5.4 Assessment of hypertension-mediated organ damage
HMOD refers to structural or functional changes in arteries or end organs (heart, blood vessels, brain, eyes, and kidney) caused by an elevated BP, and is a marker of preclinical or asymptomatic CVD [112]. HMOD is common in severe or long-standing hypertension, but can also be found in less severe hypertension. With wider use of imaging, HMOD is becoming increasingly apparent in asymptomatic patients [43]. Cardiovascular risk increases with the presence of HMOD, and more so when damage affects multiple organs [16,113,114]. Some types of HMOD can be reversed by antihypertensive treatment, especially when used early, but with long-standing hypertension, HMOD may become irreversible despite improved BP control [115,116]. Nevertheless, BP-lowering treatment is still important as it may delay the further progression of HMOD and will reduce the elevated cardiovascular risk of these patients [116]. Although poor technical provision and cost may limit the search for HMOD in some countries, it is recommended that basic screening for HMOD is performed in all hypertensive patients and more detailed assessment is performed when the presence of HMOD might influence treatment decisions. The various investigations to establish HMOD are shown in Table 15.
5.4.1 Using hypertension-mediated organ damage to help stratify risk in hypertensive patients
As discussed in Section 3, hypertensive patients with documented CVD, diabetes, CKD, grade 3 hypertension, or marked cholesterol elevation (e.g. familial hypercholesterolaemia) are already at high or very high cardiovascular risk (≥10% risk of a fatal event). Thus, the presence of HMOD is unlikely to influence treatment, as these patients should already receive lifestyle interventions, BP-lowering medications, statins, and in some cases antiplatelet therapy, to reduce their risk [35] (see Section 9).
The main advantage of detecting HMOD is that it may reclassify a patient's SCORE risk assessment from low to moderate or from moderate to high risk [117]. The specific impact of HMOD [114] with regard to the reclassification of risk estimation according to the SCORE system has not been clearly defined. The SCORE system already takes account of the grade of hypertension as SBP is included in the risk calculation. Moreover, CKD and the presence of vascular disease on imaging are already specified as high or very high risk (Table 5). Conditioning of the risk score by the presence of HMOD will be most important in middle-aged patients with hypertension, many of whom will be at moderate-risk and at higher risk if HMOD is detected. Moreover, a risk-conditioning effect of HMOD will also be important in younger hypertensive patients who are invariably classified as low risk according to the SCORE system. In addition, detecting HMOD in younger patients with grade 1 hypertension provides unequivocal evidence of hypertension-mediated damage and indicates a clear need for BP-lowering treatment in patients who may be reluctant to be treated. For the same reason, the presence of HMOD in a patient with high–normal BP would also provide a rationale to consider BP-lowering treatment.
Another important consideration is whether the presence of a specific manifestation of HMOD (e.g. LVH or CKD) might influence the selection of drug treatment for hypertension. This was considered important in the previous guidelines [17], but is now considered less important. In patients more likely to have HMOD (i.e. those with high grade 1 or grade 2–3 hypertension), we now recommend initial treatment with a combination of two drugs, usually an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) in combination with a calcium channel blocker (CCB) or thiazide-type diuretic, which would be the optimal treatment for all manifestations of HMOD (see Section 7).
5.5 Characteristics of hypertension-mediated organ damage
5.5.1 The heart in hypertension
Chronically increased left ventricular workload in hypertensive patients can result in LVH, impaired left ventricular relaxation, left atrial enlargement, an increased risk of arrhythmias, especially AF, and an increased risk of heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF).
5.5.1.1 Electrocardiogram
A 12-lead ECG should be part of the routine assessment in all hypertensive patients. The ECG is not a particularly sensitive method of detecting LVH and its sensitivity varies according to body weight. ECG LVH provides independent prognostic information, even after adjusting for other cardiovascular risk factors and echocardiographic left ventricular mass [118]. In addition to LVH, the presence of a ‘strain pattern’ on an ECG is associated with increased risk [119]. The prevalence of ECG LVH increases with the severity of hypertension [120]. The most commonly used criteria to define ECG LVH are shown in Table 16.
The ECG cannot exclude LVH because it has poor sensitivity. When detailed information on cardiac structure and function will influence treatment decisions, echocardiography is recommended. When LVH is present on the ECG, it can be used to detect changes in LVH during follow-up in untreated and treated patients [121,122].
5.5.1.2 Transthoracic echocardiography in hypertension
Echocardiographic LVH is a potent predictor of mortality in both hypertensive patients and the general population [123,124], and regression of echocardiographic LVH due to treatment of hypertension predicts an improved prognosis [125]. Two-dimensional transthoracic echocardiography (TTE) also provides information about left ventricular geometry, left atrial volume, aortic root dimensions, left ventricular systolic and diastolic function, pump performance, and output impedance [123,126,127]. Whether additional parameters other than evidence of increased left ventricular mass and left atrial dilatation are useful to help stratify cardiovascular risk is uncertain [123,126,128]. The partition values recommended for the definition of LVH by echocardiography are shown in Table 17.
Three-dimensional TTE is a more reliable method for quantitative analysis [129], specifically for left ventricular mass [130], volumes, and ejection fraction, and has superior reproducibility to two-dimensional TTE but much less prognostic validation [131]. More detailed information on the use of echocardiography to assess the hypertensive heart is available [43]. Cardiac magnetic resonance is the gold standard for cardiac anatomical and functional quantification [132–134].
Abnormal left ventricular geometry in hypertensive patients is frequently associated with diastolic dysfunction [127,135], which can be further evaluated by a combination of transmitral flow and tissue Doppler studies [136]. Left atrial size is also frequently increased in hypertensive patients and is associated with adverse cardiovascular events [128,137] and incident AF [138], and is related to diastolic dysfunction [139,140]. During the diagnostic workup for secondary hypertension, a suprasternal view should also be performed for the identification of aortic coarctation [141].
5.5.2 The blood vessels in hypertension
5.5.2.1 Carotid artery
Carotid intima–media thickness (IMT) quantified by carotid ultrasound, and/or the presence of plaques, predicts cardiovascular risk [42,142]. This holds true both for the IMT value at the carotid bifurcations (reflecting primarily atherosclerosis) and for the IMT value at the level of the common carotid artery (reflecting primarily hypertension-related hypertrophy). A carotid IMT more than 0.9 mm is considered abnormal [143], but the upper limit of normality varies with age. The presence of a plaque can be identified by an IMT at least 1.5 mm, or by a focal increase in thickness of 0.5 mm or 50% of the surrounding carotid IMT value [144]. Stenotic carotid plaques have a strong predictive value for both stroke and myocardial infarction, independent of traditional cardiovascular risk factors [42,142], and confer superior prognostic accuracy for future myocardial infarction compared with IMT [145]. The presence of carotid plaques will automatically reclassify patients from intermediate to high risk [146,147]; however, routine carotid imaging is not recommended unless clinically indicated (i.e. presence of carotid bruit, previous transient ischemic attack (TIA) or cerebrovascular disease, or as part of the assessment of patients with evidence of vascular disease).
5.5.2.2 Pulse wave velocity
Large artery stiffening is the most important pathophysiological determinant of isolated systolic hypertension and age-dependent increase in pulse pressure [148]. Carotid-femoral pulse wave velocity (PWV) is the gold standard for measuring large artery stiffness [149]. Reference values for PWV are available in healthy populations and patients at increased cardiovascular risk [150]. A PWV more than 10 m/s is considered a conservative estimate of significant alterations of aortic function in middle-aged hypertensive patients [149]. The additive value of PWV above and beyond traditional risk factors, including SCORE and the Framingham risk score, has been suggested by several studies [151]. However, routine use of PWV measurement is not practical and is not recommended for routine practice.
5.5.2.3 Ankle–brachial index
Ankle-brachial index (ABI) may be measured either with automated devices, or with a continuous wave Doppler unit and a BP sphygmomanometer. A low ABI (i.e. <0.9) indicates lower extremity artery disease (LEAD), is usually indicative of advanced atherosclerosis [152], and has predictive value for cardiovascular events [153], being associated with an almost two-fold greater 10-year cardiovascular mortality and major coronary event rate, compared with the overall rate in each Framingham category [153]. Even asymptomatic LEAD, detected by a low ABI, is associated in men with a high incidence of cardiovascular morbid and fatal events, approaching 20% in 10 years [153,154]. Routine use of ABI is not recommended in hypertensive patients, but should be considered in patients with symptoms or signs of LEAD, or in moderate-risk patients in whom a positive test would reclassify the patient as high-risk.
5.5.3 The kidney in hypertension
Hypertension is the second most important cause of CKD after diabetes. Hypertension may also be the presenting feature of asymptomatic primary renal disease. An alteration of renal function is most commonly detected by an increase in serum creatinine. This is an insensitive marker of renal impairment because a major reduction in renal function is needed before serum creatinine rises. Furthermore, BP reduction by antihypertensive treatment often leads to an acute increase in serum creatinine by as much as 20–30%, especially with renin–angiotensin system (RAS) blockers, which has a functional basis and does not usually reflect manifest renal injury, but the long-term clinical significance is unclear [155,156]. The diagnosis of hypertension-induced renal damage is based on the finding of reduced renal function and/or the detection of albuminuria. CKD is classified according to estimated glomerular filtration rate (eGFR), calculated by the 2009 CKD-Epidemiology Collaboration formula [157].
The albumin:creatinine ratio (ACR) is measured from a spot urine sample (preferably early morning urine), and is the preferred method to quantify urinary albumin excretion. A progressive reduction in eGFR and increased albuminuria indicate progressive loss of renal function, and are both independent and additive predictors of increased cardiovascular risk and progression of renal disease [158].
Serum creatinine, eGFR and ACR should be documented in all hypertensive patients, and if CKD is diagnosed, repeated at least annually [159]. One negative urinary dipstick test does not rule out albuminuria, in contrast to a normal ACR [160].
5.5.4 Hypertensive retinopathy
The prognostic significance of hypertensive retinopathy by fundoscopy has been well documented [161]. Detection of retinal haemorrhages, microaneurysms, hard exudates, cotton wool spots, and papilloedema is highly reproducible, indicates severe hypertensive retinopathy, and is highly predictive of mortality [161,162]. In contrast, evidence of arteriolar narrowing, either focal or general, and arteriovenous nicking at early stages of hypertensive retinopathy have less predictive value [163], and limited interobserver and intraobserver reproducibility, even with experienced observers [164]. Fundoscopy should be performed in patients with grade 2 or 3 hypertension or hypertensive patients with diabetes, in whom significant retinopathy is more likely. Fundoscopy may be considered in other hypertensive patients. The increasing emergence of new techniques to visualize the fundus through smartphone technologies should increase the feasibility of more routine fundoscopy [165].
5.5.5 The brain in hypertension
Hypertension increases the prevalence of brain damage, of which transient ischaemic attack (TIA) and stroke are the most dramatic acute clinical manifestations. In the asymptomatic phase, brain damage can be detected by MRI as white matter hyperintensities, silent microinfarcts, (most of which are small and deep, i.e. lacunar infarctions), microbleeds and brain atrophy [166,167]. White matter hyperintensities and silent infarcts are associated with an increased risk of stroke and cognitive decline due to degenerative and vascular dementia [166–169]. Availability and cost do not permit the widespread use of brain MRI for the evaluation of hypertensive patients, but white matter hyperintensity and silent brain infarcts should be sought in all hypertensive patients with neurological disturbances, cognitive decline, and, particularly, memory loss [168,169]. A family history of cerebral haemorrhage at middle age and early-onset dementia should prompt MRI. Cognitive impairment in older patients is, at least in part, hypertension-related, and cognitive evaluation tests should be considered in the clinical assessment of hypertensive patients with a history suggestive of early cognitive impairment. The Mini-Mental State Examination has been the most widely used method in clinical trials, but is now being superseded by more sophisticated cognitive tests that are more suitable for routine clinic visits [170].
5.6 Hypertension-mediated organ damage regression and cardiovascular risk reduction with antihypertensive treatment
As discussed above, HMOD assessment may play a role in stratifying the risk of patients with hypertension. In post-hoc analyses, BP treatment-induced regression of some (but not all) manifestations of asymptomatic HMOD, as a consequence of treatment, is associated with a reduction in cardiovascular risk, thereby providing additional information on the effectiveness of treatment in individual patients [16,104,171]. This has been best illustrated for the treatment-induced regression of LVH measured by either ECG or echocardiography [125,172,173]. A reduced incidence of cardiovascular events and slower progression of renal disease has been reported with a treatment-induced reduction in urinary protein excretion in both diabetic and nondiabetic patients, especially for microalbuminuria [174], but results are discordant [175–179]. There is also evidence that treatment-induced changes in eGFR predict cardiovascular events [180] and progression to end-stage renal disease [181,182]. Two meta-analyses [183,184] failed to document any predictive value of treatment-induced reductions in carotid IMT for cardiovascular events. Evidence on the predictive power of treatment-induced changes on other measures of HMOD (PWV and ABI) are either limited or absent. Regression of HMOD might not be possible even when BP is controlled, particularly when HMOD is advanced, because some of the changes become irreversible.
The information available on the sensitivity and timing of changes in HMOD during antihypertensive treatment is summarized in Table 18. If, when, and how often the assessment of HMOD should be performed has not been validated in follow-up studies. HMOD can also develop during the course of antihypertensive treatment [185], and this may be accompanied by increased risk [186–188].
5.7 When to refer a patient with hypertension for hospital-based care
Hypertension is a very common condition and most patients with hypertension, in most healthcare systems, will be managed in the primary care setting. However, there are circumstances in which a referral for routine hospital-based evaluation and treatment may be required, keeping in mind that in some instances out-of-office or office-based care of hypertensive patients depends on the healthcare organization of a given country:
- Patients in whom secondary hypertension is suspected (see Section 8.2)
- Younger patients (<40 years) with grade 2 or more severe hypertension in whom secondary hypertension should be excluded
- Patients with treatment-resistant hypertension (see Section 8.1)
- Patients in whom more detailed assessment of HMOD would influence treatment decisions
- Patients with sudden onset of hypertension when BP has previously been normal
- Other clinical circumstances in which the referring doctor feels more specialist evaluation is required.
There are also rarer circumstances in which a patient with hypertension should be referred to hospital for emergency care, which will often require inpatient care (see Section 8.3).
Clinical evaluation and HMOD assessment
6 GENETICS AND HYPERTENSION
A positive family history is a frequent feature in hypertensive patients, with the heritability estimated to vary between 35 and 50% in most studies [191,192]. However, hypertension is a highly heterogeneous disorder with a multifactorial aetiology. Several genome-wide association studies and their meta-analyses have identified 120 loci that are associated with BP regulation, but together these only explain about 3.5% of the trait variance [193]. Several rare, monogenic forms of hypertension have been described such as glucocorticoid-remediable aldosteronism, Liddle's syndrome, and others, where a single gene mutation fully explains the pathogenesis of hypertension and dictates the best treatment modality [194–196]. There are also inherited forms of phaeochromocytoma and paraganglioma, which are also rare causes of hypertension [197–200]. Outside of specialist clinics evaluating patients for these rare causes of secondary hypertension, there is no role for genetic testing in hypertension in routine clinical care.
Genetic testing and hypertension
7 TREATMENT OF HYPERTENSION
7.1 Beneficial effects of blood pressure-lowering therapy in hypertension
There are two well established strategies to lower BP: lifestyle interventions and drug treatment. Device-based therapy is also emerging, but is not yet proven as an effective treatment option. Lifestyle interventions can undoubtedly lower BP and in some cases cardiovascular risk (see Section 7.4.1), but most patients with hypertension will also require drug treatment. The drug treatment of hypertension is founded on very solid evidence, underpinned by the largest number of outcome-based RCTs in clinical medicine. Meta-analyses of RCTs including several hundred thousand patients have shown that a 10 mmHg reduction in SBP or a 5 mmHg reduction in DBP is associated with significant reductions in all major cardiovascular events by 20%, all-cause mortality by 10–15%, stroke by 35%, coronary events by 20%, and heart failure by 40% [2,8]. These relative risk reductions are consistent, irrespective of baseline BP within the hypertensive range, the level of cardiovascular risk, comorbidities (e.g. diabetes and CKD), age, sex, and ethnicity [2,201].
Relative outcome reductions calculated by two recent meta-analyses are similar to those provided by the original meta-analysis of the effects of BP lowering on outcomes in 1994 [202]. Thus, the benefits of antihypertensive treatment have not been attenuated by the widespread concomitant prescription of lipid-lowering and antiplatelet therapies in contemporary medicine.
Another important objective of antihypertensive therapy is to reduce the development of CKD; however, the slow rate of decline in renal function in most hypertensive patients makes the demonstration of potential benefits of BP lowering difficult. Consequently, the protective effect of BP reduction on kidney function can be less obvious and has been restricted to patients with diabetes or CKD, in whom there is a faster rate of disease progression [203]. Some, but not all, RCTs have also shown a protective effective of BP lowering on the progression of CKD towards end-stage renal disease in both diabetic and nondiabetic nephropathy [2].
The recommendations that follow are based on outcome evidence from RCTs; however, it must be acknowledged that RCTs based on clinical outcomes have limitations, the most important of which are that the data are largely limited to older and high-risk patients, preferentially recruited to increase statistical power, and over a relatively short duration of follow-up, rarely beyond 5 years. This means that recommendations for life-long treatment for younger and lower risk patients are necessarily based on considerable extrapolation. Big data, now being collected by national health system registries, health insurance companies, and prolonged observational follow-up of RCTs, are becoming an important source of long-term information on the effects of chronic treatment [204], which adds to that provided by observational studies over several decades [205–207]. Such evidence suggests that the benefit of continued treatment is maintained over decades [206].
