] [1515]
20.6.2 Psoriatic arthritis
Psoriatic arthritis is associated with an increased cardiometabolic risk leading to an excess of CV disease [1543] [1544] [1544] [1545] Table 16 ). Glucose control should be considered in patients with hypertension and psoriatic arthritis [1546]
20.6.3 Systemic lupus erythematosus
Patients with systemic lupus erythematosus have a higher burden of CV risk factors compared with the general population, and this is responsible for the high prevalence of premature CVD in the affected patients [1547] [1548] [1549] [1550,1551] [1552]
20.7 Glaucoma in hypertension
Glaucoma is a leading cause of irreversible blindness affecting more than 60 million people worldwide [1553] [1554] [1555] [1555] [1556,1557] [1557–1560]
A systematic review and meta-analysis assessed the association between BP and POAG as well as intraocular pressure [1556] [1556] [1561] [1562]
Zhao et al. [1556] [1559] [1563] [1564] [1565] [1566,1567] [1568] [1569] [1570] [1566] [1568] [1562]
Taken together, not only hypertension but also low BP values, an extreme nocturnal dipping status and high 24 h BP variability leading to frequent BP peaks and dips (especially dips) are all associated with an increased risk of POAG. Therefore, in hypertensive patients with glaucoma the BP targets recommended for the general hypertensive population should be pursued with caution, and use should be made of ABPM to avoid low nocturnal BP, extreme dipping and thus glaucoma progression.
Glaucoma and hypertension
20.8 Hypertension oncology
20.8.1 Hypertension and its association with cancer
The association between hypertension and cancer is bidirectional with overlapping risk factors (e.g. unhealthy diet, alcohol intake, physical inactivity, smoking, increased BMI) and pathophysiological mechanisms (e.g. immunoinflammation and oxidative stress) involved in both conditions [1571,1572] [1573] [1574] [1572] [1575] [1571,1572]
Due to its high prevalence, preexisting hypertension is the most common comorbidity in patients with cancer, particularly in older patients, in parallel with the high prevalence of hypertension in the old age (see Section 3.3). Careful BP monitoring and hypertension management in cancer patients is recommended, because these patients are at risk of hypertension-related complications, including hypertension emergencies [1576] [1571,1572]
20.8.2 Hypertension induced by cancer treatments
Data on incident hypertension in cancer trials are difficult to analyze due to differences in the definitions of hypertension used. The Common Terminology Criteria for Adverse Events (CTCAE) in cancer therapy uses a BP grading system with four grades starting in the normotensive range according to the definition of these guidelines. Grade 1 is defined by a SBP of 120– 139 mmHg or a DBP of 80– 89 mmHg [1577]
20.8.2.1 Hypertension induced by VEGF inhibitors
Anticancer drugs and adjunctive therapy used in oncology can induce de novo hypertension or contribute to worsening preexisting hypertension. BP elevation during therapy with various cancer drugs have been known for a long time. However, this problem has recently come to special attention due to the development of inhibitors of the vascular endothelial growth factor (VEGF), a pathway that causes some BP increase in virtually every patient [1571,1572] [1578] Table 26 ). VEGF inhibitors include i.v. administered monoclonal antibodies (VEGF-A monoclonal antibody, bevacizumab; VEGF-R2 monoclonal antibody, ramucir umab; VEGF-R1/R2 fused to Fc portion of IgG1, aflibercept), or oral small-molecule receptor tyrosine kinase inhibitors (RTKIs) targeting the VEGF-R1–33 and other receptors which mediate the downstream cellular signaling pathways essential for tumor cell survival (Table 26 ) [1571,1578,1579] [1579–1583] [1068–1071] [1571] [1571] [1580,1584] [1580,1584] [1579,1580,1585] [205,1585,1586] [205,1586] [1571,1587] [1588] [1571,1572,1589]
TABLE 26:
Hypertension induced by selected anticancer treatments
20.8.2.2 Hypertension induced by other anticancer drugs