7.2 When to initiate antihypertensive treatment
7.2.1 Recommendations in previous guidelines
All guidelines agree that patients with grade 2 or 3 hypertension should receive antihypertensive drug treatment alongside lifestyle interventions [208]. Guidelines are also consistent in recommending that patients with grade 1 hypertension and high cardiovascular risk or HMOD should be treated with BP-lowering drugs. There has been less consistency about whether BP-lowering drugs should be offered to patients with grade 1 hypertension and low–moderate cardiovascular risk or grade 1 hypertension in older patients (>60 years), or the need for BP-lowering drug treatment in patients with high–normal BP levels [17,209,210]. This uncertainty relates to the fact that low-risk patients with high–normal BP or grade 1 hypertension have rarely been included in RCTs, and that in older patients, RCTs have invariably recruited patients with at least grade 2 hypertension. New analyses and RCT data have become available in these important areas and are discussed below.
7.2.2 Drug treatment for patients with grade 1 hypertension at low-moderate cardiovascular risk
Recent meta-analyses show significant treatment-induced reductions in cardiovascular events and mortality in patients with grade 1 hypertension [8,201,211]. However, the first of these analyses included a substantial number of patients who had grade 1 hypertension despite existing treatment, and were therefore likely to have had initial BPs above the grade 1 range. Furthermore, many of the patients had diabetes and were therefore at high cardiovascular risk [211]. The second meta-analysis, limited to RCTs in patients with grade 1 hypertension and low–moderate-risk (five RCTs, 8974 patients), demonstrated a significant reduction in all major cardiovascular events by BP-lowering drug treatment [combined stroke and coronary artery disease (CAD) reduced by 34%, and all-cause mortality by 19% for an SBP reduction of 7 mmHg] [8]. A third analysis demonstrated a benefit of BP lowering in reducing death and CVD in patients with a baseline BP 140/90 mmHg or higher, but not when baseline BP was lower [201]. These findings have been supported by the results of a subgroup analysis of the Heart Outcomes Prevention Evaluation (HOPE)-3 trial, showing a significant 27% reduction in major cardiovascular outcomes in patients at intermediate cardiovascular risk and baseline SBP values in the grade 1 hypertensive range [i.e. >143.5 mmHg (mean 154 mmHg)] when SBP was lowered by drug treatment by a mean of 6 mmHg [212].
Based on these new data, this Task Force now recommends that lifestyle advice should be accompanied by BP-lowering drug treatment in patients with grade 1 hypertension at low–moderate cardiovascular risk.
7.2.3 Initiation of blood pressure-lowering drug treatment in older people with grade 1 hypertension
Discussion about the treatment of ‘the elderly’ or ‘older’ people has been complicated by the various definitions of older age used in RCTs. For example, older was defined as more than 60 years in the earliest trials, then as 65, 70 and finally 75 [51] or 80 years [213] in later trials. Chronological age is often a poor surrogate for biological age, with consideration of frailty and independence influencing the likely tolerability of BP-lowering medications. For the purposes of this guideline, the ‘old’ are defined as at least 65 years and the ‘very old’ as at least 80 years. The previous Guidelines [17] noted that all available evidence on cardiovascular event reduction by BP lowering in older patients was obtained in patients whose baseline SBP was at least 160 mmHg, and there is strong evidence that these patients should be offered BP-lowering drug treatment [210,214].
Undoubtedly, there are RCTs showing outcome benefits with BP-lowering treatment in older patients whose baseline BP was in a lower SBP range, but these patients were often on background antihypertensive treatment, thus they cannot be defined as having true grade 1 hypertension. This is also the case for the data recently published from the SPRINT trial, which included a cohort of patients older than 75 years, in whom more intense BP lowering reduced the risk of major cardiovascular events and mortality [51,215]. However, in most RCTs showing a protective effect of BP-lowering treatment in patients with an untreated baseline BP in the grade 1 hypertension range, older patients were well represented. This was further supported by the recent HOPE-3 trial, which showed beneficial effects of BP lowering on cardiovascular outcomes in patients, many with grade 1 hypertension (SBP >143 mmHg and mean BP = 154 mmHg), whose mean age was 66 years, and in whom only 22% had prior treatment of hypertension [212].
The evidence supports the recommendation that older patients (>65 years, including patients over 80 years) should be offered BP-lowering treatment if their SBP is at least 160 mmHg. There is also justification to now recommend BP-lowering treatment for old patients (aged >65 but not >80 years) at a lower BP (i.e. grade 1 hypertension; SBP = 140–159 mmHg) [201]. BP-lowering drugs should not be withdrawn on the basis of age alone. It is well established that BP-lowering treatment withdrawal leads to a marked increase in cardiovascular risk. This was exemplified in older patients by a recent subgroup analysis of the Hypertension in the Very Elderly Trial (HYVET) [213], reporting that in patients aged at least 80 years, cardiovascular risk reduction was greatest in those who continued treatment rather than in those whose treatment was discontinued [216]. As stated above, all of the above recommendations relate to relatively fit and independent older patients, because physically and mentally frail and institutionalized patients have been excluded in most RCTs of patients with hypertension [214]. Further details of the treatment of hypertension in older patients and very old patients is provided in Section 8.8.
7.2.4 Initiation of blood pressure-lowering drug treatment in patients with high-normal blood pressure
The previous (2013) Guidelines [17] recommended not to initiate antihypertensive treatment in people with high–normal BP and low–moderate cardiovascular risk. This recommendation is further supported by new evidence:
- In all RCTs (including SPRINT) [51] and meta-analyses [2] that have reported reduced major outcomes by lowering ‘baseline’ BP in the high–normal range, the ‘baseline’ BP was commonly measured on a background of antihypertensive treatment. Therefore, these studies do not provide evidence to support treatment initiation in patients without hypertension [8].
- The HOPE-3 trial [212], in which only 22% of the patients at intermediate cardiovascular risk had background antihypertensive treatment, showed that BP-lowering treatment did not reduce the risk of major cardiovascular events in patients with baseline SBP values in the high–normal range.
- A meta-analysis of 13 RCTs or RCT subgroups (involving 21 128 individuals) in patients at low–moderate cardiovascular risk and untreated baseline BP in the high–normal and normal range, showed no effect of BP-lowering treatment on any cardiovascular outcomes [217].
- Another recent analysis, including patients with high–normal BP, concluded that primary preventive BP lowering was associated with reduced risk for death and incident CVD if baseline SBP was 140 mmHg or higher, but at lower BP levels [i.e. high–normal BP (<140/90 mmHg)], treatment was not associated with any benefit in primary prevention [201].
- The situation may be different in very high-risk patients with a high–normal BP and established CVD. In a meta-analysis of 10 RCTs or RCT subgroups that also included individuals at high or very high cardiovascular risk, mostly with previous CVD and untreated high–normal and normal BP (n = 26 863), BP-lowering drug treatment, achieving an SBP reduction of 4 mmHg, reduced the risk of stroke but not any other cardiovascular events [217]. In another analysis of trials including people with previous CAD and a mean baseline SBP of 138 mmHg, treatment was associated with reduced risk for major cardiovascular events (relative risk 0.90; 95% confidence interval 0.84–0.97), but was not associated with an increased survival (relative risk 0.98; 95% confidence interval 0.89–1.07) [201]. Thus, the benefit for treating people with high–normal BP appears marginal and, if present, appears to be restricted to those at very high cardiovascular risk and established CVD, especially CAD.
We recommend that patients with high–normal BP and low–moderate cardiovascular risk should be offered lifestyle advice, because this reduces their risk of progressing to established hypertension and may further reduce their cardiovascular risk. These patients should not be offered BP-lowering drug treatment. Nevertheless, based on the data from the HOPE-3 trial, drug treatment may be considered in these patients if their BP is close to the hypertension diagnostic threshold of 140/90 mmHg, after a prolonged attempt to control BP with lifestyle changes.
BP-lowering drugs may be considered for patients with high–normal BP and established CVD, especially CAD. In these patients, monotherapy may be sufficient.
7.2.5 Should blood pressure-lowering drug treatment be initiated on the basis of blood pressure values or the level of total cardiovascular risk?
Two recent meta-analyses of RCTs [8,218] have shown that when BP-lowering data are stratified according to cardiovascular risk, the relative risk reductions do not differ across the various risk strata; not surprisingly, the absolute risk reduction is greater with increasing baseline cardiovascular risk. These data have been taken as support for the hypothesis that BP-lowering treatment should be based on cardiovascular risk and target those at greatest cardiovascular risk, irrespective of their BP [218]. However, it has recently been made that whereas patients at high or very high cardiovascular risk exhibit the greatest absolute reduction in cardiovascular outcomes with BP-lowering treatment, they also have the highest residual risk, which means failure of treatment to exert full protection [8]. It is the opinion of this Task Force that these data support earlier treatment of patients with SBP or DBP values more than 140/90 mmHg when their cardiovascular risk is still low–moderate, to prevent the accumulation of HMOD and a high incidence of late treatment failure (residual risk), which would otherwise occur if treatment was delayed by a purely cardiovascular risk-based approach. The most effective strategy to reduce risk is to prevent the development of high cardiovascular-risk situations with earlier intervention. The assessment of cardiovascular risk is at the core of the treatment strategy recommended by these Guidelines because of the frequent coexistence of multiple cardiovascular risk factors in hypertensive patients, and to inform the use of concomitant medications (e.g. statins, antiplatelet therapies, etc., see Section 9) to reduce cardiovascular risk. We conclude that, in general, the decision to use BP-lowering treatment should not be based solely on the level of cardiovascular risk because even in patients at the highest risk (with established CVD), when baseline BP is below 140/90 mmHg, the benefits of BP-lowering treatment are at best marginal and most evident in patients with CAD at the upper end of the high–normal BP range [201].
7.2.6 Initiation of blood pressure-lowering drug treatment
In patients with grade 2 or 3 hypertension, it is recommended that BP-lowering drug treatment should be initiated alongside lifestyle interventions. In patients with grade 1 hypertension at high risk or with HMOD, drug treatment should also be initiated simultaneously with lifestyle interventions. In lower-risk patients with grade 1 hypertension, BP-lowering drug treatment should be initiated after 3–6 months if BP is not controlled by lifestyle interventions alone (Fig. 3). Recommended BP thresholds for the initiation of antihypertensive drug treatment are shown in Table 19.
Initiation of hypertension treatment according to office BP
7.3 Blood pressure treatment targets
7.3.1 New evidence on SBP and diastolic blood pressure treatment targets
The 2013 ESH/ESC hypertension Guidelines [17] recommended an office BP treatment target of <140/90 mmHg, regardless of the number of comorbidities and level of cardiovascular risk. The Guidelines specifically stated that evidence from RCTs, meta-analyses, and post-hoc analysis of large-scale RCTs all showed no obvious incremental benefit of lowering BP to less than 130/80 mmHg. Since then, new information has emerged from post-hoc analyses of large outcome trials in patients at high cardiovascular risk [222–224], registries in patients with coronary disease, and, more importantly, new RCTs and meta-analyses of all available RCT evidence. In the post-hoc RCT analyses and registry data, compared with a target SBP of between 130 and 139 mmHg, lowering SBP to less than 130 mmHg was, in general, associated with no further benefit on major cardiovascular events, except perhaps for further reductions in the risk of stroke. A consistent finding was that reducing SBP to less than 120 mmHg increased the incidence of cardiovascular events and death.
A recent RCT relevant to the issue of target BP is SPRINT, which compared two different SBP targets (<140 or <120 mmHg) in more than 9000 patients at high cardiovascular risk, but excluded patients with diabetes or previous stroke. More intensive BP-lowering treatment (achieved SBP 121 vs. 136 mmHg) was associated with a 25% reduction in major cardiovascular events and a 27% reduction in all-cause death (but no significant reduction in stroke or myocardial infarction) [51]. This outcome unquestionably provides strong support for the beneficial effects of more vs. less intensive BP-lowering treatment strategies in higher risk patients. However, this RCT does not clarify the optimal BP target because the method used for office BP measurement in SPRINT (unattended automatic measurement) had not been used in any previous RCTs that provide the evidence base for the treatment of hypertension [225]. This is because unattended automated office BP measurement results in lower BP values, relative to conventional office BP measurement, due to the absence of the white-coat effect [52,54]. Thus, it has been suggested that the BP values reported in SPRINT may correspond to conventional office SBPs in the 130–140 and 140–150 mmHg ranges in the more vs. less intensive BP-lowering groups, respectively.
Some new information on SBP and DBP targets for drug treatment has been provided by two recent, large meta-analyses of RCTs of BP lowering. In the first of these meta-analyses, achieved SBP was stratified according to three SBP target ranges (149–140, 139–130 and <130 mmHg) [226]. Lowering SBP to less than 140 mmHg reduced the relative risk of all major cardiovascular outcomes (including mortality); similar benefits were seen when SBP was lowered to less than 130 mmHg (average 126 mmHg). Importantly, the latter was also true when the achieved SBP in the comparator group was 130–139 mmHg. Stratification of RCTs for achieved DBP, to either 89–80 or less than 80 mmHg, also showed a reduction in all types of cardiovascular outcomes compared with higher DBP values [226].
The second meta-analysis, which also included the SPRINT trial [2], noted that every 10 mmHg reduction in SBP reduced the rate of major cardiovascular events and death for baseline SBP values more than 160 mmHg to baseline values between 130 and 139 mmHg, implying benefit at achieved SBP values of less than 130 mmHg. Furthermore, a benefit of a 10 mmHg reduction in SBP was also reported for patients with a baseline SBP of less than 130 mmHg, thereby achieving values less than 120 mmHg. However, there were far fewer patients in these subgroups, and this last set of data will have been heavily influenced by the unusually low BP values in the SPRINT trial, due to the method of BP measurement (see above). Importantly, this analysis showed consistent benefit from intensive BP lowering in patients at all levels of risk, including those with and without existing CVD, stroke, diabetes and CKD.
Finally, in the first meta-analysis [226], the incremental benefit of BP lowering on events progressively decreased as the target BP was lowered. Furthermore, an additional meta-analysis by the same group found that permanent treatment discontinuation because of treatment-related adverse effects was significantly higher in those targeted to lower BP values [227]. Therefore, advocating more intensive BP-lowering targets for all has to be viewed in the context of an increased risk of treatment discontinuation due to adverse events, which might offset, in part or completely, the limited incremental reduction in cardiovascular risk.
Whilst considering BP targets, it is important to acknowledge that less than 50% of patients treated for hypertension currently achieve a target office SBP of less than 140 mmHg [11,12]. This is a major missed opportunity for CVD prevention in millions of people across the world.
This Task Force recommends that when BP-lowering drugs are used, the first objective should be to lower BP to <140/90 mmHg in all patients. Provided that the treatment is well tolerated, treated BP values should be targeted to 130/80 mmHg or lower in most patients, although in some groups the evidence is less compelling. In older patients (>65 years), SBP should be targeted to between 130 and 140 mmHg, and DPB to less than 80 mmHg. Treated SBP should not be targeted to less than 120 mmHg.
Importantly, we specify a target range because the lower safety boundary assumes greater importance when BP is targeted to lower levels. Furthermore, in general, when SBP is lowered to less than 120 mmHg in patients included in RCTs (i.e. older and higher-risk patients, often with comorbidities and CVD), the risk of harm appears to increase and outweigh the benefits [222].
7.3.2 Blood pressure targets in specific subgroups of hypertensive patients
7.3.2.1 Diabetes mellitus
RCTs in type 1 diabetes mellitus demonstrate that BP-lowering treatment has a renoprotective effect [228], but because these patients tend to be younger, previous RCTs have had inadequate power to study cardiovascular outcomes and to establish optimal BP targets.
In contrast, there have been many BP-lowering treatment RCTs, either exclusively dedicated to patients with type 2 diabetes or hypertension trials that have included a large cohort of patients with type 2 diabetes [2]. Most of these RCTs have shown that BP lowering to less than 140/85 mmHg is beneficial in patients with type 2 diabetes and hypertension. However, the results have been less clear about whether a lower BP target is associated with further benefits. The evidence can be summarized as follows:
- A large RCT in patients with type 2 diabetes has shown that an achieved SBP of less than 135 mmHg, compared with 140 mmHg, was associated with a significant reduction in cardiovascular and all-cause mortality [229].
- Evidence from another large RCT in patients with type 2 diabetes showed that, compared with patients with an on-treatment SBP of 135 mmHg, reducing SBP to 121 mmHg did not reduce cardiovascular morbidity and mortality or all-cause death, but substantially reduced the risk of stroke [230].
- Although one recent meta-analysis concluded that most of the benefit associated with BP lowering was obtained at higher BP targets (i.e. <150 mmHg but not <140 mmHg) [231], other large meta-analyses have confirmed that in type 2 diabetes, lowering SBP to <140 mmHg is associated with reductions in all major cardiovascular events [1,232–234].
- Two of the meta-analyses concluded that the overall benefit of lowering BP in patients with type 2 diabetes (unlike patients without type 2 diabetes) largely disappears when SBP is lowered to less than 130/80 mmHg [1,235], except for the continuing incremental benefit on stroke.
- Similar evidence for stroke benefit from lower achieved SBP has also been reported from post-hoc analysis of diabetic patients in the ONTARGET (Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) study. In addition, reanalysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) [230] trial in type 2 diabetes, after removing the interaction from the intensive glucose-lowering arm and thereby limiting the analysis to BP-lowering effects, showed an overall reduction in cardiovascular events with intensive SBP lowering to less than 130 mmHg [236].
- Further recent analysis of the ACCORD trial has shown that reducing SBP to less than 120 mmHg was associated with increased risk of major cardiovascular events [236].
- With regard to DBP, earlier evidence suggested a benefit on major cardiovascular events when DBP was lowered to less than 85 mmHg [237,238]. More recently, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron – MR Controlled Evaluation (ADVANCE) trial [229], the benefits on cardiovascular outcomes were observed at diastolic pressures of 75 mmHg. This is consistent with evidence from the meta-analyses cited above, that it is safe and effective to lower DBP to less than 80 mmHg in patients with type 2 diabetes.
In summary, in patients with diabetes receiving BP-lowering drugs, it is recommended that office BP should be targeted to an SBP of 130 mmHg [229], and lower if tolerated. In older patients (aged ≥65 years) the SBP target range should be 130–140 mmHg [213] if tolerated. SBP should not be lowered to less than 120 mmHg and DBP should be lowered to less than 80 mmHg. Attention should also be given to the consistency of BP control, because visit-to-visit BP variability is associated with increased cardiovascular and renal disease risk. Furthermore, cardiovascular protection has been found to be greater when BP control is accompanied by fewer visit-to-visit BP variations [239–241].
7.3.2.2 Older patients
The definition of ‘older’ is complex. As populations age, there is increasingly wide variation between a patient's chronological age and their functional status, ranging from fit, active, and independent, through to frail and dependent. The anticipated benefits vs. potential harm of BP treatment in older patients will be influenced by the patient's ability to tolerate treatment and their health and functional status. For the purposes of these Guidelines, ‘older’ patients are defined as those aged at least 65 years.
In the 2013 ESH/ESC hypertension Guidelines, the target SBP for older hypertensive patients was set at 140–150 mmHg because this was the range of systolic values achieved by major outcome trials demonstrating a beneficial effect of antihypertensive treatment in these patients. A similar SBP target was suggested by the HYVET trial, in which treating to an SBP target of less than 150 mmHg (achieving a mean SBP of 144 mmHg) in the very old (>80 years) demonstrated significant reductions in mortality, fatal stroke, and heart failure, with the caveat that the ‘very old’ patients in this study were active and independent [213]. More recent evidence supports a lower SBP target for older patients (≥65 years):
- The SPRINT trial included a high proportion of patients over the age of 75 years (n = 2636) and demonstrated that more intensive BP-lowering treatment (mean achieved BP = 124/62 mmHg) significantly reduced the risk of major cardiovascular events, heart failure, and all-cause death (all by >30%) compared with standard treatment (mean achieved BP = 135/67 mmHg) [215]. It has been noted above that the BP measurement technique used in SPRINT generated lower values than those provided by the conventional office BP measurement [225,242]. Consequently, the SBP of 124 mmHg achieved in the intensively treated older patients in the SPRINT trial most probably reflects a conventional office SBP range of 130–139 mmHg.
- Although HYVET and most other RCTs in older patients have recruited relatively fit and independent patients, the SPRINT study also suggested that there are benefits of more intensive treatment being extended to older patients who are at the frailer end of the spectrum of patients meeting the recruitment criteria, with reduced gait speed [215].
Based on the new data, the targets suggested by the previous Guidelines now appear too conservative for many old and very old patients, especially those who are active and independent. Consequently, we recommend that in older patients treated for hypertension, BP should be lowered to less than 140/80 mmHg, but not below an SBP of 130 mmHg. Importantly, the impact of BP-lowering on the well being of the patient should be closely monitored, because the increased risk of adverse events (e.g. injurious falls) with lower BP values could be more pronounced in older patients in the real-life setting than in the closely monitored conditions of RCTs. Further details on the approach to treatment of the frail older patient are discussed in Section 8.8.
7.3.2.3 Office vs. home and ambulatory blood pressure targets
No outcome-based RCT has used ABPM or HBPM to guide the treatment of hypertension. Thus, ABPM and HBPM BP targets are based on extrapolation from observational data rather than on outcome trials. Although we do not provide formal ABPM or HBPM BP targets for treated patients, it should be noted that:
- In population studies, the difference between office and out-of-office BP levels decreases as office BP decreases, to a point of around 115–120/70 mmHg, at which office and 24 h ABPM mean BP values are usually similar [54].
- This convergence has also been confirmed in treated patients [243] in whom the difference between office BP and ambulatory BP values diminishes and becomes negligible at an SBP of approximately 120 mmHg.
- In treated patients, a target office SBP of 130 mmHg might therefore correspond to a slightly lower mean 24 h SBP, that is approximately 125 mmHg.
- Although there are no available data, the home SBP target, to be equivalent to an office SBP target of 130 mmHg, might also be lower than 130 mmHg.
Office BP treatment targets in hypertensive patients
7.4 Treatment of hypertension
7.4.1 Lifestyle changes
Healthy lifestyle choices can prevent or delay the onset of hypertension and can reduce cardiovascular risk [17,35]. Effective lifestyle changes may be sufficient to delay or prevent the need for drug therapy in patients with grade 1 hypertension. They can also augment the effects of BP-lowering therapy, but they should never delay the initiation of drug therapy in patients with HMOD or at a high level of cardiovascular risk. A major drawback of lifestyle modification is the poor persistence over time [245,246]. The recommended lifestyle measures that have been shown to reduce BP are salt restriction, moderation of alcohol consumption, high consumption of vegetables and fruits, weight reduction and maintaining an ideal body weight, and regular physical activity [17]. In addition, tobacco smoking has an acute prolonged pressor effect that may raise daytime ambulatory BP, but smoking cessation and other lifestyle measures are also important beyond BP (i.e. for CVD and cancer prevention) [35].
7.4.2 Dietary sodium restriction
There is evidence of a causal relationship between sodium intake and BP, and excessive sodium consumption (>5 g sodium per day, e.g. one small teaspoon of salt per day) has been shown to have a pressor effect and be associated with an increased prevalence of hypertension and the rise in SBP with age [247]. Conversely, sodium restriction has been shown to have a BP-lowering effect in many trials. A recent meta-analysis of these trials showed that a reduction of 1.75 g sodium per day (4.4 g salt per day) was associated with a mean 4.2/2.1 mmHg reduction in SBP/DBP, with a more pronounced effect (−5.4/−2.8 mmHg) in people with hypertension [248]. The beneficial effect of a reduced sodium intake on BP tends to diminish with time, in part due to poor dietary persistence. The BP-lowering effect of sodium restriction is greater in black people, in older patients, and in patients with diabetes, metabolic syndrome, or CKD [249]. In people with treated hypertension, effective sodium restriction may reduce the number or dose of BP-lowering drugs that are necessary to control BP [250,251].
The effect of reduced dietary sodium on cardiovascular events remains unclear [252–255]. Prospective cohort studies have reported an overall increased risk of mortality and cardiovascular events on high sodium intake. However, they also reported that reducing sodium intake below a certain level (about 3 g of sodium per day) further reduced BP, but paradoxically was associated with an increased risk of all-cause and cardiovascular mortalities in both the general population and in hypertensive people, suggesting a J-curve phenomenon [256]. The mechanism of this apparent increased risk at low sodium intake is not well understood and might be confounded by reverse causality. There is no evidence from epidemiological studies that very low sodium intake may cause harm [257]. Although a few trials and meta-analyses suggest that reducing salt intake from high to moderate is accompanied by a lower risk of cardiovascular events [254,255,258], to date, no prospective RCT has provided definitive evidence about the optimal sodium intake to minimize cardiovascular events and mortality. Increased potassium intake is associated with BP reduction and may have a protective effect, thereby modifying the association between sodium intake, BP and CVD [259].
Globally, usual sodium intake is between 3.5 and 5.5 g/day (which corresponds to 9–12 g of salt per day), with marked differences between countries and even between regions within countries. We recommend sodium intake to be limited to approximately 2.0 g/day (equivalent to approximately 5.0 g salt per day) in the general population and to try to achieve this goal in all hypertensive patients. Effective salt reduction is not easy and there is often poor appreciation of which foods contain high salt levels. Advice should be given to avoid added salt and high-salt foods. A reduction in population salt intake remains a public health priority but requires a combined effort between the food industry, governments, and the public in general, as 80% of salt consumption involves hidden salt in processed foods.
7.4.3 Moderation of alcohol consumption
There is a long-established positive linear association between alcohol consumption, BP, the prevalence of hypertension and CVD risk. Binge drinking can have a strong pressor effect [17]. The Prevention and Treatment of Hypertension Study (PATHS) investigated the effects of alcohol reduction on BP; the intervention group had a modest 1.2/0.7 mmHg lower BP than the control group at the end of the 6-month period [260]. A Mendelian randomization meta-analysis of 56 epidemiological studies suggested that reduction of alcohol consumption, even for light–moderate drinkers, might be beneficial for cardiovascular health [261]. Hypertensive men who drink alcohol should be advised to limit their consumption to 14 and women to 8 units per week (1 unit is equal to 125 ml of wine or 250 ml of beer). Alcohol-free days during the week and avoidance of binge drinking [35] are also advised.
7.4.4 Other dietary changes
Hypertensive patients should be advised to eat a healthy balanced diet containing vegetables, legumes, fresh fruits, low-fat dairy products, whole grains, fish, and unsaturated fatty acids (especially olive oil), and to have a low consumption of red meat and saturated fatty acids [262–264]. The Mediterranean diet includes many of these nutrients and foods, with a moderate consumption of alcohol (mostly wine with meals). A number of studies and meta-analyses [262–265] have shown that the Mediterranean diet is associated with a reduction in cardiovascular events and all-cause mortality. An RCT in high-risk individuals on the Mediterranean diet over 5 years showed a 29% cardiovascular risk reduction compared with a low-fat control diet, and a 39% reduction in stroke [265]. The Mediterranean diet also significantly reduced ambulatory BP, blood glucose, and lipid levels [266]. The diet should be accompanied by other lifestyle changes such as physical exercise and weight loss [35].
With regard to coffee consumption, caffeine has been shown to have an acute pressor effect [267]. Nevertheless, coffee consumption is associated with cardiovascular benefits, as highlighted by a recent systematic review of prospective cohort studies including more than 1 million participants and 36 352 cardiovascular events [267]. Moreover, green or black tea consumption may also have a small but significant BP-lowering effect [268,269].
Regular consumption of sugar-sweetened soft drinks has been associated with overweight, metabolic syndrome, type 2 diabetes, and higher cardiovascular risk. The consumption of these drinks should be discouraged [35].
Thus, adopting a healthy and balanced diet may assist in BP reduction and also reduce cardiovascular risk.
7.4.5 Weight reduction
Excessive weight gain is associated with hypertension, and reducing weight towards an ideal body weight decreases BP [270]. In a meta-analysis, the mean SBP and DBP reductions associated with an average weight loss of 5.1 kg were 4.4 and 3.6 mmHg, respectively [271]. Both overweight and obesity are associated with an increased risk of cardiovascular death and all-cause mortality. Weight reduction is recommended in overweight and obese hypertensive patients for control of metabolic risk factors, but weight stabilization may be a reasonable goal for many. The Prospective Studies Collaboration [272] concluded that mortality was lowest at a BMI of approximately 22.5–25 kg/m2, whereas a more recent meta-analysis concluded that mortality was lowest in subjects with overweight [273,274]. Although the optimal BMI is unclear, maintenance of a healthy body weight (BMI of approximately 20–25 kg/m2 in people <60 years of age; higher in older patients) and waist circumference (<94 cm for men and <80 cm for women) is recommended for nonhypertensive individuals to prevent hypertension, and for hypertensive patients to reduce BP [35]. Weight loss can also improve the efficacy of antihypertensive medications and the cardiovascular risk profile. Weight loss should employ a multidisciplinary approach that includes dietary advice, regular exercise, and motivational counselling [35,275]. Furthermore, short-term results are often not maintained over the long-term. Weight loss can also be promoted by antiobesity drugs and, to a greater degree, bariatric surgery, which appears to decrease cardiovascular risk in severely obese patients. Further details are available in a recent document of the ESH and the European Association for the Study of Obesity [276].
7.4.6 Regular physical activity
Physical activity induces an acute rise in BP, especially SBP, followed by a short-lived decline in BP below baseline. Epidemiological studies suggest that regular aerobic physical activity may be beneficial for both the prevention and treatment of hypertension, and to lower cardiovascular risk and mortality. A meta-analysis of RCTs, which rely on self-reported exercise and are by necessity unblinded, has shown that aerobic endurance training, dynamic resistance training and isometric training reduce resting SBP and DBP by 3.5/2.5, 1.8/3.2 and 10.9/6.2 mmHg, respectively, in general populations [277]. Endurance training, but not other types of training, reduces BP more in hypertensive participants (8.3/5.2 mmHg). Regular physical activity of lower intensity and duration lowers BP less than moderate-intensity or high-intensity training, but is associated with at least a 15% decrease in mortality in cohort studies [278,279]. This evidence suggests that hypertensive patients should be advised to participate in at least 30 min of moderate-intensity dynamic aerobic exercise (walking, jogging, cycling or swimming) on 5–7 days/week. Performance of resistance exercises on 2–3 days/week can also be advised. For additional benefit in healthy adults, a gradual increase in aerobic physical activity to 300 min a week of moderate intensity or 150 min a week of vigorous-intensity aerobic physical activity, or an equivalent combination thereof, is recommended [35]. The impact of isometric exercises on BP and cardiovascular risk is less well established [280].
7.4.7 Smoking cessation
Smoking is a major risk factor for CVD and cancer. Although the rate of smoking is declining in most European countries, especially in men, it is still common in many regions and age groups, and overall the prevalence remains high at 20–35% in Europe [281]. There is also evidence suggesting ill-health effects of passive smoking [282]. Studies using ABPM have shown that both normotensive subjects and untreated hypertensive smokers present higher daily BP values than nonsmokers [283]. No chronic effect of smoking has been reported for office BP [284], which is not lowered by smoking cessation. Smoking is second only to BP in contributing risk to the global burden of disease, and smoking cessation is probably the single most effective lifestyle measure for the prevention of CVD, including stroke, myocardial infarction, and PAD [285,286]. Therefore, the history of tobacco use should be established at each patient visit and hypertensive smokers should be counselled regarding smoking cessation.
Brief advice from a physician has a small but significant effect of 1–3% over and above the unassisted 12-month quit rate [287]. This can be improved by the use of pharmacological measures, with varenicline and combination nicotine replacement therapy being superior to bupropion or single nicotine replacement therapy [288]. In comparison with placebo, nicotine replacement therapy or treatment with buproprion doubles the chance of quitting, while varenicline or combination nicotine replacement therapy triples the chance of quitting. Combining behavioural support with pharmacotherapy increases the chance of success by 70–100% compared with brief advice alone [289].
Lifestyle interventions for patients with hypertension or high-normal BP
7.5 Pharmacological therapy for hypertension
7.5.1 Drugs for the treatment of hypertension
Most patients will require drug therapy in addition to lifestyle measures to achieve optimal BP control. In the previous Guidelines, five major drug classes were recommended for the treatment of hypertension: ACE inhibitors, ARBs, beta-blockers, CCBs, and diuretics (thiazides and thiazide-like diuretics such as chlorthalidone and indapamide), based on: proven ability to reduce BP; evidence from placebo-controlled studies that they reduce cardiovascular events; and evidence of broad equivalence on overall cardiovascular morbidity and mortality, with the conclusion that benefit from their use predominantly derives from BP lowering. These conclusions have since been confirmed by recent meta-analyses [1,2,217,292]. These meta-analyses have reported cause-specific differences on outcomes between some drugs (e.g. less stroke prevention with beta-blockers, and less heart failure prevention with CCBs); however, overall, major cardiovascular outcomes and mortality were similar with treatment based on initial therapy with all five major classes of treatment. These Guidelines thus recommend that the same five major classes of drugs should form the basis of antihypertensive therapy. There are compelling or possible contraindications for each class of drug (Table 20) and preferential use of some drugs for some conditions, as discussed below. There is also evidence that there are differences in the persistence and discontinuation rates of the major drug classes [293,294].
Other classes of drugs have been less widely studied in event-based RCTs or are known to be associated with a higher risk of adverse effects [e.g. alpha-blockers, centrally acting agents, and mineralocorticoid receptor antagonists (MRAs)]. These are useful additions to the antihypertensive armamentarium in patients whose BP cannot be controlled by proven combinations of the aforementioned major drug classes.
7.5.1.1 Blockers of the renin-angiotensin system (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers)
Both ACE inhibitors and ARBs are among the most widely used classes of antihypertensive drugs. They have similar effectiveness [295,296] as each other and other major drug classes on major cardiovascular events and mortality outcomes [2,292]. ARBs are associated with significantly lower treatment discontinuation rates for adverse events than those of all other antihypertensive therapies [297], and similar rates to placebo [294]. ACE inhibitors and ARBs should not be combined for the treatment of hypertension because there is no added benefit on outcomes and an excess of renal adverse events [298,299]. Dual combination of RAS blockers also led to the premature cessation of another trial due to adverse events [291], when a renin inhibitor, aliskiren, was combined with either an ACE inhibitor or an ARB in people with diabetes. This result halted further research into the clinical utility of aliskiren for BP treatment.