A list of additional anticancer drugs that can also induce hypertension is presented in Table 26 [1571,1572] [205,1586] [1590] [1590] [1591] [1592] [1592]
20.8.2.3 Hypertension induced by adjunctive therapies, radiotherapy or surgery
Adjunctive therapies with glucocorticoids, erythropoietin (EPO) to treat anemia and NSAIDs to treat pain and/or inflammation, can contribute to the development of hypertension or the worsening of hypertension in cancer patients. Radiotherapy to the neck and/or extensive neck dissection surgery can cause baroreflex failure (see Section 14.10) leading to extreme BP variability with dramatic hypertensive surges, hypotensive episodes, and orthostatic hypotension in some patients [907–909] [1593] [1594]
20.8.3 Management of hypertension in cancer patients
20.8.3.1 BP monitoring and general management before start of cancer treatment
Before starting cancer therapy, BP control in patients with preexisting hypertension should be confirmed by appropriate office BP measurement as recommended in Section 4 and also include the use of out-of office (ABPM or HBPM) measurements whenever possible (Fig. 9 ). The use of HBPM is particularly important and should be encouraged with education on proper use (see Section 4.7), because HBPM can play an important role for BP monitoring both during cancer treatment and during FU after cancer treatment. Furthermore, BP measurements should be also performed in patients without previously documented hypertension in order to exclude hypertension and to document the baseline BP values before patients are exposed to anticancer drugs that may induce hypertension (Table 26 ). Control of pain and anxiety before BP measurements requires special attention in cancer patients. Unfavorable changes of individual risk factor profiles (e.g. increased stress, incident depression, impairment of sleep, Table 2 ) and lifestyle factors (e.g. unhealthy diet, increased alcohol intake, Section 7) may have contributed to worsening of hypertension and BP control in cancer patients and should be addressed. Drug therapy should be intensified and adapted if needed (see below) according to the general recommended strategy (Fig. 12 ).
BP monitoring and risk assessment in cancer patients
20.8.3.2 General BP-lowering therapy and management during cancer therapy
Patients with active cancer were regularly excluded from outcome-based RCTs in hypertension. Conversely, in cancer trials, patients with uncontrolled hypertension or elevated BP are commonly excluded. Consequently, no evidence from outcome-based RCTs is available to guide overall management and drug therapy for hypertension in patients with cancer. Mindful of these limitations, these guidelines recommend that, by extrapolation, the definition of hypertension, BP thresholds and targets, lifestyle interventions and drug treatment strategies recommended for the general hypertensive population should be also applied to cancer patients. In severely ill cancer patients, treatment of hypertension should be individualized according to symptoms, comorbidities and polypharmacy in a shared decision-making process. Although there is no general consensus, these guidelines recommend that the threshold for withholding anticancer therapy should be a SBP ≥ 180 mmHg and/or a DBP ≥ 110 mmHg [1572,1577]
Some considerations on drug selection and use specific for cancer patients during active cancer treatment need to be emphasized:
1. Thiazide/Thiazide-like diuretics should be used only if needed for BP control and in patients with fluid retention. They should be used with caution, because they may (i) increase serum calcium concentration in patients with bone metastasis, (ii) further increase the risk of cardiac arrhythmias induced by some anticancer drugs because of prolongation of the QT interval by inducing hypokalemia, (iii) worsen SIADH-dependent hyponatremic states occurring in some cancer patients and (iv) worsen hypovolemic states or dehydration [205,1579,1595]
A preferential use of a DHP-CCB in combination with a RAS blocker may, therefore, apply in many cancer patients (Fig. 12 ).
2. Use of non-DHP-CCBs, which are indicated for heart rate control in patients with contraindications or intolerance to BBs, is problematic and should be avoided in some cancer patients. This results from the evidence that non-DHP-CCBs (i) are moderate inhibitors of CYP3A4 or P-gp and interfere with the pharmacokinetics of some, but not all, anticancer drugs, e.g. oral RTKIs that are substrates of CYP3A4 or P-gp [1595,1596]
20.8.3.3 Treatment of hypertension induced by VEGF inhibitors
There are no data from RCTs that can help the prevention and/or treatment of de-novo hypertension induced by anticancer therapies, e.g. in response to VEGF inhibitor treatment. Nevertheless, sodium restriction may be helpful as a maximum intake of 4 g sodium per day in combination with dietary counseling has recently been shown to attenuate the VEGF inhibitor-induced BP rise by almost 50% in a small (pilot) study (16 patients) [1597] [1598] [1598]
Management of hypertension in cancer patients
20.8.4 Follow-up and management of hypertension in cancer survivors
Long-term close FU of cancer patients after active cancer treatment is important. One reason is that, acute BP changes may occur in patients who were exposed to anticancer drugs that induce short-term and reversible BP increases, requiring backtitration or eventually discontinuation of any previous BP-lowering drugs to avoid hypotension. Another reason is that cancer patients with preexisting hypertension may have developed progression of previously existing HMOD or de-novo organ damages because of the cardiorenal toxicity of anticancer drugs. Thus, depending on the individual risk profile and phenotypes, FU should include monitoring of HMOD parameters (Fig. 6 ). Overall, BP monitoring during long-term FU, preferably by HBPM, is recommended, because long-term cancer survivors are at increased risk to develop hypertension, e.g. long-term survivors of cancer in childhood [1599]
20.9 COVID-19 and hypertension
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19) pandemic, led to fundamental disruptions of many if not all aspects of people's lives. In the early acute setting [1600] [1601] [1602] [1602,1603] [1604] [1603] [1605] [1605] [217,276] [1606]
20.9.1 COVID-19 and RAS inhibitors
The findings that (i) SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor for cell entry, and (ii) in experimental settings, treatment with ACEis and ARBs may lead to an upregulation of ACE2 expression [1607] [1607] [1608,1609] [1610] [1611] [1612] [1607] [1613]
20.9.2 COVID-19 lockdown and hypertension management
In an attempt to limit the infectious spread, diagnostic and therapeutic procedures related to hypertension were dramatically reduced during the first year of the COVID-19 pandemic, with the largest reduction during the first lockdown [1614] [1615] [1616] [1617] [1618] [1618]
On top of the disruption in medical care for chronic diseases such as hypertension [1614] [17] [1616,1619] [1620] [1620] [1621]
20.9.3 Vaccination against SARS-CoV-2 and hypertension
Vaccination against SARS-CoV-2 has clearly reduced the occurrence of myocardial infarction and stroke after COVID-19 [1622,1623] [1624] [1625]
20.9.4 Long COVID-19 and hypertension
Regarding the persistent CV symptoms several months after COVID-19, i.e. Long-COVID, the CV system is frequently affected [1605] [1626,1627] [1628,1629]
21. FOLLOW-UP
21.1 Importance of follow-up
The FU of hypertensive patients is crucial not only to ascertain achievement of BP control but also to support lifestyle modifications, assess drug adherence and medication side effects and to adapt therapy and check for development or changes in HMOD (Fig. 21 ). In this context, three main questions need to be addressed: (i) how often patients should be seen, (ii) what needs to be checked and (iii) who and which setting should be involved in the management of patients during FU, in addition or alternatively to office re-visits. Unfortunately, for each of these questions, available studies are scarce. Nevertheless, these guidelines acknowledge their importance for patients’ FU and address them in some detail below. The initiation of drug therapy may be evaluated monthly until BP control is achieved [97,1352] [1630–1633] [1634]
FIGURE 21:
Follow-up of patients with hypertension.a Can be adapted according to the clinical status.
Once the BP target is reached, a visit interval of a few months seems reasonable. No difference was detected in BP control between FU visits at 3 and 6 months intervals in one study [1635] [646] [1636,1637] [1636,1638–1640]
Another useful bit of information is that BP increases under conditions of hypobaric hypoxia due to a number of factors, including sympathetic activation [1641] [1641]
Obviously, during the FU visits, BP measurements according to the recommendations of the guidelines are of fundamental importance. BP measurements should be extended to ABPM whenever indicated and feasible, at intervals usually longer than those for office BP measurements. HBPM can be advised not only before visits but also on a more regular basis as a useful tool to verify consistency of BP control as well as to improve adherence to treatment. During visits, there should be collection of the most recent medical history, including questions addressing lifestyle interventions, tolerability of drug therapy and any changes of comorbidities and comedications, including intake of over-the-counter medicines. A new physical examination should usually be dispensed with, if the medical course before the re-visit was inconspicuous. Standard laboratory investigations, electrolytes (serum potassium) and kidney function are among the parameters that should be monitored most frequently together with serum cholesterol, the lipid profile, blood glucose and other parameters based on the individual drug treatment strategies and comorbidities. Re-assessment of HMOD should be carried out according to the considerations made in Section 5.5. HMOD assessment is important, as progression or regression of HMOD at FU visits has a major influence on management strategies and scheduling of further FU visits.