Both ACE inhibitors and ARBs reduce albuminuria more than other BP-lowering drugs and are effective at delaying the progression of diabetic and nondiabetic CKD [217]. A recent meta-analysis shows that RAS blockers are the only antihypertensive agents for which evidence is available of a reduced risk of end-stage renal disease [217].
ACE inhibitors and ARBs also appear effective in preventing or regressing HMOD, such as LVH and small artery remodelling, for an equivalent reduction in BP [292]. Both drugs reduce incident AF, which may be related to improved left ventricular function and more effective left ventricular structural regression [292]. ACE inhibitors and ARBs are also indicated postmyocardial infarction and in patients with chronic HFrEF, which are frequent complications of hypertension.
ACE inhibitors are associated with a small increased risk of angioneurotic oedema, especially in people of black African origin and, in such patients, when RAS blockers are used, an ARB may be preferred.
7.5.1.2 Calcium channel blockers
CCBs are widely used for the treatment of hypertension and have similar effectiveness as other major drug classes on BP, major cardiovascular events, and mortality outcomes [2,292]. CCBs have a greater effect on stroke reduction than expected for the BP reduction achieved, but may also be less effective at preventing HFrEF [2,292]. However, in antihypertensive treatment trials, emergent heart failure is the event considered. Though clinically a very relevant event, it is a difficult endpoint to quantify precisely, either because symptoms and signs are relatively nonspecific or because oedema due to CCBs may result in misdiagnosis. Comparison with diuretics may also be difficult because fluid loss may mask signs and symptoms of incipient heart failure rather than preventing it. CCBs have also been compared with other antihypertensive agents in HMOD-based trials, and are reported to be more effective than beta-blockers in slowing the progression of carotid atherosclerosis, and in reducing LVH and proteinuria [17].
CCBs are a heterogeneous class of agents. Most RCTs demonstrating the benefits of CCBs on outcomes have used dihydropyridines (especially amlodipine). A smaller number of RCTs have compared nondihydropyridines (verapamil and diltiazem) with other drugs, and meta-analyses evaluating the two subclasses (vs. other drugs) have not shown substantial differences in effectiveness [292].
7.5.1.3 Thiazide/thiazide-like diuretics (e.g. chlorthalidone and indapamide)
Diuretics have remained the cornerstone of antihypertensive treatment since their introduction in the 1960s. Their effectiveness in preventing all types of cardiovascular morbidities and mortality has been confirmed in RCTs and meta-analyses [300]. Diuretics also appear to be more effective than other drug classes in preventing heart failure [292]. There has been debate about whether thiazide-like diuretics such as chlorthalidone and indapamide should be given preference over classical thiazide diuretics (e.g. hydrochlorothiazide and bendrofluazide), but their superiority on outcomes has never been tested in head-to-head RCTs. Chlorthalidone and indapamide have been used in a number of RCTs showing cardiovascular benefits, and these agents are more potent per milligram than hydrochlorothiazide in lowering BP, with a longer duration of action compared with hydrochlorothiazide and no evidence of a greater incidence of side effects [301]. Lower dose thiazide-like diuretics (typical of modern antihypertensive treatment regimens) also have more evidence from RCTs demonstrating reductions in cardiovascular events and mortality, when compared with lower dose thiazide diuretics [302]. That said, hydrochlorothiazide, alone or in combination with a potassium-sparing agent, has also been used in BP-lowering RCTs, with positive results [303]. A recent meta-analysis of placebo-controlled studies based on thiazides, chlorthalidone and indapamide reported similar effects on cardiovascular outcomes of the three types of diuretics [300]. Therefore, in the absence of evidence from direct comparator trials and recognizing that many of the approved single-pill combinations (SPCs) are based on hydrochlorothiazide (see below), we recommend that thiazides, chlorthalidone, and indapamide can all be considered suitable antihypertensive agents. Both thiazide and thiazide-like diuretics can reduce serum potassium and have a side effect profile that is less favourable than RAS blockers, which may account for their association with a higher rate of treatment discontinuation [293,300]. They also exhibit dysmetabolic effects that increase insulin resistance and the risk of new-onset diabetes. Potassium may attenuate these effects [304], and a recent study has shown that the adverse effect of thiazides on glucose metabolism may be reduced by the addition of a potassium-sparing diuretic [305]. Both thiazides and thiazide-like agents are less effective antihypertensive agents in patients with a reduced GFR (eGFR <45 ml/min) and become ineffective when the eGFR is less than 30 ml/min. In such circumstances, loop diuretics such as furosemide (or torasemide) should replace thiazides and thiazide-like diuretics to achieve an antihypertensive effect.
7.5.1.4 Beta-blockers
RCTs and meta-analyses demonstrate that when compared with placebo, beta-blockers significantly reduce the risk of stroke, heart failure, and major cardiovascular events in hypertensive patients [300]. When compared with other BP-lowering drugs, beta-blockers are usually equivalent in preventing major cardiovascular events, except for less effective prevention of stroke, which has been a consistent finding [1,2,217]. It is possible that the difference originated from small differences in achieved BP (including central SBP [108] between different drug treatments), to which cerebrovascular events may be especially sensitive. RCTs based on HMOD have also indicated that beta-blockers are somewhat less effective than RAS blockers and CCBs in preventing or regressing LVH, carotid IMT, aortic stiffness, and small artery remodelling [17]. In addition, a mortality benefit in postmyocardial infarction is uncertain in patients without left ventricular dysfunction [306]. Beta-blockers, as well as diuretics, and particularly their combination, are also associated with increased risk of new-onset diabetes in predisposed subjects (mostly those with the metabolic syndrome). They also exhibit a somewhat less favourable side effect profile than that of RAS blockers, with a higher rate of treatment discontinuation when assessed in real-life conditions [293].
Beta-blockers have been shown to be particularly useful for the treatment of hypertension in specific situations such as symptomatic angina, for heart rate control, postmyocardial infarction, HFrEF, and as an alternative to ACE inhibitors or ARBs in younger hypertensive women planning pregnancy or of child-bearing potential.
Finally, beta-blockers are not a homogeneous class. In recent years, the use of vasodilating beta-blockers – such as labetalol, nebivolol, celiprolol, and carvedilol – has increased. Studies on nebivolol have shown that it has more favourable effects on central BP, aortic stiffness, endothelial dysfunction, and so on. It has no adverse effect on the risk of new-onset diabetes and a more favourable side effect profile than classical beta-blockers [307,308], including less adverse effects on sexual function. Bisoprolol, carvedilol and nebivolol have been shown to improve outcomes in RCTs in heart failure [136]; however, there are no RCTs reporting patient outcomes with these beta-blockers in hypertensive patients.
7.5.1.5 Other antihypertensive drugs
Centrally active drugs were widely used in the earliest decades of antihypertensive treatment when other treatments were not available, but are less frequently used now, principally because of their poorer tolerability relative to the newer major classes of drugs. The alpha-blocker doxazosin was effective in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) as third-line therapy (with no increase in the risk of heart failure) [309], and was more effective than placebo but less effective than spironolactone at lowering BP in resistant hypertension in the Prevention And Treatment of Hypertension With Algorithm-based therapY-2 (PATHWAY-2) study [310]. Alpha-blockers may also be required in specific indications (e.g. the treatment of symptomatic prostatic hypertrophy). Antihypertensive drugs, other than the major classes already discussed above, are no longer recommended for the routine treatment of hypertension, and are primarily reserved for add-on therapy in rare cases of drug-resistant hypertension where all other treatment options have failed.
7.5.2 Drug treatment strategy for hypertension
Guidelines have generated a variety of different strategies to initiate and escalate BP-lowering medication to improve BP control rates. In previous Guidelines, the emphasis was on initial use of different monotherapies, increasing their dose, or substituting for another monotherapy. However, increasing the dose of monotherapy produces little additional BP lowering and may increase the risk of adverse effects, while switching from one monotherapy to another is frustrating, time consuming, and often ineffective. For these reasons, more recent Guidelines have increasingly focused on the stepped-care approach, initiating treatment with different monotherapies and then sequentially adding other drugs until BP control is achieved. Despite this, BP control rates have remained poor worldwide. As shown by recent observations, irrespective of the world region, whether high-income or low-income economies, or the level of sophistication of healthcare provision, only 40% of patients with hypertension are treated; of these, only 35% are controlled to a BP of less than 140/90 mmHg [12]. This failure to achieve BP control in most hypertensive patients, despite numerous iterations of previous Guidelines, suggests that these treatment strategies are not working and that a different approach is needed. This Task Force believes that one of the most important issues to address in these Guidelines is ‘how do we improve BP control in treated patients?’. This has become an even more pressing matter because, based on new evidence, current Guidelines are recommending more stringent BP targets (on-treatment values of ≤130/80 mmHg in the general population and ≤140/90 mmHg in older hypertensive people), which will make the achievement of BP control even more challenging.
Several reasons need to be considered to identify why the current treatment strategy has failed to achieve better BP control rates:
- Efficacy of pharmacological therapies. Are the best available treatments, in whatever combination, incapable of controlling BP in most patients? The evidence from RCTs demonstrating that BP control can be achieved in most recruited patients, and that no more than 5–10% of these patients exhibit resistance to the selected treatment regimen, suggests that ineffective drug therapy is not the source of the problem.
- Physician or treatment inertia. (i.e. failure to adequately uptitrate treatment). Evidence suggests that inertia [311] contributes to suboptimal BP control, with many patients remaining on monotherapy and/or suboptimal doses, despite inadequate BP control [12].
- Patient adherence to treatment. Evidence is accumulating that adherence is a much more important factor than previously recognized. Studies using urine or blood assays for the presence or absence of medication have shown that adherence to treatment is low. This is supported by studies in the general population in which adherence to treatment, based on prescription refilling, was <50% of the treatment in half of the patients [312]. Poor adherence has also been shown to be associated with increased cardiovascular risk in various studies [313] (see Section 10).
- Insufficient use of combination treatment. BP is a multiregulated variable depending on many compensating pathways. Consequently, combinations of drugs, working through different mechanisms, are required to reduce BP in most people with hypertension. Thus, monotherapy is likely to be inadequate therapy in most patients. Indeed, almost all patients in RCTs have required combinations of drugs to control their BP [314].
- Complexity of current treatment strategies. There is also evidence that adherence to treatment is adversely affected by the complexity of the prescribed treatment regimen. In a recent study, adherence to treatment was strongly influenced by the number of pills that a patient was prescribed for the treatment of hypertension [315]. Nonadherence was usually less than 10% with a single pill, rising to 20% with two pills, 40% with three pills, and very high rates of partial or complete nonadherence in patients receiving five or more pills [315].
The above considerations suggest that the most effective evidence-based treatment strategy to improve BP control is one that: encourages the use of combination treatment in most patients, especially in the context of lower BP targets; enables the use of SPC therapy for most patients, to improve adherence to treatment; and follows a treatment algorithm that is simple, applies to all patients, and is pragmatic, with the use of SPC therapy as initial therapy for most patients, except those with BP in the high–normal range and in frail older patients (see below).
7.5.2.1 Drug combinations for hypertension treatment
Among the large number of RCTs of antihypertensive therapy, only a few have directly compared different two-drug combinations, with systematic use of the two combinations in both arms. In other trials, treatment was initiated using monotherapy in either arm and another drug (and sometimes more than one drug) was added, usually in a nonrandomized fashion, according to a prespecified treatment algorithm. In a few trials, the design precluded the use of what might be considered optimal combinations because multiple monotherapies were being evaluated [e.g. the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), where the add-on therapy to either a diuretic, CCB, ACE inhibitor, or alpha-blocker was a beta-blocker, clonidine, or reserpine] [316].
With this caveat, Table 21 shows that a variety of drug combinations have been used in at least one active arm of placebo-controlled trials and have been associated with significant benefit on major cardiovascular events. In trials comparing different regimens (Table 22), all combinations have been used in a larger or smaller proportion of patients, without major differences in benefits. The only exceptions are two trials in which a large proportion of the patients received either an ARB–diuretic combination [317] or CCB–ACE inhibitor combination [318], with both regimens being superior to a beta-blocker–diuretic combination in reducing cardiovascular outcomes. However, in six other trials (with seven comparisons), beta-blockers followed by diuretics or diuretics followed by beta-blockers were not associated with a significantly different risk of any cardiovascular outcome [233,234,316,319–321], and the beta-blocker diuretic combination was significantly more effective than placebo in three trials [322–324]. It should be mentioned that the beta-blocker–diuretic combination may result in more cases of new-onset diabetes in susceptible individuals compared with other combinations [325]. A rarely used combination of thiazide and potassium-sparing diuretic (amiloride) has also been shown to be equivalent to CCB-based treatment [310,326], and was recently reported to be associated with fewer metabolic adverse effects compared with thiazide alone (less hypokalaemia and glucose intolerance) [305].
Three outcome trials directly compared two different combinations, each involving a combination of a RAS blocker (ACE inhibitor or ARB) and a CCB with other combinations. In the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial, the ACE inhibitor–CCB combination was superior to the same ACE inhibitor in combination with a thiazide diuretic at preventing major cardiovascular outcomes, despite no apparent BP difference between the two arms [327]. This finding was not confirmed in the Combination of OLMesartan and a CCB or diuretic in Japanese older hypertensive patients (COLM)[328] and Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trials [329], which reported no significant differences in cardiovascular events when a RAS blocker-CCB combination was compared with a RAS blocker–thiazide diuretic combination, but both of these trials had insufficient statistical power.
Based on the results of outcome RCTs and recent meta-analyses, and evidence of BP-lowering effectiveness, all five major drug classes can, in principle, be combined with one another, except for ACE inhibitors and ARBs, whose concomitant use may lead to no additional benefit but increased adverse effects and is thus discouraged. We recommend that the treatment of hypertension should be preferentially based on combinations of an ACE inhibitor or ARB with a CCB and/or a thiazide/thiazide-like diuretic. These combinations are now widely available in a single pill and in a range of doses, facilitating simplification of treatment, flexible prescribing, and uptitration from lower to higher doses. Combination therapy that includes an ACE inhibitor or ARB with either a CCB or thiazide/thiazide-like diuretic are complementary because both CCBs or diuretics activate the RAS, which will be counteracted by their combination with an ACE inhibitor or ARB. These combinations will also limit potential adverse effects associated with diuretic or CCB monotherapy, reducing the risk of hypokalaemia due to diuretics and reducing the prevalence of peripheral oedema due to CCBs. These combinations also ensure that the RAS is inhibited as part of the treatment strategy, which is an important consideration for many patient groups (e.g. diabetes, LVH, proteinuria).
Other combinations, such as CCB + diuretic, also have evidence from RCTs supporting their use [233,329]. These are much less widely available as SPCs and do not include blockade of the RAS, which may be desirable in many patient groups.
Beta-blockers in combination should be preferentially used when there is a specific clinical indication for their use (e.g. in patients with symptomatic angina, for patients requiring heart rate control, postmyocardial infarction, chronic HFrEF, and as an alternative to ACE inhibitors or ARBs in younger hypertensive women planning pregnancy or of child-bearing potential). SPCs of beta-blockers with an ACE inhibitor, CCB, or diuretic are available.
7.5.2.2 Rationale for initial two-drug combination therapy for most patients
As discussed above and with the emphasis in these Guidelines on achieving a BP target in most patients of less than 130/80 mmHg, the majority of patients will require combination therapy. Initial combination therapy is invariably more effective at BP lowering than monotherapy, indeed even low-dose combination therapy is usually more effective than maximal dose monotherapy [341]. Furthermore, the combination of medications targeting multiple mechanisms, such as blocking the RAS as well as inducing vasodilatation and/or diuresis, reduces the heterogeneity of the BP response to initial treatment and provides a steeper dose response than is observed with escalating doses of monotherapy [342]. Finally, two-drug combinations as initial therapy have been shown to be safe and well tolerated, with no or only a small increase in the risk of hypotensive episodes [341], even when given to patients with grade 1 hypertension [343], in which adverse events leading to treatment discontinuation are infrequent [294].
Although no RCT has compared major cardiovascular outcomes between initial combination therapy and monotherapy, observational evidence suggests that the time taken to achieve BP control is an important determinant of clinical outcomes, especially in higher risk patients, with a shorter time to control associated with lower risk [344]. Furthermore, there is evidence from the more general hypertensive population that, compared with patients on initial monotherapy, those who start treatment with a two-drug combination exhibit more frequent BP control after 1 year [341,345]. This is probably because initial combination treatment is associated with a better long-term adherence to the prescribed treatment regimen [346] and because initial two-drug administration prevents therapeutic inertia (i.e. reluctance or failure to upgrade treatment from one to more drugs when BP is uncontrolled) [347]. Studies from very large hypertension cohorts in usual care have shown that initial combination treatment results in reduced treatment discontinuation and a lower risk of cardiovascular events than initial monotherapy followed by the traditional stepped-care approach [312,346]. The usual-care settings for these studies may be especially relevant to study the true impact of treatment strategies on adherence and therapeutic inertia, because this can be difficult to replicate in a conventional RCT in which the motivation of the clinical staff and patients, and the monitoring of treatment, are very different from usual care. In this regard, the outcome of these real-life studies of the impact of initial combination therapy on adherence, BP control, and cardiovascular outcomes may be especially relevant [348].