During long-term FU, visits may be also carried out by nonphysician healthcare professionals, such as qualified nurses or pharmacists. This approach has been adopted in some European and other countries, depending on the local organization of health resources and is supported by the results of RCTs, observational studies and meta-analyses, which point towards similar BP reductions, when treatment is handled by primary care physicians, nurses or pharmacists [1642–1645] [139]
21.2 Adherence
21.2.1 Definitions
Adherence is defined as the extent to which a person's behavior, such as taking a medication, following a diet or executing lifestyle changes, corresponds with agreed prescriptions or oral recommendations from a healthcare provider. Persistence defines the length of time between the initiation of treatment and the last dose immediately preceding its discontinuation [479,1646] [1646]
21.2.2 Prevalence of nonadherence and associated burden
The estimates of the prevalence of nonadherence to antihypertensive treatment vary across studies depending on (i) the method used to assess adherence, (ii) the country/healthcare system where the research was undertaken and (iii) the clinical characteristics of hypertensive patients recruited. In general, nonadherence rates are higher in low-income and middle-income countries than in westernized societies [616] [657,669] [612,657,658] [479,1647] [1648] [657] [1649] [1650] [1651,1652] [1653,1654] [1655] [479] [478] [1008] [479] [4] [488] [32] [1656]
21.2.3 Methods to detect nonadherence to antihypertensive treatment
The ideal method of detection of nonadherence should be to prove the ingestion and provide information on how frequently this occurs over time because adherence is a dynamic process, i.e. it can vary considerably from one period to another. Today, none of the available methods fulfils these two criteria. Relying on the physician's impressions derived from interviews is convenient but is associated with a significantly biased assessment leading to an overestimation of adherence. Adherence questionnaires do not fulfil all the validity and reliability test criteria [1657] [1658] [1659] [477] [675] [479,1660]
21.2.4 Etiology of nonadherence to antihypertensive treatment
WHO multidimensional adherence model classifies barriers to nonadherence into several categories, including: (i) health system (communication with a healthcare provider, low satisfaction with pharmacy services or problems with drug reimbursements); (ii) therapy-related (side-effects, complexity of drug regime or interference with daily routine); (iii) disease-related (severity of symptoms, lack of symptoms or presence of comorbidities); (iv) patient-related (low self-efficacy or inaccurate beliefs about medications) and (v) socioeconomic status-related (poverty, lack of family support or unemployment) [1661] [479] [139,616] [1662] [619] [1663] [669] [669]
21.2.5 When and how to screen for nonadherence
Screening for nonadherence to antihypertensive treatment should be part of the routine assessment of effectiveness of BP-lowering drugs [4] [32] [32] [32,1664] [4,659] [32]
Screening for nonadherence to BP-lowering therapy improves the diagnostic approach and treatment decisions almost in all hypertensive patients. Indeed, in patients with suboptimal BP control (e.g. apparent resistant hypertension), a confirmation of nonadherence to antihypertensive treatment (i) substantiates a diagnosis of pseudoresistant hypertension, (ii) explains the cause of resistance to treatment, (iii) helps to avoid unnecessary treatment escalations and expensive additional investigations and (iv) reduces the healthcare costs [1665] [479]
21.2.6 Management of nonadherence to antihypertensive treatment
Management of nonadherence to antihypertensive treatment should be tailored to the individual modifiable drivers of nonadherence in each patient. There is not a single universal strategy that could help to manage nonadherence in all hypertensive patients. To this end, a confirmation of nonadherence to antihypertensive treatment should be followed by a nonjudgmental discussion between a patient and a healthcare professional (as partners) [669,1660,1665,1666] [616,673] [617,647,673] [616] [479] [616] [616] [616] [616,658] [479] [1667,1668] [62,1669]
Nonadherence to antihypertensive therapy
21.3 Clinical inertia
Clinical inertia in hypertension management can be divided into (i) diagnostic inertia, i.e. failure of the physician or another health-care provider to detect a BP elevation in the patient and (ii) therapeutic inertia, i.e. failure of the physician to start or modify drug treatment (drug change, dose change or drug addition) in the presence of BP values above the recommended target [1670] [532,1671,1672] n 64 000) of the hypertensive population was found to have uncontrolled BP because of therapeutic inertia [1673] [1674–1678] [1679] [1676,1678] [1675] [608] [614] [612] [1680,1681] [609]
Although only few studies have addressed the question of how to limit doctor's inertia, a few suggestions can be made. The most important step is obviously to improve doctors’ knowledge of the increased CV risk associated with hypertension, whatever the age, gender and protective effects of adequate BP reductions, a goal that needs dissemination of treatment guidelines. Patients’ knowledge and empowerment as well as home BP measurements are also important to provide appropriate and timely feed-backs to the doctor, with perhaps a further help of telemetric transmission of the home BP measurements [1682] [1683] [1684] [1685]
There are potential solutions to overcome clinical inertia in the management of hypertension. They can be classified as not only educational (i.e. improve knowledge), clinical (i.e. improve screening and detection of uncontrolled BP) and therapeutical but also organizational (improved FU). Most of the time they are directed to the physician but improving a patient's attitude can also contribute to fighting clinical inertia [479]
21.4 Patient empowerment
In order to follow a health-care plan and reach therapeutic targets, involving the patient is strongly recommended both initially and at every step of FU [931] [1683,1686] [1687]
Discrepancy between physician and patient expectations can lead to behavioral changes affecting BP control. In this situation, interventions such as goal setting, provision of feedback, self-monitoring, FU, motivational interviewing, and promotion of self-sufficiency are effective, and effectiveness is better when the interventions are combined rather than promoted individually (lower level of evidence) [137,1688]
21.5 Follow-up of low-risk hypertensive patients and deprescribing
The therapeutic management of low-risk hypertensive patients is perceived to differ from intermediate/high-risk patients, not only because monotherapy can be more frequently used as first-line (although the present guidelines recommend initial two-drug SPCs to also be used in most of these patients) but also because it may seem rational to assume that the FU of low-risk patients should be less close, as BP levels are lower and no significant comorbidities may exist. However, even these patients might benefit from closer FU visits, and more so in the initial period of therapy, because they are at high risk of nonpersistence on treatment. In a retrospective study of almost 3000 patients younger than 40 years of age and with incident hypertension, it was found that during a 2-year FU period, BP control rates were higher with shorter visit intervals [1689] [676] [1690–1694] [217]
21.6 Use of telemedicine and tele-health technologies
The advent of new technologies has allowed use of internet-based interactive digital interventions (tele-health) and health-related mobile applications that can also be installed on smartphones. This enables, at least in perspective, virtual care of hypertension [139] [17,139]
Interactive digital interventions include behavioral aids and promotional material for hypertension self-management. Several studies and meta-analyses suggest that these interventions are associated with better patient education, greater BP reduction and even reduced CV outcomes [1695–1697] [62,1698] [1699,1700] [1701] [139,1702] [1621]
21.7 Challenges of long-term follow-up
Hypertension requires lifelong therapy. Therefore, long-term FU is needed, and a proper FU organization is essential. Strategies for FU organization depend on the specialty of the treating physicians (e.g. primary or specialist care i.e. cardiologists, internists, nephrologists, etc.), the setting of the care (private office, hypertension clinic, hospital unit), and the resources available. In practice, the vast majority of hypertensive patients are taken care of by primary or family physicians and only a small percentage is seen and followed by specialists and, even more rarely, by hypertension centers. Hypertensive patients are also not candidates for hospitalization except for hypertension emergencies or when a hypertension-related clinical complication occurs. Ideally, complete electronic health records should be available for each patient and all information regarding the initial evaluation and lifelong management should be included, i.e. the records should incorporate demographic information, medical history, lifestyle habits, clinical findings, comorbidities, HMOD, concomitant medications, side effects of medications, laboratory results and hospital records. In several European countries, very little of this integrated information is made available for a number of reasons, including strict privacy rules that do not consent the sharing of clinical data. Nevertheless, physicians involved in long-term hypertension FU should build patients’ records that include crucial information, such as the trajectories of office and, if available, the out-of-office BP profile, the history of the treatment strategies and of their inconveniences, the CV risk factor profile, the diagnoses at discharge from hospital and the HMOD dynamic status.