A consideration in the current Guidelines was to persist with the current stepped-care approach to BP treatment, which has been interpreted as recommending monotherapy as initial therapy for most patients, reflecting current practice. In fact, the previous Guidelines did acknowledge the possibility of initial combination therapy for patients with grade 2 or 3 hypertension, or patients at high or very high risk. In other words, initial monotherapy was only recommended for grade 1 hypertension and low-risk or moderate-risk patients. Thus, in reality, the shift in emphasis in this new guidance is subtle. However, normalizing the concept of initiating therapy with a two-drug combination for most patients with hypertension is likely to have a major effect on clinical practice and the speed and quality of BP control. We acknowledge that some low-risk or moderate-risk patients with grade 1 hypertension may achieve their BP target with monotherapy, but this is unlikely in patients with an initial SBP more than 150 mmHg who would require a BP reduction of at least 20 mmHg. Moreover, the possibility of starting with a low-dose combination of two antihypertensive drugs, even in grade 1 hypertensive patients with low–moderate-risk, is supported by the reduction of cardiovascular events obtained by combination therapy in the upper tertile (grade 1 hypertension) in the HOPE-3 trial [212]. In patients with high–normal BP and a high cardiovascular risk or in frail older patients, treatment initiation with monotherapy may be appropriate in the former because only a small BP reduction may be required to achieve the BP target, and in the latter because in older patients baroreflex sensitivity is frequently impaired and the risk of hypotension is greater.
7.5.2.3 Uptitration of treatment to three-drug combination therapy
Studies suggest that two-drug combination therapy will control BP in approximately two-thirds of patients [341]. For patients whose BP is not controlled by two-drug combination therapy, the logical option is to increase treatment to three-drug combination therapy: usually a RAS blocker, a CCB, and a diuretic. Studies suggest that a three-drug combination should control BP in more than 80% of patients [349,350]. This rate of BP control is much greater than the current rate of BP control across Europe in treated hypertensive patients. We do not recommend three-drug combinations as initial therapy.
7.5.2.4 Rationale for single-pill combination therapy as usual therapy for hypertension
The 2013 ESH/ESC Guidelines [17] favoured the use of combinations of two antihypertensive drugs in a single pill, because reducing the number of pills to be taken daily improves adherence and increases the rate of BP control [346,351]. This recommendation is endorsed by the current Guidelines. It is further supported by data from recent studies using various methods to assess adherence to treatment, including the quantification of antihypertensive drugs in urine and blood [352,353], and estimates such as pill counting or prescription refills, which, although indirect, allow the measurement of adherence on a prolonged basis, thereby accounting for its time-variable nature [347,354]. These studies have unequivocally shown a direct inverse relationship between the number of pills and the likelihood of adherence. This approach is now facilitated by the availability of several SPCs with a range of dosages, which eliminates the often-stated disadvantage of SPC therapy (i.e. the inability to increase the dose of one drug independently of the other). It is also convenient that the most widely available SPCs mirror the major drug class combinations recommended by these Guidelines. The major advantage of an SPC as the usual therapeutic approach for hypertension is that patients can progress from 1, 2, or 3 drug treatments while remaining on a simple treatment regimen with a single pill throughout, increasing the likelihood of adherence to therapy and achieving BP control. Such an approach has the potential to double BP control rates in treated patients from the present low level of 40%. Although, at present, the availability of two-drug SPCs is largely limited to a RAS blocker with either a CCB or diuretic, it would be desirable to see the development of an expanded range of low-cost SPCs in different drug formulations, tailored to different clinical requirements.
Polypills have also emerged as SPCs (i.e. a fixed-dose combination of one or more antihypertensive agents with a statin and low-dose aspirin), with the rationale that hypertensive patients are often at sufficient cardiovascular risk to benefit from statin therapy. Studies of bioequivalence suggest that when combined in the polypill, different agents maintain all or most of their expected effect [355]. Furthermore, studies performed in the setting of secondary prevention, particularly in patients with a previous myocardial infarction, have shown that use of the polypill is accompanied by a better adherence to treatment compared with separate medications [356]. The ESC Guidelines for the management of myocardial infarction have recommended polypill use to improve long-term adherence to prescribed therapy (class IIa, level B) [353]. No data are available for primary prevention in patients with hypertension. Nevertheless, the advantage of treatment simplification and adherence suggests that use of the polypill may be considered in patients with hypertension as substitution therapy, when the need and effectiveness of each polypill component has been previously established by their administration in separate tablets [355].
7.5.2.5 Further uptitration of antihypertensive therapy
When BP remains uncontrolled with three-drug combination therapy, the patient is classified as having resistant hypertension, assuming that secondary causes of hypertension and poor adherence to treatment have been excluded, and that the elevation in BP has been confirmed by repeated office BP measurement, ABPM, or HBPM (see Section 8.1). Such patients should be considered for specialist evaluation. Additional treatment options include the addition of low-dose spironolactone (25–50 mg daily)[310] or another additional diuretic therapy [higher-dose amiloride 10–20 mg daily [357], higher dose thiazide or thiazide-like diuretics, loop diuretics in patients with significant renal impairment (eGFR <45 ml/min/m2), beta-blockers, alpha-blockers, centrally acting agents (e.g. clonidine), or, rarely, minoxidil] (see Section 8.1).
7.5.3 The drug treatment algorithm for hypertension
Reflecting on the evidence above, and recognizing the urgent need to address the factors contributing to the poor control of BP in treated hypertensive patients (see Section 7.5.1), this drug treatment algorithm has been developed to provide a simple and pragmatic treatment recommendation for the treatment of hypertension, based on a few key recommendations:
- The initiation of treatment in most patients with an SPC comprising two drugs, to improve the speed, efficiency, and predictability of BP control.
- Preferred two-drug combinations are a RAS blocker with a CCB or a diuretic. A beta-blocker in combination with a diuretic or any drug from the other major classes is an alternative when there is a specific indication for a beta-blocker, for example angina, postmyocardial infarction, heart failure, or heart rate control.
- Use monotherapy for low-risk patients with stage 1 hypertension whose SBP is <150 mmHg, very high-risk patients with high–normal BP, or frail older patients.
- The use of a three-drug SPC comprising a RAS blocker, a CCB, and a diuretic if BP is not controlled by a two-drug SPC.
- The addition of spironolactone for the treatment of resistant hypertension, unless contraindicated (see Section 8.1.4).
- The use of other classes of antihypertensive drugs in the rare circumstances in which BP is not controlled by the above treatments.
- Information on availability and recommended doses of individual drugs, as well as SPCs and free combinations, can be found in national formularies.
This treatment algorithm focuses on the five major classes of drugs: ACE inhibitors, ARBs, CCBs, thiazide or thiazide-like diuretics, and beta-blockers. The algorithm recommends initial therapy for most patients with a two drug-combination, ideally as an SPC. Variations from the core drug treatment algorithm for uncomplicated hypertension shown in Figure 4 are specified in Figures 5–8. Recommended BP target ranges for treated hypertension are shown in Table 23.
The drug treatment strategy for patients with hypertension should be based on the algorithm shown (Figures 4–8), unless there are contraindications to these drugs (Table 20), or concomitant conditions or diseases are present that require specific modification of the drugs, as outlined in the recommendations below.
Drug treatment strategy for hypertension
7.6 Device-based hypertension treatment
Various device-based therapies have emerged, principally targeted at the treatment of resistant hypertension. These are discussed below.
7.6.1 Carotid baroreceptor stimulation (pacemaker and stent)
Carotid baroreceptor stimulation or baroreflex amplification therapy – externally via an implantable pulse generator or internally via an implantable device designed to increase the strain on the carotid bulb – can lower BP in patients with resistant hypertension. An RCT with the first generation of an implantable pulse generator showed sustained BP-lowering efficacy (and sympathetic nervous system inhibition), but with some concerns about procedural and longer-term safety [358]. A second-generation unilateral device has been developed to improve safety and sustained efficacy. A propensity score-matched comparison of the first-generation and second-generation systems revealed that BP at 12 months post-implantation was similar, with a better safety profile for the second-generation device [359]. However, no RCT is currently available with this second-generation device. Another consideration is that implantation is costly and requires a complex surgical intervention. This has led to the development of an endovascular carotid baroreflex amplification device using a dedicated stent-like device designed to stretch the carotid bulb and increase baroreflex stimulation. Preliminary data in humans have shown evidence of BP-lowering efficacy of this new approach [360], but data from ongoing RCTs are needed to definitively understand its longer-term efficacy and safety.
7.6.2 Renal denervation
The rationale for renal denervation lays with the importance of sympathetic nervous system influences on renal vascular resistance, renin release and sodium reabsorption [361], the increased sympathetic tone to the kidney and other organs in hypertensive patients [361], and the pressor effect of renal afferent fibres documented in experimental animals [362]. Catheter-based renal denervation using radiofrequency, ultrasound, or perivascular injection of neurotoxic agents such as alcohol has been introduced as a minimally invasive treatment option for patients with resistant hypertension [363]. However, the clinical evidence in support of renal denervation as an effective BP-lowering technique is conflicting. Several observational studies and national and international registries [364] support the BP-lowering efficacy of renal denervation originally reported in the Symplicity HTN-1 and HTN-2 trials [365]. A reduction in sympathetic activity following renal denervation has also been observed [366]. However, two RCTs with a sham procedure control [367,368] failed to document the superiority of renal denervation compared with the sham procedure in reducing BP, but did confirm the safety of the procedure. Another RCT, the Renal Denervation for Hypertension (DENERHTN) trial [369], showed the superiority of renal denervation in combination with optimized pharmacotherapy compared with pharmacotherapy alone. The PRAGUE-15 study [370] documented similar effects between renal denervation and optimized pharmacotherapy (mainly by adding spironolactone) with respect to BP-lowering efficacy; however, the latter was associated with more side effects and high discontinuation rates. Beyond resistant hypertension, interim data in the first 80 patients treated with renal denervation but with no background antihypertensive therapy showed a modest effect of renal denervation vs. sham control on 24 h ambulatory BP after 3 months [366]. This study is ongoing.
Evaluating the efficacy of renal denervation has been challenging because the procedure needs to be applied to a population with a high probability of BP response. This is complicated by the complex pathophysiology of hypertension, the lack of clinically applicable measures of sympathetic activity, the absence of predictors of the long-term BP response following renal denervation, and the absence of reliable markers of procedural success to immediately establish whether denervation has been achieved [371]. There is evidence indicating that isolated systolic hypertension, characterized by increased aortic stiffness, is associated with a limited response to renal denervation [372,373] and baroreceptor stimulation (see above). Except for rare problems related to the catheterization procedure (access site complications, vessel dissection, etc.), no major complications or deterioration of renal function have been reported.
Major uncertainties remain as to the clinical role of renal denervation outside of clinical studies, which should be performed in carefully selected patients at specialist hypertension centres and by experienced operators.
7.6.3 Creation of an arteriovenous fistula
The central iliac arteriovenous anastomosis creates a fixed-calibre (4 mm) conduit between the external iliac artery and vein using a stent-like nitinol device (ROX arteriovenous coupler) [374,375]. Device deployment can be verified and is reversible, resulting in the diversion of arterial blood (0.8–1 l/min) into the venous circuit with immediate, verifiable reductions in BP [374,375]. The BP-lowering effect of arteriovenous anastomosis was first observed in a study of patients with chronic obstructive pulmonary disease (COPD), in whom a moderate improvement in the 6 min walking test was shown [376]. In the ROX CONTROL HTN trial, patients with resistant hypertension were randomized to receive either standard care or insertion of an arteriovenous coupler in combination with standard care [377]. At 6 months, office and ambulatory BP were significantly reduced in the coupler group compared with the control group. Some important safety aspects need to be considered. Ipsilateral venous stenosis, which needed venoplasty and/or stenting, occurred in 29% of patients. There were no reports of right heart failure or high-output cardiac failure after device implantation over the short-term, but longer follow-up is clearly needed [377,378].
7.6.4 Other devices
The carotid body is located at the bifurcation of the common carotid. It is innervated by nerve fibres from the vagus nerve through the cervical ganglion and the carotid sinus nerve [379]. Stimulation of the carotid body drives sympathetic tone, resulting in an increase in BP and minute ventilation. Surgical resection of the carotid body is associated with reductions in BP [380] and sympathetic overactivity in patients with heart failure [381]. Devices for endovascular carotid body modification by ultrasound-guided ablation have been developed and are currently under investigation.
In summary, device-based therapy for hypertension is a fast-moving field. Further sham-controlled studies are needed before device-based therapies can be recommended for the routine treatment of hypertension outside of the framework of clinical trials.
Device-based therapies for hypertension
8 HYPERTENSION IN SPECIFIC CIRCUMSTANCES
8.1 Resistant hypertension
8.1.1 Definition of resistant hypertension
Hypertension is defined as resistant to treatment when the recommended treatment strategy fails to lower office SBP and DBP values to less than 140 mmHg and/or less than 90 mmHg, respectively, and the inadequate control of BP is confirmed by ABPM or HBPM in patients whose adherence to therapy has been confirmed. The recommended treatment strategy should include appropriate lifestyle measures and treatment with optimal or best-tolerated doses of three or more drugs, which should include a diuretic, typically an ACE inhibitor or an ARB, and a CCB. Pseudo-resistant hypertension (see below) and secondary causes of hypertension should also have been excluded (see Section 8.2).
Prevalence studies of resistant hypertension have been limited by variation in the definition used, and reported prevalence rates range from 5 to 30% in patients with treated hypertension. After applying a strict definition (see above) and having excluded causes of pseudo-resistant hypertension (see Section 8.1.2), the true prevalence of resistant hypertension is likely to be less than 10% of treated patients. Patients with resistant hypertension are at higher risk of HMOD, CKD and premature cardiovascular events [382].
8.1.2 Pseudo-resistant hypertension
Several possible causes of pseudo-resistant hypertension should be evaluated and ruled out before concluding that the patient has resistant hypertension:
- Poor adherence to prescribed medicines is a frequent cause of pseudo-resistant hypertension, occurring in at least 50% of patients assessed by therapeutic drug monitoring, and is directly related to the number of tablets prescribed [315] (see Section 10).
- White-coat phenomenon (in which office BP is elevated but BP is controlled at ABPM or HBPM) is not uncommon in these patients, hence the recommendation to confirm office hypertension with ABPM or HBPM before confirming the diagnosis of resistant hypertension.
- Poor office BP measurement technique, including the use of cuffs that are too small relative to the arm circumference, can result in a spurious elevation of BP.
- Marked brachial artery calcification, especially in older patients with heavily calcified arteries.
- Clinician inertia, resulting in inadequate doses or irrational combinations of BP-lowering drug therapies.
Other causes of resistant hypertension
- Lifestyle factors, such as obesity or large gains in weight, excessive alcohol consumption, and high sodium intake.
- Intake of vasopressor or sodium-retaining substances, drugs prescribed for conditions other than hypertension, some herbal remedies, or recreational drug use (cocaine, anabolic steroids, etc.) (see Table 24).
- Obstructive sleep apnoea (usually, but not invariably, associated with obesity).
- Undetected secondary forms of hypertension (see Section 8.2).
- Advanced HMOD, particularly CKD or large-artery stiffening.
Resistant hypertension is associated with older age (especially >75 years), male sex, black African origin, higher initial BP at diagnosis of hypertension, highest BP ever reached during the patient's lifetime, frequent outpatient visits, obesity, diabetes, atherosclerotic disease and HMOD, CKD, and a Framingham 10=year coronary risk score more than 20% [383,384].
8.1.3 Diagnostic approach to resistant hypertension
Diagnosis of resistant hypertension requires detailed information about:
- The patient's history, including lifestyle characteristics, alcohol and dietary sodium intake, interfering drugs or substances, and sleep history.
- The nature and dosing of the antihypertensive treatment.
- A physical examination, with a particular focus on determining the presence of HMOD and signs of secondary hypertension.
- Confirmation of treatment resistance by out-of-office BP measurements (i.e. ABPM or HBPM).
- Laboratory tests to detect electrolyte abnormalities (hypokalaemia), associated risk factors (diabetes), organ damage (advanced renal dysfunction), and secondary hypertension.
- Confirmation of adherence to BP-lowering therapy.
Patients should be screened for a secondary cause of hypertension, especially primary aldosteronism [386] or atherosclerotic renal artery stenosis, particularly in older patients or patients with CKD. Poor adherence to treatment should be considered, but its identification may be challenging in routine clinical practice [387]. Some methods are easy to use but of limited value (e.g. standardized questionnaires), whereas others, such as drug screening of urine or blood, show considerable promise but are not yet widely available [388]. Other methods include the measurement of BP after directly observed treatment intake [389], which has been used in clinical trials [390] but may be more difficult to implement in routine clinical practice.