21.8 Role of general physician, pharmacies and team-based care
Physicians in primary care, i.e. general and family physicians, play a pivotal role in hypertension management. However, primary care workload has increased markedly over the last decades and appears to be close to or to have reached the saturation point in many countries. A key component of this workload is the diagnosis and management of long-term chronic conditions, among which hypertension-related consultations play an important role. It is likely that the hypertension-related fraction of this workload will further increase because the prevalence of hypertension is increasing, and lower BP targets make antihypertensive treatment more complex and medical visits more frequently needed. In order to avoid this problem, it is of fundamental importance that medical visit time should not be shortened. Visit times are already too short and frequently even below the time needed to properly measure BP. Attention should rather be directed to healthcare plans that carefully quantify the ‘time needed to treat’ by primary or specialist care physicians, including the one necessary for management of hypertension [1703] [1704] [1705] [1667,1706] [1707] [1708] [1709–1716] [1668,1713]
21.9 Hypertension clinics
Outpatient Hypertension Units are available in most large hospitals and can offer a high-quality care to a considerable number of hypertensive patients, including patients with complicated hypertension, resistant hypertension or suspected secondary hypertension. The importance of these centers can be illustrated by the Hypertension Excellence Centers that have been established by ESH throughout Europe, fulfilling prespecified criteria regarding the ability to provide multidisciplinary services and offer high-quality inpatient and outpatient care [1717] [1614,1718]
21.10 Health risks at workplace
Industrialization and globalization have highlighted the role of occupational medicine reviving the previous concept of ‘blue collar’ and ‘white collar’ hypertension. Several occupational factors have been associated with hypertension and CVD and should be given attention by physicians responsible for hypertensive patients during FU. Long working hours have been associated with unhealthy lifestyles, obesity and physical inactivity [410,1719] [1720] [1721] [1719] [1722] [1723] [1724] [1725] [16] [1726] [1727]
21.11 Patient organizations
Patient organizations are becoming increasingly important for chronic diseases. They are nonprofit organizations formed by patients or those who care for them. Although they were initially created mainly to provide patients with support and advice (e.g. Alcoholics Anonymous), their role is constantly expanding. An advocacy role aiming not only to reach public awareness but also to exert political pressure has been attained with large campaigns in mass and social media as well as with the inclusion of organization representatives on official advisory and decision-making boards. In some cases, patient organizations are even actively involved in research and clinical trials and operate to guide future research towards their needs. The structure and the size of patient organizations vary significantly between diseases and geographic regions. Large patient organizations for hypertension exist in a few European countries (e.g. Germany and France) but unlike for other diseases (HF, CKD or diabetes mellitus) they are absent or only nominally active in other countries. This has negative implications, because patient organizations may help patients to better share their experience with others and better cope with the multiple problems posed by a chronic disease. An example is the involvement of patients in programs that evaluate the role of RDN as a therapeutic intervention in hypertension [769]
Hypertension management during follow-up
22. GAPS IN EVIDENCE AND FUTURE OPPORTUNITIES
As mentioned in Section 1, the present guidelines have placed RCTs at the top of the evidence on which to base the recommendations on hypertension management. This acknowledges a fundamental advantage of this research approach, i.e. the identical composition or at least close similarity of the compared groups at baseline and thus the possibility to safely ascribe their FU differences to the intervention studied. However, RCTs have limitations, and their adoption over almost 60 years has not been ableto provide an answer to many important clinical problems posed bya BP elevation. For example, RCTs can last no more than a small fraction of the life expectancy of most hypertensive patients, which means that the current recommendation of life-long hypertension treatment is necessarily based on extrapolation from much shorter time data. Recommendations in very old (>85 years of age) and young people pose unsurmountable difficulties because RCTs, have never been done at these extreme ages. Whether BP-lowering interventions (drug-based or device-based) lead to patient protection in true resistant hypertension is unknown and this is the case also for BP reduction in common conditions such as MH and WCH. Even the popular use of ABPM and HBPM is not validated by any trial in which traditional office BP-guided treatment is compared with out-of-office BP-guided treatment or the two intervention strategies together are compared with one or the other intervention strategy alone. Furthermore, even when RCTs are available, the transferability of their results to clinical practice can be problematic because RCTs are conducted with a superior level of expertise and in an environment, that guarantees fewer errors, a much better treatment adherence [1728] [477] [477] [1729] [1730,1731] [1732] [1733,1734] [1735,1736] Table 27 ).