8.1.4 Treatment of resistant hypertension
Effective treatment combines lifestyle changes (especially the reduction of sodium intake), discontinuation of interfering substances, and the sequential addition of antihypertensive drugs to the initial triple therapy. Ultimately, replacing all current drugs by a simpler treatment regimen using SPC treatment is recommended to reduce pill burden and improve adherence to treatment. The optimal drug treatment of resistant hypertension has been poorly studied. The most effective strategy seems to be additional diuretic treatment to decrease volume overload, together with the restriction of salt intake, particularly in patients with CKD. BP control may be improved by increasing the dose of the existing diuretic or by switching to a more potent thiazide-like diuretic (chlorthalidone or indapamide). A loop diuretic should replace thiazides/thiazide-like diuretics if the eGFR is less than 30 ml/min. Although resistant hypertension may show a BP reduction if the existing diuretic dose is further increased, most patients require the administration of additional drugs. There is growing evidence to suggest that the fourth-line treatment should involve a blockade of the biological effects of aldosterone through the use of MRAs [391] (spironolactone up to 50 mg/day), as shown in the PATHWAY 2 study [357] and supported by other studies and their meta-analysis [392–394]. Not all patients will be able to tolerate spironolactone due to antiandrogenic side effects resulting in breast tenderness or gynaecomastia (in 6%), impotence in men, and menstrual irregularities in women. Moreover, the efficacy and safety of spironolactone for the treatment of resistant hypertension has not yet been established in patients with significant renal impairment. As such, the use of spironolactone for resistant hypertension should usually be restricted to patients with an eGFR at least 45 ml/min and a plasma potassium concentration of ≤4.5 mmol/l. Moreover, electrolytes and eGFR should be monitored soon after initiation and at least annually thereafter. On theoretical grounds, alternative additional diuretic therapy to spironolactone (when it is not tolerated due to androgen-like side effects) could include the MRA eplerenone (50–100 mg/day). Amiloride (10–20 mg/day) has recently been shown to be as effective as spironolactone 25–50 mg daily) in reducing BP in the PATHWAY2 study [357]. It is emphasized that the same cautions about the use of these agents should be considered in patients with reduced eGFR and baseline potassium levels more than 4.5 mmol/l. The PATHWAY-2 study also evaluated bisoprolol (5–10 mg/day) or doxazosin modified release (4–8 mg/day) as alternatives to spironolactone. Neither was as effective as spironolactone, but they did reduce BP significantly vs. placebo when added to background treatment in resistant hypertension [310]. Thus, bisoprolol and doxazosin have an evidence base for the treatment of resistant hypertension when spironolactone is contraindicated or not tolerated. Direct vasodilators, such as hydralazine or minoxidil, are infrequently used because they may cause severe fluid retention and tachycardia.
New BP-lowering drugs (nitric oxide donors, vasopressin antagonists, aldosterone synthase inhibitors, neutral endopeptidase inhibitors, and endothelin antagonists) are all under investigation [388].
Resistant hypertension
8.2 Secondary hypertension
Secondary hypertension is hypertension due to an identifiable cause, which may be treatable with an intervention specific to the cause. A high index of suspicion and early detection of secondary causes of hypertension are important because interventions may be curative, especially in younger patients [e.g. corrective surgery for aortic coarctation, renal angioplasty in younger patients with renal artery fibromuscular dysplasia, reversal of an endocrine cause of hypertension (e.g. by removal of an adrenal adenoma), or drug treatment of a monogenic disorder affecting a specific drug-sensitive ion channel (e.g. selective use of amiloride in Liddle's syndrome)]. Interventions that treat the cause of secondary hypertension later in life are less likely to be curative (i.e. remove the need for antihypertensive medication) because longstanding hypertension results in vascular and other organ damage that sustains the elevated BP, but intervention is still important because it will often result in much better BP control with less medication.
The prevalence of secondary hypertension is reported to be 5–15% [396] of people with hypertension. Screening all hypertensive patients for secondary hypertension is not feasible or cost-effective; however, there are some general patient characteristics that suggest those more likely to have secondary hypertension and in whom screening should be considered after confirming that BP is elevated with ABPM (Table 25).
It is beyond the scope of these Guidelines to describe the detailed clinical management of specific causes of secondary hypertension. However, the commoner causes of secondary hypertension, clinical history, and screening tests are described in Table 26, and the typical age distribution of these causes of secondary hypertension is shown in Table 27. Review of these tables demonstrates that most screening can be undertaken with blood and urine tests, abdominal ultrasound, and echocardiography. Referral to a specialist centre is recommended for additional investigations to confirm a suspected diagnosis of secondary hypertension and for clinical management. Other causes of secondary hypertension due to drugs and substances, and rarer monogenic causes, are described below and are summarized in Tables 28 and 29.
8.2.1 Drugs and other substances that may cause secondary hypertension
Medications and other substances may cause a sufficient increase in BP to raise the suspicion of secondary hypertension [397] (Table 28). Consequently, a careful drug history is important when considering a diagnosis of secondary hypertension. Moreover, other commonly used drugs such as nonsteroidal anti-inflammatory drugs or glucocorticoids can antagonize the BP-lowering effect of antihypertensive medications in patients treated for hypertension and may contribute to a loss of BP control.
8.2.2 Genetic causes of secondary hypertension
Genetic causes of secondary hypertension are usually due to single-gene disorders (see Section 6) [194,195]. They are rare but important causes of secondary hypertension because identifying the cause can point to a specific drug treatment (Table 29) [194,195]. Common features of these genetic disorders are that they usually present with hypertension in children, adolescents, or young adults, and most monogenic disorders induce hypertension by increasing the renal tubular reabsorption of sodium. Thus, they are usually associated with a suppressed plasma renin concentration (PRC) or plasma renin activity (PRA), which is unusual in younger patients and especially those treated with antihypertensive medications (e.g. RAS blockers, CCBs, or diuretics), that would be expected to increase PRC or PRA. Thus, the finding of a suppressed PRC or PRA, especially while taking these drugs, should raise the suspicion of secondary hypertension due a salt-retaining state. Importantly, beta-blockers in particular, but also nonsteroidal anti-inflammatory drugs, alpha-methyl dopa, or clonidine, suppress PRC and PRA. These drugs should be discontinued (if clinically feasible) for at least 2 weeks before measuring PRC or PRA.
8.3 Hypertension urgencies and emergencies
Hypertension emergencies are situations in which severe hypertension (grade 3) is associated with acute HMOD, which is often life-threatening and requires immediate but careful intervention to lower BP, usually with intravenous (i.v.) therapy [398]. The rate and magnitude of an increase in BP may be at least as important as the absolute level of BP in determining the magnitude of organ injury [399]. Typical presentations of a hypertension emergency are:
- Patients with malignant hypertension, characterized by severe hypertension (usually grade 3) associated with funduscopic changes (flame haemorrhages and/or papilloedema), microangiopathy, and disseminated intravascular coagulation, and can be associated with encephalopathy (in about 15% of cases) [400], acute heart failure, and acute deterioration in renal function. The hallmark of this condition is small artery fibrinoid necrosis in the kidney, retina, and brain. The term ‘malignant’ reflects the very poor prognosis for this condition if untreated [401–404].
- Patients with severe hypertension associated with other clinical conditions who are likely to require an urgent reduction of BP, for example acute aortic dissection, acute myocardial ischaemia, or acute heart failure.
- Patients with sudden severe hypertension due to phaeochromocytoma, associated with organ damage.
- Pregnant women with severe hypertension or preeclampsia (see Section 8.9.1).
The most common emergency symptoms will depend of the organs affected but may include headache, visual disturbances, chest pain, dyspnoea, dizziness, and other neurological deficits. In patients with hypertensive encephalopathy, the presence of somnolence, lethargy, tonic clonic seizures and cortical blindness may precede a loss of consciousness; however, focal neurological lesions are rare and should raise the suspicion of stroke.
Acute stroke, especially intracerebral haemorrhage, when associated with severe hypertension has often been termed a hypertension emergency, but a more cautious approach is now recommended for acute BP lowering in the emergency setting of acute stroke (see Section 8.15).
The term ‘hypertension urgency’ has also been used to describe severe hypertension in patients presenting to the emergency department in whom there is no clinical evidence of acute HMOD [405]. Whilst these patients require BP reduction, they do not usually require admission to hospital, and BP reduction is best achieved with oral medication according to the drug treatment algorithm presented in Figure 4. However, these patients will require urgent outpatient review to ensure that their BP is coming under control.
Acute and severe increases in BP can sometimes be precipitated by ingestion of sympathomimetics such as meta-amphetamine or cocaine. This can result in a hypertension emergency when there is evidence of acute HMOD.
It is emphasized that many patients in an emergency department with acute pain or distress may experience an acute elevation in BP that will be restored to normal when the pain and distress are relieved, rather than requiring any specific intervention to lower BP.
For patients with a suspected hypertension emergency, a diagnostic workup is shown in Table 30.
8.3.1 Acute management of hypertensive emergencies
Apart from acute BP lowering in stroke, there are no RCTs evaluating different treatment strategies for hypertensive emergencies. The key considerations in defining the treatment strategy are:
- Establishing the target organs that are affected, whether they require any specific interventions other than BP lowering, and whether there is a precipitating cause for the acute rise in BP that might affect the treatment plan (e.g. pregnancy);
- The recommended timescale and magnitude of BP lowering required for safe BP reduction;
- The type of BP-lowering treatment required. With regard to drug treatment, in a hypertension emergency, i.v. treatment with a drug with a short half-life is ideal to allow careful titration of the BP response to treatment in a higher dependency clinical area with facilities for continuous haemodynamic monitoring.
Recommended drug treatments for specific hypertension emergencies [398,406] are shown in Table 31 and an expanded range of possible drug choices [398] is shown in Table 32. Rapid uncontrolled BP lowering is not recommended as this can lead to complications [397].
Although i.v. drug administration is recommended for most hypertension emergencies, oral therapy with ACE inhibitors, ARBs, or beta-blockers is sometimes very effective in malignant hypertension because the renin system is activated by renal ischaemia. However, low initial doses should be used because these patients can be very sensitive to these agents and treatment should take place in hospital. Further comprehensive details on the clinical management of hypertension emergencies are available [398].
8.3.2 Prognosis and follow-up
The survival of patients with hypertension emergencies has improved dramatically over past decades [407], but these patients remain at high risk [408,409] and should be screened for secondary hypertension (see Section 8.2). After discharge from hospital, when BP has reached a safe and stable level on oral therapy, we recommend frequent, at least monthly, visits in a specialized setting until the optimal target BP is achieved and long-term specialist follow-up thereafter.
8.4 White-coat hypertension
As discussed in Section 4, white-coat hypertension is defined as an elevated office BP despite a normal out-of-office BP. White-coat hypertension may be present in many people with an increased office BP, with a maximum in grade 1 hypertension, and very old people (>50%). Compared with normotensive people, white-coat hypertension is associated with an increased prevalence of dysmetabolic risk factors and asymptomatic organ damage. It is also associated with a greater risk of developing type 2 diabetes and sustained hypertension, as well as an overall increased risk of cardiovascular events [68,410–412]. It is recommended that people with white-coat hypertension should have an accurate assessment of their cardiovascular risk profile, including a search for HMOD. Office and out-of-office BP (both home and ambulatory BP) should be measured frequently, for example no less than every 2 years. Treatment should consider lifestyle changes to reduce the elevated cardiovascular risk [85,86,89].
Whether or not patients with white-coat hypertension should receive antihypertensive drugs is unresolved. In white-coat hypertension, antihypertensive drugs have been shown to effectively and persistently lower office BP, with no concomitant reduction (indeed, even a small increase) of ambulatory BP values [413,414]. Whether these BP changes lead to cardiovascular protection has not been investigated with adequately powered outcome studies and remains unknown. However, it should be considered that people with white-coat hypertension have inevitably been well represented in trials documenting the protective effect of antihypertensive drugs [415], particularly those addressing conditions in which white-coat hypertension is more common, such as grade 1 hypertension or hypertension in older patients. In a recent subanalysis of the HYVET trial of the very old with hypertension, white-coat hypertension was reported to account for 55% of the trial population [416]. Thus, antihypertensive drug treatment cannot definitively be excluded for patients with white-coat hypertension and may be considered, in particular, in white-coat hypertensive people with a higher cardiovascular risk profile, such as those with HMOD, an uncertain out-of-office BP normality pattern (i.e. ambulatory but not home BP normality or vice versa), or a persistent office BP elevation at repeated visits [417–420]. No cardiovascular risk excess has been reported in patients in whom white-coat hypertension results from treatment-dependant normalization of out-of-office BP only [418,421]. Thus, whether this condition benefits from an uptitration of the existing drug treatment regimen (to also achieve office BP normalization) remains to be determined.
8.5 Masked hypertension
As reported in Section 4.7.2, masked hypertension is defined in people whose BP is normal in the office but elevated on out-of-office BP measurements. Such people usually have dysmetabolic risk factors and asymptomatic organ damage, which are substantially more frequent than in people who are truly normotensive [93,410–412,422]. The challenge is how to diagnose masked hypertension, because most hypertension screening programmes use office BP measurement, which is normal in these people. Masked hypertension is commoner in younger rather than older individuals, and in those with an office BP in the borderline hypertension range (i.e. 130–139/80–89 mmHg). It is uncommon in people whose office BP is less than 130/80 mmHg. Masked hypertension is associated with progression to sustained office hypertension, increased frequency of developing type 2 diabetes, and the presence of HMOD. The long-term risk of fatal and nonfatal cardiovascular events approaches that of patients with sustained hypertension [68,81,93,95,423]. Patients with masked hypertension should have an accurate initial assessment of their cardiovascular risk profile. Cardiovascular risk factors (including organ damage and ideally both home and ambulatory BP) should then be periodically monitored. Factors contributing to the out-of-office BP elevation (e.g. smoking) should be discouraged and lifestyle interventions implemented to improve out-of-office BP levels. The impact of antihypertensive drug treatment on cardiovascular outcomes in people with masked hypertension has never been studied. Nevertheless, treatment with BP-lowering medication should be considered because these patients are at high cardiovascular risk, often have HMOD, and the adverse prognostic importance of out-of-office BP elevations has been well documented [68,74].
8.6 Masked uncontrolled hypertension
MUCH occurs in some treated patients in whom the office BP appears controlled to recommended BP targets, but BP is elevated and thus uncontrolled according to out-of-office BP measurements (ABPM or HBPM) [84]. Registry-based studies in Spain have suggested that MUCH occurs in as many as 30% of treated hypertensive patients [84], and is more common with comorbidities such as diabetes and CKD and in those at highest risk. Moreover, MUCH was more commonly due to poorly controlled nocturnal rather than daytime pressures on ABPM. Presently, no data are available from outcome trials for patients with MUCH; however, mindful of their high cardiovascular risk, treatment uptitration should be considered to ensure that that both office and out-of-office BP are controlled [84].
Management of white coat and masked hypertension
8.7 Hypertension in younger adults (age <50 years)
The prevalence of hypertension increases with age. Most hypertension across the age span is due to systolic hypertension; however, elevations of DBP and isolated diastolic hypertension, when they occur, are more common in younger rather than older patients [211]. There is a greater likelihood of detecting secondary hypertension in younger patients (<50 years), where the prevalence of secondary hypertension may be as high as 10% and should be considered, especially in those with more severe hypertension (see Section 3).
All younger adults with grade 2 or more severe hypertension should be offered lifestyle advice and drug treatment, as well as high-risk younger adults with grade 1 hypertension (i.e. with HMOD, CVD, diabetes, CKD, or those at high CVD risk, although cardiovascular risk is often underestimated in younger adults over shorter-term projections, such as 10 years) [35].
There is controversy about whether younger adults with uncomplicated grade 1 hypertension should be treated because of the obvious difficulty in conducting conventional clinical outcome trials in younger adults in whom the outcomes only occur after many years [424]. There is little doubt that treating stage 1 hypertension in older patients, even those at low–moderate-risk, reduces cardiovascular morbidity and mortality [425]. Moreover, long-term epidemiological studies have demonstrated a clear relationship between BP and longer-term risk of cardiovascular events and mortality in young adults with a BP more than 130/80 mmHg [424,426]. Furthermore, earlier treatment [23] can prevent more severe hypertension [427] and the development of HMOD, which may not be completely reversible with later treatment. Thus, despite the absence of RCT evidence demonstrating the benefits of antihypertensive treatment in younger adults with uncomplicated grade 1 hypertension, treatment with BP-lowering drugs may be considered prudent. If a decision is taken not to offer treatment or treatment is declined, lifestyle advice should be prescribed, and longer-term follow-up is essential as BP will invariably rise. In younger patients with hypertension treated with BP-lowering medication, office BP should be reduced to at least 130/80 mmHg if treatment is well tolerated. Other interventions, for example statins or antiplatelet therapy, should also be considered for higher-risk patients (see Section 7.2.5).
8.7.1 Isolated systolic hypertension in the young
Some young, healthy people, and men in particular, may present with isolated grade 1 systolic hypertension (i.e. brachial SBP at least 140–159 mmHg and a normal DBP <90 mmHg), and this may be associated with a normal central aortic SBP due to excessive peripheral systolic pressure amplification [428]. It is unclear whether isolated systolic hypertension in the context of a normal aortic pressure is benign. A recent examination of prospective data from the Chicago Heart Association Detection Project found that young men with isolated systolic hypertension had a cardiovascular risk similar to that of individuals with high–normal BP and that isolated systolic hypertension in the young was closely associated with smoking [429]. On the basis of current evidence, these young individuals should receive recommendations on lifestyle modification (particularly cessation of smoking); whether they should receive drug treatment is unclear, but they do require longer-term follow-up as many will develop sustained hypertension [430].
8.8 Hypertension in older patients (age 65 years)
The prevalence of hypertension increases with age, with a prevalence of 60% over the age of 60 years and 75% over the age of 75 years. For the purposes of these Guidelines, older is defined as at least 65 years and the very old as at least 80 years.