Table 27 - Gaps in the evidence
Epidemiology and risk
- Association between BP levels in children and adolescents and the risk for clinical CV and kidney outcomes
- Trajectories of BP and hypertension phenotypes throughout life and their association with CV and kidney outcomes
- The optimal SBP and DBP level at different time points in life
- Predictive ability and therapeutic responsiveness of HMOD
- Incremental benefit of more advanced risk estimation (SCORE2 => HMOD => vascular imaging/polygenic risk scores)
- Incremental accuracy of risk estimation by use of short and long term BP variability
Diagnostic procedures
- Benefits of screening
- Optimal interval for reassessment of BP in nonhypertensive patients
- Does the incremental prognostic ability of ABPM and HBPM substantially improve diagnosis and treatment?
- Association of ABPM and HBPM with CV and kidney outcomes by serial ABPM and HBPM measurements
- Validity and application of cuffless BP measurement devices
- Optimal BP measurement methods and interpretation of BP values in AF
Treatment strategies
- Optimal time-point and BP level to initiate treatment in young patients
- Optimal and safe BP thresholds and targets in very old and frail patients
- Office vs out-of-office guided treatment on clinical outcomes
- BP thresholds and targets in low-to moderate risk individuals
- BP thresholds and targets in specific patient groups (LVH, ISH, CKD, people aged 80 years or older)
- BP thresholds and targets using ABPM and HBPM
- Treatment effect on clinical outcomes in MH and WCH
- Effect of nocturnal BP reduction by treatment on clinical outcomes
- Effect of lifestyle interventions of CV outcomes
- Strategies to implement lifestyle recommendations effectively
- Choice of first-line antihypertensive agent and sequence of titration from a population and individual level perspective
- Effectiveness and implementation strategies for individualized antihypertensive treatment
- Effect of device-based therapy (RDN) on CV and kidney outcomes
- Effect of drug treatment of true resistant hypertension on CV and kidney events
- Effects of down-titration and treatment withdrawal in different clinical settings
Follow-up
- Optimal timing and frequency of follow-up
- Optimal BP measurement modality (OBP, HBPM, ABPM) for follow-up
- The role of cuff-less devices for monitoring
- Effect of distance monitoring and digital alert systems on clinical outcomes
- Evaluation of, and interventions to improve, adherence
ACKNOWLEDGEMENTS
We wish to sincerely thank Medycyna Praktyczna Publishers, Krakow (Poland), and in particular Doctor Wiktoria Leśniak and Jacek Zieliński for their excellent support in the preparation of the graphical content of the Guidelines. We also express our sincere gratitude to Mandy Elgner (ESH coordinator) and Clara Sincich for their assistance and help during the preparation of the Guidelines.
Conflicts of interest
The conflict of interest declaration of Task Force members were compiled into one file that can be found on the ESH website: https://www.eshonline.org/guidelines/2023-guidelines/
The Task Force received its entire financial support exclusively from ESH.
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