For many years, advanced age has been a barrier to the treatment of hypertension because of concerns about potentially poor tolerability, and even harmful effects of BP-lowering interventions in people in whom mechanisms preserving BP homeostasis and vital organ perfusion may be more frequently impaired. This approach is not appropriate, because evidence from RCTs has shown that in old and very old patients, antihypertensive treatment substantially reduces cardiovascular morbidity and cardiovascular and all-cause mortality [220,431] (see Section 7). Moreover, treatment has been found to be generally well tolerated. However, older patients are more likely to have comorbidities such as renal impairment, atherosclerotic vascular disease, and postural hypotension, which may be worsened by BP-lowering drugs. Older patients also frequently take other medications, which may negatively interact with those used to achieve BP control. A further important caveat is that RCTs have not included very frail patients, dependent patients, and patients with postural hypotension. It is thus uncertain whether, and to what extent, such patients would benefit from BP-lowering treatment in the context of their comorbidities and reduced life expectancy. Thus, in older hypertensive patients, treatment presents more difficulties than in younger people, because the decision to treat hypertension must take into account the patient's clinical condition, concomitant treatments, and frailty. That said, age alone must never be a barrier to treatment because high BP is an important risk factor even at the most advanced ages. Furthermore, a recent study of a cohort of older patients from the general population (thus including those with frailty) has shown that better adherence to antihypertensive treatment was associated with a reduced risk of cardiovascular events and mortality, even when age was more than 85 years (mean 90 years) [432].
It is recommended that older patients are treated according to the treatment algorithm outlined in Section 7. In very old patients, it may be appropriate to initiate treatment with monotherapy. In all older patients, when combination therapy is used, it is recommended that this is initiated at the lowest available doses. In all older patients, and especially very old or frail patients, the possible occurrence of postural BP should be closely monitored and symptoms of possible hypotensive episodes checked by ABPM. Unless required for concomitant diseases, loop diuretics and alpha-blockers should be avoided because of their association with injurious falls [433,434]. Renal function should be frequently assessed to detect possible increases in serum creatinine and reductions in eGFR as a result of BP-related reductions in renal perfusion. When treated, BP should be lowered to a systolic value of 130–139 mmHg and a diastolic value of less than 80 mmHg if tolerated. Treated SBP values of less than 130 mmHg should be avoided. A key emphasis in treating older patients, and especially the very old, is to carefully monitor for any adverse effects or tolerability problems associated with BP-lowering treatment, keeping in mind that adverse effects can be more frequent than reported in RCTs, in which specific medical expertise and close patient supervision may minimize adverse effects and tolerability problems.
An important consideration is frail, dependent older patients, including those with orthostatic hypotension. These have been excluded from RCTs. The SPRINT trial showed the benefits of BP-lowering treatment being extended to recruited patients who were at the frailer end of the spectrum, including those with reduced gait speed [215]. This suggests that the benefit of treatment is not limited to fit and independent older patients; however, to what extent BP-lowering treatment benefits the very frail [214] and institutionalized patients remains to be determined.
In some patients, the best achievable BP may be higher than the recommended target, but it should be recognized that any amount of BP lowering is likely to be worthwhile and associated with a reduced risk of major cardiovascular events (especially stroke and heart failure) and mortality.
8.9 Women, pregnancy, oral contraception and hormone-replacement therapy
8.9.1 Hypertension and pregnancy
Hypertensive disorders in pregnancy affect 5–10% of pregnancies worldwide and remain a major cause of maternal, foetal, and neonatal morbidity and mortality. Maternal risks include placental abruption, stroke, multiple organ failure, and disseminated intravascular coagulation. The fetus is at high risk of intrauterine growth retardation (25% of cases of preeclampsia), prematurity (27% of cases of preeclampsia), and intrauterine death (4% of cases of preeclampsia) [435].
8.9.1.1 Definition and classification of hypertension in pregnancy
The definition of hypertension in pregnancy is based on office BP values, SBP at least 140 mmHg and/or DBP at least 90 mmHg [436,437], and is classified as mild (140–159/90–109 mmHg) or severe (≥160/110 mmHg), in contrast to the conventional hypertension grading.
Hypertension in pregnancy is not a single entity but comprises:
- Preexisting hypertension: precedes pregnancy or develops before 20 weeks of gestation, and usually persists for more than 6 weeks postpartum and may be associated with proteinuria.
- Gestational hypertension: develops after 20 weeks of gestation and usually resolves within 6 weeks postpartum.
- Preexisting hypertension plus superimposed gestational hypertension with proteinuria.
- Preeclampsia: gestational hypertension with significant proteinuria (>0.3 g/24 h or ≥30 mg/mmol ACR). It occurs more frequently during the first pregnancy, in multiple pregnancy, in hydatidiform mole, in antiphospholipid syndrome, or with preexisting hypertension, renal disease, or diabetes. It is often associated with foetal growth restriction due to placental insufficiency and is a common cause of prematurity [438]. The only cure for preeclampsia is delivery. As proteinuria may be a late manifestation of preeclampsia, it should be suspected when de-novo hypertension is accompanied by headache, visual disturbances, abdominal pain, or abnormal laboratory tests, specifically low platelets and/or abnormal liver function.
- Antenatally unclassifiable hypertension: this term is used when BP is first recorded after 20 weeks of gestation and it is unclear if hypertension was preexisting. Reassessment 6 weeks postpartum will help distinguish preexisting from gestational hypertension.
8.9.1.2 Blood pressure measurement in pregnancy
BP in pregnancy should be measured in the sitting position (or the left lateral recumbent during labour) with an appropriately sized arm cuff at heart level and using Korotkoff V for DBP. Manual auscultation remains the gold standard for BP measurement in pregnancy, because automated devices tend to under-record the BP and are unreliable in severe preeclampsia. Only validated devices should be used in pregnancy [439]. ABPM is superior to office BP measurement for the prediction of pregnancy outcome [440]. ABPM devices recommended for use in pregnancy are more accurate than those used for office measurement or HBPM. ABPM helps avoid unnecessary treatment of white-coat hypertension, and is useful in the management of high-risk pregnant women with hypertension and those with diabetic or hypertensive nephropathy.
8.9.1.3 Investigation of hypertension in pregnancy
Basic laboratory investigations recommended for monitoring pregnant hypertensive women include urine analysis, blood count, haematocrit, liver enzymes, serum creatinine and serum uric acid (increased in clinically evident preeclampsia). Hyperuricaemia in hypertensive pregnancies identifies women at increased risk of adverse maternal and foetal outcomes [441].
All pregnant women should be assessed for proteinuria in early pregnancy to detect preexisting renal disease and, in the second half of pregnancy, to screen for preeclampsia. A dipstick test of at least 1+ should prompt evaluation of ACR in a single spot urine sample and a value less than 30 mg/ mmol can reliably rule out proteinuria in pregnancy [442].
In addition to basic laboratory tests, the following investigations may be considered:
- Ultrasound investigation of the kidneys and adrenals, and plasma or urinary fractionated metanephrine assays in pregnant women with a history suggestive of phaeochromocytoma.
- Doppler ultrasound of uterine arteries (performed after 20 weeks of gestation) to detect those at higher risk of gestational hypertension, preeclampsia, and intrauterine growth retardation [443].
- A soluble fms-like tyrosine kinase 1:placental growth factor ratio of at least 38 can be used to exclude the development of preeclampsia in the next week when suspected clinically [444].
8.9.1.4 Prevention of hypertension and preeclampsia
Women at high or moderate-risk of preeclampsia should be advised to take 100–150 mg of aspirin daily from weeks 12–36 [445]. High risk of preeclampsia includes any of the following:
- Hypertensive disease during a previous pregnancy
- CKD
- Autoimmune disease such as systemic lupus erythematosus or antiphospholipid syndrome
- Type 1 or type 2 diabetes
- Chronic hypertension
Moderate-risk of preeclampsia includes one or more of the following risk factors:
- First pregnancy
- Age of at least 40 years
- Pregnancy interval of more than 10 years
- BMI of at least 35 kg/m2 at first visit
- Family history of preeclampsia
- Multiple pregnancy
8.9.1.5 Clinical management of hypertension in pregnancy
Mild hypertension of pregnancy (BP 140–159/90–109 mmHg). The goal of drug treatment of hypertension in pregnancy is to reduce maternal risk; however, the agents selected must be safe for the fetus. The benefits of drug treatment for mother and fetus in hypertension in pregnancy have not been extensively studied, with the best data from a single trial using alpha-methyldopa, performed 40 years ago [446–448]. A further study suggested that tighter vs. less tight control of BP in pregnancy showed no difference in the risk of adverse perinatal outcomes and overall serious maternal complications. However, secondary analysis suggested that tighter control of BP may reduce the risk of developing more severe hypertension and preeclampsia [446].
Most women with preexisting hypertension and normal renal function will not have severe hypertension and are a low risk for developing complications during pregnancy. Indeed, some of these women may be able to withdraw their medication in the first half of pregnancy because of the physiological fall in BP. Despite the paucity of evidence, European Guidelines [17,449,450] have recommended initiating drug treatment:
- In all women with persistent elevation of BP at least 150/95 mmHg;
- In women with gestational hypertension (with or without proteinuria), preexisting hypertension with the superimposition of gestational hypertension, or hypertension with subclinical HMOD, when BP is more than 140/90 mmHg.
Women with preexisting hypertension may continue their current antihypertensive medication, but ACE inhibitors, ARBs, and direct renin inhibitors are contraindicated due to adverse foetal and neonatal outcomes. Methyldopa, labetalol, and CCBs are the drugs of choice. Beta-blockers may induce foetal bradycardia; consequently, if used, their type and dose should be carefully selected, with atenolol best avoided. Diuretic therapy is generally avoided because plasma volume is reduced in women who develop preeclampsia.
There are no data to define the optimal BP treatment target in pregnant women. Nevertheless, for pragmatic reasons, if treatment is initiated it is important to suggest a treatment target to calibrate how much treatment to give. A BP target of less than 140/90 is suggested for pregnant women receiving antihypertensive therapy.
Severe hypertension of pregnancy (160/110 mmHg). There is no agreed definition of severe hypertension, with values ranging between 160 and 180 mmHg/more than 110 mmHg. The 2018 ESC Task Force on CVD during pregnancy [435] considers an SBP of at least 170 mmHg or DBP of at least 110 mmHg an emergency in a pregnant woman, who should be immediately admitted to hospital for treatment. The selection of the antihypertensive drug and its route of administration depends on the expected time of delivery. Pharmacological treatment with i.v. labetalol, oral methyldopa, or CCB should be initiated. Intravenous hydralazine is no longer the drug of choice as it is associated with more perinatal adverse effects than other drugs [451]. However, hydralazine is still used when other treatment regimens fail to achieve adequate BP control. Intravenous urapidil can also be considered.
In hypertensive crises, that is in patients with eclampsia or severe preeclampsia (with or without haemolysis, elevated liver enzymes, and low platelets syndrome), hospitalization and BP-lowering therapy is essential, and delivery needs to be considered after the maternal condition has stabilized [435]. Intravenous magnesium sulfate is recommended for the prevention of eclampsia and treatment of seizures. The consensus is to lower BP to less than 160/105 mmHg to prevent acute hypertensive complications in the mother. Both labetalol and nicardipine have shown to be safe and effective for the treatment of severe preeclampsia if i.v. BP-lowering therapy is necessary [452]. In both cases, monitoring of foetal heart rate is necessary. To prevent foetal bradycardia, the cumulative dose of labetalol should not exceed 800 mg/24 h. Intravenous sodium nitroprusside is contraindicated in pregnancy because of an increased risk of foetal cyanide poisoning. The drug of choice when preeclampsia is associated with pulmonary oedema is nitroglycerin (glyceryl trinitrate), given as an i.v. infusion of 5 μg/min, and gradually increased every 3–5 min to a maximum dose of 100 μg/min.
Delivery is indicated urgently in preeclampsia with visual disturbances or haemostatic disorders, and at 37 weeks in asymptomatic women [453].
Blood pressure postpartum. Postpartum hypertension is common in the first week. Any drug recommended can be used according to the hypertension treatment algorithm shown in Figure 4, with the caveats: methyldopa should be avoided because of the risk of postpartum depression and consideration should be given to drug choice in breastfeeding women.
8.9.1.6 Hypertension and breastfeeding
All antihypertensive drugs taken by the nursing mother are excreted into breast milk. Most are present at very low concentrations except for propranolol and nifedipine, with breast milk concentrations similar to those in maternal plasma. Reference to prescribing information in breastfeeding women is important.
8.9.1.7 Risk of recurrence of hypertensive disorders in a subsequent pregnancy
Women experiencing hypertension in their first pregnancy are at increased risk in a subsequent pregnancy. The earlier the onset of hypertension in the first pregnancy, the higher the risk of recurrence in a subsequent pregnancy.
8.9.1.8 Long-term cardiovascular consequences of gestational hypertension
Women who develop gestational hypertension or preeclampsia are at increased risk of hypertension, stroke, and ischaemic heart disease in later adult life [454,455]. Lifestyle modifications are indicated to avoid complications in subsequent pregnancies and to reduce maternal cardiovascular risk in the future. Therefore, annual visits to a primary care physician to check BP and metabolic factors are recommended for these patients.
Further detail on the management of hypertension and other cardiovascular disorders in pregnancy is available [435].
Management of hypertension in pregnancy
8.9.2 Oral contraceptive pills and hypertension
Combined oestrogen–progesterone oral contraceptive pills can be associated with a small but significant increase in BP and the development of hypertension in about 5% of users [456,457]. BP usually decreases promptly following cessation of these pills; consequently, BP should be monitored before and during oral contraceptive pill treatment. The rise in BP appears to be related to the oestrogen content and may be less likely with the progestogen-only oral contraceptive pill. Older studies have demonstrated a relationship between the oral contraceptive pill and venous thrombosis and venous thromboembolism, and, to a lesser extent, myocardial infarction (especially with concomitant smoking history) and stroke [458]. More recent studies with newer-generation oral contraceptive pills have reported conflicting results. Thus, the use of oral contraceptives should consider the risks and benefits for the individual patient. Changes in BP should be carefully evaluated with follow-up readings [459]. Concomitant cardiovascular risk factors (e.g. smoking history) should be assessed and oral contraceptive pill use is not recommended if BP is elevated. In such patients, alternative forms of contraception should be offered. Discontinuation of combined oestrogen–progestin oral contraceptives in women with hypertension may improve their BP control [460].
8.9.3 Hormone-replacement therapy and hypertension
Cross-sectional studies have long established that menopause doubles the risk of developing hypertension, even after adjusting for factors such as age and BMI [461]. Although hormone-replacement therapy contains oestrogens, there is no convincing evidence that significant rises in BP will occur in otherwise normotensive menopausal women due to this therapy, or that BP will increase further due to hormone-replacement therapy in menopausal hypertensive women [462]. Hormone-replacement therapy and selective oestrogen receptor modulators should not be used for primary or secondary prevention of CVD. In summary, current evidence suggests that the use of hormone-replacement therapy is not associated with an increase in BP. Moreover, it is not contraindicated in women with hypertension, and women with hypertension may be prescribed hormone-replacement therapy as long as BP levels can be controlled by antihypertensive medication.
8.10 Hypertension in different ethnic groups
In comparison with the nonblack population, hypertension is more prevalent in the black population living in Europe [463], similarly to that reported for the USA [464]. As for the European white population, the black European population is heterogenous in nature [463], although in almost all European countries the largest ethnic group originates from the Sub-Saharan African region [463]. Hypertension epidemiology, diagnosis, and treatment have been thoroughly studied in black (i.e. Afro-American) US patients [464], in contrast to the much scarcer database available for European black people, and thus we extrapolate from US data. However, this extrapolation requires some caution as differences between the North American and the European black population exist, especially with regard to socioeconomic status, cardiovascular risk [465,466], and the response to antihypertensive drug treatment [467]. BP-related HMOD, as well as cardiovascular and renal complications, are more common and severe in black patients compared with age-matched white patients at any BP level [464]. Black hypertensive patients exhibit a similar proportional reduction of cardiovascular and renal events in response to BP-lowering treatment as white patients, with somewhat different treatment modalities. However, to achieve an effective BP reduction and BP control, salt restriction is particularly important in black patients, in whom it may lead to greater BP falls and more favourably impact on the effectiveness of BP-lowering drug treatment [468]. Hypertensive black patients also show a reduced antihypertensive response to RAS-blocker monotherapy, whereas they usually respond more effectively to thiazide or thiazide-like diuretics and CCBs [316,469,470], which in black patients may be combined with each other or with a RAS blocker, making the latter more effective. Angioedema appears more common with ACE inhibitors in black patients, which may favour the preferred use of ARBs in this population. Despite some progress in recent years, data on hypertension prevalence, management, and control in European black patients (and in other immigrant populations such as European individuals from South Asia) are still scarce [463,471], which makes this field an important area for future research. There is no evidence that the BP response to treatment in other ethnic groups differs from that reported in the general population in Europe.
8.11 Hypertension in diabetes mellitus
High BP is a common feature of type 1 and, particularly, type 2 diabetes. Moreover, masked hypertension and a blunted nocturnal fall in BP are not infrequent in people with diabetes [472]. Recording 24 h ABPM in apparently normotensive people with diabetes may be a useful diagnostic procedure, especially in those with HMOD. Substantial evidence supports the benefits of BP reduction in people with diabetes to reduce major macrovascular and microvascular complications of diabetes, as well as reducing mortality. Proven benefits of BP-lowering treatment in diabetes also include a significant reduction in the rate of end-stage renal disease [231,235], retinopathy [1], and albuminuria [1]. Diabetic neuropathy has never been included as an outcome in RCTs of BP-lowering treatment.
When considering treatment for hypertension, it is important to exclude significant postural hypotension, which can be marked in people with diabetes due to autonomic neuropathy [235]. Initiation of antihypertensive drug therapy is recommended when the office BP is more than 140/90 mmHg. Alongside lifestyle interventions, treatment should usually be initiated with a two-drug combination of an ACE inhibitor or ARB with a CCB or thiazide/thiazide-like diuretic, and treatment escalated according to the recommended treatment algorithm (see Section 7). This approach ensures that the treatment strategy includes an ACE inhibitor or ARB, which has been shown to reduce albuminuria and the appearance or progression of diabetic nephropathy more effectively than other drug classes [235]. Combination of an ACE inhibitor with an ARB is contraindicated because it is accompanied by an excess of renal adverse events [298,473,474].
Recent RCTs have shown that some antidiabetic agents (the selective inhibitors of sodium glucose cotransporter 2 in the kidney) can reduce office and ambulatory BP by several mmHg [475,476], and that this occurs even when people are treated with antihypertensive drugs. This may help improve BP control (see below), which is especially difficult in diabetes [477], and may reduce the progression of CKD [478–481] (see also Section 8.12).
There has been considerable debate about the target BP that should be achieved in people with diabetes (see Section 7). We recommend that in people with diabetes, the first objective should be to lower BP to less than 140/80 mmHg, aiming at an SBP of 130 mmHg. Provided that the treatment is well tolerated, treated SBP values of less than 130 mmHg should be considered because of the benefits on stroke prevention. Achieved SBP values of less than 120 mmHg should always be avoided. BP targets for renoprotection for patients with diabetic kidney disease are discussed in Section 8.12.
Treatment strategies in people with diabetes
8.12 Hypertension and chronic kidney disease
Hypertension is a major risk factor for the development and progression of CKD, irrespective of the cause of CKD. In patients with CKD, resistant hypertension, masked hypertension, and elevated nighttime BP are common, and are associated with a lower eGFR, higher levels of albuminuria, and HMOD [483,484].
The effects of lowering BP in patients with CKD have been the subject of many meta-analyses. A recent meta-analysis has shown that BP lowering significantly reduced end-stage renal disease in patients with CKD, but only in those with albuminuria and without any beneficial effect on cardiovascular events [203]. However, a more recent and larger meta-analysis has shown a significant reduction in all-cause mortality following BP reduction in patients with CKD [485].
Reduction of albuminuria has also been considered as a therapeutic target. Analyses of data from RCTs have reported that changes in urinary albumin excretion are predictors of renal and cardiovascular events [186,486]. However, there are also studies in which treatment that was less effective at reducing albuminuria was more effective at reducing cardiovascular events [175] and vice versa [176,291]. Thus, whether reducing albuminuria per se is a proxy for CVD prevention remains unresolved.
Patients with CKD should receive lifestyle advice, especially sodium restriction, and drug treatment when their office BP is more than 140/90 mmHg. Achieving recommended BP targets in CKD usually requires combination therapy, which should be initiated as a combination of a RAS blocker with a CCB or diuretic in these patients. The combination of two RAS blockers is not recommended [291]. Loop diuretics should replace thiazide diuretics when the estimated GFR is less than 30 ml/min/1.73 m2.
The evidence with respect to BP targets in patients with CKD is complex. In patients with nondiabetic CKD, one meta-analysis showed that the slowest progression on CKD was obtained with a treated SBP in the range of 110–119 mmHg in patients with albuminuria more than 1 g/day [487]. In contrast, in patients with a proteinuria less than 1 g/day, the lowest risk of developing CKD (not cardiovascular risk) was obtained with an SBP of less than 140 mmHg [487]. Another systematic review failed to demonstrate that a BP target of less than 130/80 mmHg improved clinical outcomes more than a target of less than 140/90 mmHg in nondiabetic CKD [488]. In a large retrospective cohort containing 398 419 treated hypertensive patients (30% with diabetes), the nadir SBP and DBP for the lowest risk of end-stage renal disease and mortality were 137 and 71 mmHg, respectively, with a clear increase in mortality risk at SBP less than 120 mmHg [489].
Current evidence suggests that in patients with CKD, BP should be lowered to less than 140/90 mmHg and towards 130/80 mmHg. Lifestyle advice, especially sodium restriction, may be especially effective at aiding BP lowering in patients with CKD. Because BP lowering reduces renal perfusion pressure, it is expected and not unusual for eGFR to be reduced by 10–20% in patients treated for hypertension. Thus, careful monitoring of blood electrolytes and eGFR is essential, but clinicians should not be alarmed by the anticipated decline in GFR when treatment is initiated. This decline usually occurs within the first few weeks of treatment and stabilizes thereafter. If the decline in GFR continues or is more severe, the treatment should be stopped, and the patient investigated to determine the presence of renovascular disease.
Therapeutic strategies for treatment of hypertension in CKD
8.13 Hypertension and chronic obstructive pulmonary disease
Hypertension is the most frequent comorbidity in patients with COPD, and coincidence of the two diseases may affect 2.5% of the adult population [490]. Patients with hypertension and COPD are at particularly high cardiovascular risk [490,491]. Both conditions share similar environmental risks and, in addition, hypoxia may exacerbate the risk [490,491]. Treatment of COPD with anticholinergic agents and long-acting beta-2 adrenoceptor agonists may adversely affect the cardiovascular system (increase heart rate and BP). The presence of COPD also has an impact on the selection of antihypertensive drugs, which should consider their effects on pulmonary function. Concern has been predominantly directed to the use of beta-blockers, although there is evidence that in COPD these drugs maintain their cardiovascular-protective effects [492,493]. Beta-blockers may negatively affect the reduced basal lung function in patients with COPD, diminish the effectiveness of emergency beta-agonist administration, reduce the benefit of long-acting beta-agonist treatment, and make the discrimination of asthma and COPD more difficult. That said, when tolerated, the use of cardiac beta1-selective beta-blockers in patients with COPD has proven to be safe in different settings, including hypertension [494]. It should also be noted that diuretics may decrease the plasma level of potassium (in addition to the hypokalaemic effects of glucocorticoids and beta2-adrenoceptor agonists), worsen carbon dioxide retention (including metabolic alkalosis-related hypoxia in hypoventilated patients), increase haematocrit, and deteriorate mucus secretion in bronchi. Therefore, in general, diuretics are not recommended for widespread use in hypertensive patients with COPD [490,495].
In conclusion, management of hypertensive patients with COPD should include lifestyle changes, among which cessation of smoking is essential. CCBs, ARBs or ACEIs, or the CCB/RAS blocker combination are recommended as the initial drugs of choice. If the BP response is poor, or depending on other comorbidities, thiazides or thiazide-like diuretics and beta1-selective beta-blockers can be considered.
8.14 Hypertension and heart disease
8.14.1 Coronary artery disease
There are strong epidemiological relationships between CAD and hypertension. The INTERHEART study showed that 50% of the population-attributable risk of a myocardial infarction can be accounted for by lipids, with hypertension accounting for 25% [10]. Another registry-based study of over 1 million patients showed that ischaemic heart disease (angina and myocardial infarction) accounted for most (43%) of the CVD-free years of life lost due to hypertension from the age of 30 years [7].
More compelling is the beneficial effect of BP treatment on reducing the risk of myocardial infarction. A recent meta-analysis of RCTs of antihypertensive therapy showed that for every 10 mmHg reduction in SBP, CAD was reduced by 17% [2]. A similar risk reduction has been reported by others with more intensive BP control [496]. The benefits of reducing cardiac events are also evident in high-risk groups, such as those with diabetes [231,425].
There remains some inconsistency over the optimal BP target in less than patients with overt CAD, and especially whether there is a J-curve relationship between achieved BP and cardiovascular outcomes in CAD [497–500]. A recent analysis [501] of 22 672 patients with stable CAD who were treated for hypertension found that, after a median follow-up of 5.0 years, an SBP of at least 140 mmHg and a DBP of at least 80 mmHg were each associated with increased risk of cardiovascular events. An SBP of less than 120 mmHg was also associated with increased risk, as was a DBP of less than 70 mmHg. Similar findings were also reported from another analysis of RCT data evaluating the relationships between achieved BP and risks of cardiovascular outcomes [222]. Whether a J-curve phenomenon exists in patients with CAD who have been revascularized remains uncertain. Other analyses do not support the existence of a J-curve, even in hypertensive patients at increased cardiovascular risk [239]. For example, in patients with CAD and initially free from congestive heart failure enrolled in ONTARGET, a BP reduction from baseline over the examined BP range had little effect on the risk of myocardial infarction and predicted a lower risk of stroke [502]. Thus, a target BP of approximately less than 130/80 mmHg in patients with CAD appears safe and can be recommended, but achieving a BP less than 120/80 mmHg is not recommended.
In hypertensive patients with CAD, beta-blockers and RAS blockers may improve outcomes in postmyocardial infarction [503]. In patients with symptomatic angina, beta-blockers and calcium antagonists are the preferred components of the drug treatment strategy.
Therapeutic strategies in hypertensive patients with CAD
8.14.2 Left ventricular hypertrophy and heart failure
Hypertension is the leading risk factor for the development of heart failure [7], and most patients with heart failure will have a history of hypertension. This may be a consequence of CAD, which results in HFrEF. Hypertension also causes LVH, which impairs left ventricular relaxation (so-called diastolic dysfunction) and is a potent predictor of heart failure, even when left ventricular systolic function is normal and there is no preceding myocardial infarction (HFpEF). Hypertension-dependent fibrosis and structural alteration of large and small arteries (microvascular disease) also contribute.
Treating hypertension has a major impact on reducing the risk of incident heart failure and heart failure hospitalization, especially in old and very old patients [51,213,316]. This has been observed using diuretics, beta-blockers, ACE inhibitors, or ARBs, with CCBs being less effective in comparative trials [504].
Reducing BP can also lead to the regression of LVH, which has been shown to be accompanied by a reduction of cardiovascular events and mortality [125]. The magnitude of LVH regression is associated with baseline left ventricular mass, duration of therapy, the SBP reduction [505,506], and the drugs used, with ARBs, ACE inhibitors, and CBBs causing more effective LVH regression than beta-blockers [173] or diuretics.
In patients with HFrEF, antihypertensive drug treatment should start (if not already initiated) when BP is more than 140/90 mmHg. It is unclear how low BP should be lowered in patients with heart failure. Outcomes for patients with heart failure have repeatedly been shown to be poor if BP values are low, which suggests (although data interpretation is made difficult by the possibility of reversed causality) that it may be wise to avoid actively lowering BP to less than 120/70 mmHg. However, some patients may achieve even lower BP levels than this because of the desirability to remain on treatment with guideline-directed heart failure medications, which, if tolerated, should be continued because of their protective effect [136].
Heart failure guideline-directed medications are recommended for the treatment of hypertension in patients with HFrEF [136]. ACE inhibitors, ARBs, beta-blockers, and MRAs (e.g. spironolactone and epleronone) are all effective in improving clinical outcome in patients with established HFrEF, whereas for diuretics, evidence is limited to symptomatic improvement. If further BP lowering is required, a dihydropyridine CCB may be considered. Sacubutril/valsartan lowers BP has also been shown to improve outcomes in patients with HFrEF, and is indicated for the treatment of HFrEF as an alternative to ACE inhibitors or ARBs [507]. Nondihydropiridine CCBs (diltiazem and verapamil), alpha-blockers, and centrally acting agents, such as moxonidine, should not be used.
Antihypertensive treatment is commonly needed in patients with HFpEF; the same BP threshold and target for drug treatment indicated for HFrEF should be used. The optimal treatment strategy for hypertensive patients with HFpEF is not known, but the strategy outlined above for HFrEF patients might also be the one to adopt in HFpEF patients. HFpEF patients commonly have multiple comorbidities that may adversely affect outcomes and complicate management.
Therapeutic strategies in hypertensive patients with heart failure or LVH
8.15 Cerebrovascular disease and cognition
Hypertension is a major risk factor for haemorrhagic and ischaemic stroke, and a risk factor for recurrent stroke. BP management during the acute phase of haemorrhagic and ischaemic stroke remains an area of uncertainty. BP is often elevated at presentation with acute stroke, but often declines without intervention [508].
8.15.1 Acute intracerebral haemorrhage
In acute intracerebral haemorrhage, an increased BP is common and is associated with a greater risk of haematoma expansion, increased risk of death, and a worse prognosis for neurological recovery [509,510]. Results from an RCT suggested that immediate BP lowering (within 6 h) to less than 140/90 mmHg did not show benefit on the primary outcome of disability or death at 3 months, but might reduce haematoma expansion and improve functional recovery, and was generally safe [511]. A subsequent RCT, in which SBP was immediately reduced (<4.5 h) from a mean of 200 mmHg to two different target intervals (140–170 vs. 110–139 mmHg), showed that more intensive BP lowering had no benefit on the same primary outcome and was associated with more renal adverse events [512]. Thus, we do not recommend treatment to immediately lower BP in patients with acute intracerebral haemorrhage. One possible caveat to this recommendation is patients with acute intracerebral haemorrhage and very severe hypertension (SBP ≥220 mmHg), for whom there are much fewer data. A meta-analysis [513] and secondary outcome data from one RCT [511] have suggested a possible benefit on functional recovery at 3 months, and that acute lowering of SBP to less than 180 mmHg in these patients might be beneficial. Thus, careful lowering of BP via i.v. infusion may be considered in patients with markedly elevated BP (SBP ≥220 mmHg).
8.15.2 Acute ischaemic stroke
The beneficial effects of BP reduction are even less clear in acute ischaemic stroke. A key consideration is whether the patient will receive thrombolysis, because observational studies have reported an increased risk of intracerebral haemorrhage in patients with a markedly elevated BP who received thrombolysis [514,515]. In patients receiving i.v. thrombolysis, BP should be lowered and maintained at less than 180/105 mmHg for at least the first 24 h after thrombolysis. The benefit of acute BP lowering in patients with acute ischaemic stroke who do not receive thrombolysis is uncertain. A meta-analysis suggested that BP lowering early after acute ischaemic stroke had a neutral effect on the prevention of death or dependency [516,517]. In such patients with markedly elevated SBP or DBP (i.e. ≥220 or ≥120 mmHg, respectively), clinical judgement should define whether to intervene with drug therapy, in which case a reasonable goal may be to lower BP by 15%, with close monitoring, during the first 24 h after stroke onset [516,518–520]. Patients with acute ischaemic stroke and a BP lower than this in the first 72 h after stroke do not seem to benefit from the introduction or reintroduction of BP-lowering medication [516,521]. For stable patients who remain hypertensive (≥140/90 mmHg) more than 3 days after an acute ischaemic stroke, initiation or reintroduction of BP-lowering medication should be considered [522].
8.15.3 Previous stroke or transient ischaemic attack
RCTs of antihypertensive treatment (placebo controlled) in patients with a previous stroke or TIA, in a stable clinical condition, and with BP more than 140/90 mmHg, have shown that BP lowering reduces the risk of recurrent stroke [338,523]. No evidence is yet available that recurrent stroke is prevented by initiating therapy when BP is in the high–normal range. We recommend resumption of BP-lowering therapy several days after stroke, or immediately after TIA, for previously treated or untreated patients with hypertension, for prevention of both recurrent stroke and other cardiovascular events.
The appropriate BP targets to prevent recurrent stroke are uncertain, but should be considered in the context of a consistent finding in many meta-analyses that stroke is the one major cardiovascular event that is reduced at lower achieved BP levels. This is supported by the results from the recent Secondary Prevention of Small Subcortical Strokes 3 study [244,524] in patients with a recent lacunar stroke, which suggested an SBP target of less than 130 mmHg [525], and other studies [526].
Prevention of stroke is a consistent benefit of antihypertensive therapy and has been observed in all large RCTs using different drug regimens. However, individual RCTs comparing modern treatment regimens [317,527] and meta-analyses suggest that beta-blockers are less effective at stroke prevention than other classes of antihypertensive agents [2,528]. Although the beta-blocker in these studies was atenolol, there are no data with more modern beta-blockers with regards to stroke prevention in hypertension. Thus, optimal antihypertensive treatment for stroke prevention should not include beta-blockers unless there is a compelling indication for their use, mindful of the fact that the most common recurrent event after stroke is a further stroke rather than myocardial infarction [529].
8.15.4 Cognitive dysfunction and dementia
Several epidemiological and clinical studies have shown that hypertension in midlife predicts cognitive decline and dementia (both Alzheimer's disease and vascular dementia) in older patients [530–533]. However, evidence on the beneficial effects of BP lowering on cognitive decline is scant and conflicting. A meta-analysis [534] of 12 studies investigating the impact of different antihypertensive drugs on dementia and cognitive function concluded that BP lowering reduced the incidence and risk of cognitive impairment and dementia by 9%. One study showed that achieving better BP control over 4 years reduced the progression of cerebral white matter lesions and the decrease in global cognitive performance [535].
Trials are urgently needed to better define the potential impact of BP lowering on preventing cognitive decline or in delaying dementia when cognitive dysfunction is already present.
8.16 Hypertension, atrial fibrillation, and other arrhythmias
Hypertension predisposes to cardiac arrhythmias, including ventricular arrhythmias, but most commonly AF [536–538], which should be considered a manifestation of hypertensive heart disease [539]. Even high–normal BP is associated with incident AF [540,541], and hypertension is the most prevalent concomitant condition in AF patients. AF adds to the risk of stroke and heart failure. AF necessitates stroke prevention with oral anticoagulation, with monitoring of the associated risks and prevention of bleeding [542].
Most pat
